ISSN (online) World Journal of Clinical Oncology World J Clin Oncol 2017 August 10; 8(4): Published by Baishideng Publishing Group I

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1 ISSN (online) World Journal of Clinical Oncology World J Clin Oncol 2017 August 10; 8(4): Published by Baishideng Publishing Group Inc

2 W J C O World Journal of Clinical Oncology Editorial Board The World Journal of Clinical Oncology Editorial Board consists of 297 members, representing a team of worldwide experts in oncology. They are from 41 countries, including Argentina (1), Australia (6), Austria (2), Belgium (1), Brazil (1), Bulgaria (1), Canada (6), China (43), Cuba (1), Denmark (4), France (4), Germany (11), Greece (1), Hungary (1), India (7), Iran (2), Ireland (1), Israel (1), Italy (33), Japan (27), Malaysia (3), Netherlands (8), Norway (3), Peru (1), Poland (1), Portugal (2), Qatar (1), Romania (1), Russia (1), Saudi Arabia (3), Singapore (2), South Korea (12), Spain (11), Sri Lanka (1), Sweden (2), Switzerland (1), Syria (1), Turkey (7), United Kingdom (3), United States (78), and Viet Nam (1). EDITOR-IN-CHIEF Godefridus J Peters, Amsterdam ASSOCIATE EDITOR Masato Abei, Tsukuba Kun Cheng, Kansas City Ritsuro Suzuki, Izumo Tian Yang, Shanghai GUEST EDITORIAL BOARD MEMBERS Wei-Fan Chiang, Tainan Chien Chou, Taipei Shuang-En Chuang, Zhunan Township Wen-Liang Fang, Taipei Chao-Cheng Huang, Kaohsiung Huang-Kai Kao, Taoyuan Chun-Yen Lin, Kweishan Jun-Yang Liou, Zhunan See-Tong Pang, Taoyuan Neng-Yao Shih, Tainan Che-Chun Su, Changhua Hao-Wei Teng, Taipei Kuo-Wang Tsai, Kaohsiung MEMBERS OF THE EDITORIAL BOARD Argentina Marina Simian, Buenos Aires Australia David Alexander Brown, Sydney Belamy B Cheung, Sydney Angela Hong, Sydney Helen Kavnoudias, Melbourne Kum Kum Khanna, Brisbane Feng Pan, Hobart Austria Andreas Leithner, Graz Okay Saydam, Vienna Belgium Gérald E Piérard, Liège Brazil Katia Ramos Moreira Leite, Sao Paulo Bulgaria Julian Ananiev, Stara Zagora Canada Slimane Belbraouet, Moncton Francesco Crea, Vancouver Sharlene Gill, Vancouver Anil Kapoor, Hamilton Saroj Niraula, Winnipeg Siyaram Pandey, Windsor China Nian-Yong Chen, Chengdu James CS Chim, Hong Kong William Chi-shing Cho, Hong Kong Yong-Song Guan, Chengdu Yi Ji, Chengdu Fu Li, Tianjin Lin-Wei Li, Zhengzhou Xin-Xiang Li, Shanghai Liu Liu, Hefei Yun-Ping Luo, Beijing Mao-Bin Meng, Tianjin Tzi Bun Ng, Hong Kong Yang-Lin Pan, Xian Xiu-Feng Pang, Shanghai Shu-Kui Qin, Nanjing Xiao-Juan Sun, Shenzhen Jian Suo, Changchun Xing-Huan Wang, Wuhan Yun-Shan Yang, Hangzhou Lei Yao, Shanghai Pei-Wu Yu, Chongqing Yin-Hua Yu, Shanghai Guo Yu, Yangzhou Ke Zen, Nanjing Li-Duan Zheng, Wuhan Zhao-Hua Zhong, Harbin Hai-Meng Zhou, Beijing Sen-Lin Zhu, Guangzhou Hong-Qing Zhuang, Tianjin Cuba Elia Neninger, Havana Denmark Pavel Gromov, Copenhagen Andreas Kjaer, Copenhagen Cathy Mitchelmore, Roskilde Henrik Toft Sorensen, Aarhus France Gilles Houvenaeghel, Marseille Fabrice Lecuru, Paris Clara Nahmias, Villejuif Palma Rocchi, Marseille I February 10, 2015

3 Germany Malgorzata Banys-Paluchowski, Hamburg Alexandr Bazhin, Munich Wolfgang M Brueckl, Nuremberg Klaus Felix, Heidelberg Jan G Hengstler, Dortmund Jorg Kleeff, Munich Michael Pinkawa, Aachen Daniel Reim, Munich Rajkumar Savai, Bad Nauheim Manfred Schmitt, Munich Jurgen Veeck, Aachen Greece Vasilis Androutsopoulos, Heraklion Hungary Zsuzsa Schaff, Budapest India Imran Ali, New Delhi Sudhir Chandna, Delhi Subhojit Dey, Gurgaon Sachin B Ingle, Latur Chanakya Nath Kundu, Bhubaneswar Syed Musthapa Meeran, Iucknow Suprava Patel, Raipur Iran Mojgan Hosseini, Tehran Ali Kabir, Tehran Ireland Michael Joseph Kerin, Galway Israel Rina Rosin-Arbesfeld, Tel Aviv Italy Luca Arcaini, Pavia Luigi Bagella, Sassari Giovanni Blandino, Rome Guido Bocci, Pisa Guido Cavaletti, Monza Fulvio Chiacchiera, Milan Anita De Rossi, Padova Giuseppe Di Lorenzo, NapAPOLI Nicola Fazio, Milan Giammaria Fiorentini, Pesaro Robert Fruscio, Monza Marilena Valeria Iorio, Milan Marco La Torre, Rome Matteo Landriscina, Foggia Giuseppe Lombardi, Padua Monica Mangoni, Florence Michele N Minuto, Genoa Simone Mocellin, Padova Luca Mologni, Monza Massimo Nabissi, Camerino Silvio Naviglio, Naples Nicola Normanno, Naples Francesca Pentimalli, Avellino Roberto Petrioli, Siena Giuseppe Procopio, Milan Tiziana Rancati, Milan Gian-Luigi Russo, Avellino Bruna Scaggiante, Trieste Alessandro Sciarra, Rome Giuseppe Servillo, Perugia Gilbert Spizzo, Merano Roberta Venturella, Catanzaro Giovanni Vitale, Cusano Milanino Japan Ujjal K Bhawal, Matsudo Xing Cui, Chiba Takanori Goi, Yoshida-gun Shuichi Hironaka, Chiba Mikito Inokuchi, Tokyo Hideki Kawai, Akita Naoko Iwahashi Kondo, Fukuoka Hiroki Kuniyasu, Kashihara Shoji Nagao, Akashi Jun Nakamura, Saga Atsushi Nanashima, Nagasaki Takuma Nomiya, Chiba Kojun Okamoto, Hidaka Youngjin Park, Sendai Hidefumi Sasaki, Tokyo Hirotomo Shibaguchi, Fukuoka Koichi Suzuki, Saitama Kazuki Takakura, Tokyo Yoshifumi Takei, Nagoya Toshihiko Torigoe, Sapporo Masahiko Watanabe, Kanagawa Hiroko Yamashita, Sapporo Shozo Yokoyama, Wakayama Kazuhiro Yoshida, Gifu Yoichiro Yoshida, Fukuoka Malaysia Batoul Sadat Haerian, Kuala Lumpur Chee-Onn Leong, Kuala Lumpur Shing Cheng Tan, Kubang Kerian Netherlands Vikram Rao Bollineni, Groningen Elisa Giovannetti, Amsterdam Lukas Hawinkels, Leiden Martijn Ruben Meijerink, Amsterdam Godefridus J Peters, Amsterdam Judith Evelyn Raber-Durlacher, Amsterdam Pieter Christiaan van der Sluis, Utrecht Astrid AM van der Veldt, Amsterdam Norway Ingfrid S Haldorsen, Bergen Line Merethe Oldervoll, Trondheim Shanbeh Zienolddiny, Oslo Peru Carlos A Castaneda, Lima Poland Antoni Mariusz Szczepanik, Cracow Portugal Antonio MF Araujo, Porto Ana Cristina Ramalhinho, Covilha Qatar Julie VCM Decock, Doha Romania Valeriu Marin Surlin, Craiova Russia Alex Lyakhovich, Novosibirsk Saudi Arabia Mostafa Ahmed Arafa, Riyadh Ziyad Binkhathlan, Riyadh Mazen Hassanain, Riyadh Singapore Eddie Yin Kwee Ng, Singapore Veronique Kiak Mien Tan, Singapore South Korea Cheol-Hee Choi, Gwangju Ik-Soon Jang, Daejeon Chaeyong Jung, Gwangju Jong Duk Kim, Daejeon Gwang Ha Kim, Busan Eun Ju Kim, Seoul Lee Su Kim, Anyang Hee Sung Kim, Seoul Kwang dong Kim, Jinju Sang Moo Lim, Seoul Seong Woo Yoon, Seoul Dae Young Zang, Anyang-si Spain Emiliano Calvo, Madrid Manuel Fuentes, Salamanca Enrique Grande, Madrid Matilde Esther Lleonart, Barcelona II February 10, 2015

4 José Antonio Lopez-Guerrero, Valencia Gracia Merino, Leon Jordi Muntane, Seville Ernest Nadal, L'Hospitalet Amalia Palacios-Eito, Cordoba Isabel T Rubio, Barcelona Albert Selva-O'Callaghan, Barcelona Sri Lanka Kemal I Deen, Dehiwela Sweden Yihai Cao, Stockholm Hong Xie, Stockholm Switzerland Nicolas C Buchs, Geneva Syria Roger von Moos, Chur Turkey Ahmet Altun, Sivas Beste Atasoy, Istanbul Ahmet Dirier, Gaziantep Ozkan Kanat, Bursa Serhan Kupeli, Adana Kazim Sahin, Elazig Isik G Yulug, Ankara United Kingdom Andrew Gaya, London Konstantinos Lasithiotakis, York Sebastian Oltean, Bristol United States ARM Ruhul Amin, Atlanta Soley Bayraktar, Ardmore Amer Beitinjaneh, Charlottesville Maurizio Bocchetta, Maywood Deliang Cao, Springfield Daniel VT Catenacci, Chicago Zhe-Sheng Chen, Queens Guan Chen, Milwaukee Duc Phuc Do, Chicago Cathy Eng, Houston Jeffrey M Farma, Philadelphia Markus H Frank, Boston Sidney Wang Fu, Washington Mei R Fu, New York Siqing Fu, Houston Song Gao, Houston Mamdooh Ghoneum, Los Angeles Ruben Rene Gonzalez-Perez, Atlanta Rachel Nicole Grisham, New York Sanjay Gupta, Cleveland Gerald M Higa, Morgantown Chung-Tsen Hsueh, Loma Linda GK Jayaprakasha, College Station Johnny Kao, West Islip Nimmi Singh Kapoor, Orange Arianna L Kim, New York Mark Alan Klein, Minneapolis Sunil Krishnan, Houston Melanie Haas Kucherlapati, Boston Mahmoud N Kulaylat, Buffalo Adeyinka O Laiyemo, Washington Marie Catherine Lee, Tampa James W Lillard, Atlanta Shiaw-Yih Lin, Houston Wei Liu, Frederick Zhao-Jun Liu, Miami Jirong Long, Nashville Jianrong Lu, Gainesville James L Mulshine, Chicago Ronald B Natale, Los Angeles Matthew E Nielsen, Chapel Hill Kutluk Oktay, Valhalla Chung S Park, Fargo Tayebeh Pourmotabbed, Memphis Raj Pruthi, Chapel Hill Jay Dilip Raman, Hershey Jianyu Rao, Los Angeles Gaiane M Rauch, Houston William C Reinhold, Bethesda Monica Rizzo, Atlanta Eben L Rosenthal, Birmingham Joan J Ryoo, Los Angeles Virgilio S Sacchini, New York Neeraj K Saxena, Baltimore Caner Saygin, Cleveland Masood A Shammas, Boston Amar B Singh, Omaha Khalid Sossey-Alaoui, Cleveland Lu-Zhe Sun, San Antonio Weijing Sun, Pittsburgh Viqar Syed, Bethesda Li Tao, Fremont Anish Thomas, Bethesda Reid Thompson, Philadelphia Shahid Umar, Kansas City Huan N Vu, Richmond Chong-Zhi Wang, Chicago Bin Wang, Chester Jin Wang, Houston Guojun Wu, Detroit Michiko Yamagata, Waltham Wannian Yang, Danville Eddy S Yang, Birmingham Jennifer Yunyan Zhang, Durham Bin Zhang, New York Shaying Zhao, Athens Jin-Rong Zhou, Boston Viet Nam Phuc Van Pham, Ho Chi Minh III February 10, 2015

5 w W J C O World Journal of Clinical Oncology Contents Bimonthly Volume 8 Number 4 August 10, 2017 REVIEW 305 Magnetic resonance imaging for prostate cancer before radical and salvage radiotherapy: What radiation oncologists need to know Couñago F, Sancho G, Catalá V, Hernández D, Recio M, Montemuiño S, Hernández JA, Maldonado A, del Cerro E MINIREVIEWS 320 Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors Tibaldi C, Lunghi A, Baldini E 329 Platinum-induced neurotoxicity: A review of possible mechanisms Kanat O, Ertas H, Caner B ORIGINAL ARTICLE Retrospective Study 336 Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists Beck JC, Chen B, Gordon BG 343 Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients Gruber-Rouh T, Langenbach M, Naguib NNN, Nour-Eldin NEM, Vogl TJ, Zangos S, Beeres M Observational Study 351 Rescue associating liver partition and portal vein ligation for staged hepatectomy after portal embolization: Our experience and literature review Maulat C, Philis A, Charriere B, Mokrane FZ, Guimbaud R, Otal P, Suc B, Muscari F CASE REPORT 360 BRAF V600Q-mutated lung adenocarcinoma with duodenal metastasis and extreme leukocytosis Qasrawi A, Tolentino A, Abu Ghanimeh M, Abughanimeh O, Albadarin S 366 Intimal sarcoma of the pulmonary artery with multiple lung metastases: Long-term survival case García-Cabezas S, Centeno-Haro M, Espejo-Pérez S, Carmona-Asenjo E, Moreno-Vega AL, Ortega-Salas R, Palacios-Eito A 371 Long-term stabilization of metastatic melanoma with sodium dichloroacetate Khan A, Andrews D, Shainhouse J, Blackburn AC August 10, 2017 Volume 8 Issue 4

6 Contents World Journal of Clinical Oncology Volume 8 Number 4 August 10, 2017 ABOUT COVER Editorial Board Member of World Journal of Clinical Oncology, Che-Chun Su, MD, PhD, Associate Professor, Attending Doctor, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan AIM AND SCOPE World Journal of Clinical Oncology (World J Clin Oncol, WJCO, online ISSN , DOI: ) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians. WJCO covers a variety of clinical medical topics, including etiology, epidemiology, evidence-based medicine, informatics, diagnostic imaging, endoscopy, tumor recurrence and metastasis, tumor stem cells, radiotherapy, chemotherapy, interventional radiology, palliative therapy, clinical chemotherapy, biological therapy, minimally invasive therapy, physiotherapy, psycho-oncology, comprehensive therapy, and oncology-related nursing. Priority publication will be given to articles concerning diagnosis and treatment of oncology diseases. The following aspects are covered: Clinical diagnosis, laboratory diagnosis, differential diagnosis, imaging tests, pathological diagnosis, molecular biological diagnosis, immunological diagnosis, genetic diagnosis, functional diagnostics, and physical diagnosis; and comprehensive therapy, drug therapy, surgical therapy, interventional treatment, minimally invasive therapy, and robot-assisted therapy. We encourage authors to submit their manuscripts to WJCO. We will give priority to manuscripts that are supported by major national and international foundations and those that are of great clinical significance. Indexing/Abstracting World Journal of Clinical Oncology is now indexed in PubMed, PubMed Central and Scopus. FLYLEAF I-III Editorial Board EDITORS FOR THIS ISSUE Responsible Assistant Editor: Xiang Li Responsible Electronic Editor: Ya-Jing Lu Proofing Editor-in-Chief: Lian-Sheng Ma Responsible Science Editor: Fang-Fang Ji Proofing Editorial Office Director: Ze-Mao Gong NAME OF JOURNAL World Journal of Clinical Oncology ISSN ISSN (online) LAUNCH DATE November 10, 2010 FREQUENCY Bimonthly EDITOR-IN-CHIEF Godefridus J Peters, PhD, Professor, Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam 1081 HV, Netherlands EDITORIAL BOARD MEMBERS All editorial board members resources online at EDITORIAL OFFICE Xiu-Xia Song, Director World Journal of Clinical Oncology Baishideng Publishing Group Inc 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA Telephone: Fax: editorialoffice@wjgnet.com Help Desk: PUBLISHER Baishideng Publishing Group Inc 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA Telephone: Fax: bpgoffice@wjgnet.com Help Desk: PUBLICATION DATE August 10, 2017 COPYRIGHT 2017 Baishideng Publishing Group Inc. Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. SPECIAL STATEMENT All articles published in journals owned by the Baishideng Publishing Group (BPG) represent the views and opinions of their authors, and not the views, opinions or policies of the BPG, except where otherwise explicitly indicated. INSTRUCTIONS TO AUTHORS ONLINE SUBMISSION II August 10, 2017 Volume 8 Issue 4

7 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.305 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) REVIEW Magnetic resonance imaging for prostate cancer before radical and salvage radiotherapy: What radiation oncologists need to know Felipe Couñago, Gemma Sancho, Violeta Catalá, Diana Hernández, Manuel Recio, Sara Montemuiño, Jhonathan Alejandro Hernández, Antonio Maldonado, Elia del Cerro Felipe Couñago, Elia del Cerro, Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Madrid, Spain Felipe Couñago, Elia del Cerro, Clinical Department, Faculty of Biomedicine, Universidad Europea, Madrid, Spain Gemma Sancho, Department of Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Violeta Catalá, Jhonathan Alejandro Hernández, Department of Radiology, Fundació Puigvert, Barcelona, Spain Diana Hernández, Department of Radiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Manuel Recio, Department of Radiology, Hospital Universitario Quirónsalud Madrid, Madrid, Spain Sara Montemuiño, Department of Radiation Oncology, Hospital Universitario de Fuenlabrada, Madrid, Spain Antonio Maldonado, Department of Nuclear Medicine, Hospital Universitario Quirónsalud Madrid, Madrid, Spain Author contributions: All authors contributed to this manuscript. Conflict-of-interest statement: Authors declare no conflicts of interest for this article. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Felipe Couñago, MD, Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Calle Diego de Velázquez 1, Pozuelo de Alarcón, Madrid, Spain. felipe.counago@quironsalud.es Telephone: Received: January 26, 2017 Peer-review started: February 8, 2017 First decision: March 27, 2017 Revised: March 30, 2017 Accepted: June 12, 2017 Article in press: June 13, 2017 Published online: August 10, 2017 Abstract External beam radiotherapy (EBRT) is one of the principal curative treatments for patients with prostate cancer (PCa). Risk group classification is based on prostate-specific antigen (PSA) level, Gleason score, and T-stage. After risk group determination, the treatment volume and dose are defined and androgen deprivation therapy is prescribed, if appropriate. Traditionally, imaging has played only a minor role in T-staging due to the low diagnostic accuracy of conventional imaging strategies such as transrectal ultrasound, computed tomography, and morphologic magnetic resonance imaging (MRI). As a result, a notable percentage of tumours are understaged, leading to inappropriate and imprecise EBRT. The development of multiparametric MRI (mpmri), an imaging technique that combines morphologic studies with functional diffusion-weighted sequences and dynamic contrastenhanced imaging, has revolutionized the diagnosis and management of PCa. As a result, mpmri is now used in staging PCa prior to EBRT, with possible implications for both risk group classification and treatment decisionmaking for EBRT. mpmri is also being used in salvage 305 August 10, 2017 Volume 8 Issue 4

8 Couñago F et al. Multiparametric MRI before radiotherapy radiotherapy (SRT), the treatment of choice for patients who develop biochemical recurrence after radical prostatectomy. In the clinical context of biochemical relapse, it is essential to accurately determine the site of recurrence - pelvic (local, nodal, or bone) or distant - in order to select the optimal therapeutic management approach. Studies have demonstrated the value of mpmri in detecting local recurrences - even in patients with low PSA levels ( ng/ml) - and in diagnosing bone and nodal metastasis. The main objective of this review is to update the role of mpmri prior to radical EBRT or SRT. We also consider future directions for the use and development of MRI in the field of radiation oncology. Key words: Prostate cancer; Staging; Radical radiotherapy; Multiparametric magnetic resonance imaging; Biochemical failure; Radical prostatectomy; Salvage radiotherapy The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Multiparametric magnetic resonance imaging (mpmri) has revolutionized the management of prostate cancer, including external beam radiotherapy (EBRT). mpmri has also improved local staging and recurrence detection after radical prostatectomy, even in patients with low prostate-specific antigen levels, and it has increased the accuracy of EBRT, potentially improving survival outcomes while reducing side effects. For these reasons, mpmri is an essential tool in the evaluation and treatment of prostate cancer. Couñago F, Sancho G, Catalá V, Hernández D, Recio M, Montemuiño S, Hernández JA, Maldonado A, del Cerro E. Magnetic resonance imaging for prostate cancer before radical and salvage radiotherapy: What radiation oncologists need to know. World J Clin Oncol 2017; 8(4): Available from: URL: wjgnet.com/ /full/v8/i4/305.htm DOI: org/ /wjco.v8.i4.305 INTRODUCTION In the last decade, the growing use of multiparametric magnetic resonance imaging (mpmri) in the diagnosis and treatment of prostate cancer (PCa) has revolutionized patient management. Numerous studies confirm the emerging and increasingly important role of mpmri in PCa in a wide range of clinical contexts, including: Tumour screening and detection [1] ; prostate biopsy guidance [2] ; staging [3] ; assessment of tumour aggressiveness [4] ; active surveillance protocols [5] ; treatment planning (surgery, radiotherapy, and focal therapies) [6-8] ; and detection of recurrence after radical prostatectomy (RP) or external beam radiotherapy (EBRT) [9,10]. There are two main indications for radiotherapy in PCa: (1) the initial treatment of patients with a recent diagnosis of Pca; and (2) salvage treatment in patients with recurrent disease after RP. In both of these clinical scenarios, conventional diagnostic strategies [digital rectal examination (DRE), transrectal ultrasound (TRUS) with blind biopsies, computed tomography (CT), and bone scintigraphy] all have a low yield for establishing the T stage and in detecting recurrences post RP, all of which could result in undertreatment. In this context, the objective of this review is to update the role of mpmri in the radical treatment of PCa with EBRT and in salvage radiotherapy (SRT) after RP. In addition, we discuss future directions for the use and development of MRI in the field of radiation oncology. WHAT IS PROSTATE MPMRI? mpmri is an imaging technique that allows for the noninvasive assessment of the prostate gland. It is called multiparametric because various pulse sequences (i.e., multiple parameters) are used to help detect and characterize the prostate lesions. Currently, mpmri includes both morphologic (T1 and T2) and functional sequences [diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) imaging with gadolinium]. Spectroscopy no longer plays an important role and is thus not included in current MRI guidelines [11,12]. MORPHOLOGIC IMAGING T1-weighted pulse sequence The T1 sequence consists of a T1-weighted (T1W) Fast Spin Eco (FSE) from the aortic bifurcation to the symphysis pubis, assessed on the axial plane (Figure 1). The T1W sequence cannot discriminate various prostate gland zones and therefore its main utility is in detecting the presence of post-biopsy bleeding (a common cause of false positives in PCa diagnosis) (Figure 2), nodal disease, and bone metastasis [13]. T2-weighted pulse sequence The T2 sequence consists of a T2-weighted (T2W) FSE sequence that includes the prostate gland and seminal vesicles (Figure 1B-D). The T2W sequence is normally performed in three spatial planes (axial, coronal, and sagittal). T2W sequence is capable of discriminating various anatomic zones of the prostate, including the peripheral, central, and transitional zones, as well as the anterior fibromuscular stroma, neurovascular plexus, surgical pseudocapsule, and the prostate capsule. In normal prostates, the peripheral zone is homogeneous and hyperintense on MRI (Figure 1B). In adults, the transitional zone is larger, with a heterogenous signal and hyperplastic nodules of varying appearance, thus this zone can sometimes present diagnostic difficulties [13]. Cancerous prostate lesions usually appear as nodules or hypointense areas on T2W images, with less well-defined margins at the transitional zone. A 306 August 10, 2017 Volume 8 Issue 4

9 Couñago F et al. Multiparametric MRI before radiotherapy A B A B C D C D Figure 1 Normal prostate anatomy on magnetic resonance imaging - T1 and T2-weighted images. A: T1-weighted axial image of a normal prostate: Homogeneous gland, isointense to the adjacent pelvic muscles. It is not possible to differentiate any anatomical detail; B: Axial image of the prostate shows peripheral zone (PZ - black arrow) as a hyperintense area with a U-shape. The transitional zone (TZ - white asterisk) has a hypointense multinodular pattern ( organized chaos ). Anterior fibromuscular stroma (white arrow) is seen as a hypointense area anterior to the TZ and medial to both anterior PZ horns. The capsule (arrowhead) is seen as a hypointense rim surrounding the gland; C: Coronal image shows the hyperintense seminal vesicles located cephalad to the base of the prostate (black arrows). Ampulla of vas deferens (VD - black arrowhead) can be seen as paired structures medial to both seminal vesicles (SV). Prostate central zone (asterisk) is seen as a hypointense area located in the base of the prostate gland. Urethra (white arrow), levator ani muscle (white asterisk) and external sphincter (white arrowhead) are also shown; D: Sagittal image shows the vas deferens (black arrow), seminal vesicles (arrowhead) and the ejaculatory duct (white arrow). A Figure 2 T1 (A) and T2-weighted images (B) of the midgland of the prostate. The left peripheral zone has a hyperintense area (white arrow, A) in T1-weighted image that correlates with a hypointensity (white arrow in B) in T2-weighted image, suggestive of bleeding in a patient with a recent transrectal ultrasound prostate biopsy. limitation of the T2W sequence is that benign and malignant alterations often overlap. According to the Prostate Imaging Reporting and Data System (PIRADS) B Figure 3 A 71-year-old patient. A: T2-weighted axial image at the level of the midgland of the prostate shows a hypointense nodular lesion at the transitional zone/anterior fibromuscular stroma, with a diameter of 26 mm (arrow); B and C: ADC map (B) and DWI image (C) show a marked hypo- and hyperintensity, respectively, in relation to restriction of diffusion (white arrows); D: DCE image with significant enhancement of the lesion (arrow). The characteristics of the nodule are compatible with a PIRADS 5 lesion and the marked restriction of the diffusion suggests a high-grade clinically significant prostate carcinoma, confirmed by the results of a MRI-guided transrectal ultrasound prostate biopsy (Gleason 4 + 4). v2 model (see PIRADS reporting and interpretation model, version 2), the T2W sequence is key to the diagnosis of PCa in the transition zone [11] (Figure 3A). It is also useful in the diagnosis of local dissemination [14]. FUNCTIONAL SEQUENCES Diffusion sequences Diffusion sequences [diffusion-weighted MRI (DW-MRI) and apparent diffusion coefficient (ADC)] are performed in the axial plane and include the prostate and seminal vesicles (Figure 3B and C). These sequences are used primarily to evaluate the movement of the free water molecules in the interstitial space and through the cellular membrane. The behavior of lesions on DW-MRI and ADC is conditioned by cell density, the extracellular space, the integrity of cell membranes, and the extent of glandular organization. A correct assessment is based on a qualitative (high b-value DWI) and quantitative (ADC map) evaluation of the images. In PCa, the presence of impeded diffusion appears as a high signal intensity on the DWI and low intensity on the ADC map [13]. PCa presents architectural changes that restrict water diffusion. The more aggressive the tumour, the more pronounced these changes tend to be. For this 307 August 10, 2017 Volume 8 Issue 4

10 Couñago F et al. Multiparametric MRI before radiotherapy A B A B C D C D Figure 4 Prostate magnetic resonance imaging of a 64-year-old patient. A: T2-weighted image shows an area of hypointensity in the right peripheral zone of the midgland of the prostate (black arrow); B: A discrete restriction of diffusion in ADC map (white arrow); C: DWI image (white arrow); D: Enhancement on DCE image (white arrow), suggestive of prostatitis, confirmed by transrectal ultrasound biopsy. Figure 5 An 82-year-old patient with PIRADS 5 lesion in the basal left peripheral zone showing hypointensity (white arrows) in T2-weighted image (A), restriction of diffusion in apparent diffusion coefficient map (B) and diffusion-weighted magnetic resonance image (C), DCE shows significant early enhancement of the suspicious area (D). MRI-guided transrectal ultrasound biopsy confirmed a clinically significant prostatic carcinoma (Gleason 5 + 4). DCE: Dynamic contrast enhancement; MRI: Magnetic resonance imaging. reason, diffusion sequences are valuable not only to characterise lesions likely to be malignant, but also to help to predict the Gleason score of the lesions [15,16] (Figure 3). Benign lesions, such as those occurring secondary to prostatitis, usually present less diffusion restriction (Figure 4) [17]. According to the PIRADS v2 model, diffusion sequences are crucial to the diagnosis of PCa in the peripheral zone and in characterising indeterminate lesions in the transition zone [12] (Figure 5B and C). Dynamic contrast-enhanced sequences Dynamic contrast-enhanced (DCE)-MRI is performed in the axial plane and includes the prostate and seminal vesicles. This sequence is performed prior to endovenous gadolinium administration and up to 4 min afterwards (Figure 5D). In malignant lesions, the most common phenomenon observed on DCE-MRI is early uptake of the contrast material and early washout (Figure 5D). However, this behaviour is relatively variable and sometimes overlaps with that of benign lesions. According to PIRADS v2, although DCE sequences have a secondary value, their main value is in their contribution to the characterization of indeterminate lesions in the peripheral zone [12]. Pharmacokinetic models of DCE-MRI perfusion allow us to quantify various parameters to evaluate contrast perfusion, including k trans (the volume transfer constant, which reflects the efflux rate of gadolinium contrast from the vascular compartment through the endothelium to the interstitial space), kep (rate of return to the vascular space), and Ve (the fractional volume of the extracellular tumour space). Using these data, it is possible to build parametric maps that represent the intratumoral heterogeneity of the spatial distribution of these parameters. However, at present, no conclusive results are available to support the use of these parameters for diagnostic purposes. PIRADS ACQUISITION, INTERPRETATION, AND REPORTING MODEL, VERSION 2.0 A consensus-based model - PIRADS v2 - has been developed for interpreting and scoring mpmri results. Several organizations, including the European Society of Urogenital Radiology (ESUR), American College of Radiology (ACR), and the AdMeTech Foundation, participated in the development of this model. The main objective of the model - aside from standardizing acquisition, interpretation and reporting protocols - is to predict the probability of clinically significant PCa by hierarchically organizing the information obtained in each MRI sequencing modality according to whether the lesion is located in the peripheral or transitional zone [11,12]. Although this model has some limitations, its implementation has served to reduce intra- and inter- 308 August 10, 2017 Volume 8 Issue 4

11 Couñago F et al. Multiparametric MRI before radiotherapy A B C Figure 6 Prostate carcinoma with extracapsular extension in a 72-year-old patient. A: T2-weighted axial image of the pelvis at the level of midgland of the prostate shows a marked hypointensity in the left peripheral zone and disruption of the capsule, distorting the normal anatomy of the left neurovascular bundle with measurable extracapsular extension (ESUR Score 5); B and C: ADC map (B) and DWI-images (C) demonstrate a significant restriction of diffusion, with hypointensity in the ADC and hyperintensity in the DWI-images that extend beyond the prostate capsule (arrows). Surgical specimen confirmed a pt3a prostate carcinoma. ADC: Apparent diffusion coefficient; DWI: Diffusion-weighted magnetic resonance imaging. Table 1 European Society of Urogenital Radiology scoring of extracapsular extension in prostate cancer Findings observer variability as well as to increase the diagnostic yield of mpmri. EQUIPMENT The minimum technological requirements necessary to guarantee that mpmri assessment is performed to an acceptable quality standard have been defined by consensus agreement [11]. This consensus establishes, as a minimum requirement, that MRI equipment should be at least 1.5T magnetic field strength. The use of endorectal coil is only essential in older 1.5T equipment because newer MRI equipment at 1.5T and 3T are both capable of obtaining reliable image quality without the need for coils. The elimination of the need for endorectal coils is beneficial because it reduces imaging time, thus increasing patient comfort [11]. STAGING Score Abutment 1 Irregularity 3 Neurovascular bundle thickening 4 Bulge, loss of capsule 4 Measurable extra-capsular disease 5 Local staging MRI is the imaging technique of choice to determine whether the tumor is organ-confined or extra-glandular. In the year 2012, the ESUR proposed a 5-point scale to establish the probability of extracapsular extension (ECE) based on direct and indirect signs [14] (Table 1 and Figure 6). Schieda et al [18] evaluated the ability of this 5-point scoring system to predict ECE compared to a nonstandardized reporting modality. Those authors concluded that the optimal sensitivity/specificity was achieved with a score of 3. In addition, the scale was more sensitive than the non-standardized modality (59.5% vs 24.5%, P = 0.01) without significant differences in specificity (68.0% vs 75.0%, P = 0.06). Several clinical nomograms are available to predict the likelihood of ECE. The two most common nomograms are the Partin tables (which include several variables: PSA, biopsy-based Gleason score, and clinical stage) [19] and the nomogram developed at the Memorial Sloan-Kettering (MSK) Cancer Center (which adds prostate biopsy results - specifically, the percentage of positive cylinders) [20]. Recently, Feng et al [21] conducted a retrospective study of 112 patients who underwent mpmri prior to RP to determine if mpmri could improve the predictive capacity of the Partin tables and the MSK nomogram for ECE. The authors found that the area under the curve (AUC) for the Partin and MSK nomograms for predicting ECE was 0.85 and 0.86, respectively. When mpmri was added, the AUC increased, respectively, to 0.92 and In the most recent guidelines published by the European Society of Urology, mpmri has been included as a local staging technique in the following patient risk groups: High-risk disease; intermediate risk disease with predominantly Gleason pattern 4; and low-risk disease if mpmri is considered necessary for treatment planning [11]. Staging of distant disease The diagnosis of metastatic disease is essential to ensure proper therapeutic management and MRI has proven its value as a diagnostic tool for metastasis (Figure 7). In a recently published meta-analysis, Shen et al [22] compared the relative utility of choline PET/CT, MRI, and bone scintigraphy in the diagnosis of bone metastasis in patients with PCa. The authors reported sensitivity values, respectively of 91%, 97%, and 79% and specificity values of 99%, 95%, and 82%. These differences between these imaging modalities 309 August 10, 2017 Volume 8 Issue 4

12 Couñago F et al. Multiparametric MRI before radiotherapy A B C D E Figure 7 A 54-year-old patient with recently diagnosed prostate carcinoma. A: T2-weighted axial image of the pelvis shows an ill-defined hyperintense area in the right pubis (arrow); B and C: ADC map (B) and DWI images (C) show restriction of diffusion in the same area (arrow); D: DCE image presents enhancement of the lesion after IV gadolinium (arrow). MRI findings were suspicious for pelvic bone metastasis, with no evidence of such lesion on staging abdomino-pelvic CT scan performed a week earlier (E) and in a previous bone scintigraphy (not shown). Bone metastasis was confirmed on clinical evolution. MRI: Magnetic resonance imaging; DCE: Dynamic contrast-enhanced; CT: Computed tomography. were statistically significant, with bone scintigraphy significantly less sensitive and less specific than the other two techniques. By contrast, MRI presented the highest diagnostic sensitivity for detecting metastasis. Lecouvet et al [23] evaluated 100 patients at a high risk of metastasis to compare the diagnostic yield of whole-body DW-MRI vs CT and bone scintigraphy with Technetium Tc 99m (supported by simple X-ray when necessary) in the diagnosis of bone and nodal metastasis. Bone scintigraphy (± X-ray) plus CT had a sensitivity of 84% vs 91%-94% for whole-body DW- MRI (P < 0.05); specificity values were, respectively, 94%-97% vs 91%-96% (P > 0.05). The authors conclude that one-step, whole-body MRI can effectively assess nodal and bone metastasis in patients with highrisk PCa, thus eliminating the need for multimodal diagnosis (Figure 8). Conde-Moreno et al [24] compared whole-body DW- MRI to choline PET/CT in the diagnosis of metastatic disease, finding that choline PET/CT had a greater sensitivity whereas whole-body DW-MRI had a greater specificity. Given these findings, the authors conclude that these techniques are complementary. The value of MRI in the diagnosis of bone and nodal metastasis has been recognized by the ESUR [14]. The European Society of Urology also contemplates the use of MRI as an alternative technique to detect possible metastasis in intermediate and high-risk patients [11]. Re-staging following recurrence after radiotherapy Reported 5-year biochemical relapse rates after radiotherapy range from 15% in low-risk patients to 67% in high-risk cases [9]. Both DW-MRI and DCE- MRI allow us to detect recurrences after radiotherapy. In a group of 24 patients who developed biochemical relapse following radiotherapy, Kim et al [25] performed prostate mpmri at 3T (phased array coil), followed by TRUS-guided biopsy. They assessed the diagnostic performance of both DW-MRI and DCE-MRI to detect recurrent disease. The sensitivity, specificity, and diagnostic accuracy of DW-MRI were 49%, 93%, and 82%, respectively, vs 49%, 92% and 81% for DCE- MRI. Combined DW-MRI and DCE-MRI resulted in a sensitivity, specificity, and diagnostic accuracy of 59%, 91% and 83%, respectively. Tamada et al [26] demonstrated the diagnostic value of mpmri to assess recurrence after brachytherapy, reporting a sensitivity of 77%, specificity of 92%, and diagnostic accuracy of 90%. IMPACT OF MPMRI ON TREATMENT DE- CISIONS FOR RADIOTHERAPY Impact on the therapeutic strategy (EBRT) Several studies have evaluated the impact of mpmri staging on PCa risk group classification and on treatment decisions for EBRT (Table 2). Couñago et al [6] assessed 310 August 10, 2017 Volume 8 Issue 4

13 Couñago F et al. Multiparametric MRI before radiotherapy A B C Figure 8 A 51-year-old patient with a history of Gleason prostate carcinoma treated with hormone therapy. A: Re-staging bone scintigraphy was negative for bone metastases; B and C: Sagittal (B) and coronal (C) images of abdominal CT scan show a diffuse axial bone altered density that could not rule out bone metastases, along with multiple retroperitoneal and pelvic enlarged nodes suggesting malignant adenopathies (white arrows in C); D and E: Sagittal (D) and coronal (E) wholebody MRI images clearly show multiple bone metastases and adenopathies, along with hepatic nodules (black arrows in F, axial abdominal MRI) suspicious for metastatic disease. MRI: Magnetic resonance imaging. D E F 274 patients staged initially by DRE and TRUS and subsequently by 3T mpmri prior to the final EBRT treatment decision. The risk group classification shifted after mpmri in 32.8% of cases after all factors (PSA, Gleason score and T-stage) were considered. In addition, in 43.8% of cases (52.5% depending on criteria used to indicate or not ADT in intermediate-risk patients), this led to a change in some aspect(s) of the radiotherapy treatment (treatment volume, dose, and ADT). Finally, the mpmri results were validated in the subgroup of surgical patients, showing a 70.0% sensitivity and 93.8% specificity for ECE. Panje et al [8] evaluated 122 patients staged using 1.5T or 3T (38% of sample) phased-array-body coil MRI. Most (53.3%) patients had received ADT prior to the mpmri. The authors found that the use of mpmri resulted in risk group modification in 28.7% of cases. Because the influence of 1.5T MRI and the use of ADT prior to mpmri on the results is not known, it is difficult to perform a direct comparison with other studies. Liauw et al [27] evaluated the role of endorectal coil mpmri at 3T prior to EBRT in a group of 122 PCa patients, finding that mpmri resulted in a change in therapeutic approach (indication for active surveillance, brachytherapy in monotherapy and dose modification, treatment volume, and use of ADT in EBRT) in 18% of patients. Recently, Pullini et al [28] prospectively evaluated 44 patients with PCa to determine the impact of mpmri at 3T on staging and treatment decisions for EBRT, finding that staging by mpmri resulted in a change in risk group classification in 41% of patients, thus potentially impacting the EBRT treatment decision. Based on the studies described above, it is clear that mpmri staging has a significant impact on radiotherapy treatment decisions, with risk group modifications ranging from 18% to 41% of patients, depending on the study. This wide variability may be attributable to numerous different factors, including the following: The MRI (magnet and coil, protocol used, experience of the radiologist); the initial clinical staging (experience of the clinician with DRE/TRUS, the use of CT to evaluate pelvic lymph nodes, etc.); the clinical characteristics of the patient cohort; the treatment protocol at each centre (dose, fractionation, target volume, indication for ADT, use of brachytherapy, etc.); the use of ADT prior to MRI; and finally the inclusion (or not) of metastatic patients in the final results. Despite this heterogeneity, one finding common to all these studies is that a large percentage of patients staged by mpmri are upstaged compared to conventional clinical staging. As a consequence, mpmri staging implies that more patients will be classified as intermediate risk, high-to-very high risk, or metastatic patients. Nevertheless, it is worth noting that risk group downgrading has been reported in a small percentage (4%-12%) of patients [8,28]. Despite the clear influence of mpmri staging on EBRT treatment decisions, numerous questions remain unresolved. For instance, we do not know which patient groups would benefit most, in terms of cost-effectiveness, from mpmri staging. Nor is it clear if changes in therapeutic management based on MRI findings will increase survival and/or quality of life in these patients. The clearest example of this can be seen in low-risk patients in which upstaging after mpmri is common (20%-50%) even though long-term biochemical control 311 August 10, 2017 Volume 8 Issue 4

14 Couñago F et al. Multiparametric MRI before radiotherapy Table 2 Studies evaluating the impact of the staging using magnetic resonance imaging in prostate cancer patients treated with radiotherapy Ref. Year Type of MRI No. of patients Field strength Coil Tumor stage shift (%) Risk group changes (%) Change in RT (CTV, doses, HT) (%) Technique validation Jackson et al [75] 2005 Morphological T PAB 55 NR No Couñago et al [76] 2014 Multiparametric 103 3T PAB Yes Chang et al [77] 2014 Morphological T PAB No Panje et al [8] 2015 multiparametric T and 3T PAB No Horsley et al [78] 2015 Morphological T PAB No Yamaguchi et al [79] 2015 Morphological T PAB No Couñago et al [6] 2015 Multiparametric 274 3T PAB or Yes Pullini et al [28] 2016 Multiparametric 44 3T PAB NR No Liauw et al [27] 2016 Multiparametric 122 3T PAB NR No 1 Exclusive assessment of the CTV change; 2 Data from T1-T2 to T3-T4 upstaging; 3 Values according to the HT criteria in intermediate-risk patients. PAB: Phased-array-bodycoil; NR: Not reported; CTV: Clinical target volume; HT: Hormonal therapy. in this risk cohort (staged exclusively by conventional DRE) and treated with EBRT is excellent (93% at 10 years follow up) [29]. Therefore, we must exercise caution with regard to the changes in tumour stage that can result from the use of these newer, more precise imaging tests. In this sense, more prospective, multicentric studies are needed to better clarify the role of mpmri prior to EBRT. Contouring and treatment planning in EBRT MRI has proven to be highly useful in radiation oncology in improving the accuracy of treatment volume delineation. The use of MRI allows for more precise identification of the prostate gland location and thus more accurate contouring, especially of the prostate apex, which can help to avoid over- or under-estimation of the microscopic volume that commonly occurs with CT-based contouring [30]. mpmri can also help to rule out the presence of high-grade disease in the transition zone at the anterior base, thus allowing for lower doses to the bladder neck. In addition, MRI is highly useful in identifying the anatomic structures involved in erections: The internal pudenda artery, the periprostatic nerve fibers, and the penile bulb. The improved anatomic definition of these structures with mpmri could help to limit the radiation dose to these areas, which could potentially lead to higher rates of erectile function preservation and, consequently, better quality of life [30]. Therefore, compared to CT-based treatment volumes, MRI allows for the delineation of a smaller clinical target volume (CTV), distinguishing the CTV from normal tissue, suggesting that MRI-based contouring can reduce treatment-related toxicity in PCa [8]. The reliability of mpmri in tumour staging plays an increasingly important role in advanced radiotherapy techniques such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). In these highly-conformal techniques with narrow treatment margins, it is vitally important to accurately detect the presence of extracapsular disease or seminal vesicle invasion and to include these areas within the treatment volume to avoid geographic loss and, consequently, underdosing [8]. DETECTION OF RELAPSE AFTER RADI- CAL PROSTATECTOMY PSA levels become undetectable after RP; however, depending on the pathological stage and other risk factors, up to 60% of patients with PCa will eventually develop biochemical relapse (defined as PSA > 0.2 ng/ml with two consecutive rises) [31]. Current cancer treatment guidelines recommend SRT after RP if the PSA remains elevated or if biochemical relapse is detected during follow-up [32]. In both of these clinical scenarios, the elevated PSA may be secondary to local disease (associated or not with a significant risk of metastasis) and/or distant disease. Although SRT is one of the potentially curative treatments in these cases, with cause-specific survival rates up to 3 times greater than observation alone [33], up to 50% of patients will develop a recurrence in the 10 years following SRT. These poor outcomes may be due to a variety of factors, including: (1) tumour-related factors associated with a greater risk of biochemical progression and worse disease-free survival, including the following: Initial PSA; Gleason 8; involvement of the seminal vesicles; infiltrated resection margins; early biochemical relapse; and PSADT; (2) delayed initiation of SRT when the PSA is > 1 ng/ml and palpable disease is evident on DRE; and (3) SRT-related factors (which merit more research to define the optimal therapeutic strategy for disease control): If the exact location of the relapse site is unknown, this can result in an inadequate CTV, underdosing, and the need for systemic treatment. SRT is most effective when administered before the PSA reaches 0.5 ng/ml [34]. However, with such low PSA levels, conventional imaging tests - TRUS, bone scintigraphy, and CT - are of little use in detecting the recurrence. In recent years, mpmri has become more widely used in the detection of local recurrences. Indeed, it is the only imaging technique recommended by the ESUR to evaluate pelvic recurrences in patients 312 August 10, 2017 Volume 8 Issue 4

15 Couñago F et al. Multiparametric MRI before radiotherapy A B C D E F G Figure 9 Multiparametric magnetic resonance imaging of local recurrence. A: Morphological study: Axial T2-weighted fast-spin echo image. No recurrence is detected; B-F: Functional study; B and C: Axial diffusion sequences showing restricted diffusion in ADC map (arrow); D-G: Axial gradient-echo T1-weighted images showing focal enhancement in dynamic study (D) (arrow), color map (E) and curve (G). with low (0.2-2 ng/ml) PSA levels [14]. Although no protocol has yet been established for the use of MRI in SRT, in most published studies the approach does not differ from that used to assess the prostate in cases with a suspected tumour or local dissemination. In local relapse, the most common patterns observed on MRI are slightly hyperintense lesions on T2W sequences and hypervascular lesions on the DCE- MRI. Cirillo et al [35] showed that adding DCE to T2W sequences improved detection rates for local relapse after RP: Unenhanced and contrast-enhanced MRI yielded, respectively, the following outcomes: Sensitivity (61.4% vs 84.1%), specificity (82.1% vs 89.3%), positive predictive value (84.4% vs 92.5%), negative predictive value (57.5% vs 78.1%), and accuracy (69.4% vs 86.1%). In diffusion imaging, the radiological appearance of local recurrence may be similar to the tumour, with high signals in the diffusion sequences and low signals in the ADC map (Figure 9). PIRADS v2 is not applicable in local relapses, although it may be in the future. Incidence of recurrences detected by mpmri Multiple authors have investigated the capacity of mpmri to detect post-prostatectomy relapses, with detection rates ranging from 84%-95% in series that use endorectal coil MRI in patients with median PSA > 1 ng/ml, many of whom also had palpable disease on DRE [9,35,36]. Other studies carried out in patients with lower PSA levels (median PSA, ng/ml) by endorectal coil MRI [37,38] and/or pelvic MRI have reported recurrence rates ranging from 24%-91% [39-42] (Table 3). This variability among studies is likely due to several factors, including: Retrospective study design; sample size and sample heterogeneity; differences in the radiologists experience level; the use of different MRI sequencing modalities; and difference in relapse criteria. Results from a retrospective study [43] and from a meta-analysis [44] suggest that the 11 C or 18 F-choline PET/CT has a higher detection rate for local, nodal, or metastatic recurrences post RP when the PSADT is < 6 mo and PSA values are > 1 ng/ml. By contrast, in patients with lower PSA values, mpmri has proven to be more sensitive in detecting local recurrences [22,45-48] and in small-sized (< 10 mm) local relapses [47]. Other authors have found that diagnostic rates for visible pelvic relapses are higher when mpmri and PET/CT are combined vs MRI or choline PET/CT alone [49-51]. Recently, studies that investigated the use of PET/CT with PSMA (prostate-specific membrane antigen) ligands have reported higher detection rates for local relapse compared to choline PET/CT, even in cases with low PSA levels [52]. However, other authors, including Freitag et al [53], have found that adding MRI to PET provides additional value even when 68Ga-PSMA-11 is used as a tracer in PET/CT. 313 August 10, 2017 Volume 8 Issue 4

16 Couñago F et al. Multiparametric MRI before radiotherapy Table 3 Studies on multiparametric magnetic resonance imaging with low prostate-specific antigen levels for the diagnosis of local recurrence after radical prostatectomy Ref. Year Desing Coil and Magnet Linder et al [38] 2007 Retrospective PAC + ERC 1.5T and 3T Rischke et al [39] 2012 Retrospective PAC 1.5T Liauw et al [37] 2013 Retrospective ERC 1.5T and 3T Park et al [56] 2014 Retrospective PAC 1.5T and 3T Verma et al [42] 2014 Retrospective PAC 3T Couñago et al [40] 2015 Retrospective PAC 3T Hernandez et al [41] 2015 Retrospective PAC 3T No. of patients PSA (mean or median) Mean or median lesion size ng/ml 10 mm TRUS biopsy, PSA reduction after SRT or increased lesion size on serial imaging ng/ml 11 mm PSA reduction after SRT and changes in MRI after SRT Reference standard % rrl MRI sequences, Se, Spe, PPV, NPV, Acc 91 T2 + DCE Se: 91% Spe: 45% PPV: 85% NPV: 60% 67 T2 + DCE Se: 67% Spe: 100% PPV: 100% NPV: 83% Acc: 83% ng/ml 0.26 cc None 24 T2 + DCE + DWI ng/ml 12 mm TRUS biopsy NR T2 + DCE ng/ml negative MRI 0.40 ng/ml positive MRI NR None 22.2 T2 + DCE + DWI ng/ml 15.2 mm None 24.6 T2 + DCE + DWI ng/ml 8.5 mm None 47 (local + lymph nodes) 38.6 (local) T2 + DCE + DWI mpmri: Multiparametric MRI; RP: Radical prostatectomy; rrl: Radiographic local recurrence; T2: T2-weighted imaging; DCE: Dynamic contrast-enhanced imaging; DWI: Diffusion-weighted imaging; Se: Sensitivity; Spe: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; Acc: Accuracy; PAC: Phased-array coil; ERC: Endorectal coil; NR: Not reported, SRT: Salvage radiation therapy. Clinical factors associated with mpmri findings Several factors, including PSA levels at recurrence, the PSADT, and the presence of compromised resection margins, have all been significantly associated with mpmri findings. Several authors have defined preradiotherapy PSA cut-off values, ranging from > 0.3 [37] to > 0.5 [40] or 0.54 [39] ng/ml, as clinical predictors of MRI positivity. Eifler et al [19] reported a higher probability of visible local relapse in patients with PSADT > 14 mo. In addition, a PSADT < 6 mo has been associated with higher incidence of nodal relapse, even with PSA levels < 1 ng/ml. Hernández et al [41] reported a median PSADT of 5.12 mo in patients with nodal recurrence vs 12.7 mo in patients without evidence of nodal disease on MRI (P = 0.17). Finally, a study that used MRI lymphography (ferumoxtran-10) to assess nodal involvement found that patients with positive lymphography presented a median PSADT of 3.8 mo [54]. Topography of recurrences Most local recurrences occur in the peri-anastomotic and retrovesical regions [41,55,56], although up to 22% of recurrences have been diagnosed at the resection site of the vas deferens [57]. Efficacy of mpmri to detect nodal relapse Data on the efficacy of MRI to detect nodal relapses after RP are scant, particularly in patients with low PSA values. However, an incidence between 5%-10% has been estimated [37,41], most commonly involving the external iliac lymph node chains. It has been suggested that DW-MRI could increase the detection of nodal relapses, with a reported 90% efficacy rate in nodes < 1 cm [58] (Figure 10). The two studies that used MRI with ferromagnetic contrast (ferumoxtran-10) to evaluate patients with biochemical relapse after RP reported positive nodes (< 1 cm) in 72% and 20% of patients, respectively, even with low PSA levels [54,59]. The main limitation of these studies is that ferumoxtran-10 was authorized only for research purposes. Detection of bone metastasis Recent research suggests that the use of whole-body MRI (WB-MRI), together with WB-DW-MRI, may allow assessment of nodal recurrence and bone metastasis with a single imaging modality. These approaches show greater sensitivity and specificity than conventional imaging and will facilitate the evaluation and monitoring of response to systemic treatments [60]. IMPACT OF MPMRI ON SRT TREATMENT DECISIONS The impact of mpmri on the efficacy of SRT is not known, but use of mpmri is becoming increasingly 314 August 10, 2017 Volume 8 Issue 4

17 Couñago F et al. Multiparametric MRI before radiotherapy A B C D E F Figure 10 Lymph node study. A: Axial T2-weighted fast-spin echo image shows right external iliac lymph nodes; B and C: Axial diffusion sequences; C: Restricted diffusion in ADC map; D: Axial gradient-echo T1-weighted perfusion image showing a high peak enhancement; E: Color map; F: Curve; ADC: Apparent diffusion coefficient. common in the evaluation of disease dissemination in patients with biochemical relapse after RP. The information provided by mpmri is integrated into the decision-making process for SRT planning, as follows. Definition of the CTV Individualized treatment planning should assure that the relapse site is included within the CTV in accordance with published guidelines. Irradiation (or not) of the lymph node stations: The benefits of elective pelvic irradiation in SRT is controversial since currently available data include only retrospective studies; however, findings from those studies suggest that pelvic irradiation increases both biochemical control [61] and biochemical relapse-free survival [62]. It has been suggested that RP may lead to changes in the lymphatic drainage pattern and that these are not adequately included in the CTV when contoured according to current recommendations [63,64]. Irradiation of oligometastatic bone disease: Currently, the decision to irradiate oligometastatic bone lesions is considered on an individual basis by consensus at multidisciplinary urological tumour boards, or in the context of a clinical trial. It would be interesting to investigate the impact of irradiating only the nodal stations in patients with a short PSADT whose mpmri images indicate the presence of nodal disease without prostate bed involvement. Similarly, it would also be interesting to conduct a study in which patients with a long PSADT (> 10 mo) and local disease alone received irradiation only to the local disease site. In both of these scenarios, the impact of ablative RT techniques such as stereotactic body radiotherapy (SBRT) should be investigated. Dose escalation We hypothesize that treating the prostatectomy bed at conventional doses while simultaneously increasing the dose to the relapse site detected on MRI could improve outcomes without increasing toxicity [65]. In fact, high dose irradiation delivered exclusively to the relapse site could be curative and this approach would also minimize irradiation of healthy tissue, thus reducing the risk of side effects. Adjuvant systemic treatment The addition of hormonotherapy to SRT remains controversial. In clinical practice, the trend is to administer combined treatment in patients with high-risk disease and/or poor prognostic factors. The RTOG 9601 study showed a significant increase in overall survival at 10 years in patients with post-rp biochemical relapse who were treated with SRT (64.8 Gy) plus bicalutamide 150 mg for 2 years vs patients who received RT alone [82% vs 78%, hazard ratio: 0.75 (95%CI: ), P = 0.036] [66]. The results of studies currently underway, such as RADICALS and RTOG 0534, should definitively determine the benefit of hormonotherapy in patients 315 August 10, 2017 Volume 8 Issue 4

18 Couñago F et al. Multiparametric MRI before radiotherapy who undergo postoperative radiotherapy. However, it should be pointed out that none of the aforementioned trials have included mpmri or PET/CT for the purpose of diagnosing and locating tumour recurrences. As we have suggested above, more intensive treatment at the relapse site could improve SRT outcomes, with or without hormonotherapy. FUTURE DIRECTIONS The future of MRI in radiotherapy includes the following: Monitoring response to radiotherapy Various studies have shown the potential utility of ADC and K trans to monitor response to radiotherapy in patients with PCa [67,68]. This application of MRI could be used to investigate the impact of new focal therapies administered early in patients with persistent disease or local relapse. Technological advancements that increase detection rates [PET/MRI and new radiotracers (PSMA)] PET/MRI is a new multimodal imaging technique that improves diagnostic imaging, with a promising future in the evaluation of PCa. In addition to diagnosis and staging, PET/MRI plays an important role in detecting recurrences in patients with biochemical relapse. In bone metastasis, the use of PET/MRI improves the detection and characterization of bone lesions, especially with the use of new radiotracers ( 18 F-FNa, PSMA, choline), providing functional information as well as greater anatomic information due to the incorporation of MRI [50,69,70]. These data are essential for ablative radiotherapy. The future of imaging in PCa will be marked by improvements in equipment and in the sequences and antennas used, especially 3T equipment, diffusion sequences, and multichannel surface coils ( 128 channels). Implementation of MRI in the workflow of radiation oncology departments It is worth highlighting the incipient but growing use of MRI in radiation oncology departments. MRI is used not only for simulations, workflow, and treatment planning, but it is also being incorporated into linear accelerators to guide radiotherapy treatment [71]. Genetic testing and MRI At least one study has been conducted showing that MRI and genetic testing can improve the reliability for risk stratification in patients with PCa [72]. Guidelines for focal treatments Several studies have assessed the role of MRI-guided dose escalation (EBRT or brachytherapy) to the dominant intraprostatic lesion [73,74]. CONCLUSION The data obtained from mpmri imaging are increasingly being integrated into PCa staging, recurrence detection, and therapeutic management. mpmri is also being incorporated into the workflow of radiation oncology departments due to its capacity to help define target volumes for radical radiotherapy and SRT after prostatectomy. Technological advances, such as PET/MRI combined with new radiotracers such as PSMA, can improve staging and recurrence detection, and assist in planning more accurate treatments. REFERENCES 1 Fütterer JJ, Briganti A, De Visschere P, Emberton M, Giannarini G, Kirkham A, Taneja SS, Thoeny H, Villeirs G, Villers A. Can Clinically Significant Prostate Cancer Be Detected with Multiparametric Magnetic Resonance Imaging? A Systematic Review of the Literature. Eur Urol 2015; 68: [PMID: DOI: / j.eururo ] 2 Nassiri N, Natarajan S, Margolis DJ, Marks LS. Targeted Prostate Biopsy: Lessons Learned Midst the Evolution of a Disruptive Technology. Urology 2015; 86: [PMID: DOI: /j.urology ] 3 de Rooij M, Hamoen EH, Witjes JA, Barentsz JO, Rovers MM. Accuracy of Magnetic Resonance Imaging for Local Staging of Prostate Cancer: A Diagnostic Meta-analysis. Eur Urol 2016; 70: [PMID: DOI: /j.eururo ] 4 Loffroy R, Chevallier O, Moulin M, Favelier S, Genson PY, Pottecher P, Crehange G, Cochet A, Cormier L. Current role of multiparametric magnetic resonance imaging for prostate cancer. Quant Imaging Med Surg 2015; 5: [PMID: DOI: /j.issn ] 5 Guo R, Cai L, Fan Y, Jin J, Zhou L, Zhang K. Magnetic resonance imaging on disease reclassification among active surveillance candidates with low-risk prostate cancer: a diagnostic meta-analysis. Prostate Cancer Prostatic Dis 2015; 18: [PMID: DOI: /pcan ] 6 Couñago F, Del Cerro E, Díaz-Gavela AA, Marcos FJ, Recio M, Sanz-Rosa D, Thuissard I, Olaciregui K, Mateo M, Cerezo L. Tumor staging using 3.0 T multiparametric MRI in prostate cancer: impact on treatment decisions for radical radiotherapy. Springerplus 2015; 4: 789 [PMID: DOI: /s ] 7 Marshall S, Taneja S. Focal therapy for prostate cancer: The current status. Prostate Int 2015; 3: [PMID: DOI: / j.prnil ] 8 Panje C, Panje T, Putora PM, Kim SK, Haile S, Aebersold DM, Plasswilm L. Guidance of treatment decisions in risk-adapted primary radiotherapy for prostate cancer using multiparametric magnetic resonance imaging: a single center experience. Radiat Oncol 2015; 10: 47 [PMID: DOI: /s ] 9 Barchetti F, Panebianco V. Multiparametric MRI for recurrent prostate cancer post radical prostatectomy and postradiation therapy. Biomed Res Int 2014; 2014: [PMID: DOI: / 2014/316272] 10 Murray JR, McNair HA, Dearnaley DP. Rationale and development of image-guided intensity-modulated radiotherapy post-prostatectomy: the present standard of care? Cancer Manag Res 2015; 7: [PMID: DOI: /CMAR.S51955] 11 Barentsz JO, Weinreb JC, Verma S, Thoeny HC, Tempany CM, Shtern F, Padhani AR, Margolis D, Macura KJ, Haider MA, Cornud F, Choyke PL. Synopsis of the PI-RADS v2 Guidelines for Multiparametric Prostate Magnetic Resonance Imaging and Recommendations for Use. Eur Urol 2016; 69: [PMID: DOI: /j.eururo ] 316 August 10, 2017 Volume 8 Issue 4

19 Couñago F et al. Multiparametric MRI before radiotherapy 12 Weinreb JC, Barentsz JO, Choyke PL, Cornud F, Haider MA, Macura KJ, Margolis D, Schnall MD, Shtern F, Tempany CM, Thoeny HC, Verma S. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol 2016; 69: [PMID: DOI: /j.eururo ] 13 Catalá VG, Algaba F, Martí T. MRI and prostate cancer: what s new? Radiología 2017; In press 14 Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G, Rouviere O, Logager V, Fütterer JJ; European Society of Urogenital Radiology. ESUR prostate MR guidelines Eur Radiol 2012; 22: [PMID: DOI: /s y] 15 Donati OF, Mazaheri Y, Afaq A, Vargas HA, Zheng J, Moskowitz CS, Hricak H, Akin O. Prostate cancer aggressiveness: assessment with whole-lesion histogram analysis of the apparent diffusion coefficient. Radiology 2014; 271: [PMID: DOI: / radiol ] 16 Rosenkrantz AB, Triolo MJ, Melamed J, Rusinek H, Taneja SS, Deng FM. Whole-lesion apparent diffusion coefficient metrics as a marker of percentage Gleason 4 component within Gleason 7 prostate cancer at radical prostatectomy. J Magn Reson Imaging 2015; 41: [PMID: DOI: /jmri.24598] 17 Afaq A, Koh DM, Padhani A, van As N, Sohaib SA. Clinical utility of diffusion-weighted magnetic resonance imaging in prostate cancer. BJU Int 2011; 108: [PMID: DOI: / j x x] 18 Schieda N, Quon JS, Lim C, El-Khodary M, Shabana W, Singh V, Morash C, Breau RH, McInnes MD, Flood TA. Evaluation of the European Society of Urogenital Radiology (ESUR) PI-RADS scoring system for assessment of extra-prostatic extension in prostatic carcinoma. Eur J Radiol 2015; 84: [PMID: DOI: /j.ejrad ] 19 Eifler JB, Feng Z, Lin BM, Partin MT, Humphreys EB, Han M, Epstein JI, Walsh PC, Trock BJ, Partin AW. An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to BJU Int 2013; 111: [PMID: DOI: / j x x] 20 Ohori M, Kattan MW, Koh H, Maru N, Slawin KM, Shariat S, Muramoto M, Reuter VE, Wheeler TM, Scardino PT. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. J Urol 2004; 171: ; discussion 1849 [PMID: DOI: /01.ju d] 21 Feng TS, Sharif-Afshar AR, Wu J, Li Q, Luthringer D, Saouaf R, Kim HL. Multiparametric MRI Improves Accuracy of Clinical Nomograms for Predicting Extracapsular Extension of Prostate Cancer. Urology 2015; 86: [PMID: DOI: / j.urology ] 22 Shen G, Deng H, Hu S, Jia Z. Comparison of choline-pet/ct, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis. Skeletal Radiol 2014; 43: [PMID: DOI: /s ] 23 Lecouvet FE, El Mouedden J, Collette L, Coche E, Danse E, Jamar F, Machiels JP, Vande Berg B, Omoumi P, Tombal B. Can wholebody magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for singlestep detection of metastases in patients with high-risk prostate cancer? Eur Urol 2012; 62: [PMID: DOI: / j.eururo ] 24 Conde-Moreno AJ, Herrando-Parreño G, Muelas-Soria R, Ferrer- Rebolleda J, Broseta-Torres R, Cozar-Santiago MP, García-Piñón F, Ferrer-Albiach C. Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) vs choline-positron emission tomographycomputed tomography (choline-pet/ct) for selecting treatments in recurrent prostate cancer. Clin Transl Oncol 2017; 19: [PMID: DOI: /s ] 25 Kim CK, Park BK, Park W, Kim SS. Prostate MR imaging at 3T using a phased-arrayed coil in predicting locally recurrent prostate cancer after radiation therapy: preliminary experience. Abdom Imaging 2010; 35: [PMID: DOI: /s ] 26 Tamada T, Sone T, Jo Y, Hiratsuka J, Higaki A, Higashi H, Ito K. Locally recurrent prostate cancer after high-dose-rate brachytherapy: the value of diffusion-weighted imaging, dynamic contrast-enhanced MRI, and T2-weighted imaging in localizing tumors. AJR Am J Roentgenol 2011; 197: [PMID: DOI: / AJR ] 27 Liauw SL, Kropp LM, Dess RT, Oto A. Endorectal MRI for risk classification of localized prostate cancer: Radiographic findings and influence on treatment decisions. Urol Oncol 2016; 34: 416.e e21 [PMID: DOI: /j.urolonc ] 28 Pullini S, Signor MA, Pancot M, Zuiani C, Bazzocchi M, Fongione S, Girometti R. Impact of multiparametric magnetic resonance imaging on risk group assessment of patients with prostate cancer addressed to external beam radiation therapy. Eur J Radiol 2016; 85: [PMID: DOI: /j.ejrad ] 29 Kuban DA, Levy LB, Cheung MR, Lee AK, Choi S, Frank S, Pollack A. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011; 79: [PMID: DOI: /j.ijrobp ] 30 Moghanaki D, Turkbey B, Vapiwala N, Ehdaie B, Frank SJ, McLaughlin PW, Harisinghani M. Advances in Prostate Cancer Magnetic Resonance Imaging and Positron Emission Tomography- Computed Tomography for Staging and Radiotherapy Treatment Planning. Semin Radiat Oncol 2017; 27: [PMID: DOI: /j.semradonc ] 31 Pfister D, Bolla M, Briganti A, Carroll P, Cozzarini C, Joniau S, van Poppel H, Roach M, Stephenson A, Wiegel T, Zelefsky MJ. Early salvage radiotherapy following radical prostatectomy. Eur Urol 2014; 65: [PMID: DOI: /j.eururo ] 32 Valicenti RK, Thompson I Jr, Albertsen P, Davis BJ, Goldenberg SL, Wolf JS, Sartor O, Klein E, Hahn C, Michalski J, Roach M 3rd, Faraday MM; American Society for Radiation Oncology/American Urological Association. Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines. Int J Radiat Oncol Biol Phys 2013; 86: [PMID: DOI: /j.ijrobp ] 33 Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008; 299: [PMID: DOI: /jama ] 34 Ohri N, Dicker AP, Trabulsi EJ, Showalter TN. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression metaanalysis with radiobiological modelling. Eur J Cancer 2012; 48: [PMID: DOI: /j.ejca ] 35 Cirillo S, Petracchini M, Scotti L, Gallo T, Macera A, Bona MC, Ortega C, Gabriele P, Regge D. Endorectal magnetic resonance imaging at 1.5 Tesla to assess local recurrence following radical prostatectomy using T2-weighted and contrast-enhanced imaging. Eur Radiol 2009; 19: [PMID: DOI: / s ] 36 Sella T, Schwartz LH, Swindle PW, Onyebuchi CN, Scardino PT, Scher HI, Hricak H. Suspected local recurrence after radical prostatectomy: endorectal coil MR imaging. Radiology 2004; 231: [PMID: DOI: /radiol ] 37 Liauw SL, Pitroda SP, Eggener SE, Stadler WM, Pelizzari CA, Vannier MW, Oto A. Evaluation of the prostate bed for local recurrence after radical prostatectomy using endorectal magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2013; 85: [PMID: DOI: /j.ijrobp ] 38 Linder BJ, Kawashima A, Woodrum DA, Tollefson MK, Karnes J, Davis BJ, Rangel LJ, King BF, Mynderse LA. Early localization of recurrent prostate cancer after prostatectomy by endorectal coil magnetic resonance imaging. Can J Urol 2014; 21: [PMID: ] 39 Rischke HC, Schäfer AO, Nestle U, Volegova-Neher N, Henne K, Benz MR, Schultze-Seemann W, Langer M, Grosu AL. Detection of local recurrent prostate cancer after radical prostatectomy in terms of salvage radiotherapy using dynamic contrast enhanced-mri without endorectal coil. Radiat Oncol 2012; 7: 185 [PMID: DOI: 317 August 10, 2017 Volume 8 Issue 4

20 Couñago F et al. Multiparametric MRI before radiotherapy / X-7-185] 40 Couñago F, del Cerro E, Recio M, Díaz AA, Marcos FJ, Cerezo L, Maldonado A, Rodríguez-Luna JM, Thuissard I, Martin JL. Role of 3T multiparametric magnetic resonance imaging without endorectal coil in the detection of local recurrent prostate cancer after radical prostatectomy: the radiation oncology point of view. Scand J Urol 2015; 49: [PMID: DOI: / ] 41 Hernandez D, Salas D, Giménez D, Buitrago P, Esquena S, Palou J, de la Torre P, Pernas J, Gich I, de Segura GG, Craven-Bartle J, Sancho G. Pelvic MRI findings in relapsed prostate cancer after radical prostatectomy. Radiat Oncol 2015; 10: 262 [PMID: DOI: /s ] 42 Verma V, Chen L, Michalski JM, Hu Y, Zhang W, Robinson K, Verma S, Eschen L, Fergus S, Mullen D, Strope S, Grubb R 3rd, Gay HA. Evaluation of 3 T pelvic MRI imaging in prostate cancer patients receiving post-prostatectomy IMRT. World J Urol 2015; 33: [PMID: DOI: /s ] 43 Castellucci P, Ceci F, Graziani T, Schiavina R, Brunocilla E, Mazzarotto R, Pettinato C, Celli M, Lodi F, Fanti S. Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-Choline PET/CT scan before salvage radiation therapy? J Nucl Med 2014; 55: [PMID: DOI: /jnumed ] 44 Treglia G, Ceriani L, Sadeghi R, Giovacchini G, Giovanella L. Relationship between prostate-specific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab Med 2014; 52: [PMID: DOI: /cclm ] 45 Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, Soloviev D, Hany TF, Miralbell R. 18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values (<1 ng/ml) after radical prostatectomy. BJU Int 2007; 99: [PMID: DOI: /j X x] 46 Giovacchini G, Picchio M, Coradeschi E, Bettinardi V, Gianolli L, Scattoni V, Cozzarini C, Di Muzio N, Rigatti P, Fazio F, Messa C. Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging 2010; 37: [PMID: DOI: / s ] 47 Panebianco V, Sciarra A, Lisi D, Galati F, Buonocore V, Catalano C, Gentile V, Laghi A, Passariello R. Prostate cancer: 1HMRS-DCEMR at 3T versus [(18)F]choline PET/CT in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (RRP). Eur J Radiol 2012; 81: [PMID: DOI: /j.ejrad ] 48 Kitajima K, Murphy RC, Nathan MA, Froemming AT, Hagen CE, Takahashi N, Kawashima A. Detection of recurrent prostate cancer after radical prostatectomy: comparison of 11C-choline PET/CT with pelvic multiparametric MR imaging with endorectal coil. J Nucl Med 2014; 55: [PMID: DOI: / jnumed ] 49 Couñago F, Recio M, Maldonado A, Del Cerro E, Díaz-Gavela AA, Thuissard IJ, Sanz-Rosa D, Marcos FJ, Olaciregui K, Mateo M, Cerezo L. Evaluation of tumor recurrences after radical prostatectomy using 18F-Choline PET/CT and 3T multiparametric MRI without endorectal coil: a single center experience. Cancer Imaging 2016; 16: 42 [PMID: DOI: /s ] 50 Lindenberg L, Ahlman M, Turkbey B, Mena E, Choyke P. Evaluation of Prostate Cancer with PET/MRI. J Nucl Med 2016; 57: 111S-116S [PMID: DOI: /jnumed ] 51 Sobol I, Zaid HB, Haloi R, Mynderse LA, Froemming AT, Lowe VJ, Davis BJ, Kwon ED, Karnes RJ. Contemporary Mapping of Post-Prostatectomy Prostate Cancer Relapse with ¹¹c- Choline Positron Emission Tomography and Multiparametric Magnetic Resonance Imaging. J Urol 2017; 197: [PMID: DOI: /j.juro ] 52 Kratochwil C, Afshar-Oromieh A, Kopka K, Haberkorn U, Giesel FL. Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnostics and Therapy for Prostate Cancer. Semin Nucl Med 2016; 46: [PMID: DOI: /j.semnuclmed ] 53 Freitag MT, Radtke JP, Afshar-Oromieh A, Roethke MC, Hadaschik BA, Gleave M, Bonekamp D, Kopka K, Eder M, Heusser T, Kachelriess M, Wieczorek K, Sachpekidis C, Flechsig P, Giesel F, Hohenfellner M, Haberkorn U, Schlemmer HP, Dimitrakopoulou- Strauss A. Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in ⁶⁸ga-psma-11- PET of PET/CT and PET/MRI: comparison with mpmri integrated in simultaneous PET/MRI. Eur J Nucl Med Mol Imaging 2017; 44: [PMID: DOI: /s z] 54 Meijer HJ, van Lin EN, Debats OA, Witjes JA, Span PN, Kaanders JH, Barentsz JO. High occurrence of aberrant lymph node spread on magnetic resonance lymphography in prostate cancer patients with a biochemical recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2012; 82: [PMID: DOI: / j.ijrobp ] 55 Poortmans P, Bossi A, Vandeputte K, Bosset M, Miralbell R, Maingon P, Boehmer D, Budiharto T, Symon Z, van den Bergh AC, Scrase C, Van Poppel H, Bolla M; EORTC Radiation Oncology Group. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol 2007; 84: [PMID: DOI: /j.radonc ] 56 Park JS, Park W, Pyo HR, Park BK, Park SY, Choi HY, Lee HM, Jeon SS, Seo SI, Jeong BC, Jeon HG. Suggestion for the prostatic fossa clinical target volume in adjuvant or salvage radiotherapy after a radical prostatectomy. Radiother Oncol 2014; 110: [PMID: DOI: /j.radonc ] 57 Nguyen DP, Giannarini G, Seiler R, Schiller R, Thoeny HC, Thalmann GN, Studer UE. Local recurrence after retropubic radical prostatectomy for prostate cancer does not exclusively occur at the anastomotic site. BJU Int 2013; 112: E243-E249 [PMID: DOI: /j X x] 58 Thoeny HC, Froehlich JM, Triantafyllou M, Huesler J, Bains LJ, Vermathen P, Fleischmann A, Studer UE. Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging. Radiology2014; 273: [PMID: DOI: / radiol ] 59 Heesakkers RA, Jager GJ, Hövels AM, de Hoop B, van den Bosch HC, Raat F, Witjes JA, Mulders PF, van der Kaa CH, Barentsz JO. Prostate cancer: detection of lymph node metastases outside the routine surgical area with ferumoxtran-10-enhanced MR imaging. Radiology 2009; 251: [PMID: DOI: / radiol ] 60 Pasoglou V, Larbi A, Collette L, Annet L, Jamar F, Machiels JP, Michoux N, Vande Berg BC, Tombal B, Lecouvet FE. One-step TNM staging of high-risk prostate cancer using magnetic resonance imaging (MRI): toward an upfront simplified all-in-one imaging approach? Prostate 2014; 74: [PMID: DOI: / pros.22764] 61 Moghanaki D, Koontz BF, Karlin JD, Wan W, Mukhopadhay N, Hagan MP, Anscher MS. Elective irradiation of pelvic lymph nodes during postprostatectomy salvage radiotherapy. Cancer 2013; 119: [PMID: DOI: /cncr.27712] 62 Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys 2007; 69: [PMID: DOI: /j.ijrobp ] 63 Lawton CA, Michalski J, El-Naqa I, Kuban D, Lee WR, Rosenthal SA, Zietman A, Sandler H, Shipley W, Ritter M, Valicenti R, Catton C, Roach M 3rd, Pisansky TM, Seider M. Variation in the definition of clinical target volumes for pelvic nodal conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2009; 74: [PMID: DOI: /j.ijrobp ] 64 Harris VA, Staffurth J, Naismith O, Esmail A, Gulliford S, Khoo V, Lewis R, Littler J, McNair H, Sadoyze A, Scrase C, Sohaib A, 318 August 10, 2017 Volume 8 Issue 4

21 Couñago F et al. Multiparametric MRI before radiotherapy Syndikus I, Zarkar A, Hall E, Dearnaley D; PIVOTAL Trialists. Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys 2015; 92: [PMID: DOI: /j.ijrobp ] 65 (S010) A Phase III Randomized Trial of MRI-Mapped Dose-Escalated Salvage Radiotherapy Post-Prostatectomy: The MAPS Trial- Feasibility and Acute Toxicity. Oncology (Williston Park) 2015; 29: [PMID: ] 66 Shipley WU, Seiferheld W, Lukka H, Major P, Heney NM, Grignon D, Sartor O, Patel M, Bahary JP, Zietman AL, Pisansky TM, Zeitzer K, Lawton CAF, Feng FY, Lovett RD, Balogh A, Souhami L, Rosenthal SA, Kerlin KJ, Sandler HM. Report of NRG Oncology: RTOG 9601, A Phase 3 Trial in Prostate Cancer: Anti-androgen Therapy (AAT) With Bicalutamide During and After Radiation Therapy (RT) in Patients Following Radical Prostatectomy (RP) With pt2-3pn0 Disease and an Elevated PSA. Int J Radiat Oncol Biol Phys 2016; 94: 3 [DOI: /j.ijrobp ] 67 Song I, Kim CK, Park BK, Park W. Assessment of response to radiotherapy for prostate cancer: value of diffusion-weighted MRI at 3 T. AJR Am J Roentgenol 2010; 194: W477-W482 [PMID: DOI: /AJR ] 68 Low RN, Fuller DB, Muradyan N. Dynamic gadolinium-enhanced perfusion MRI of prostate cancer: assessment of response to hypofractionated robotic stereotactic body radiation therapy. AJR Am J Roentgenol 2011; 197: [PMID: DOI: / AJR ] 69 Souvatzoglou M, Eiber M, Takei T, Fürst S, Maurer T, Gaertner F, Geinitz H, Drzezga A, Ziegler S, Nekolla SG, Rummeny EJ, Schwaiger M, Beer AJ. Comparison of integrated whole-body [11C]choline PET/MR with PET/CT in patients with prostate cancer. Eur J Nucl Med Mol Imaging 2013; 40: [PMID: DOI: /s y] 70 Lee MS, Cho JY, Kim SY, Cheon GJ, Moon MH, Oh S, Lee J, Lee S, Woo S, Kim SH. Diagnostic value of integrated PET/MRI for detection and localization of prostate cancer: Comparative study of multiparametric MRI and PET/CT. J Magn Reson Imaging 2017; 45: [PMID: DOI: /jmri.25384] 71 Torresin A, Brambilla MG, Monti AF, Moscato A, Brockmann MA, Schad L, Attenberger UI, Lohr F. Review of potential improvements using MRI in the radiotherapy workflow. Z Med Phys 2015; 25: [PMID: DOI: /j.zemedi ] 72 Porpiglia F, Cantiello F, De Luca S, Manfredi M, Veltri A, Russo F, Sottile A, Damiano R. In-parallel comparative evaluation between multiparametric magnetic resonance imaging, prostate cancer antigen 3 and the prostate health index in predicting pathologically confirmed significant prostate cancer in men eligible for active surveillance. BJU Int 2016; 118: [PMID: DOI: /bju.13318] 73 Arrayeh E, Westphalen AC, Kurhanewicz J, Roach M 3rd, Jung AJ, Carroll PR, Coakley FV. Does local recurrence of prostate cancer after radiation therapy occur at the site of primary tumor? Results of a longitudinal MRI and MRSI study. Int J Radiat Oncol Biol Phys 2012; 82: e787-e793 [PMID: DOI: /j.ijrobp ] 74 Gomez-Iturriaga A, Casquero F, Urresola A, Ezquerro A, Lopez JI, Espinosa JM, Minguez P, Llarena R, Irasarri A, Bilbao P, Crook J. Dose escalation to dominant intraprostatic lesions with MRItransrectal ultrasound fusion High-Dose-Rate prostate brachytherapy. Prospective phase II trial. Radiother Oncol 2016; 119: [PMID: DOI: /j.radonc ] 75 Jackson AS, Parker CC, Norman AR, Padhani AR, Huddart RA, Horwich A, Husband JE, Dearnaley DP. Tumour staging using magnetic resonance imaging in clinically localised prostate cancer: relationship to biochemical outcome after neo-adjuvant androgen deprivation and radical radiotherapy. Clin Oncol (R Coll Radiol) 2005; 17: [PMID: ] 76 Couñago F, Recio M, Del Cerro E, Cerezo L, Díaz Gavela A, Marcos FJ, Murillo R, Rodriguez Luna JM, Thuissard IJ, Martin JL. Role of 3.0 T multiparametric MRI in local staging in prostate cancer and clinical implications for radiation oncology. Clin Transl Oncol 2014; 16: [PMID: DOI: /s ] 77 Chang JH, Lim Joon D, Nguyen BT, Hiew CY, Esler S, Angus D, Chao M, Wada M, Quong G, Khoo V. MRI scans significantly change target coverage decisions in radical radiotherapy for prostate cancer. J Med Imaging Radiat Oncol 2014; 58: [PMID: DOI: / ] 78 Horsley PJ, Aherne NJ, Edwards GV, Benjamin LC, Wilcox SW, McLachlan CS, Assareh H, Welshman R, McKay MJ, Shakespeare TP. Planning magnetic resonance imaging for prostate cancer intensitymodulated radiation therapy: Impact on target volumes, radiotherapy dose and androgen deprivation administration.asia Pac J Clin Oncol 2015; 11: [PMID: DOI: /ajco.12266] 79 Yamaguchi S, Ohguri T, Fujii M, Yahara K, Hayashida Y, Fujimoto N, Korogi Y. Definitive 3D-CRT for clinically localized prostate cancer: modifications of the clinical target volume following a prostate MRI and the clinical benefits. Springerplus 2015; 4: 347 [PMID: DOI: /s ] P- Reviewer: Cihan YB, Shoji S S- Editor: Kong JX L- Editor: Wang TQ E- Editor: Lu YJ 319 August 10, 2017 Volume 8 Issue 4

22 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.320 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) MINIREVIEWS Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors Carmelo Tibaldi, Alice Lunghi, Editta Baldini Carmelo Tibaldi, Alice Lunghi, Editta Baldini, Division of Oncology, Department of Oncology, S. Luca Hospital, Lucca, Italy Author contributions: Tibaldi C, Lunghi A and Baldini E contributed equally to this work. Conflict-of-interest statement: None of the authors have any potential conflicts of interest associated with this research. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Dr. Carmelo Tibaldi, Division of Oncology, Department of Oncology, S. Luca Hospital, Via Guglielmo Lippi Francesconi 1, Lucca, Italy. carmelo.tibaldi@uslnordovest.toscana.it Telephone: Fax: Received: February 13, 2017 Peer-review started: February 14, 2017 First decision: April 14, 2017 Revised: May 15, 2017 Accepted: May 22, 2017 Article in press: May 24, 2017 Published online: August 10, 2017 Abstract The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death protein ligand 1 (PD-L1) monoclonal antibodies, has opened new scenarios in the management of non-small cell lung cancer (NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered (tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC. Key words: Predictive biomarkers; Immunotherapy; Checkpoint inhibitors; Programmed cell death protein ligand 1; Non-small cell lung cancer The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Use of programmed cell death protein ligand 1 (PD-L1) assay to predict the outcomes of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. This minireview underlines promises and pitfalls of the PD-L1 expression to predict the activity and efficacy of programmed cell death protein 1/PD-L1 inhibitors in NSCLC. 320 August 10, 2017 Volume 8 Issue 4

23 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Tibaldi C, Lunghi A, Baldini E. Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors. World J Clin Oncol 2017; 8(4): Available from: URL: DOI: INTRODUCTION Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 85% of primary lung cancers. Approximately two-thirds of NSCLC patients are diagnosed at an advanced stage and their prognosis remains poor [1]. The discovery of driver oncogene alterations such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and identification of their targeted inhibitors, have dramatically improved the outcomes in highly selected patients [2,3]. Conversely, the last generation chemotherapy regimens date back more than 15 years and, unfortunately, the clinical results obtained with this strategy have reached a plateau. The recent improvements in the knowledge of cancer immunoediting and the discovery of immune checkpoint inhibitors have led to new opportunities in the treatment of NSCLC and have paved the way to improve the outcomes for a considerable number of patients [4-6]. The immunoresponse, driven by T-lymphocytes, is regulated by a complicated balance between inhibitory checkpoints and activating signals. Some key immune checkpoint proteins have been identified: Cytotoxic T-lymphocytes antigen 4 (CTLA-4) and programmed death-1 (PD-1). In the priming phase, which occurs in lymph-nodes, the CTLA-4 receptor, located on the surface of the lymphocyte T cells binds the B7-receptor on the cellular membrane of the dendritic cell. In the effector phase, which occurs peripherally, the PD-1 located on the cellular membrane of lymphocyte T cells, binds programmed cell death protein ligand 1 (PD-L1) and PD-L2, which are expressed by tumor cells, stromal cells, or both. These observations have led to the development of a monoclonal antibody-directed against CTLA4 and PD1/PD-L1 proteins such as ipilimumab (anti-ctla-4), nivolumab and pembrolizumab (anti PD1), atezolizumab, durvalumab, avelumab (anti- PD-L1). These new classes of drugs have gained a rising development in the treatment of NSCLC: So far, nivolumab, pembrolizumab and atezolizumab have been approved by the Food and Drug Administration for second-line treatment of advanced NSCLC. In this setting, all the above-mentioned drugs have shown a clear superiority in terms of activity and efficacy compared to standard chemotherapy. However, although well tolerated, these new drugs are highly effective only in a limited subset of patients; this fact, together with the high economic impact, has evidenced the need to identify of biomarkers able to select patients with the highest likelihood of benefit [7]. The attention of researchers and clinicians has focused mainly on the expression of PD-L1 on tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC), since this protein seems to be critical in the PD-1/PDL-1 pathway. Unfortunately, the heterogeneity of tests, targets and scores has produced conflicting results in the literature. ANTI-PD-1 ANTIBODIES Nivolumab beyond first-line treatment In a pivotal phase Ⅰ study published by Gettinger et al [8], 296 patients with advanced solid tumors, including 122 NSCLCs, were treated with an escalating dose of anti PD-1 antibody (BMS ). PD-L1 expression was evaluated by using a non-commercial anti PD-L1 monoclonal antibody (5H1) in formalin-fixed tumor specimens and fresh tumor tissues. Positivity was defined as 5% tumor cell membrane staining in a minimum number of 100 evaluable cells. PD-L1 expression was retrospectively evaluated in 10 patients: None of the 5 patients with negative tumors had an objective response whereas 1 out of 5 patients bearing positive tumors responded to treatment. This phase Ⅰ trial has been recently updated by recruiting an additional 129 patients who reported an overall response rate of 17%. A total of 68 samples were retrospectively tested for PD-L1 expression: Patients with positive tumors achieved an overall response rate of 15%, a median progression free survival (mpfs) of 3.3 mo (95%CI: ), and a median overall survival (mos) of 7.8 mo (95%CI: ). Patients with negative tumors achieved an objective response rate of 14%, an mpfs of 1.8 mo (95%CI: ), and a mos of 10.5 mo (95%CI: ). Responses were obtained regardless of histology (squamous or non-squamous), EGFR and KRAS status, PD-L1 positivity or negativity. Conversely, a smoking history seemed to be an interesting parameter: patients smoking more than 5 pack-years did much better (overall response rate of 30% vs 0% for < 5 pack-years). One intriguing observation, subsequently confirmed, was that some patients, who discontinued therapy for toxicity, maintained clinical remission in the absence of more than 9 months treatment (Table 1). In the CheckMate 063 multicenter phase Ⅱ study the nivolumab 3 mg/kg q 14 activity was evaluated in heavily pre-treated advanced squamous cell carcinoma of the lung [9]. The patient population was highly refractory to chemotherapy, with almost twothirds having previously received three or more systemic treatments. A total of 117 patients were enrolled: The overall response rate, evaluated by an independent radiology review Committee, was 14.5% (95%CI: ). Seventy-six tumors were retrospectively assessed for PD-L1 expression on formalin-fixed, paraffin-embedded (FFPE) 321 August 10, 2017 Volume 8 Issue 4

24 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Table 1 Correlation between nivolumab activity and outcome and programmed cell death protein ligand 1 immunohistochemestry score Author/study Marker antibody Tumor type Treatment line PD-L1 cutoff N pts Response (%) mpfs mo (95%CI) mos mo (95%CI) Nivolumab Gettinger et al [8] Dako 28-8 NSCLC > 2 5 % ( ) 7.8 ( ) Phase Ⅰ < 5% ( ) 10.5 ( ) Rizvi et al [9] CM 063 Dako 28-8 Squamous 2 5% NR NR Phase Ⅱ NSCLC < 5% NR NR Brahmer et al [10] Dako 28-8 Squamous > 1 10% (NR) 11 (NR) CM 017 NSCLC < 10% (NR) 8.2 (NR) Phase Ⅲ 5% (NR) 10 (NR) < 5% (NR) 8.5 (NR) 1% (NR) 9.3 (NR) < 1% (NR) 8.7 (NR) Borgheai et al [11] Dako 28-8 Non squamous > 1 10% (NR) 19.9 (NR) CM 057 NSCLC < 10% (NR) 9.9 (NR) Phase Ⅲ 5% (NR) 19.4 (NR) < 5% (NR) 9.8 (NR) 1% (NR) 17.7 (NR) < 1% (NR) 10.5 (NR) Gettinger et al [12] Dako 28-8 NSCLC 1 50% NR NR CM 012 < 50% NR NR Phase Ⅰ 25% NR NR < 25% NR NR 10% NR NR < 10% NR NR 5% NR NR < 5% NR NR 1% NR NR < 1% NR NR Rizvi et al [13] CM012 Dako 28-8 NSCLC 1 1% (< 0.1 ± 21.8) 20.2 ( ) phase Ⅰ < 1% (0.9 ± 28.7+) 19.2 ( ) Socinski et al [14] Dako 28-8 NSCLC 1 5% NR NR NR CM 026 < 5% NR NR NR NR phase Ⅲ 25% NR NR NR < 25% NR NR NR NR 50% NR NR NR < 50% NR NR NR NR 75% NR NR NR < 75% NR NR NR NR CM: CheckMate; NR: Not reported; pts: Patients; NSCLC: Non-small cell lung cancer; PD-L1: Programmed cell death protein ligand 1; mpfs: Median progression free survival; mos: Median overall survival. specimens with a commercially validated, automated immunohistochemical assay (Dako, Carpinteria, CA, United States) by using a 28-8 clone (rabbit anti-human PD-L1) with a 5% expression threshold to define PD-L1 positivity. Response rates were 24% and 14% in patients with positive vs negative tumors respectively (Table 1). In the CheckMate 017 phase Ⅲ trial a total of 272 pre-treated patients with advanced squamous lung tumors were randomized to receive 3 mg/kg of nivolumab every 2 wk or 75 mg/m 2 of docetaxel every 3 wk. The primary end-point was overall survival OS [10]. This pivotal trial demonstrated a statistically and clinically significant survival advantage in favor of immunotherapy with a reduction in risk death of 41% [hazard ratio (HR) = 0.59, 95%CI: 0.44 to 0.79, P < 0.001]. The mos was 9.2 mo (95%CI: 7.3 to 13.3) for nivolumab vs 6.0 mo (95%CI: 5.1 to 7.3) for docetaxel and the response rates were 20% and 9% respectively (P = ). PD-L1 protein expression was retrospectively evaluated in pretreatment tumorbiopsies with the Dako assay and the response rate was compared at pre-specified expression levels of 1%, 5% or 10%. The response rate was 17% in tumours with PD-L1 positivity 1%; this rate of response was indistinguishable from that observed in PD-L1 negative specimens (< 1%). The response rate was 21% in tumors with PDL-1 positivity 5% and 15% in tumors with PD-L1 < 5%. Ultimately, the response rates were 19% and 16% in PD-L1 positive tumors 10% or < 10%, respectively (Table 1). It is noteworthy that the benefit of OS in this study was independent of the PD-L1 scores. In the CheckMate 057 randomized phase Ⅲ trial, 582 pretreated advanced non squamous NSCLC patients received 3 mg/kg of nivolumab every 2 wk or 75 mg/m 2 of docetaxel every 3 wk [11]. Also in this study, the primary end-point was OS; mos in the nivolumab arm was significantly longer than in the docetaxel arm, 12.2 mo vs 9.4 mo, respectively; the overall 322 August 10, 2017 Volume 8 Issue 4

25 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment response rates were 19% with nivolumab and 12% with docetaxel. The PD-L1 protein was retrospectively assessed with the Dako assay in pre-treatment archival or recent tumor-biopsy specimens. The response rate was compared at pre-specified expression levels of 1%, 5% and 10%. The response rate was 31% and 9% in tumors with PD-L1 positivity 1% or < 1% respectively; the response rate was 36% and 10% in PD-L1 positive tumors 5% or < 5%, and the response rate was 37% or 11% in PD-L1 positive tumors 10% or < 10% respectively (Table 1). Nivolumab for first-line treatment In the CheckMate 012 study 52 treatment-naive advanced NSCLC patients received nivolumab at the dose of 3 mg/kg every 2 wk [12]. The response rate was 23% and the efficacy data were very encouraging: mpfs was 3.6 mo and mos was 19.4 mo. On the whole, tumor shrinkage was obtained independently of the PD-L1 expression; however, the greater the PD-L1 positivity increase, the higher the probability of response. Conversely, there was no clear association between mpfs and mos and PDL-1 expression (Table 1). In the Rizvi et al [13] s trial, patients with advanced NSCLC received 10 mg/kg of nivolumab every 2 wk in combination with cisplatin plus gemcitabine or pemetrexed or carboplatin plus paclitaxel; or, they received 5 mg/kg of nivolumab 5 mg/kg every 2 wk with carboplatin plus paclitaxel. The response rates were 33% in the nivolumab plus cisplatin/gemcitabine group, 47% in the cisplatin plus pemetrexed group, 47% in the carboplatin and paclitaxel group and 43% in the nivolumab 5 mg/kg plus carboplatin/paclitaxel group. In patients with PDL-1 expression 1%, the response rate was 48%, whereas in patients with PD-1 < 1% the response rate was 43%. No relationship was observed between PDL-1 expression and mpfs and mos (Table 1). In the CheckMate 026 phase Ⅲ trial, patients with untreated advanced NSCLC and PD-L1 tumor positivity > 1% were randomized to receive 3 mg/kg IV of nivolumab 3 mg/kg IV every 2 wk or platinum-based chemotherapy every 3 wk for 6 cycles [14]. The primary end-point of the study was to demonstrate an improved PFS for patients with PD-L1 tumor-expression 5%. Median PFS was 4.2 and 5.9 mo with nivolumab and platinum-based chemotherapy, respectively (HR = 1.15, 95%CI: , P = 0.25). Median OS was 14.4 mo for immunotherapy and 13.2 mo for chemotherapy. The preliminary results of this study presented at the ESMO meeting showed that the PD-L1 score did not predict the response rate (Table 1). Pembrolizumab beyond first-line treatment KEYNOTE-001 was a large phase Ⅰ study with an NSCLC expansion cohort including a total of 495 advanced NSCLC patients who received 2 mg or 10 mg/kg of pembrolizumab every 3 wk or 10 mg/kg every 2 wk [15]. One hundred and eighty-two patients were assigned to the training group recruited to define the PD-L1 positivity threshold on pre-treatment tumor biopsy (using the antibody clone 22C3-Dako-IHC assay). The remaining 313 patients were treated in the validation group. According to the data obtained from the training group, a PD-L1 tumor expression of 50% was identified as threshold of positivity. The validation group patients with a tumor PD-L1 score 50% had a response rate of 45.2% (95%CI: ): This figure was 17% (95%CI: ) in patients with a score 1%-49% and 3% (95%CI: ) in patients with PD-L1 < 1% (Table 2). Noteworthy, a deterioration of the PD-L1 antigen was observed in tumor samples sectioned more than 6 mo before staining. The response rates were higher in former or current smokers compared to nonsmokers (22.5% vs 10.3%). Treatment was effective at all tested doses and schedules, therefore an every-3-wk schedule was chosen for the phase Ⅲ study. These data were confirmed in a large prospective randomized phase Ⅱ/Ⅲ trial (KEYNOTE-010). This study enrolled 1034 previously treated PD-L1-positive NSCLC patients (PD-L1 expression 1% of tumour cells) and compared 2 mg or 10 mg/kg pembrolizumab every 3 wk vs 75 mg/m 2 docetaxel every 3 wk in terms of OS and PFS [16]. PD-L1 expression was evaluated in the archival tumor samples of 456 patients, while new biopsy material was collected before a study entry for the remaining patients. No differences in mpfs emerged between immunotherapy and chemotherapy. Overall survival was significantly longer in both pembrolizumab arms compared to the docetaxel arm: The HRs were 0.71 (95%CI: , P = ) and 0.61 (95%CI: , P < ) respectively for the two dose-levels of pembrolizumab. However, in patients with PD-L1 positivity 50% the HRS for OS were 0.54 (P = ) in the pembrolizumab 2 mg/kg arm and 0.50 (P ) in the Pembrolizumab 10 mg/kg treatment arm respectively; in addition, in this PD-L1 selected subgroup of patients also PFS was significantly longer than with chemotherapy (Table 2). In the total population, the response rates were 18% with pembrolizumab and 9% with docetaxel; in patients with PD-L1 positivity 50% the response rate was about 30%, while it was 8% in patients with tumors showing a PD-L1 expression level < 50% (Table 2). Consistent with the results from the nivolumab trials, pembrolizumab was more tolerable than docetaxel and did significantly better in both squamous and nonsquamous histology. Similarly, patients with EGFR mutated tumors seemed to have no survival advantage with immunotherapy over chemotherapy despite the small number of patients. Pembrolizumab in first-line treatment The KEYNOTE-024 was a phase Ⅲ trial in which 350 untreated NSCLC patients with a PDL-1 tumor 323 August 10, 2017 Volume 8 Issue 4

26 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Table 2 Correlation between pembrolizumab activity and outcome and programmed cell death protein ligand 1 immunohistochemestry score Author/study Marker antibody Tumor type Treatment line PD-L1 cutoff N pts Response mpfs mo (95%CI) mos mo (95%CI) Pembrolizumab Garon et al [15] KN001 Dako 22C3 NSCLC 1 50% % 6.4 (4.2-NR) NR (NR-NR) 1%-49% % 4.1 ( ) 10.6 (7.3-NR) < 1% 28 3% 4 ( ) 10.4 (5.8-NR) Herbst et al [16] KN010 Dako 22C3 NSCLC 2 50% % 14.9 (10.4-NR) 5.0 ( ) 1%-49% % 17.3 (11.8-NR) 5.2 ( ) Reck et al [17] KN024 Dako 22C3 NSCLC 1 50% % 10.3 (6.7-NR) NA phase Ⅲ Langer et al [18] KN021 Dako 22C3 Non squamous 1 50% 20 80% 13 (8.3-NR) NA phase Ⅲ NSCLC 1%-49% 19 29% < 1% 21 57% KN: KeyNote; NR: not reported; pts: Patients; NA: Not available; NSCLC: Non-small cell lung cancer; PD-L1: Programmed cell death protein ligand 1; mpfs: Median progression free survival; mos: Median overall survival. score of 50% or greater were randomized to receive pembrolizumab at a flat dose of 200 mg every 3 wk, or platinum-based chemotherapy for 4-6 cycles [17]. PD-L1 expression was assessed in formalin-fixed tumor specimens obtained at the time of diagnosis of the metastatic disease. Fine-needle aspirates were not considered appropriate. The primary endpoint of the study was PFS. A total of 1653 out of 1934 screened patients had evaluable PD-L1 material, and 500 (30.2%) patients had a PD-L1 positivity of 50% or greater. Median PFS was significantly longer in the pembrolizumab group [10.3 mo (95%CI: 6.7 to not reached )] than in the chemotherapy group [6.0 mo (95%CI: )] with HR for disease progression or death of 0.50 (95%CI: , P < 0.001). The overall response rate was 44.8% (95%CI: 36.8%-53.0%) in the pembrolizumab group and 27.8% (95%CI: 20.8%-35.7%) in the chemotherapy group. At the time of the second interim analysis, OS was significantly longer with immunotherapy (HR for death: 0.60, 95%CI: , P = 0.005). In the KEYNOTE-021 phase Ⅱ trial, a total of 123 treatment-naive advanced non-squamous NSCLC patients were randomized to receive 4 cycles of pembrolizumab (200 mg flat dose) plus carboplatin (AUC 5) and pemetrexed (500 mg/m 2 ) every 3 wk, followed by pemetrexed and pembrolizumab for 2 years, or to undergo the same strategy without pembrolizumab [18]. Randomisation was stratified by PDL-1 tumor proportion score (< 1% vs 1%) assessed by the IHC 22C3 clone (Dako North America) in formalin-fixed tumour samples obtained at the time of diagnosis of metastatic disease. The primary end-point was the proportion of patients achieving an objective response. The response rate was 55% (95%CI: 42%-68%) in the pembrolizumab plus chemotherapy arm and 29% (95%CI: 18%-41%) in the standard arm with a 26% of difference in the response rate thus reaching statistical significance (95%CI: 9%-42%, P = ). In the experimental arm the response rate was 57% (95%CI: 34%-79%) in patients with a PDL-1 tumor score < 1% and 54% (95%CI: 37%-70%) in patients with a PDL-1 score of 1% or greater. Nevertheless, the probability of response increased according to the PD-L1 positivity level: 29% response rate in patients with PDL-1 positive tumors ranging from 1% to 49% and 80% response rate in those patients whose tumors scored 50% or greater (Table 2). Median PFS was longer with Pembrolizumab plus chemotherapy [13 mo (95%CI: 8.3 to not reached )] with respect to chemotherapy alone [8.9 mo (95%CI: mo)] with an HR of 0.53 (95%CI: , P = 0.01). However, no difference was observed in OS (HR = 0.90, 95%CI: , P = 0.39). Anti- PD-L1 monoclonal antibodies Atezolizumab In the paper by Herbst and colleagues a total of 277 patients with advanced cancer were treated with escalating doses of MPDL3280A intravenously every 3 wk [19]. In advanced NSCLC patients (53/277 in total) the overall response rate was 21%. In this case PD-L1 was determined by using a novel IHC assay (Ventana SP142 North America) and positivity was categorized according to the expressing cell type [tumor cell (TC) or immune cell (IC)] and then scored along a gradient [< 1% (TC0 or IC0), 1%-4% (TC1 or IC1), 5%-49% (TC2) or 5%-10% (IC2), and 50% (TC3) or <10% (IC3)]. A relationship was observed between PD-L1 scores and response rate: 83% of patients with score 3 responded to treatment, while only 20% of those with scores 0-2 obtained a remission (Table 3). However, not surprisingly, also 20% of patients with score 0 achieved a clinical response. In the subsequent randomized phase Ⅱ study (POPLAR) atezolizumab was compared to docetaxel, in terms of OS, in 285 pretreated advanced NSCLCs [20]. Patients were stratified according to the PD-L1 expression that was determined on TC as well as on IC by using the SP142 PD-L1 IHC assay (Ventana Medical Systems, Tucson, AZ, United States). The IHC scores were defined as follows: Score 0 = 324 August 10, 2017 Volume 8 Issue 4

27 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Table 3 Correlation between atezolizumab activity and outcome and programmed cell death protein ligand 1 immunohistochemestry score Author/study Marker antibody Tumor type Treatment line PD-L1 cutoff N pts Response (%) mpfs mo (95%CI) mos mo (95%CI) Atezolizumab NR NR NR NR NR NR NR NR Herbst et al [19] Ventana SP142 NSCLC 2 Score ( ) 15.5 (9.8-NA) phase Ⅰ Score ( ) 15.1 (8.4-NA) Score ( ) 15.5 (11.1-NA) Score ( ) 9.7 ( ) Fehrenbacher et al [20] POPLAR Ventana SP142 NSCLC 2 Score ( ) 20.5 (17.5-NA) PHASE Ⅱ Score ( ) 16.3 ( ) Score ( ) 15.7 ( ) Score ( ) 12.6 ( ) Rittmeyer et al [21] Ventana NSCLC 2 Score ( ) 26.9 (12.0-NA) OAK SP142 Score ( ) 23.5 (18.1-NA) Phase Ⅲ Score Score ( ) 23.5 (18.1-NA) Wakelee et al [22] and Antonia et al [23] Ventana NSCLC 1 Score BIRCH SP142 TC2/3 or IC2/ phase Ⅱ Score Score 3: PDL1 expression levels TC3 or IC3 ( 50% on TC or 10% on IC); Score 2: TC2 or IC2 ( 5%-< 50% on TC or 5% -< 10% IC); Score 1: TC1 or IC1 ( 1% - < 5% on TC or IC); Score 0: TC0 and IC0 (< 1% on TC and IC). IC: Tumor-infiltrating immune cell; TC: Tumor cell; NR: Not reported; pts: Patients; NA: Not available; NSCLC: Non-small cell lung cancer; PD-L1: Programmed cell death protein ligand 1; mpfs: Median progression free survival; mos: Median overall survival. PD-L1 expression on IC or TC < 1%; score = 1 TC or IC PD-L1 positivity between 1 and < 5%; score = 2 positivity between 5 and < 50% on TC or PD-L1 expression on IC between 5 and < 10%; score = 3 PD-L1 positive TC 50% or PD-L1 positive IC 10%. Median OS in the atezolizumab arm was 12.6 mo (95%CI: ) compared to 9.7 mo (95%CI: ) in the docetaxel arm (HR = 0.73, 95%CI: ; P = 0.04). Overall survival improves according to the PD-L1 score level: TC3 or IC3 HR 0.49, TC2/3 or IC2/3 HR 0.54, TC 1/2/3 or IC1/2/3 HR 0.59; TC0 or IC0 HR PFS also varied according to the different PD-L1 subgroups, but the differences did not reach any statistical significance (Table 3). In the immunotherapy arm the overall response rate was 37.5%, 22.0%, 18.3% and 16.7% in TC3 or IC3, TC2/3 or IC2/3, TC 1/2/3 or IC1/2/3. In the subgroup TC0 or IC0, the response rates were similar (14.6%) in both arms (Table 3). In the phase Ⅲ OAK trial, patients with squamous or non-squamous advanced NSCLC, pretreated with one or two chemotherapy regimens, were randomly assigned to 1200 mg of atezolizumab or 75 mg/m 2 of docetaxel every 3 wk [21]. The primary endpoint was OS. The mos was 13.8 mo (95%CI: ) in the atezolizumab arm and 9.6 mo (95%CI: ) in the docetaxel arm (HR = 0.73, 95%CI: , P = ). Median OS was also analyzed according to the criteria of the previous study (20): In the TC1/2/3 or IC1/2/3 populations OS was 15.7 mo (95%CI: ) with atezolizumab vs 10.3 (95%CI: ) with docetaxel (HR = 0.74, 95%CI: , P = ) and in the TC0 or IC0 groups mos was 12.6 mo vs 8.9 mo with atezolizumab and docetaxel respectively (HR = 0.75, 95%CI: ). In the intention to treat population PFS did not differ between the two arms (HR = 0.95, 95%CI: , P = ) and in the different PD-L1 subgroups. Objective responses for atezolizumab were 30.6% in the TC3/IC3 subgroup, 22.5% in the TC 2/3 or IC 2/3 aubgroups, 17.8% and 7.8% in the TC 1/2/3 or IC1/2/3 and TC0 or IC0 subgroups, respectively (Table 3). In phase Ⅱ Birch trial patients with advanced NSCLC received atezolizumab in first or subsequent line of treatment at a flat dose of 1200 mg every three weeks [22]. The PDL-1 expression was evaluated by using the Ventana SP142 IHC assay and the study enrolled only patients with PDL1 expression > 5% in tumor cells or in immune cells (TC2/3 or IC 2/3). Efficacy data in the first line setting have been reported in a recent update [23]. Patients with PDL-1 TC3 or IC3 showed a 34% response rate and a mos of 26.9 mo; PDL-1 TC2/3 or IC2/3 scores had an overall response rate of 25% and a mos of 23.5 mo, and patients with PDL-1 TC2 or IC2 scores had an overall response rate of 18% and a mos of 23.5 mo (Table 3). Durvalumab An ongoing phase 1/2 study is evaluating the safety and efficacy of durvalumab in patients with advanced NSCLC or with other solid tumor types [23]. Durvalumab was administered at 10 mg/kg every two weeks in previously untreated advanced NSCLC. Fifteen patients were initially enrolled regardless of the PD-L1 status. After a protocol amendment, enrolment was restricted to PD-L1 positive patients. PD-L1 status was assessed 325 August 10, 2017 Volume 8 Issue 4

28 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Table 4 Correlation between durvalumab and avelumab activity and outcome and programmed cell death protein ligand 1 immunohistochemestry score Author/study Marker antibody Tumor type Treatment line PD-L1 cutoff N pts Response (%) mpfs mo (95%CI) mos mo (95%CI) Durvalumab Gulley et al [24] Ventana SP263 NSCLC 1 25% Phase 1/2 < 5% 8 12 Avelumab Verschraegen et? NSCLC 2 1% wk NR al [25] Phase 1b < 1% wk NR Sheng et al [26]? NSCLC 1 1% NR NR Javelin < 1% 10 0 NR NR phase Ib NR: Not reported; pts: Patients; NSCLC: Non-small cell lung cancer; PD-L1: Programmed cell death protein ligand 1; mpfs: Median progression free survival; mos: Median overall survival. with the companion Ventana SP263 assay. PD-L1 positivity was defined as a tumor cell membrane staining of 25%. A total of 59 patients (48 PD-L1 positive; 9 PD-L1 negative) were included in the trial. The overall response rate was 25% in PDL-1 positive patients and 12% in PDL-1 negative patients (Table 4). Avelumab A phase-1b trial was designed to investigate the safety and activity of avelumab (MSB C) in patients with advanced NSCLC progressing after platinum-based chemotherapy [24]. Patients were treated with avelumab at 10 mg/kg every two weeks. Tumor PD-L1 expression was assessed by immunohistochemistry. Objective responses were observed in 22 patients [12% (95%CI: 7.6%-17.5%)], while 70 patients (38%) achieved a stable disease. Median PFS was 11.6 wk (95%CI: ). One hundred and eighteen (86%) evaluable patients were PDL1 positive (1% threshold of positivity). The overall response rate was 14.4% and 10.0% in PD-L1 positive and negative tumors, respectively. Median PFS in PD-L1 positive patients was 11.7 wk and 5.9 in PD-L1-negative patients. The safety and activity of avelumab in chemotherapy-naive advanced NSCLC patients were investigated in a phase 1b trial [25]. Patients received 10 mg/kg of avelumab IV every 2 wk; PD-L1 expression was assessed by IHC with 1% positivity threshold on tumor cell staining. The overall response rate was 18.7% (95%CI: 10.6, 29.3) and a disease stabilization was reported in 34 patients (45.3%). In 35 PD-L1 positive tumors the overall response rate was 20.0%; no patients with PD-L1 negative tumors achieved a response. Median PFS was 11.6 wk (95%CI: ) for all treated patients (Table 4). CONCLUSION The literature data have clearly shown that immune checkpoint inhibitors might represent an important therapeutic option for NSCLC patients. However, in spite of exciting overall treatment outcomes, a considerable number of patients failed to achieve long-term clinical benefit. Since the cost of these molecules impacts significantly on health care systems, the identification of predictive biomarkers to select patients who are more likely to benefit is a challenging area of ongoing research. The PD-L1 expression was early identified as potential indicator of benefit and the literature on this topic is plentiful. Several critical aspects might explain the conflicting results shown in clinical trials by using retrospective or prospective PD-L1 assays. Some of these results are strictly related to the PD-L1 nature, while others derive from the methodologies and material that have been used for testing. PD-L1 is a constitutively but also a functionally inducible receptor/ligand potentially expressed by tumor cells, stromal cells, inflammatory cells at tumor sites; it is heterogeneous and subject to pre-analytical variables. Furthermore, its expression is continuously distributed, it has varied significantly over time and may be affected by concurrent or prior treatments (radiation or chemotherapy) [26-28]. Classical predictive biomarkers such as hormone receptors, HER2 protein over-expression or gene amplification, EGFR activating mutations and ALK rearrangements are always present: These indicators define more clearly distinct tumor subgroups with different biology and clinical behavior. The PD-L1 expression is very dynamic, according to a constantly evolving immune response. Therefore, questions regarding reliability, consistency, feasibility and selection of an expression as a threshold remain artificial and controversial. This might explain why a significant proportion of PD-L1 negative patients benefited from treatment with immunotherapy in all studies. Conversely, even in highly PD-L1 selected cohorts, 25% to 50% of patients achieved no benefit. Moreover, it is not clear whether PD-L1 positivity has a different effect on outcome/response to treatment, compared to PD-L1 positivity on immune cells. PDL-1 expression was evaluated in tumor cells in the majority of studies. The immunoresponse is a delicate balance between inhibitory checkpoints and activating signals 326 August 10, 2017 Volume 8 Issue 4

29 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment such as LAG-3, OX40, etc. The discovery of these proteins has paved the way to new therapy strategies, whereas their potential predictive role as biomarkers of immunoresponse is actually unknown. Technical aspects may also result in inconsistent data; tissue fixation, storage, and antigen recovery are not standardized. The quality of commercially available antibodies is also a reason for concern: The PD-L1 diagnostic test for nivolumab (Dako 28-8 pharmdx), pembrolizumab (Dako 22C3 pharmdx), atezolizumab (Ventana SP142) and durvalumab (Ventana SP263) showed variability in staining intensity and patterns creating uncertainties and doubts for their use in everyday practice. To address these concerns, someyears ago a task force was set up, formed by pharmaceutical companies, by representatives from Dako and Ventana, and by the scientific companies FDA, AACR, ASCO and IASCLC (International Association for the Study of Lung Cancer). The aim was to compare the performance of the four major PD-L1 companion assays. The recently published results of the pilot phase of the Blueprint PDL1 IHC assay comparison project [29] indicates that interchanging assays and cut-offs will lead to the misclassification of PD-L1 status for some patients, and therefore more data are required. Summing up, the PD-L1 expression is likely to be related to the curative efficacy of immune checkpoint inhibitors. However, its role seems to be more informative in terms of probability and magnitude of the treatment effect rather than prediction of the effect itself, given that none of the available assays can conclusively identify non-benefitting patients. REFERENCES 1 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, CA Cancer J Clin 2015; 65: [PMID: DOI: /caac.21262] 2 Lee JK, Hahn S, Kim DW, Suh KJ, Keam B, Kim TM, Lee SH, Heo DS. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014; 311: [PMID: DOI: / jama ] 3 Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368: [PMID: DOI: / NEJMoa ] 4 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: [PMID: DOI: /annurev.immunol ] 5 Avogadri F, Yuan J, Yang A, Schaer D, Wolchok JD. Modulation of CTLA-4 and GITR for cancer immunotherapy. Curr Top Microbiol Immunol 2011; 344: [PMID: DOI: /82_2010_49] 6 Chen DS, Mellman I. Oncology meets immunology: the cancerimmunity cycle. Immunity 2013; 39: 1-10 [PMID: DOI: /j.immuni ] 7 Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371: [PMID: DOI: /NEJMoa ] 8 Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS , ONO-4538) in Patients With Previously Treated Advanced Non- Small-Cell Lung Cancer. J Clin Oncol 2015; 33: [PMID: DOI: /JCO ] 9 Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-pd-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; 16: [PMID: DOI: /S (15) ] 10 Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: [PMID: DOI: /NEJMoa ] 11 Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non- Small-Cell Lung Cancer. N Engl J Med 2015; 373: [PMID: DOI: /NEJMoa ] 12 Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, Shepherd FA, Antonia S, Goldman JW, Juergens RA, Laurie SA, Nathan FE, Shen Y, Harbison CT, Hellmann MD. Nivolumab Monotherapy for First-Line Treatment of Advanced Non- Small-Cell Lung Cancer. J Clin Oncol 2016; 34: [PMID: DOI: /JCO ] 13 Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, Chow LQ, Gerber DE, Laurie SA, Goldman JW, Shepherd FA, Chen AC, Shen Y, Nathan FE, Harbison CT, Antonia S. Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34: [PMID: DOI: /JCO ] 14 Socinski M, Creelan B, Horn L, Reck M, Paz-Ares L, Steins M, Felip E, van den Heuvel M, Ciuleanu TE, Badin F, Ready N, Hiltermann TJN, Nair S, Juergens R, Peters S, Minenza E, Geese WJ, Bhagavatheeswaran P, Chen A, Carbone DP. NSCLC, metastatic CheckMate 026: A phase 3 trial of nivolumab vs investigator s choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PD-L1)- positive NSCLC. Ann Oncol 2016; 27: LBA7_PR [DOI: / annonc/mdw435.39] 15 Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: [PMID: DOI: /NEJMoa ] 16 Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled- 327 August 10, 2017 Volume 8 Issue 4

30 Tibaldi C et al. Predictive role of PD-L1 in NSCLC treatment Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387: [PMID: DOI: /S (15) ] 17 Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375: [PMID: DOI: /NEJMoa ] 18 Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, nonsquamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17: [PMID: DOI: /S (16) ] 19 Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-pd-l1 antibody MPDL3280A in cancer patients. Nature 2014; 515: [PMID: DOI: /nature14011] 20 Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387: [PMID: DOI: / S (16) ] 21 Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389: [PMID: DOI: /S (16)32517-X] 22 Wakelee H, Patel JD, Heist R, Balmanoukian A, Besse B, Felip E, Carcereny Costa E, Chow LQ, Koczywas M, Garassino MC, Christoph D, Toh CK, Johnson ML, Chaft J, Kurata T, Qiu J, Kowanetz M, Coleman S, Mocci S, Sandler A, Gettinger SN, Peters S. ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD- L1-Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology. J Thorac Oncol 2016; 11: S251-S252 [PMID: DOI: / j.jtho ] 23 Antonia SJ, Kim S-W, Spira AI, Ahn M-J, Ou S-HI, Stjepanovic N, Fasolo A, Jäger D, Ott PA, Wainberg ZA, Wakelee HA, Goldman JW, Kurland J, Rebelatto MC, Yao W, Gupta AK, Blake-Haskins JA, Howard Segal N. Safety and clinical activity of durvalumab (MEDI4736), an anti- PD-L1 antibody, in treatment-naïve patients with advanced non smallcell lung cancer. J Clin Oncol 2016; 34: 9029 [DOI: /JCO _suppl.9029] 24 Gulley JL, Spigel D, Kelly K, Chandler JC, Rajan A, Hassan R, Wong DJL, Leach J, Edenfield WJ, Wang D, Vrindavanam N, Weiss GJ, Gurtler JS, Grote HJ, von Heydebreck A, Chin KM, Iannotti N. Avelumab (MSB C), an anti-pd-l1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J Clin Oncol 2015; 33: 8034 [DOI: /jco _suppl.8034] 25 Verschraegen CF, Chen F, Spigel DR, Iannotti N, McClay EF, Redfern CH, Bennouna J, Taylor MH, Kaufman H, Kelly K, Bajars M, von Heydebreck A, Cuillerot JM, Jerusalem GHM. Avelumab (MSB C; anti-pd-l1) as a first-line treatment for patients with advanced NSCLC from the JAVELIN Solid Tumor phase 1b trial: Safety, clinical activity, and PD-L1 expression. J Clin Oncol 2016; 34: 9036 [DOI: /JCO _suppl.9036] 26 Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y, Yang Y, Huang Y, Zhao H, Zhang L. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep 2016; 6: [PMID: DOI: /srep20090] 27 Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-pd-l1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124: [PMID: DOI: /JCI67313] 28 Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: [PMID: DOI: / nature14292] 29 Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, Richardson W, Towne P, Hanks D, Vennapusa B, Mistry A, Kalamegham R, Averbuch S, Novotny J, Rubin E, Emancipator K, McCaffery I, Williams JA, Walker J, Longshore J, Tsao MS, Kerr KM. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017; 12: [PMID: DOI: / j.jtho ] P- Reviewer: Sigalotti L, Sun XY, Turner AM S- Editor: Song XX L- Editor: A E- Editor: Lu YJ 328 August 10, 2017 Volume 8 Issue 4

31 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.329 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) Platinum-induced neurotoxicity: A review of possible mechanisms MINIREVIEWS Ozkan Kanat, Hulya Ertas, Burcu Caner Ozkan Kanat, Hulya Ertas, Burcu Caner, Department of Medical Oncology, Uludag University Faculty of Medicine, Bursa, Turkey Author contributions: Kanat O assigned the issue and performed the majority of the writing, prepared the figure; Ertas H and Caner B both designed the outline and coordinated the writing of the manuscript. Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Ozkan Kanat, MD, PhD, Professor, Department of Medical Oncology, Uludag University Faculty of Medicine, Gorukle, Bursa, Turkey. ozkanat@uludag.edu.tr Telephone: Received: April 10, 2017 Peer-review started: April 12, 2017 First decision: May 22, 2017 Revised: June 13, 2017 Accepted: June 30, 2017 Article in press: July 3, 2017 Published online: August 10, 2017 Abstract Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations. Key words: Cisplatin; Dorsal root ganglion; Mechanism; Oxaliplatin; Neurotoxicity; Neuropathic pain; Sodium channel The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Platinum drug-based chemotherapies may lead to intolerable neuropathic symptoms, preventing their administration at the optimal effective doses and duration. A better understanding of potential mechanisms underlying these symptoms can help clinicians better manage patients experiencing acute and/or cumulative neurotoxicity during treatment with platinum-containing chemotherapy. Kanat O, Ertas H, Caner B. Platinum-induced neurotoxicity: A review of possible mechanisms. World J Clin Oncol 2017; 8(4): Available from: URL: full/v8/i4/329.htm DOI: INTRODUCTION Platinum drugs, including cisplatin (cis-diamminedi- 329 August 10, 2017 Volume 8 Issue 4

32 Kanat O et al. Platinum drugs/neurotoxicity chloroplatinum Ⅱ), carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum Ⅱ), and oxaliplatin (trans-r,r-cyclohexane-1,2-diamineoxalatoplatinum Ⅱ) have become an important part of the combination chemotherapy regimens used to treat different types of solid tumors. Despite their favorable anti-tumor properties, platinum drugs can cause serious side effects such as neurotoxicity [1-3]. Carboplatin neurotoxicity is negligible compared with that of cisplatin and oxaliplatin, however, it can develop, particularly high doses are administered [3,4]. Exposure of rat sensory neurons in culture to cisplatin, oxaliplatin or carboplatin in vitro caused a concentration-dependent increase in cell death and apoptotic cells [5]. However, carboplatin required a 10-fold higher drug concentration than cisplatin to induce a similar degree of cytotoxic effect. In addition, both cisplatin and oxaliplatin led to increased reactive oxygen species production and 8-oxoguanine DNA damage, but carboplatin did not [5]. These preclinical observations may partly explain why carboplatin has less neurotoxic effects. Conversely, conventional-dose cisplatin- or oxaliplatin-based therapies can sometimes lead to intolerable neuropathic symptoms, preventing their administration at the optimal effective doses and duration. Large-diameter sensory nerve fibers appear to be the most affected by platinum drugs, leading to symmetrical glove and stocking type of sensory loss, numbness, tingling, pain, and burning sensation [4]. Some of these symptoms may persist for months or even years. Furthermore, in some cases, they may continue to worsen even after treatment cessation, a phenomenon known as coasting [6]. Platinum-induced neurologic symptoms become evident when certain cumulative drug doses have been administered. Cumulative doses of cisplatin and oxaliplatin of 350 mg/m 2 and 550 mg/m 2, respectively, have been considered as the threshold values for neurotoxicity development [6]. Some clinical and genetic features of patients may make them more susceptible to developing severe neurotoxicity during treatment with platinum drugs. A recent study by Velasco et al [7] found that among patients treated with oxaliplatin-based chemotherapy, male patients, patients experiencing more severe acute neuropathic symptoms, patients with abnormal findings on mid-treatment nerve conduction velocity studies, and patients receiving higher cumulative oxaliplatin doses have an increased risk of developing significant neuropathic symptoms. Several recent pharmacogenomics studies have suggested that patients with polymorphisms in the Glutathione S-transferases genes (GSTM1, GSTT1, and GSTP1) are more likely to develop grade 3-4 cumulative neuropathy during oxaliplatin treatment due to decreased drug detoxification [8]. Oxaliplatin may also cause acute dose-independent neurotoxicity, which can occur in approximately 90% of patients during or shortly after infusion, and is characterized by transient cold-induced paresthesias and dysesthesias affecting the distal extremities, and perioral and pharyngolaryngeal regions [9,10]. A better understanding of the potential mechanisms underlying cisplatin or oxaliplatin neurotoxicity will certainly help clinicians identify the optimal clinical management of this side effect. The aim of this review was, therefore, to summarize the current knowledge on the neuronal events induced during platinum-based therapy. Nuclear DNA damage in dorsal root ganglion neurons The accumulation of platinum compounds and their metabolites in the dorsal root ganglion (DRG) after their systemic administration and formation of platinum- DNA adducts are considered key steps in neurotoxicity development (Figure 1) [2,11]. The presence of an abundant fenestrated capillary network and the absence of blood-brain barrier in DRG allow platinum drugs to preferentially accumulate in DRG with easy access to sensory neurons [2,11,12]. Recently, it was demonstrated that the uptake of platinum drugs into DRG neurons may be facilitated by two different types of neuronal membrane transporters: Copper transporter-1 (CTR1) and organic cation transporter-2 (OCT2) [13-15]. The overexpression of these transporters in neurons, therefore, can contribute to the development or aggravation of neurotoxicity. For example, a 16- to 35-fold increase in the cellular oxaliplatin uptake was observed in neurons overexpressing mouse OCT2 or human OCT2, and this process resulted in significantly increased DNA platination and neurotoxicity [15]. Once the platinum drugs reach the neuronal cell nucleus, they attack the nuclear DNA to form adducts. They usually form same types of adducts on the same DNA sites, including 1,2-intrastrand d (GpG) (between adjacent guanine bases on the same DNA strand) and 1,2-intrastrand d (ApG) (between adenine and adjacent guanine bases on the same DNA strand) crosslinks. A correlation between adduct levels and the degree of neurotoxicity has been reported [16]. The platinum-dna adduct levels produced by cisplatin were found to be approximately three times higher than those generated by equimolar oxaliplatin doses. Concordantly, in vitro cisplatin caused significantly more neuronal cell death than oxaliplatin [16]. DNA repair ability of DRG neurons for adducts (primarily performed by the nucleoid excision repair) is an important factor determining neurotoxicity severity [17]. Chronic cisplatin administration resulted in an accelerated accumulation of unrepaired platinum- DNA adducts in DRG neurons of DNA repair-deficient mice, which induced early neurophysiological alterations and led to an increase in neuronal cell death [17]. Inhibition of the global transcriptional activity of DRG neurons is one of the major consequences of DNA adduct formation [18]. DRG neurons need a high level of active transcription to sustain their large size, high metabolism, and long axons. Therefore, platinuminduced DNA damage leads to neuronal atrophy and disruption of their distant axonal connections [18]. 330 August 10, 2017 Volume 8 Issue 4

33 Kanat O et al. Platinum drugs/neurotoxicity Cell death DRG neuron Caspases activation ATP depletion ROS overproduction ETC defect Cyt C Mitochondrion CTR1 ndna adducts OCT2 mtdna adducts Na + channel K + channel Ca 2+ channel TRPA1, TRPMB, TRVP1 expression Figure 1 Proposed mechanisms of platinum-induced neurotoxicity. Dorsal root ganglion (DRG) is the main target of platinum drugs that preferentially accumulate in DRG neurons. Membrane transporters, copper transporter-1 (CTR1) and organic cation transporter-2 (OCT2), can facilitate the cellular uptake of platinum drugs. Platinum-DNA adducts inhibit replication and transcription, which results in caspase activation and subsequent cell death. Neuronal mitochondrial damage leads to cellular ATP depletion and increased reactive oxygen species (ROS) production. The voltage-gated sodium (Na + ), potassium (K + ) and calcium (Ca 2+ ) channels dysfunction, and the enhanced expression and responsiveness of transient receptor potential channels (TRPA1, transient receptor potential ankyrin-1; TRPM8, transient receptor potential melastatin 8; TRPV1, transient receptor potential vanilloid 1) play an important role in the development of platinuminduced neurotoxicity. Several preclinical studies have reported that platinum-induced DNA damage also induces apoptosis and neuron loss in DRG both in vivo and in vitro [19-22]. Cisplatin has been shown to initiate several apoptotic events in neuronal cells, including p53 activation, Bax translocation, mitochondrial cytochrome c release, and activation of caspase-3 and caspase-9. Gill and Windebank demonstrated that following exposure to cisplatin, DRG neurons attempt to re-enter the cell cycle from G0 phase, and this event can be a prelude to triggering neuronal cell death [22]. Mitochondrial DNA damage Mitochondrial dysfunction in DRG neurons was first described as a potential mechanism for platinum drugs neurotoxicity by Podratz et al [23]. They demonstrated that cisplatin also directly binds to mitochondrial DNA with similar binding affinity as nuclear DNA. Cisplatinmitochondrial DNA adducts inhibit mitochondrial DNA transcription and replication, and cause morphological changes in the mitochondria. This can lead to disruption of the electron transport chain, loss of adenosine triphosphate (ATP) generation, energy failure, and overproduction of reactive oxygen species. All these events cause the opening of mitochondrial permeability transition pores, mitochondrial membrane depolarization, intracellular calcium accumulation, and expression of apoptotic proteins. Cisplatin may also impair mitochondrial transport dynamics in neurons [24]. Proper mitochondrial transport in neurons is critical to cellular homeostasis. A new study in Drosophila has shown that cisplatin can significantly reduce mitochondrial movement frequency in axons [24]. This is probably caused by both ATP depletion and cellular calcium accumulation. Some studies have demonstrated that cisplatin can alter the expression of mitochondrial fusion and fission proteins in peripheral nerves [25]. These proteins regulate mitochondrial shape, size, and number. Bobylev et al [25] detected a significant decrease in the mitochondrial fusion protein mitofusin 2 expression levels in DRG and tibial nerves of cisplatin-treated mice, resulting in mitochondrial swelling and vacuolization. Voltage-gated ion channels dysfunction (channelopathies) Oxaliplatin exhibits a tetrodotoxin-like inhibitory effect on the neuron voltage-gated sodium (Na + ) channels [26-30]. It remarkably slows their inactivation and reduces the peak Na + current, leading to an increase in the duration of the relative refractory period of sensory neurons. Oxaliplatin may also affect the Na + channels indirectly via the chelation of extracellular calcium ions by its metabolite oxalate (diaminocyclohexaneplatinum-c2o4) [26]. Because of Na + channel dysfunction, sensory neurons become hyperexcitable and eventually generate spontaneous ectopic discharges. Oxaliplatin can display isoform-specific effects on voltage-gated Na + channels leading to the development of unique neuropathy symptoms such as cold-aggravated peripheral pain [31,32]. It has been suggested that oxaliplatin-induced Nav1.6 dysfunction may play a 331 August 10, 2017 Volume 8 Issue 4

34 Kanat O et al. Platinum drugs/neurotoxicity role in cold allodynia development [33,34]. Cooling in the presence of oxaliplatin increased Nav1.6-mediated persistent and resurgent Na + currents in large-diameter DRG neurons and resulted in the generation of action potential burst firing [31]. Peripheral nerve axonal excitability studies performed before and immediately after oxaliplatin administration have confirmed the above mentioned in vitro findings and revealed acute abnormalities in sensory nerve function related to Na + channel dysfunction, including decreased refractoriness and increased superexcitability [35]. Interestingly, it was shown that these excitability abnormalities can be detected in the initial oxaliplatin treatment cycles and may serve as a predictive tool to identify patients who are more likely to develop moderate or severe neurotoxicity. Kagiava et al [33] suggested that altered voltagegated potassium channel activity may be involved in oxaliplatin-induced neurotoxicity development. In their study, the effects of oxaliplatin on the compound action potential of rat sciatic nerve were observed to be similar to those with the potassium channel blockers 4-aminopyridine and tetraethylammonium. Oxaliplatin was found to cause broadening of action potentials and repetitive firing, suggesting its antagonistic effect on neuronal fast and slow potassium channels. This finding is indirectly supported by Sittl et al [34]. They showed that enhancement of axonal potassium conductance by flupirtine may reduce oxaliplatin-induced peripheral nerve hyperexcitability. Conversely, voltage-gated potassium channels are unlikely to be the primary target for oxaliplatin because patch-clamp studies failed to show any effect of oxaliplatin on Shaker-type potassium channels [36]. Kagiava et al [37] found some evidence indicating that potassium channel dysfunction during oxaliplatin treatment can occur due to malfunction of the gap junction (GJ) channels and hemichannels in myelinated fibers. According to their findings, oxaliplatin causes prolonged opening of GJ channels and hemichannels, leading to excessive potassium accumulation in the periaxonal space and its osmotic swelling. This event is likely to have a disturbing effect on the voltage-gated potassium channel function. Cisplatin does not appear to have a prominent effect on the neuronal sodium or potassium channel function. Initial studies using whole cell patch-clamp electrophysiological technique reported that cisplatin decreases the calcium channel currents, particularly in small-diameter neurons of rat DRG [38]. However, a new study revealed an increase in calcium influx through N-type calcium channels in rat DRG neurons after exposure to cisplatin [39]. This was mainly caused by the upregulation of the N-type calcium channels. Increased intracellular calcium levels led to caspase-3 activation and apoptosis induction. Enhanced responsiveness of thermosensitive transient receptor potential ion channels Sensory neurons express various types of transient receptor potential (TRP) channels, including TRPA1, TRPM8, and TRVP1, which all play an important role in the generation and sensation of inflammatory and neuropathic pain [40-45]. Nassini et al [40] showed that oxaliplatin- and cisplatininduced mechanical and cold hyperalgesia in rats are mediated by transient receptor potential ankyrin-1 (TRPA1), and TRPA1 activation is most likely caused by glutathione-sensitive molecules. Subsequently, Zhao et al [44] reported that oxaliplatin-induced cold hyperalgesia could be related to increased responsiveness of TRPA1. Pretreatment of the cultured DRG neurons with oxaliplatin resulted in an increase in the number of allylisothiocyanate (a TRPA1 agonist)-sensitive neurons. The results of a recent study suggested that aluminum accumulation in DRG may augment oxaliplatininduced neuropathic pain through activation of TRPA1 and stimulation of apoptotic cell death [46]. In this study, aluminum concentration of in DRG was greater in mice treated with aluminum chloride and oxaliplatin than in those treated with aluminum chloride alone. Gauchan et al [43] revealed that oxaliplatin treatment increased the cold receptor transient receptor potential melastatin 8 (TRPM8) expression in rat DRG neurons, which resulted in enhanced sensitivity to cooling stimulation. Capsazepine, a blocker of both TRMP8 and TRPV1 channels, but not the selective TRV1 blocker 5 -Iodoresiniferatoxin, was able to inhibit oxaliplatininduced cold allodynia. These findings suggested that TRPM8 plays a role in cold allodynia caused by oxaliplatin. Ta et al [41] showed that mice DRG neurons treated with cisplatin or oxaliplatin displayed an increase in transient receptor potential vanilloid 1 (TRPV1), TRPA1, and TRMP8 mrna expression. Trigeminal ganglion neurons from the cisplatin-treated animals showed increased TRPV1 and TRPA1 mrna expression, and this was associated with enhanced heat and mechanical hypersensitivity. Conversely, oxaliplatin affected only TRPA1 expression, which induced cold and mechanic hypersensitivity. Glial activation Di Cesare Mannelli et al [47,48] first suggested a link between oxaliplatin-induced neuropathic pain and glial activation. In a rat model with oxaliplatin-induced peripheral neuropathy, they showed a transient activation of microglia and astrocytes in the spinal cord and supraspinal areas involved with pain modulation accompanied by a decrease in mechanical and thermal pain thresholds following intraperitoneal oxaliplatin administration [48]. Intrathecal co-administration of microglial inhibitor minocycline was able to prevent microglial activation, but had no effect on the response of astrocytes. The astrocytic activation could be inhibited by intrathecal injection of fluorocitrate, an astrocyte specific metabolic inhibitor. Fluorocitrate did not influence oxaliplatin-induced microglial activation. Both drugs increased pain tolerance, but fluorocitrate produced greater pain relief than minocycline. However, neither minocycline nor fluorocitrate prevented oxaliplatin- 332 August 10, 2017 Volume 8 Issue 4

35 Kanat O et al. Platinum drugs/neurotoxicity dependent morphological alterations in DRG neurons [48]. These findings provide some evidence for the participation of glial cells in oxaliplatin-induced neuropathy. Involvement of nicotinic receptors Oxaliplatin treatment was found to induce down regulation of alpha7 nicotinic acetylcholine receptor (nachr) in the rat sciatic nerve, DRG, and spinal cord [49]. The administration of the selective alpha7 nachr agonists (R)-ICH3 and PNU could prevent receptor down regulation and increase the pain threshold by oxaliplatin. These two agonists also could inhibit oxaliplatin-induced morphological changes in DRG and peripheral nerves, and upregulate glial cell density in the spinal cord, thalamus, and somatosensory area 1. CDP-choline, the other selective alpha7 nachr agonist, was also found to be effective in reducing oxaliplatin-induced mechanical hyperalgesia when administered into the cerebral ventricles [50]. These findings suggested a neuroprotective role of alpha7 nachr during oxaliplatin treatment. DETECTION AND ASSESSMENT OF PLATINUM-INDUCED NEUROTOXICITY Currently, no standard clinical method for the early detection and comprehensive assessment of platinuminduced neurotoxicity is known. The use of self-reporting questionnaires developed by the United States National Cancer Institute and European Organization for Research and Treatment of Cancer throughout the treatment course has been recommended as a simple clinical tool for determining and grading a pre-existing or new neuropathy [51,52]. These questionnaires contain items that evaluate the occurrence, severity, degree of distress, and frequency of neuropathic symptoms and their negative impacts on the patient daily activities. Among neurophysiological techniques, nerve conduction velocity studies and electromyography remain the gold standard technique for detecting the location and extent of neuronal damage due to treatment with platinum drugs [1,6]. Nerve excitability studies performed before and immediately after oxaliplatin infusion have emerged as novel non-invasive tests for early identification of patients at high risk for severe neurotoxicity [35,53]. PREVENTION AND TREATMENT STRATEGIES A recent Cochrane review examined the effects of the potential chemo-protective agents against neurotoxicity of platinum analogs [54]. This review included 29 randomized controlled trials (RCTs) and analyzed data from 2906 participants who received platinum-containing chemotherapy (cisplatin, carboplatin, or oxaliplatin) alone or in combination with a potential chemo-protectant, including amifostine, calcium/magnesium infusion, glutathione, Org 2766, acetylcysteine, oxcarbazepine, or vitamin E [54]. The data obtained in this study were found to be insufficient to recommend any particular agent to prevent or limit platinum drug neurotoxicity. In 2014, the American Society of Clinical Oncology convened an expert panel to develop a clinical practice guideline for the prevention and treatment of chemotherapy-induced neuropathies in adult cancer survivors [55]. The experts reviewed 48 RCTs that investigated the efficacy of pharmacological agents, including antiepileptic drugs (carbamazepine and oxcarbazepine), antidepressants (amitriptyline, nortriptyline, venlafaxine and duloxetine), vitamins/minerals (calcium/magnesium infusions, vitamin E, and glutamine), and antioxidants (glutathione, N-acetylcysteine, and amifostine) against neuropathic pain caused by platinum compounds, paclitaxel or vinca alkaloids. They concluded that enough evidence to support routine clinical implementation of these agents for the prevention of platinum-induced peripheral neurotoxicity was not found. Conversely, duloxetine was found potentially useful for treating oxaliplatin-induced neuropathic pain. CONCLUSION The apoptotic loss of DRG neurons plays a central role in the initiation and progression of platinuminduced neurotoxicity. Recent evidence suggests that secondary mitochondrial dysfunction can mediate and aggravate cisplatin-mediated neuronal damage. Impaired activity of voltage-gated ion channels and/ or increased sensitivity of TRP channels in sensory neurons seem to be the major events leading to the development of oxaliplatin-induced acute neurological side effects, including cold-induced paresthesias and painful dysesthesias. The potential roles of glial cells and nachrs in platinum-induced neurotoxicity deserve further investigation to explore new strategies to prevent and to treat this side effect. REFERENCES 1 Avan A, Postma TJ, Ceresa C, Avan A, Cavaletti G, Giovannetti E, Peters GJ. Platinum-induced neurotoxicity and preventive strategies: past, present, and future. Oncologist 2015; 20: [PMID: ] 2 Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett 2015; 596: [PMID: ] 3 Amptoulach S, Tsavaris N. Neurotoxicity caused by the treatment with platinum analogues. Chemother Res Pract 2011; 2011: [PMID: DOI: /2011/843019] 4 Chiorazzi A, Semperboni S, Marmiroli P. Current view in platinum drug mechanisms of peripheral neurotoxicity. Toxics 2015; 3: [DOI: /toxics ] 5 Kelley MR, Jiang Y, Guo C, Reed A, Meng H, Vasko MR. Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PLoS One 2014; 9: e [PMID: DOI: /journal.pone ] 6 Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 2013; 63: [PMID: DOI: /caac.21204] 333 August 10, 2017 Volume 8 Issue 4

36 Kanat O et al. Platinum drugs/neurotoxicity 7 Velasco R, Bruna J, Briani C, Argyriou AA, Cavaletti G, Alberti P, Frigeni B, Cacciavillani M, Lonardi S, Cortinovis D, Cazzaniga M, Santos C, Kalofonos HP. Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients. J Neurol Neurosurg Psychiatry 2014; 85: [PMID: DOI: /jnnp ] 8 Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol 2011; 12: [PMID: DOI: /S (11) ] 9 Pasetto LM, D Andrea MR, Rossi E, Monfardini S. Oxaliplatinrelated neurotoxicity: how and why? Crit Rev Oncol Hematol 2006; 59: [PMID: ] 10 Lucchetta M, Lonardi S, Bergamo F, Alberti P, Velasco R, Argyriou AA, Briani C, Bruna J, Cazzaniga M, Cortinovis D, Cavaletti G, Kalofonos HP. Incidence of atypical acute nerve hyperexcitability symptoms in oxaliplatin-treated patients with colorectal cancer. Cancer Chemother Pharmacol 2012; 70: [PMID: DOI: /s ] 11 McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther 2009; 8: [PMID: DOI: / MCT ] 12 Jimenez-Andrade JM, Herrera MB, Ghilardi JR, Vardanyan M, Melemedjian OK, Mantyh PW. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemicalinduced peripheral sensory neuropathies. Mol Pain 2008; 4: 10 [PMID: DOI: / ] 13 Cavaletti G, Ceresa C, Nicolini G, Marmiroli P. Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity. Anticancer Res 2014; 34: [PMID: ] 14 Ciarimboli G. Membrane transporters as mediators of Cisplatin effects and side effects. Scientifica (Cairo) 2012; 2012: [PMID: DOI: /2012/473829] 15 Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, Janke LJ, Cavaletti G, Shields AF, Sparreboom A. Oxaliplatininduced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci USA 2013; 110: [PMID: DOI: /pnas ] 16 Ta LE, Espeset L, Podratz J, Windebank AJ. Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-dna binding. Neurotoxicology 2006; 27: [PMID: ] 17 Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon MS, Kaube H, Limmroth V, Thomale J. Repair capacity for platinum- DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci 2007; 27: [PMID: ] 18 Yan F, Liu JJ, Ip V, Jamieson SM, McKeage MJ. Role of platinum DNA damage-induced transcriptional inhibition in chemotherapyinduced neuronal atrophy and peripheral neurotoxicity. J Neurochem 2015; 135: [PMID: DOI: /jnc.13355] 19 McDonald ES, Randon KR, Knight A, Windebank AJ. Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis 2005; 18: [PMID: ] 20 Alaedini A, Xiang Z, Kim H, Sung YJ, Latov N. Up-regulation of apoptosis and regeneration genes in the dorsal root ganglia during cisplatin treatment. Exp Neurol 2008; 210: [PMID: DOI: /j.expneurol ] 21 Cavaletti G, Tredici G, Petruccioli MG, Dondè E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 2001; 37: [PMID: ] 22 Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest 1998; 101: [PMID: DOI: / JCI1130] 23 Podratz JL, Knight AM, Ta LE, Staff NP, Gass JM, Genelin K, Schlattau A, Lathroum L, Windebank AJ. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 2011; 41: [PMID: DOI: / j.nbd ] 24 Podratz JL, Lee H, Knorr P, Koehler S, Forsythe S, Lambrecht K, Arias S, Schmidt K, Steinhoff G, Yudintsev G, Yang A, Trushina E, Windebank A. Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve. Neurobiol Dis 2017; 97: [PMID: DOI: /j.nbd ] 25 Bobylev I, Joshi AR, Barham M, Neiss WF, Lehmann HC. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. Mol Neurobiol 2017 Jan 21; Epub ahead of print [PMID: DOI: /s ] 26 Adelsberger H, Quasthoff S, Grosskreutz J, Lepier A, Eckel F, Lersch C. The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 2000; 406: [PMID: ] 27 Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC. Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity. PLoS One 2011; 6: e18469 [PMID: DOI: /journal.pone ] 28 Krishnan AV, Goldstein D, Friedlander M, Kiernan MC. Oxaliplatin and axonal Na+ channel function in vivo. Clin Cancer Res 2006; 12: [PMID: ] 29 Wu SN, Chen BS, Wu YH, Peng H, Chen LT. The mechanism of the actions of oxaliplatin on ion currents and action potentials in differentiated NG neuronal cells. Neurotoxicology 2009; 30: [PMID: DOI: /j.neuro ] 30 Webster RG, Brain KL, Wilson RH, Grem JL, Vincent A. Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels. Br J Pharmacol 2005; 146: [PMID: ] 31 Sittl R, Lampert A, Huth T, Schuy ET, Link AS, Fleckenstein J, Alzheimer C, Grafe P, Carr RW. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc Natl Acad Sci USA 2012; 109: [PMID: DOI: / pnas ] 32 Deuis JR, Zimmermann K, Romanovsky AA, Possani LD, Cabot PJ, Lewis RJ, Vetter I. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. Pain 2013; 154: [PMID: DOI: / j.pain ] 33 Kagiava A, Tsingotjidou A, Emmanouilides C, Theophilidis G. The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat. Neurotoxicology 2008; 29: [PMID: DOI: /j.neuro ] 34 Sittl R, Carr RW, Fleckenstein J, Grafe P. Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy. Neurotoxicology 2010; 31: [PMID: DOI: /j.neuro ] 35 Park SB, Lin CS, Kiernan MC. Nerve excitability assessment in chemotherapy-induced neurotoxicity. J Vis Exp 2012; (62): 3439 [PMID: DOI: /3439] 36 Broomand A, Jerremalm E, Yachnin J, Ehrsson H, Elinder F. Oxaliplatin neurotoxicity--no general ion channel surface-charge effect. J Negat Results Biomed 2009; 8: 2 [PMID: DOI: / ] 37 Kagiava A, Theophilidis G, Sargiannidou I, Kyriacou K, Kleopa KA. Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and hemichannels and can be prevented by octanol. Neuropharmacology 2015; 97: [PMID: DOI: /j.neuropharm ] 38 Tomaszewski A, Büsselberg D. Cisplatin modulates voltage gated channel currents of dorsal root ganglion neurons of rats. Neurotoxicology 2007; 28: [PMID: ] 39 Leo M, Schmitt LI, Erkel M, Melnikova M, Thomale J, Hagenacker T. Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons. Exp Neurol 2017; 288: [PMID: DOI: /j.expneurol ] 40 Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto 334 August 10, 2017 Volume 8 Issue 4

37 Kanat O et al. Platinum drugs/neurotoxicity N, Failli P, Preti D, Marchetti N, Cavazzini A, Mancini F, Pedretti P, Nilius B, Patacchini R, Geppetti P. Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain 2011; 152: [PMID: DOI: /j.pain ] 41 Ta LE, Bieber AJ, Carlton SM, Loprinzi CL, Low PA, Windebank AJ. Transient Receptor Potential Vanilloid 1 is essential for cisplatininduced heat hyperalgesia in mice. Mol Pain 2010; 6: 15 [PMID: DOI: / ] 42 Kono T, Satomi M, Suno M, Kimura N, Yamazaki H, Furukawa H, Matsubara K. Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation. Brain Behav2012; 2: [PMID: DOI: /brb3.34] 43 Gauchan P, Andoh T, Kato A, Kuraishi Y. Involvement of increased expression of transient receptor potential melastatin 8 in oxaliplatininduced cold allodynia in mice. Neurosci Lett 2009; 458: [PMID: DOI: /j.neulet ] 44 Zhao M, Isami K, Nakamura S, Shirakawa H, Nakagawa T, Kaneko S. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. Mol Pain 2012; 8: 55 [PMID: DOI: / ] 45 Nativi C, Gualdani R, Dragoni E, Di Cesare Mannelli L, Sostegni S, Norcini M, Gabrielli G, la Marca G, Richichi B, Francesconi O, Moncelli MR, Ghelardini C, Roelens S. A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain. Sci Rep 2013; 3: 2005 [PMID: DOI: /srep02005] 46 Park JH, Chae J, Roh K, Kil EJ, Lee M, Auh CK, Lee MA, Yeom CH, Lee S. Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation. PLoS One 2015; 10: e [PMID: DOI: /journal.pone ] 47 Di Cesare Mannelli L, Pacini A, Bonaccini L, Zanardelli M, Mello T, Ghelardini C. Morphologic features and glial activation in rat oxaliplatin-dependent neuropathic pain. J Pain 2013; 14: [PMID: DOI: /j.jpain ] 48 Di Cesare Mannelli L, Pacini A, Micheli L, Tani A, Zanardelli M, Ghelardini C. Glial role in oxaliplatin-induced neuropathic pain. Exp Neurol 2014; 261: [PMID: DOI: / j.expneurol ] 49 Di Cesare Mannelli L, Pacini A, Matera C, Zanardelli M, Mello T, De Amici M, Dallanoce C, Ghelardini C. Involvement of α7 nachr subtype in rat oxaliplatin-induced neuropathy: effects of selective activation.neuropharmacology 2014; 79: [PMID: DOI: /j.neuropharm ] 50 Kanat O, Bagdas D, Ozboluk HY, Gurun MS. Preclinical evidence for the antihyperalgesic activity of CDP-choline in oxaliplatin-induced neuropathic pain. J BUON 2013; 18: [PMID: ] 51 Alberti P, Rossi E, Cornblath DR, Merkies IS, Postma TJ, Frigeni B, Bruna J, Velasco R, Argyriou AA, Kalofonos HP, Psimaras D, Ricard D, Pace A, Galiè E, Briani C, Dalla Torre C, Faber CG, Lalisang RI, Boogerd W, Brandsma D, Koeppen S, Hense J, Storey D, Kerrigan S, Schenone A, Fabbri S, Valsecchi MG, Cavaletti G; CI-PeriNomS Group. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin. Ann Oncol 2014; 25: [PMID: DOI: /annonc/mdt409] 52 Curcio KR. Instruments for Assessing Chemotherapy-Induced Peripheral Neuropathy: A Review of the Literature. Clin J Oncol Nurs 2016; 20: [PMID: DOI: /16.CJON.20-01AP] 53 Hill A, Bergin P, Hanning F, Thompson P, Findlay M, Damianovich D, McKeage MJ. Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability. BMC Cancer 2010; 10: 451 [PMID: DOI: / ] 54 Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev 2014; (3): CD [PMID: DOI: / CD005228] 55 Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner- Johnston N, Bak K, Loprinzi CL; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014; 32: [PMID: DOI: /JCO ] P- Reviewer: Chen CJ, Levine JD, Lotti M S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 335 August 10, 2017 Volume 8 Issue 4

38 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.336 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) Retrospective Study ORIGINAL ARTICLE Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists Jill C Beck, Baojiang Chen, Bruce G Gordon Jill C Beck, Baojiang Chen, Bruce G Gordon, Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE , United States Author contributions: Beck JC designed the study and gathered data; Chen B provided statistical analysis of results; Beck JC and Gordon BG wrote the manuscript. Institutional review board statement: The Institutional Review Board at University of Nebraska Medical Center (UNMC) in Omaha, Nebraska reviewed and approved the study. Conflict-of-interest statement: None. Data sharing statement: None. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Jill C Beck, MD, Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE , United States. jill.beck@unmc.edu Telephone: Fax: Received: October 31, 2016 Peer-review started: November 4, 2016 First decision: April 27, 2017 Revised: May 4, 2017 Accepted: July 14, 2017 Article in press: July 17, 2017 Published online: August 10, 2017 Abstract AIM To evaluate personnel involved in scarce drug prioritization and distribution and the criteria used to inform drug distribution during times of shortage among pediatric hematologists/oncologists. METHODS Using the American Society of Pediatric Hematology/ Oncology (ASPHO) membership list, a 20 question survey of pediatric hematologists/oncologists was conducted via to evaluate personnel involved in scarce drug prioritization and distribution and criteria used to inform scarce drug distribution. RESULTS Nearly 65% of the 191 study respondents had patients directly affected by drug shortages. Most physicians find out about shortages from the pharmacist (n = 179, 98%) or other doctors (n = 75, 41%). One third of respondents do not know if there is a program or policy for handling drug shortages at their institution. The pharmacist was the most commonly cited decision maker for shortage drug distribution (n = 128, 70%), followed by physicians (n = 109, 60%). One fourth of respondents did not know who makes decisions about shortage drug distribution at their institution. The highest priority criterion among respondents was use of the shortage drug for curative, rather than palliative intent and lowest priority criterion was order of arrival or first-come first-served. CONCLUSION Despite pediatric hematology/oncology physicians and patients being heavily impacted by drug shortages, institutional processes for handling shortages are lacking. There is significant disparity between how decisions for distribution of shortage drugs are currently made and how study respondents felt those decisions should be made. An institution-based, and more importantly, a societal 336 August 10, 2017 Volume 8 Issue 4

39 Beck JC et al. Physician approaches to drug shortages approach to drug shortages is necessary to reconcile these disparities. Key words: Pediatric hematology/oncology; Chemotherapy; Ethics The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: The frequency of drug shortages are increasing and heavily impact physicians and patients. However, processes for handling drug shortages are lacking. An institution-based, and more importantly, a societal approach to drug shortages are necessary to reconcile these disparities. Beck JC, Chen B, Gordon BG. Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/ oncologists. World J Clin Oncol 2017; 8(4): Available from: URL: htm DOI: INTRODUCTION Drug shortages occur whenever demand for a medication is greater than the available supply. The frequency of drug shortages has increased considerably over the last decade due to decreased availability of raw materials, disruptions along the supply chain, economic decisions by drug companies and health care systems, and increased demand [1-5]. Although drug shortages are a global issue, they have significantly impacted the United States due to low pharmaceutical company reimbursement rates for generic drugs with narrow cost margins [4,5]. Important ethical issues arise whenever the supply of an effective drug is insufficient to meet demand. The principles of beneficence, non-maleficence, and justice can guide prioritization of scarce drug distribution, but an individual s application of those principles may vary widely. The ethical principle of autonomy, which so commonly drives ethical decision making, is not relevant to drug shortages, perhaps making these decisions more difficult. Several reports have evaluated the impact of drug shortages and ethical frameworks have been proposed for handling shortages, however, no studies have evaluated the key factors physicians use to determine drug distribution during times of shortage [3,6-13]. A more thorough understanding of the decision-making processes physicians are using will assist in developing frameworks and policies to more effectively manage drug shortages. MATERIALS AND METHODS Study review The Institutional Review Board at University of Nebraska Medical Center (UNMC) in Omaha, Nebraska reviewed and approved the study. Study population The online membership directory from the American Society of Pediatric Hematology/Oncology (ASPHO) was used to identify pediatric hematology/oncology physicians in the United States. Survey A twenty question survey of pediatric hematologists/ oncologists was conducted via to evaluate demographics of study respondents, personnel involved in scarce drug prioritization and distribution, and criteria used to inform scarce drug distribution (Appendix Ⅰ). The survey was developed and piloted by the authors. The questions evaluating demographics and personnel involved in prioritization were multiple-choice closedended questions. Demographic information included current position, type of patients seen, practice type, and years since completing fellowship. Survey questions regarding experiences with drug shortages included whether drug shortages had directly affected the provider s patients and whether the provider knew of drug shortages at the institution but the shortage had not resulted in the provider s patient not receiving a needed medication. In addition, respondents were asked to identify whether the shortage drugs were chemotherapy or non-chemotherapy, however further specifics were not requested. Questions also addressed whether the respondent s institution has a program or policy to handle drug shortages, whether the provider felt a program or policy was necessary, who makes decisions about shortage drug distribution at their institution, and who should make decisions about shortage drug distribution. Respondents were asked to choose all decision makers with no limit on the number of answers and were asked to specify with an open-ended response if they chose other. The criteria for scarce drug distribution provided eight statements which were evaluated using a Likert scale ranging from 0 (strongly disagree) to 100 (strongly agree). Survey questions did not specify definitions for relative terms such as length of survival, age, type or length of therapy, or dose. Study data was collected and managed using REDCap electronic data capture tools hosted at UNMC. REDCap is a secure, webbased application designed to support data capture for research studies. The invitation provided an explanation of and electronic link to the voluntary survey. Participants entered responses directly into the online REDCap survey and responses were deidentified. Survey population At the time of this study, 1259 physicians in the United States had available addresses in the ASPHO online membership roster and were ed survey invitations. Twenty-nine addresses were undeliverable. 337 August 10, 2017 Volume 8 Issue 4

40 Beck JC et al. Physician approaches to drug shortages Table 1 Demographics Table 2 Decision makers for shortage drug distribution Characteristic n (%) Current position Attending physician 161 (84.7) Fellow 23 (12.1) Non-practicing physician 2 (1.1) Type of patients Oncology 162 (85.7) Hematology 145 (76.7) Stem cell transplant 54 (28.6) Do not see patients 2 (1.1) Type of practice Academic medical center 160 (83.8) Community/private institution 39 (15.7) Years since completing fellowship Less than 5 64 (34.4) (23.7) (17.7) More than (24.2) Gender Female 104 (55) Male 85 (45) Of the 1230 remaining physicians, 191 (15.5%) responded and were included in the study analysis. The majority of respondents were attending pediatric hematologist/oncologists currently practicing (n = 161, 84.7%) and 12.1% (n = 23) were fellows in pediatric hematology/oncology (Table 1). The types of patients seen by the surveyed physicians were mostly oncology (n = 162) and hematology (n = 145), with 54 physicians seeing stem cell transplant patients. Sixtyseven percent of physicians saw multiple patient types. Most respondents practice in an academic medical center (n = 160, 83.8%) with the remainder practicing in a community or private institution (n = 30, 15.7%). The number of years since completing pediatric hematology/oncology fellowship was nearly evenly divided among respondents. Statistical analysis χ 2 or Fisher s Exact test was used to obtain P-values to evaluate association among categorical responses. A P-value less than 0.05 indicates statistical significance. Logistic regression was used to determine the odds ratios to study the association of the outcomes with all variables simultaneously. Responses to scaled questions were reported as means and compared using analysis of variance. RESULTS Nearly 65% of study respondents had patients directly affected by drug shortages where the provider was not able to prescribe a needed medication for his/ her patient due to a shortage and 79% of study respondents knew of drug shortages at their institution, but the shortage did not result in a patient under the provider s care not receiving a needed drug. Physicians Who makes the decision about distribution of shortage drugs at your institution? % Who should make the decision about distribution of shortage drugs at your institution? Pharmacist Physician Hospital administration Panel/group Ethics committee Nurse Parent Do not know Total responses practicing in an academic medical center were more likely to have patients directly affected than physicians practicing in a community or private institution (OR = 2.61, 95%CI: ). The physician s type of patients (hematology, oncology and/or stem cell transplant) did not impact the rate of patients directly affected by shortages. Most physicians find out about drug shortages from the pharmacist (n = 179, 98%) or other doctors (n = 75, 41%). Other sources of information about drug shortages include a list or website (n = 69, 38%) and nurses (n = 13, 7%). Three respondents receive information from the Pharmacy and Therapeutics Committee or a drug shortage task force. Sixty-six percent found out from more than one of the above sources. One respondent stated they do not find out about drug shortages. Sixty-two percent of respondents work at institutions that have a program or policy to handle drug shortages and 4% of institutions do not have a program or policy. One third of respondents do not know if there is a program or policy for handling drug shortages at their institution. However, 95% of respondents felt that a program or policy is necessary. The pharmacist was the most commonly cited decision maker for shortage drug distribution (n = 128, 70%), followed by physicians (n = 109, 60%), hospital administration (n = 41, 23%), a panel or group (n = 32, 18%), ethics committee (n = 8, 4%), parent (n = 1, 0.5%), and nurse (n = 1, 0.5%) (Table 2). Sixty-six percent reported multiple decision makers. One fourth of respondents did not know who makes decisions about shortage drug distribution at their institution. In contrast, respondents felt that the physician (n = 152, 83%) and pharmacist (n = 147, 80%) should be the decision maker for shortage drug distribution. Other responses included a panel or group (n = 77, 42%), ethics committee (n = 35, 19%), hospital administration (n = 35, 19%), nurse (n = 8, 4%), and parent (n = 6, 3%). Seven percent of respondents did not know who should make the decision about distribution of shortage % 338 August 10, 2017 Volume 8 Issue 4

41 Beck JC et al. Physician approaches to drug shortages Table 3 Prioritization of distribution criteria Mean Criteria Ethical Framework Strongly 0.0 disagree 37.1 Order of arrival should impact the priority given to a patient 41.8 A patient with fewer comorbidities should be given priority over a patient who has more co-morbidities 44.3 Younger patients should receive priority over older patients 47.3 A patient with longer anticipated survival should be given priority over a patient with shorter anticipated survival 51.8 A patient needing a small dose of a shortage drug should be prioritized over a patient needing a larger dose 57.2 A patient using a drug for an approved indication should have priority over a patient using the drug for off-label use 61.0 A patient who is starting therapy should be prioritized over a patient who has nearly completed therapy 74.3 A patient using the shortage drug for curative intent should be prioritized over a patient using the drug for palliation Strongly agree First-come first-served Sickest first Fair innings Saving the most Saving the most Saving the most Saving the most Saving the most drugs. Respondents ranked criteria for prioritizing scarce drug distribution on a scale of 0 (strongly disagree, low priority) to 100 (strongly agree, high priority) (Table 3). Respondents prioritized use of the shortage drug for curative, rather than palliative intent (a patient using the shortage drug for curative intent should be prioritized over a patient using the shortage drug for palliation, mean 74) as the most important criteria in determining which patient should receive a shortage drug. Prioritization of patients starting vs completing therapy (a patient who is starting therapy should be prioritized over a patient who has nearly completed therapy, mean 61), using a drug for an approved indication (a patient using a drug for an approved indication should have priority over a patient using the drug for off-label use, mean 57), dose (a patient needing a small dose of a shortage drug should be prioritized over a patient needing a larger dose, mean 52), anticipated survival (a patient with longer anticipated survival should be given priority over a patient with shorter anticipated survival, mean 47), patient age (younger patients should receive priority over older patients, mean 44), and number of comorbidities (a patient with fewer co-morbidities should be given priority over a patient who has more comorbidities, mean 42) had closely ranked means. The priority ranking for anticipated survival (mean 44 vs 58, P = 0.005) and patient age (mean 40 vs 58, P = 0.008) was lower for physicians practicing at academic medical centers compared to community or private institutions. The priority ranking for using a drug for an approved indication was higher for fellows than attendings (mean 72 vs 54, P = 0.02). As the years after fellowship increased, the priority of mean rank of prioritizing patients starting vs completing therapy also increased (< 5 years mean 53, 5-10 years mean 63, years mean 64, > 20 years mean 66, P = 0.04). The lowest priority criterion was order of arrival [order of arrival (first come-first served) should impact the priority given to a patient, mean 37]. The priority ranking for order of arrival for physicians practicing at academic medical centers was significantly lower than physicians in community or private institutions (mean 34 vs 45, P = 0.03). Physicians whose patients were directly affected by drug shortages gave lower priority to order of arrival than physicians who did not have patients directly affected by shortages (mean 33 vs 42, P = 0.01). DISCUSSION While numerous reports have detailed the impact of drug shortages and several ethical frameworks have been proposed for handling shortages, this is the first survey of physicians evaluating individual approaches to prioritization [3,6-13]. The frequency of drug shortages have increased over the last decade and have disproportionately affected oncology due to quality issues, limited manufacturers, and complex production processes with specialized equipment [3,4]. In addition, chemotherapy medications often have no equivalent for substitution, whereas other drugs may have several alternatives within a medication class [5]. Unique issues arise when dealing with drug shortages in pediatric oncology due to the increased use of off-label drugs in pediatrics compared to adult medicine and dosing based on weight and size [2,3,7,14]. In addition, pediatric patients have surrogate decision makers, usually parents, determining the child s best interest in a situation in which no alternative may be ideal. In this study, nearly 65% of respondents had patients unable to receive a needed drug due to shortages and 79% knew of drug shortages at their institution that had not directly affected their patients. Overall, physicians report they are informed about drug shortages from a variety of sources, most commonly pharmacists, other doctors, and/or a list or website. Despite being heavily impacted by and well informed about drug shortages, 339 August 10, 2017 Volume 8 Issue 4

42 Beck JC et al. Physician approaches to drug shortages institutional processes for handling shortages are lacking, or at least are not well known to the physicians caring for the patients: One third of respondents did not know if there is a program or policy for handling drug shortages at their institution. There is significant disparity between how decisions for distribution of shortage drugs are made and how study respondents felt those decisions should be made. Currently, the pharmacist was the most commonly cited decision maker for shortage drug distribution, followed by physicians. Although respondents felt that physicians and pharmacists should be included in decisions regarding shortage drugs, many believed that a panel, group, or ethics committee should also be involved. This is not currently the practice at most institutions surveyed and may reflect the need to systematically involve more members of the health care team. Physicians in academic medical centers were more likely to have patients directly affected by shortages than those in community or private institutions. It is not clear why this is the case, however, a report of adult oncologists found private practice providers were more likely to use brand name rather than generic drugs which more frequently have shortages [5]. The criteria of using a drug for an approved indication was given higher priority by fellows than attendings, likely reflecting increased comfort with using off-label medications as experience increased. Important ethical issues arise whenever the supply of an effective drug is insufficient to meet demand. The principles of beneficence, non-maleficence, and justice can guide prioritization of scarce drug distribution, but as is demonstrated in this study, an individual s application of those principles may vary widely. The ethical principle of autonomy, which so commonly drives ethical decision making, is not relevant to drug shortages perhaps making these decisions even more difficult. Beneficence encourages safe and effective care such as utilizing evidence-based medicine and optimizing resource utilization. Nonmaleficence promotes minimizing pain and suffering, a major potential effect on a patient unable to obtain a needed medication. Justice demands reasonable access to resources and is threatened by the many causes of shortages as well as institutional stockpiling of shortage drugs. Prioritization frameworks have been proposed, some of which include sickest first, fair innings, first-come first-served, and saving the most, among others (Table 3) [3,13,15]. Sickest first prioritizes patients based on degree of illness. Therefore, using the sickest first criteria to distribute shortage drugs, patients with the worst disease and the most co-morbidities would have highest priority. The fair innings approach argues that each person should have an equal opportunity to live a normal lifespan. The prioritization criterion of patient age relies on the fair innings approach. First-come firstserved distributes shortage drug based on order of arrival. Finally, the goal of saving the most is to provide the most good to the most patients. In the case of drug shortages, this method focuses on the indication of the drug and goals of care while balancing risks and benefits [3]. In this survey, the highest priority criterion was use of the shortage drug for curative, rather than palliative, intent, which evokes the ethical framework of saving the most. The criteria of starting vs completing therapy, using a drug for an approved indication, dose, and anticipated survival completed the top five highest ranked criteria and all rely on the concept of saving the most. Therefore, the ethical framework of saving the most is used most often by pediatric hematologist/ oncologists in the United States when considering shortage drug distribution. Drug shortages require the physician to consider both the good of an individual patient and society at large. Using the framework of saving the most necessitates physicians to prioritize their patient within the larger context of the population. An institutionbased, and more importantly, a societal approach to drug shortages is necessary to reconcile the physicianpatient relationship with that of the larger population. Cooperative groups and medical societies can play an important role in this process. Several groups have begun to address drug shortages in pediatric oncology. The Working Group on Drug Shortages in Pediatric Oncology has created recommendations for responding to drug shortages, COG gives guidelines for management of shortages within treatment protocols, the American Society of Health-System Pharmacists has provided guidelines and recommendations, and the American Board of Pediatrics, American Society of Clinical Oncology, and American Society of Pediatric Hematology/Oncology have provided commentary and position statements [6,7,11,16]. However, given the continued prevalence of drug shortages and their widespread impact, a continued coordinated effort is needed to ensure consistency and provide guidance for implementation. The recently published follow-up recommendations to the Working Group on Drug Shortages in Pediatric Oncology by Unguru et al [13] provides much needed concrete methods for shortage drug distribution in pediatric oncology that can ideally be adopted within and across institutions. Pediatric oncology is a prime subspecialty to formulate this coordinated endeavor given its established history of collaboration and could potentially set the stage as a model for other subspecialties impacted by drug shortages. The lowest priority criterion in this survey was firstcome first-served. Interestingly, this criterion may actually be used frequently in practice. One third of respondents did not know if there is a program or 340 August 10, 2017 Volume 8 Issue 4

43 Beck JC et al. Physician approaches to drug shortages policy for handling drug shortages at their institution. In addition, respondents who had patients directly affected by drug shortages gave first-come first-served lower priority than physicians who did not have patients directly affected by shortages. At those institutions, shortage drugs are rationed at the bedside and priority for shortage drug distribution is likely first-come firstserved by default. If a program or policy for handling drug shortages is not in place, advance decision-making is unlikely to occur resulting in a process that may not be reasonable or transparent. This discrepancy between aims and reality highlights the need for clear institutional and ideally national guidelines developed prior to a drug shortage. Limitations to this study include the limited sample size and voluntary nature of the survey resulting in possible selection bias. The small sample size offers trends in approaches to prioritization of shortage drug distribution. Non-practicing physicians were included because the decision processes are not limited to practicing providers. The survey statements were left purposefully broad to allow respondent interpretation, as is the case in clinical practice, however this approach may impact validity. However, this is the first national survey of physicians on the topic of physician prioritization criteria used for shortage drugs. The crucial finding of this study is the disparity between how decisions are made and how respondents feel they should occur, reinforcing the need for continued attention to organizational frameworks and policy development. Perspectives of other physician subspecialty groups, health professionals, patients, or family members are an important area for follow-up and such studies are underway by the authors. COMMENTS Background The frequency of drug shortages is increasing. Important ethical issues arise whenever the supply of an effective drug is insufficient to meet demand. The principles of beneficence, non-maleficence, and justice can guide prioritization of scarce drug distribution, but an individual s application of those principles may vary widely. The ethical principle of autonomy, which so commonly drives ethical decision making, is not relevant to drug shortages, perhaps making these decisions more difficult. Research frontiers Little data is available evaluating the key factors physicians use to determine drug distribution in times of shortage. A more thorough understanding of the decision-making processes physicians are using will assist in developing frameworks and policies to more effectively manage drug shortages. Innovations and breakthroughs The frequency of drug shortages are increasing and heavily impact physicians and patients. However, processes for handling drug shortages are lacking. An institution-based, and more importantly, a societal approach to drug shortages is necessary to reconcile these disparities. Applications While numerous reports have detailed the impact of drug shortages and several ethical frameworks have been proposed for handling shortages, this is the first survey of physicians evaluating individual approaches to prioritization. Unique issues arise when dealing with drug shortages in pediatric oncology due to the increased use of off-label drugs in pediatrics compared to adult medicine and dosing based on weight and size. Given the continued prevalence of drug shortages and their widespread impact, a continued coordinated effort is needed to ensure consistency and provide guidance for distribution of shortage drugs. Pediatric oncology is a prime subspecialty to formulate this coordinated endeavor given its established history of collaboration and could potentially set the stage as a model for other subspecialties impacted by drug shortages. Peer-review The manuscript is well written and the topic is quite relevant. REFERENCES 1 Printz C. Medication shortages threaten cancer care: the oncology community and the FDA tackle ongoing drug shortage problem. Cancer 2012; 118: [PMID: DOI: /cncr.27386] 2 Butterfield L, Cash J, Pham K; Advocacy Committee for the Pediatric Pharmacy Advocacy Group. Drug shortages and implications for pediatric patients. J Pediatr Pharmacol Ther 2015; 20: [PMID: DOI: / ] 3 Beck JC, Smith LD, Gordon BG, Garrett JR. An ethical framework for responding to drug shortages in pediatric oncology. Pediatr Blood Cancer 2015; 62: [PMID: DOI: / pbc.25461] 4 Haninger K, Jessup A, Koehler K. Economic Analysis of the Causes of Drug Shortages. ASPE Issue Brief 2011: Link MP, Hagerty K, Kantarjian HM. Chemotherapy drug shortages in the United States: genesis and potential solutions. J Clin Oncol 2012; 30: [PMID: DOI: / JCO ] 6 ASHP Expert Panel on Drug Product Shortages, Fox ER, Birt A, James KB, Kokko H, Salverson S, Soflin DL. ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. Am J Health Syst Pharm 2009; 66: [PMID: DOI: /ajhp090026] 7 Decamp M, Joffe S, Fernandez CV, Faden RR, Unguru Y; Working Group on Chemotherapy Drug Shortages in Pediatric Oncology. Chemotherapy drug shortages in pediatric oncology: a consensus statement. Pediatrics 2014; 133: e716-e724 [PMID: DOI: /peds ] 8 Rosoff PM. Unpredictable drug shortages: an ethical framework for short-term rationing in hospitals. Am J Bioeth 2012; 12: 1-9 [PMID: DOI: / ] 9 Rosoff PM, Patel KR, Scates A, Rhea G, Bush PW, Govert JA. Coping with critical drug shortages: an ethical approach for allocating scarce resources in hospitals. Arch Intern Med 2012; 172: [PMID: DOI: /archinternmed ] 10 Gogineni K, Shuman KL, Emanuel EJ. Survey of oncologists about shortages of cancer drugs. N Engl J Med 2013; 369: [PMID: DOI: /NEJMc ] 11 G Salazar E, Bernhardt MB, Li Y, Aplenc R, Adamson PC. The impact of chemotherapy shortages on COG and local clinical trials: a report from the Children s Oncology Group. Pediatr Blood Cancer 2015; 62: [PMID: DOI: /pbc.25445] 12 Kehl KL, Gray SW, Kim B, Kahn KL, Haggstrom D, Roudier M, Keating NL. Oncologists experiences with drug shortages. J Oncol Pract 2015; 11: e154-e162 [PMID: DOI: / JOP ] 13 Unguru Y, Fernandez CV, Bernhardt B, Berg S, Pyke-Grimm K, Woodman C, Joffe S. An Ethical Framework for Allocating Scarce Life-Saving Chemotherapy and Supportive Care Drugs for Childhood Cancer. J Natl Cancer Inst 2016; 108: djv392 [PMID: DOI: /jnci/djv392] 14 Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Neville KA, Paul 341 August 10, 2017 Volume 8 Issue 4

44 Beck JC et al. Physician approaches to drug shortages IM, Van Den Anker JN; American Academy of Pediatrics Committee on Drugs. Off-label use of drugs in children. Pediatrics 2014; 133: [PMID: DOI: /peds ] 15 Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet 2009; 373: [PMID: DOI: /S (09) ] 16 Testimony for the record on behalf of the American Academy of Pediatrics before the Energy and Commerce Committee Health Subcommittee. USA: Energy and Commerce Committe Health Subcomittee, 2012 P- Reviewer: Yellanthoor RB S- Editor: Kong JX L- Editor: A E- Editor: Lu YJ 342 August 10, 2017 Volume 8 Issue 4

45 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.343 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) Retrospective Study ORIGINAL ARTICLE Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients Tatjana Gruber-Rouh, Marcel Langenbach, Nagy NN Naguib, Nour-Eldin M Nour-Eldin, Thomas J Vogl, Stephan Zangos, Martin Beeres Tatjana Gruber-Rouh, Marcel Langenbach, Nagy NN Naguib, Nour-Eldin M Nour-Eldin, Thomas J Vogl, Stephan Zangos, Martin Beeres, Institute for Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt am Main, Germany Author contributions: Gruber-Rouh T and Beeres M designed and performed the research, statistical analysis and wrote the paper; Zangos S designed the research and supervised the report; Langenbach M designed the research and contributed to the analysis; Naguib NNN, Nour-Eldin NEM and Vogl TJ provided clinical advice; Vogl TJ and Zangos S supervised the report. Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Goethe University Hospital, Frankfurt, Germany. Conflict-of-interest statement: The authors have no financial relationships to disclose. Data sharing statement: No additional data are available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Unsolicited manuscript Correspondence to: Tatjana Gruber-Rouh, MD, Institute for Diagnostic and Interventional Radiology, University Hospital Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, Germany. tatjana.gruber-rouh@kgu.de Telephone: Fax: Received: October 19, 2016 Peer-review started: October 23, 2016 First decision: January 14, 2017 Revised: April 27, 2017 Accepted: May 3, 2017 Article in press: May 5, 2017 Published online: August 10, 2017 Abstract AIM To evaluate the clinical value and efficiency of transarterial chemoperfusion (TACP) in patients with liver metastases from breast cancer (BC) and colorectal cancer (CRC). METHODS We treated 36 patients with liver metastases of BC (n = 19, 19 females) and CRC (n = 17; 8 females, 9 males) with repeated TACP. The treatment interval was 4 wk. TACP was performed with gemcitabine (1000 mg/m 2 ) and mitomycin (10 mg/m 2 ), administered within 1 h after positioning the catheter tip in the hepatic artery. Before treatment, the size, location, tumour volume, vascularization and number of liver tumours were evaluated using magnetic resonance imaging (MRI). Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS TACP using gemcitabine and mitomycin for metastases from CRC and BC was performed without any serious side effects. The follow-up MRI showed a therapeutic response in 84.2% of the BC patients - stable disease 47.4% and partial response 36.8%. A progression was seen in 15.8%. 343 August 10, 2017 Volume 8 Issue 4

46 Gruber-Rouh T et al. TACP treatment for palliative liver metastases CRC patients showed a therapeutic response in 52.9% of cases. A progression of the disease was documented in 47.1% of the patients with CRC. These data show that TACP in patients with liver metastases of BC leads to a significantly better therapeutic response compared with CRC patients (P = 0.042). The median survival time was 13.2 mo for the BC patients, which is significantly longer than for CRC patients at 9.3 mo (P = 0.001). CONCLUSION TACP for liver metastases of BC appears to be a safe and effective palliative treatment with improved outcomes in comparison to patients with CRC. Key words: Colorectal neoplasms; Breast neoplasms; Neoplasm metastasis; Neoplasms; Drug therapy The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Trans-arterial chemoperfusion could be an alternative treatment option for advanced stage palliative patients suffering from liver-dominant metastatic disease. blood from the portal venous system, while the metastases predominantly use the arterial system for their blood supply [4]. As higher concentrations of the chemotherapeutic agent can be used, using the first pass mechanism of the liver, less cytotoxic medication arrives in the systemic circulation resulting in only minimal side effects. In our study, 36 patients with unresectable, therapyresistant advanced hepatic metastases of colorectal and breast cancer were treated with hepatic intra-arterial chemotherapy (HIC). Our palliative patient cohort consisted in most cases of patients with symptomatic disease. Gemcitabine as an antimetabolite was chosen because of its tolerable hematologic toxicity and its effect in tumour biology similar to fluorouracil (5-FU). Mitomycin C was added to the chemotherapy protocol because in previous studies at our department it has demonstrated good response rates, especially in HIC pre-treated patients [5]. Primary endpoints of our retrospective analysis were tumour response, patient survival and the time at which the maximum therapeutic effect could be observed. Gruber-Rouh T, Langenbach M, Naguib NNN, Nour-Eldin NEM, Vogl TJ, Zangos S, Beeres M. Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients. World J Clin Oncol 2017; 8(4): Available from: URL: wjgnet.com/ /full/v8/i4/343.htm DOI: org/ /wjco.v8.i4.343 INTRODUCTION Liver metastases are often found in malignant disease. In most cases, the appearance of liver metastases is associated with a poor prognosis of the disease. One third of all patients have metastases even at the time of the primary diagnosis of their cancer. Half of patients resected in an early tumour stage will develop metastases, especially in the liver. Currently, the surgical approach is seen as the only curative treatment for liver metastases. However, only in 20% of patients can curative surgery of their liver metastases be performed [1,2]. Here, other treatment options have to be considered, such as systemic chemotherapy, loco-regional chemotherapy or selective internal radiation therapy (SIRT). In all, the treatment of liver metastases is an interdisciplinary decision that should be discussed in an interdisciplinary tumour board. Reasonable results have been achieved in the past using intra-arterial chemotherapy, especially in metastases of colorectal cancer (CRC), breast cancer (BC) and neuroendocrine tumours [3]. The main idea underlying the intra-arterial delivery of cytotoxic medication is that the liver predominantly derives its MATERIALS AND METHODS Pre-treatment evaluation The patients medical histories were evaluated and documented in detail. Patients were included if the liver was the only organ with metastases, except for BC patients who were included if they also had bone metastases. Patients were only included if the metastases could not be resected and other ablative treatment, e.g., radiofrequency ablation (RFA), microwave ablation (MWA) or laser-induced thermotherapy (LITT), could not be performed. All patients had undergone surgery for their primary tumour and some of the patients (n = 13) also for their liver metastases. Each patient had undergone several therapies before, which were stopped because of progression of the disease or side effects with following progressive disease. Only adult patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 and an estimated remaining survival time of 12 wk were treated. Female patients who were pregnant or breastfeeding were excluded. A minimum of three sessions in 4-wk intervals were performed in an outpatient setting. Sufficient coagulation parameters, bone marrow, renal and hepatic function were required. These parameters in general were evaluated before each treatment session. In the case of acute infection, dysfunction of the liver, kidney or bone marrow, as well as worsening of the general condition, therapeutic intervals were extended or the therapy was discontinued (Table 1). Before treatment, the size, location, vascularization and number of the liver tumours were evaluated using contrast-enhanced magnetic resonance imaging (MRI; 1.5 T; Magnetom Symphony, Siemens, Erlangen, Germany) as a baseline evaluation. Unenhanced T1- and T2-weighted spinecho (SE) and gradient-echo (GE) sequences, as well as 344 August 10, 2017 Volume 8 Issue 4

47 Gruber-Rouh T et al. TACP treatment for palliative liver metastases Table 1 Indications and contraindications of trans-arterial chemoperfusion Indications Unresectable liver metastases Liver-dominant metastatic disease Minimum of three different chemotherapies before No systemic chemotherapy available Symptomatic liver metastases Contraindications ECOG >1 Tumour burden of the liver > 75% Poor liver function (quick < 40%, PTT < 45 s, albumin < 2 g/dl) Extensive amounts of ascites Obstructive icterus (bilirubin > 3 mg/dl) Acute infection Myelodepression (leucocytes < 2000/mL, platelets < /µL) Limited kidney function (creatinine > 2 mg/dl) Extensive heart insufficiency ( > NYHA Ⅱ) ECOG: Eastern Cooperative Oncology Group; PTT: Prothrombin time test; NYHA: New York Heart Association. contrast-enhanced T1 sequences (True Fisp, HASTE, TSE, FLASH-2D in-phase and opposed phase and dynamic sequences), were used. Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Intervention All patients were informed of the risks, side effects and other therapeutic options at least 24 h before the start of therapy. Informed consent was obtained. As preand concomitant medication for the most common side effects pethidine (Dolantin, Sanofi-Aventis, Frankfurt, Germany), granisetron (Kevatril, Roche, Mannheim, Germany) and dexamethasone were administered. After applying local anaesthesia, a commercially available angiographic catheter was introduced through the femoral artery using the Seldinger technique. In our cases, 4 or 5F gate (Introducer Ⅱ, Terumo, Eschborn, Germany) and Pigtail, Renegade (Boston Scientific, Munich, Germany), Sidewinder and Headhunter (Terumo, Eschborn, Germany) catheters were used. After an angiography of the aorta to rule out an abnormal anatomy of the vessels or atypical tumour vessels, an angiography of the upper abdomen was performed to evaluate the vascularization of the liver and the metastases. The catheter was then selectively placed in the right, the left or the common hepatic artery, depending on the tumour localization. In cases of anatomic variants or accessory hepatic arteries supplying the tumour, these arteries were selectively catheterized. Following our procedure, the two chemotherapeutic drugs were administered over 60 min using a perfusor (Perfusor, B. Braun; Melsungen, Germany). Our therapy consisted of 1000 mg/m 2 gemcitabine (Gemzar, Lilly, Bad-Homburg, Germany) and 10 mg/m 2 body surface mitomycin C (Mitomycin, Medac, Hamburg, Germany). Response evaluation Therapy response was evaluated after the third therapy Table 2 Response Evaluation Criteria in Solid Tumors Category RECIST CR Disappearance of all tumour lesions PR Reduction of > 30% in total tumour size SD Reduction of < 30% or a growth of < 20% PD Growth of > 20% or occurrence of new lesions RECIST: Response Evaluation Criteria in Solid Tumors; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease. cycle according to the RECIST criteria. Complete response (CR) was defined as the disappearance of all tumour lesions, partial response (PR) as a reduction of > 30%, stable disease (SD) as a reduction of < 30% or a growth of < 20% and progressive disease (PD) as a growth of > 20% or the occurrence of new lesions; all changes were relative to the baseline imaging (Table 2). Therapeutic response was defined as complete response, partial response or stable disease. The trans-arterial chemoperfusion (TACP) therapy was discontinued if tumour progression had occurred. In that case, alternative therapy options were discussed in an interdisciplinary tumour board and subsequently discussed with the patient. In the case of tumour response, therapy was continued as long as tumour growth could be controlled, or until it was possible to follow up with surgery or an interventional approach to remove the remaining tumour lesions. Statistical analysis Institutional Review Board approval for this retrospective study was obtained. All statistical analyses were performed in SPSS (SPSS Inc.; United States, 2006). Survival data were assessed according to the Kaplan-Meier method. Groups were compared using the χ 2 test and the Cochran-Armitage trend test, as appropriate. The Mann-Whitney U test was used to evaluate tumour volumes because these data were not normally distributed. Survival times were compared with the log rank test. For each test, a P-value < 0.05 was considered to indicate a statistically significant difference. Patients In total, 36 patients with liver metastases of CRC (n = 17; 8 females, 9 males) and BC (n = 19, 19 females) were treated with repeated hepatic transarterial chemoperfusion (TACP). The median age of our patients at the start of the therapy was 60.5 years. In the patients with CRC (n = 17; 8 females, 9 males) the median age at the beginning was 64 years (range years); in the patients with BC (n = 19, 19 females) the median age was 55 years (range 37-77). The median survival from the start of the TACP therapy in BC patients was 13.2 mo and survival from diagnosis was 75.2 mo. The median survival from the beginning of the TACP therapy in CRC patients was 9.3 mo and the median survival from diagnosis was 36.9 mo. Defining complete response, partial response and 345 August 10, 2017 Volume 8 Issue 4

48 Gruber-Rouh T et al. TACP treatment for palliative liver metastases Table 3 Responders vs non-responders 1 n (%) Carcinoma Therapy response (CR + PR + SD) Non responders (PD) CRC 9 (52.9) 8 (47.1) Breast-Ca 16 (84.2) 3 (15.8) Table 5 Partial response, stable disease, progressive disease Carcinoma Partial response Stable disease Progressive disease Total Colon Breast The difference between responders and non-responders reached statistical significance (P = 0.042, χ 2 test). CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; CRC: Colorectal cancer. Table 4 Number of treatments 1 Carcinoma Mean Median Min Max CRC Breast-Ca The difference reached significance (P = , Mann-Whitney U test). CRC: Colorectal cancer. stable disease as the overall response and progressive disease as non-response, the results are shown in Table 3. Colorectal carcinoma: In all, seventeen patients in our study suffered from CRC. All patients had undergone surgery for their primary tumour and a minimum of three courses of chemotherapy. Three patients had metastases of 2-4 cm, four patients had metastases of 4-7 cm and in ten patients the metastases were larger than 7 cm. Concerning the number of liver metastases, no patient had one metastasis, two patients had two metastases, one patient had 3-4 metastases, four patients had 5-9 metastases and ten patients had multiple liver metastases. Breast cancer: This group consisted of 19 patients, all female. All patients had undergone surgery for their primary tumour and a minimum of three courses of chemotherapy. Four patients had metastases of 2-4 cm in size, nine patients had metastases of 4-7 cm and in six patients the metastases were larger than 7 cm. Concerning the number of liver metastases in BC patients, one patient had only one metastasis (> 7 cm), one patient had two metastases, two patients had 3-4 metastases, two patients had 5-9 metastases and thirteen patients had multiple metastases. Table 4 shows the number of treatments. RESULTS Trans-arterial chemoperfusion as a palliative treatment was tolerated well by all patients. During our therapy sessions no major technical problems occurred. Concerning therapy side effects, we did not observe severe common toxicity criteria (CTC) grade Ⅲ, Ⅳ or Ⅴ adverse events. CTC grade Ⅰ and Ⅱ side effects were common in our therapy cohort. These emerged in most cases as fatigue, nausea, vomiting and reduced appetite. The typical duration of these found to be 2-6 d after TACP. Haematological adverse events such as mild thrombocytopenia (grade Ⅰ and Ⅱ), dropped white blood cell count and reduced Hb values were observed as well. No serious side effects occurred that require hospitalisation or any other major medical intervention or treatment. Albeit we did not record a specific survey, all patients of our cohort rated the therapy side-effects as less severe compared to previous systemic chemotherapy treatment they all had undergone before. Overall, we had 0 CR, 9 PR, 16 SD and 11 PD (Table 5). Comparing the success rates and the therapeutic responses, the difference between the two tumour groups reached statistical significance (P = 0.042, χ 2 test and P = , Cochran-Armitage trend test). Patients with liver metastases of BC survived significantly longer compared to patients with CRC (median 13.2 mo vs 9.3 mo, P = log rank test). Survival data Comparing the overall response (OR = CR, PR and SD) vs PD for each tumour group, there was a significant difference between BC (OR = 16 patients, 84.2%) and CRC (OR = 9 patients, 52.9%). The difference reached statistical significance (P = 0.042, χ 2 test), which means that our treatment is more effective in BC patients than in CRC patients. Colorectal carcinoma Median survival time after the first HIC session was 9.3 mo, and after initial diagnosis of the primary tumour 36.9 mo (Figure 1). We found no CR, two PR, seven SD and eight PD after the third cycle of TACP. However, none of the CRC patients are now alive, which might be due to the palliative setting of our study. Breast carcinoma The median survival after the first HIC session was 13.2 mo (Figure 1), after initial diagnosis of the primary tumour 75.2 mo. We found no CR, seven PR, nine SD and three PD after the third cycle of TACP. Two patients with PR were treated by LITT and microwave ablation to treat their last remaining metastasis and they are both alive today - 55 and 61 mo after the first therapy with TACP. DISCUSSION The main idea for this study was that in many cases of CRC or BC, liver metastases are a main factor influencing survival. In recent years, many advances 346 August 10, 2017 Volume 8 Issue 4

49 Gruber-Rouh T et al. TACP treatment for palliative liver metastases Survival (%) Kaplan-Meier-survival Figure 1 Kaplan-Meier survival curves. Survival time for BC vs CRC (P = 0.042, χ 2 test). 1: Survival data of all patients with liver metastases of BC after TACP (n = 19). Median survival time 13.2 mo; 2: Survival data of patients with liver metastases of CRC after TACP (n = 17). Median survival time 9.3 mo. BC: Breast cancer; CRC: Colorectal cancer; TACP: Trans-arterial chemoperfusion Time (mo) in therapy have been achieved. Without therapy, the median survival time with liver metastases of CRC is about 7.5 mo [6]. In BC, the time is about 6 mo [7,8]. The treatment of liver metastases is nowadays normally an interdisciplinary approach involving various departments, such as surgery, gynaecology, oncology and radiology. The standard therapy for liver metastases is still surgery, with the most promising outcome and the best long-term survival considering isolated liver metastases as a curable disease. Interventional radiological techniques, such as RFA, LITT and MWA have also been used as curative treatments of liver metastases. The limitations of such resection or ablative therapies are local spreading of tumours and unfavourable anatomical tumour localization [9]. Systemic chemotherapy can be viewed as standard in advanced disease. Nowadays, the systemic therapy regime consists of combinations of 5-FU, folinic acid, oxaliplatin, irinotecan, capecitabine and monoclonal antibodies bevacizumab or cetuximab. However, in general, such treatments are not suitable for all patients because of co-morbidities, major problems with the heart, liver or the kidneys (together with the tumour) or other disease. Loco-regional treatments can be an alternative to such general treatment. The loco-regional intra-arterial application of anti-tumour medication has now been an object of research for decades. In several studies, high tumour response rates have been achieved using this technique, but this does not necessarily lead to improved survival. In our study, this observation can be confirmed (overall response rate 69.5%; median survival 11 mo). The patients enrolled in this study were all in palliative care, they had all undergone surgery for their primary tumour and three courses of intravenous chemotherapy. Most patients had a high number of lesions concerning the liver (29 of 36 patients had more than 5 lesions and therefore disseminated liver disease), they were all multiply pretreated and therapy-resistant patients. Gemcitabine has not yet demonstrated high activity in CRC, but it has a more favourable toxicity profile compared to other cytostatic drugs and is well known in our institute as a treatment for palliative therapy [5]. Without therapy, the median survival time of patients with CRC liver metastases is between 3.8 to 21 mo [6,10,11]. The five-year survival rate is 3%-6.1% [6,8]. In liver metastases of BC, the median survival time is often less than 10 mo [12,13]. Currently, there are many different therapeutic strategies used for the treatment of liver metastases. Therapy for liver metastases now tends to be an interdisciplinary approach involving different clinical partners. For modern oncological therapy, concepts such as quality of life and the side effects of a therapy are increasingly important. These aspects are even more important in a palliative situation or when the malignant disease progresses. The gold standard therapy for liver metastases is the surgical approach, but this is only possible for 25% of patients with liver metastases with a curative intention [1,6,8,14]. If a complete R0 resection of the liver metastases is possible, this leads to 5-year survival rates in 10%-49% of patients and a median survival of up to 84 mo [6,15-17]. With adjuvant systemic chemotherapy, the 5-year survival time can be improved from 47.8% to 51.2% [18]. In a cohort study, the median survival time of the group treated with adjuvant chemotherapy (5-FU/FS) was 62 mo vs 46 mo in the control group [19]. The FOLFOX regimen is often used as an adjuvant chemotherapy protocol [20]. The indication for a surgical approach for metastases of BC is only given in patients with isolated liver metastases. However, only around 3%-5% of all BC patients show isolated metastases of the liver. With R0 resection of liver metastases in BC patients, 5-year survival rates of 33%-40% can be attained compared with R1 resection, depending on patient selection criteria [21]. In metastasized BC, chemotherapy is often used. Current therapy regimes are normally based on anthracycline or taxan chemotherapy protocols [22]. In some combination therapy studies, a median survival time of mo and a 5-year survival rate of 18% maximum have been attained [23,24]. Many patients, even if their tumour is progressive, suffer from a liver-dominant metastatic disease. The side effects of loco-regional chemotherapy are often better tolerated by patients, which might be due 347 August 10, 2017 Volume 8 Issue 4

50 Gruber-Rouh T et al. TACP treatment for palliative liver metastases to the first pass effect of the chemotherapy in the liver [25,26]. Side effects are very rare during intra-arterial chemotherapy. For this reason, the therapy is performed on an outpatient basis [27]. We had no severe side effects (no CTC > 3). Intra-arterial chemotherapy remains a palliative treatment. In our study, we have shown a good response rate of 69.4%. In those patients, we achieved a partial response or stable disease after three courses of HIC. Especially in patients treated for liver metastases from BC, good tumour control was attained after the third session of TACP. In contrast to the stable disease or partial response in 84.2% of BC patients, the rate was only 52.9% among CRC patients, a statistically significant difference (P = 0.042, χ 2 test). Thus, our results are similar to those of other studies. In 1999 a meta-analysis was published that showed a better response to HIC than systemic chemotherapy (41% vs 14%, P-value < 0.001) and a better median survival time (15 mo vs 11 mo, P-value < 0.009) [28]. Another study showed median survival in a group of patients receiving systemic chemotherapy of 20 mo compared to a median survival of 24.4 mo among patients treated with intra-arterial regional chemotherapy. Tumour response after systemic chemotherapy was 24% compared to 47% treated by intraarterial chemotherapy [29]. The only limitation of this study was extrahepatic tumour progression, which the regional approach stopped for only 7.7 mo. The systemic approach in contrast stopped such progression for around 14.8 mo median. Intrahepatic tumour progression was better in the intra-arterial group (9.8 mo vs 7.3 mo). In recent years, more chemotherapeutic drugs have become available for intra-arterial chemotherapy. It has been documented that oxaliplatin, folinic acid and 5-FU intra-arterially administered (via a port system) attained a median survival time of 36.1 mo. The 2- and 3-year survival rates were 62% and 52% respectively [30]. The chemotherapy used in our study is normally used for the treatment of pancreatic cancer or BC [31]. For BC, gemcitabine is often administered, especially in second or third-line therapy [22]. In our institute, we have had good results using this combination [5]. In the treatment of liver metastases of CRC, many studies have shown that loco-regional treatment using intra-arterial chemotherapy is very promising [32-34]. Currently, for liver metastases of BC, intra-arterial chemotherapy is only rarely used [35]. If response to intra-arterial chemotherapy is documented, a repetition of the treatment is reasonable and generally the therapy can be repeated an unlimited number of time. This can lead to longer median survival and fewer side effects [29,31,36]. However, it is still a palliative therapy: Metastases can only be reduced and normally no general necrosis can be achieved. Nonetheless, intra-arterial chemotherapy in combination with local ablative procedures or with other therapeutic procedures is increasingly being used, for example in SIRT [37,38]. One study showed good response rates in primary and secondary liver tumours using combined TACE and LITT in a neoadjuvant setting [39]. Other promising studies have shown good response rates in combination with SIRT. This therapy might show good response rates especially in palliative care, without serious side effects [37,38,40]. Our results show that in the palliative care setting, a rather good response rate can be achieved using intraarterial chemotherapy for liver metastases. However, perhaps the dosage of gemcitabine (1000 mg/m 2 ) was too low, or we should have used some embolization material in combination with our therapy protocol. In comparison to another study from our institute, we increased the mitomycin dosage to 10 mg/m 2 without serious side effects, but the effect was not as high as we expected [5]. Our palliative therapy should at least make the patient feel better, improve quality of life and suppress the symptoms of the disease. To achieve this, we used chemotherapy based on gemcitabine as, among the cytostatic drugs available, it has a good toxicity profile and provides clinical benefits. Based on the promising observations at our institute concerning the use of embolization material and SIRT, we aim to see what these therapy options will bring in further studies and we intend to use embolization material, other cytotoxic drugs and SIRT in earlier tumour stages. In conclusion, our data indicate that repeated hepatic intra-arterial chemotherapy for liver metastases, especially of breast cancer appears to be a safe and effective palliative treatment with significantly improved outcomes in comparison to patients with colorectal cancer [χ 2 test P-value < 0.05 (= 0.042); statistically significant]. We observed good tumour response rates; indeed, although our treatment intention was palliative, two patients are still alive. In those two patients, suffering from breast cancer, an interventional ablative approach was performed following the intra-arterial chemotherapy to destroy their remaining lesions. Our survival data lie within what we expected from the literature and our experience at the institute in the past. Selective and super-selective intra-arterial chemotherapy using gemcitabine and mitomycin for metastases from colorectal and breast cancer was performed without any serious side effects (CTC < 3). This is most likely due to the relatively low toxicity profile of gemcitabine and the loco-regional drug application, which resulted in lower systemic drug levels and lower side effects. More studies in the field of palliative care need to be undertaken to evaluate clearly the role of intra-arterial chemotherapy in the oncological therapy regime. Based on our findings to date, we think that this technique is an important therapy option that should be considered when a patient becomes palliative. COMMENTS Background In malignant disease liver metastases can often be found. Currently, the surgical approach is seen as the only curative treatment for liver metastases. 348 August 10, 2017 Volume 8 Issue 4

51 Gruber-Rouh T et al. TACP treatment for palliative liver metastases However, only in 20% of patients can curative surgery of their liver metastases be performed. Here other treatment options have to be considered, such as systemic chemotherapy, locoregional chemotherapy, selective internal radiation therapy. Intraarterial chemotherapy showed reasonable results in the past, especially in metastases of colorectal cancer (CRC), breast cancer (BC) and neuroendocrine tumors. As higher concentrations of the chemotherapeutic agent can be used and, using the first pass mechanism of the liver, less cytotoxic medication arrives in the systemic circulation with only minimal side effects. Thuas, leading to the research question: To evaluate loco-regional chemoperfusion of liver metastases for tumor response, survival rate and therapy effect. Research frontier Loco-regional chemoperfusion is not in daily practise for tumor patients so far. However, the authors wanted to add this therapy as an additional tool for palliative cancer treatment, to open up this treatment as additional option to think of. Innovations and breakthrough In this study, the median survival time of CRC patients after the first hepatic intraarterial chemotherapy (HIC) session was 9.3 mo, and after initial diagnosis of the primary tumor 36.9 mo. In breast cancer patients, the median survival time after first HIC session was 13.2 mo, and after initial diagnosis of the primary tumor 75.2 mo. This strengthened the authors idea to keep this therapy as another option in mind. Applications This study suggests that loco-regional chemotherapy is useful in a palliative setting to treat liver dominant metastases without serious side effects. Peer-review The scientific question proposed in the manuscript were the results achieved with intra-arterial hepatic chemotherapy in 36 patients suffering from unresectable and therapy-resistant advanced and hepatically metastasized CRC and BC tumor response. It is a promising study to add another tool to the basket of palliative patient treatment; however, large population trials would be valuable in the future. REFERENCES 1 Bechstein WO, Golling M. [Standard surgical resection of colorectal liver metastases]. Chirurg 2005; 76: [PMID: DOI: /s ] 2 de Jong KP. Review article: Multimodality treatment of liver metastases increases suitability for surgical treatment. Aliment Pharmacol Ther 2007; 26 Suppl 2: [PMID: DOI: / j x] 3 Vogl TJ, Zangos S, Balzer JO, Thalhammer A, Mack MG. [Transarterial chemoembolization of liver metastases: Indication, technique, results]. Rofo 2002; 174: [PMID: DOI: /s ] 4 Vogl TJ, Zangos S, Eichler K, Yakoub D, Nabil M. Colorectal liver metastases: regional chemotherapy via transarterial chemoembolization (TACE) and hepatic chemoperfusion: an update. Eur Radiol 2007; 17: [PMID: DOI: /s ] 5 Vogl TJ, Zangos S, Eichler K, Selby JB, Bauer RW. Palliative hepatic intraarterial chemotherapy (HIC) using a novel combination of gemcitabine and mitomycin C: results in hepatic metastases. Eur Radiol 2008; 18: [PMID: DOI: / s ] 6 Grundmann RT, Hermanek P, Merkel S, Germer CT, Grundmann RT, Hauss J, Henne-Bruns D, Herfarth K, Hermanek P, Hopt UT, Junginger T, Klar E, Klempnauer J, Knapp WH, Kraus M, Lang H, Link KH, Löhe F, Merkel S, Oldhafer KJ, Raab HR, Rau HG, Reinacher-Schick A, Ricke J, Roder J, Schäfer AO, Schlitt HJ, Schön MR, Stippel D, Tannapfel A, Tatsch K, Vogl TJ. [Diagnosis and treatment of colorectal liver metastases - workflow]. Zentralbl Chir 2008; 133: [PMID: DOI: /s ] 7 Lehnert T, Golling M. [Indications and outcome of liver metastases resection]. Radiologe 2001; 41: [PMID: DOI: /s ] 8 Ott R, Wein A, Hohenberger W. [Liver metastases--primary or multimodal therapy?]. Chirurg 2001; 72: [PMID: DOI: /s ] 9 Vogl T, Mack M, Straub R, Zangos S, Woitaschek D, Eichler K, Engelmann K. [Thermal ablation of liver metastases. Current status and prospects]. Radiologe 2001; 41: [PMID: DOI: /s ] 10 Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet 1994; 343: [PMID: DOI: /S (94) ] 11 Nordlinger B, Peschaud F, Malafosse R. Resection of liver metastases from colorectal cancer--how can we improve results? Colorectal Dis 2003; 5: [PMID: DOI: / j x] 12 Wyld L, Gutteridge E, Pinder SE, James JJ, Chan SY, Cheung KL, Robertson JF, Evans AJ. Prognostic factors for patients with hepatic metastases from breast cancer. Br J Cancer 2003; 89: [PMID: DOI: /sj.bjc ] 13 Selzner M, Morse MA, Vredenburgh JJ, Meyers WC, Clavien PA. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000; 127: [PMID: DOI: /msy ] 14 Schlag PM, Benhidjeb T, Kilpert B. [Principles of curative resection of liver metastases]. Chirurg 1999; 70: [PMID: DOI: /PL ] 15 Scheele J, Altendorf-Hofmann A, Grube T, Hohenberger W, Stangl R, Schmidt K. [Resection of colorectal liver metastases. What prognostic factors determine patient selection?]. Chirurg 2001; 72: [PMID: DOI: /s ] 16 Tanaka K, Shimada H, Ohta M, Togo S, Saitou S, Yamaguchi S, Endo I, Sekido H. Procedures of choice for resection of primary and recurrent liver metastases from colorectal cancer. World J Surg 2004; 28: [PMID: DOI: /s x] 17 Antoniou A, Lovegrove RE, Tilney HS, Heriot AG, John TG, Rees M, Tekkis PP, Welsh FK. Meta-analysis of clinical outcome after first and second liver resection for colorectal metastases. Surgery 2007; 141: 9-18 [PMID: DOI: /j.surg ] 18 Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006; 24: [PMID: DOI: / JCO ] 19 Parks R, Gonen M, Kemeny N, Jarnagin W, D Angelica M, DeMatteo R, Garden OJ, Blumgart LH, Fong Y. Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg 2007; 204: ; discussion [PMID: ] 20 André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah- Fisch I, de Gramont A. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: [PMID: DOI: /NEJMoa032709] 21 Kollmar O, Moussavian MR, Richter S, Bolli M, Schilling MK. Surgery of liver metastasis in gynecological cancer - indication and results. Onkologie 2008; 31: [PMID: DOI: / ] 22 Schmid P, Possinger K. [Chemotherapy for metastatic breast cancer]. Zentralbl Gynakol 2006; 128: [PMID: DOI: /s ] 23 Schmid P, Krocker J, Schulz CO, Michniewicz K, Dieing A, Eggemann H, Heilmann V, Blohmer JU, Sezer O, Elling D, Possinger K. Primary chemotherapy with gemcitabine, liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer: results of a phase I trial. Anticancer Drugs 2005; 16: [PMID: DOI: / ] 24 Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky 349 August 10, 2017 Volume 8 Issue 4

52 Gruber-Rouh T et al. TACP treatment for palliative liver metastases EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003; 21: [PMID: DOI: /JCO ] 25 Collins JM. Pharmacologic rationale for regional drug delivery. J Clin Oncol 1984; 2: [PMID: DOI: / JCO ] 26 Lubienski A, Simon M, Lubienski K, Gellissen J, Hoffmann RT, Jakobs TF, Helmberger T. [Update on chemoinfusion and chemoembolization treatments]. Radiologe 2007; 47: , 1108 [PMID: DOI: /s ] 27 Vogl TJ, Schwarz W, Eichler K, Hochmuth K, Hammerstingl R, Jacob U, Scheller A, Zangos S, Heller M. Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy. J Cancer Res Clin Oncol 2006; 132: [PMID: DOI: /s ] 28 Link KH, Kornmann M, Formentini A, Leder G, Sunelaitis E, Schatz M, Pressmar J, Beger HG. Regional chemotherapy of non-resectable liver metastases from colorectal cancer - literature and institutional review. Langenbecks Arch Surg 1999; 384: [PMID: DOI: /s ] 29 Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, Weeks JC, Sigurdson ER, Herndon JE, Zhang C, Mayer RJ. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006; 24: [PMID: DOI: / JCO ] 30 Del Freo A, Fiorentini G, Sanguinetti F, Muttini MP, Pennucci C, Mambrini A, Pacetti P, Della Seta R, Lombardi M, Torri T, Cantore M. Hepatic arterial chemotherapy with oxaliplatin, folinic acid and 5-fluorouracil in pre-treated patients with liver metastases from colorectal cancer. In Vivo 2006; 20: [PMID: ] 31 Vogl TJ, Zangos S, Heller M, Hammerstingl RM, Böcher E, Jacob U, Bauer RW. [Transarterial chemoperfusion with gemcitabine and mitomycin C in pancreatic carcinoma: results in locally recurrent tumors and advanced tumor stages]. Rofo 2007; 179: [PMID: DOI: /s ] 32 Kelly RJ, Kemeny NE, Leonard GD. Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer. Clin Colorectal Cancer 2005; 5: [PMID: DOI: /CCC.2005.n.027] 33 Kemeny N. Management of liver metastases from colorectal cancer. Oncology (Williston Park) 2006; 20: , 1179; discussion , [PMID: ] 34 Hildebrandt B, Pech M, Nicolaou A, Langrehr JM, Kurcz J, Bartels B, Miersch A, Felix R, Neuhaus P, Riess H, Dörken B, Ricke J. Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach. BMC Cancer 2007; 7: 69 [PMID: DOI: / ] 35 Camacho LH, Kurzrock R, Cheung A, Barber DF, Gupta S, Madoff DC, Wallace MJ, Kim EE, Curley SA, Hortobagyi GN, Mavligit G. Pilot study of regional, hepatic intra-arterial paclitaxel in patients with breast carcinoma metastatic to the liver. Cancer 2007; 109: [PMID: DOI: /cncr.22672] 36 Spangenberg HC, Mohr L, Blum HE. [Regional therapy of liver tumors]. Internist (Berl) 2007; 48: [PMID: DOI: /s z] 37 Hoffmann RT, Jakobs TF, Kubisch CH, Stemmler HJ, Trumm C, Tatsch K, Helmberger TK, Reiser MF. Radiofrequency ablation after selective internal radiation therapy with Yttrium90 microspheres in metastatic liver disease-is it feasible? Eur J Radiol 2010; 74: [PMID: ] 38 Sato KT, Lewandowski RJ, Mulcahy MF, Atassi B, Ryu RK, Gates VL, Nemcek AA, Barakat O, Benson A, Mandal R, Talamonti M, Wong CY, Miller FH, Newman SB, Shaw JM, Thurston KG, Omary RA, Salem R. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology 2008; 247: [PMID: DOI: /radiol ] 39 Vogl TJ, Mack MG, Balzer JO, Engelmann K, Straub R, Eichler K, Woitaschek D, Zangos S. Liver metastases: neoadjuvant downsizing with transarterial chemoembolization before laser-induced thermotherapy. Radiology 2003; 229: [PMID: DOI: /radiol ] 40 Jakobs TF, Hoffmann RT, Tatsch K, Trumm C, Reiser MF, Helmberger TK. [Developments and perspectives in radioablative techniques]. Radiologe 2007; 47: [PMID: DOI: /s y] P- Reviewer: Stanojevic GZ S- Editor: Kong JX L- Editor: A E- Editor: Lu YJ 350 August 10, 2017 Volume 8 Issue 4

53 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.351 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) Observational Study ORIGINAL ARTICLE Rescue associating liver partition and portal vein ligation for staged hepatectomy after portal embolization: Our experience and literature review Charlotte Maulat, Antoine Philis, Bérénice Charriere, Fatima-Zohra Mokrane, Rosine Guimbaud, Philippe Otal, Bertrand Suc, Fabrice Muscari Charlotte Maulat, Antoine Philis, Bérénice Charriere, Bertrand Suc, Fabrice Muscari, Department of Visceral Surgery, Toulouse- Rangueil University Hospital, Toulouse Cedex 9, France Fatima-Zohra Mokrane, Philippe Otal, Department of Radiology, Toulouse-Rangueil University Hospital, Toulouse Cedex 9, France Rosine Guimbaud, Department of Digestive Oncology, Toulouse- Rangueil University Hospital, Toulouse Cedex 9, France Author contributions: Maulat C, Philis A, Charriere B and Muscari F performed research and wrote the paper; Mokrane FZ, Guimbaud R, Otal P and Suc B provided critical revision of the manuscript for important intellectual content. Institutional review board statement: This study was reviewed and approved by the Toulouse University Hospital Review Board. Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent. Conflict-of-interest statement: There are no conflicts of interest to report. Data sharing statement: No additional data are available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Dr. Fabrice Muscari, Professor, Department of Visceral Surgery, Toulouse-Rangueil University Hospital, 1 Avenue du Pr Jean Poulhès, Toulouse Cedex 9, France. muscari.f@chu-toulouse.fr Telephone: Fax: Received: January 26, 2017 Peer-review started: February 8, 2017 First decision: May 10, 2017 Revised: June 5, 2017 Accepted: July 7, 2017 Article in press: July 10, 2017 Published online: August 10, 2017 Abstract AIM To report a single-center experience in rescue associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), after failure of previous portal embolization. We also performed a literature review. METHODS Between January 2014 and December 2015, every patient who underwent a rescue ALPPS procedure in Toulouse Rangueil University Hospital, France, was included. Every patient included had a project of major hepatectomy and a previous portal vein embolization (PVE) with insufficient future liver remnant to body weight ratio after the procedure. The ALPPS procedure was performed in two steps (ALPPS-1 and ALPPS-2), separated by an interval phase. ALPPS-2 was done within 7 to 9 d after ALPPS-1. To estimate the FLR, a computed tomography scan examination was performed 3 to 6 wk after the PVE procedure and 6 to 8 d after ALPPS-1. A transcystic stent was placed during ALPPS-1 and remained opened during 351 August 10, 2017 Volume 8 Issue 4

54 Maulat C et al. Rescue ALPPS: Experience and literature review the interval phase, in order to avoid biliary complications. Postoperative liver failure was defined using the criteria. Postoperative complications were assessed according to the Dindo-Clavien Classification. RESULTS From January 2014 to December 2015, 7 patients underwent a rescue ALPPS procedure. Median FLR before PVE, ALPPS-1 and ALPPS-2 were respectively 263 cc ( ), 450 cc ( ), and 660 cc ( ). Median FLR/ BWR before PVE, ALPPS-1 and ALPPS-2 were respectively 0.4% ( ), 0.6% ( ), and 1% ( ). Median volume growth of FLR was 69% (18-92) after PVE, and 45% (36-82) after ALPPS-1. The combination of PVE and ALPPS induced a growth of median initial FLR of +408 cc ( ), leading to an increase of +149% (68-199). After ALPPS-2, 4 patients had stage Ⅰ- Ⅱ complications. Three patients had more severe complications (one stage Ⅲ, one stage Ⅳ and one death due to bowel perforation). Two patients suffered from postoperative liver failure according to the 50/50 criteria. None of our patients developed any biliary complication during the ALPPS procedure. CONCLUSION Rescue ALPPS may be an alternative after unsuccessful PVE and could allow previously unresectable patients to reach surgery. Biliary drainage seems to reduce biliary complications. Key words: Rescue associating liver partition and portal vein ligation for staged hepatectomy; Associating liver partition and portal vein ligation for staged hepatectomy; Portal vein embolization; Liver resection; Future liver remnant The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Hepatic surgery appears as the best curative option for patients with primary or secondary malignant hepatic tumors. Several strategies have been developed to avoid postoperative liver failure, such as portal vein embolization (PVE). In 2012, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) was developed. It induces rapid and extensive hypertrophy of the future liver remnant, but with high morbidity and mortality. Therefore, some authors have suggested that ALPPS should be performed only as a rescue, after failed PVE. We describe our results of rescue ALPPS after failure of previous PVE and we perform a literature review. Maulat C, Philis A, Charriere B, Mokrane FZ, Guimbaud R, Otal P, Suc B, Muscari F. Rescue associating liver partition and portal vein ligation for staged hepatectomy after portal embolization: Our experience and literature review. World J Clin Oncol 2017; 8(4): Available from: URL: /full/v8/i4/351.htm DOI: wjco.v8.i4.351 INTRODUCTION Hepatic surgery appears as the best curative option for patients with primary or secondary malignant tumors of the liver [1,2]. As complete resection of the tumor load is directly linked to overall survival, it is sometimes necessary to perform major hepatectomies in order to achieve such a goal. The main complication after major hepatectomy is liver failure. Several studies have shown that the size of the future liver remnant (FLR) is a key element [3-5], as it is directly correlated to the postoperative liver function [6,7]. In 2013, a consensus statement established a FLR cut-off above which the risk of postoperative liver failure was considered too high for safe surgery: 20% in normal liver, 30% in liver pretreated with chemotherapy, and 40% in cirrhotic liver [8]. The FLR to body weight ratio (FLR-BWR) (%) is also used as a predictive factor for hepatic dysfunction: Patients with FLR-BWR < 0.5% have a major risk of liver failure and postoperative mortality [9,10]. Several strategies have been developed to lower the risk of postoperative liver failure, such as portal vein occlusion (PVO), either by ligature (PVL) or embolization (PVE). The aim of these techniques is to decrease the portal blood flow to the ipsilateral liver, inducing atrophy of the ipsilateral liver and hypertrophy of the contralateral liver [11]. It enables previously unresectable patients to have access to a surgical treatment by achieving an appropriate FLR volume [12]. Indeed, the PVE leads to an average hypertrophy of the contralateral liver (usually the left lobe) of 40% in 4-8 wk [13]. In 2012, a new surgical technique has been developed, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) [14]. This procedure induces rapid and extensive hypertrophy of the FLR in two steps. During the first surgical step of the original ALPPS procedure, called the in situ splitting, the right portal vein is ligated (if there were no previous PVE), and the surgeon performs a transection of the hepatic parenchyma for extended right hepatectomy. The right hepatic artery, the right bile duct and the drainage veins are not ligated at this point. After the in situ splitting, the right extended lobe is covered by a membrane or a bag to prevent adhesions. Several variations of ALLPS were later developed such as left ALPPS, allowing left lobectomy, or right ALPPS, allowing right posterior sectoriectomy [15]. The second surgery is usually performed within 7 to 15 d after the first step. During this step, the right liver is removed, after having dissected and ligated the remaining artery, bile duct and hepatic veins [14,16]. Although promising results were published by Schnitzbauer et al [14], several studies have described high perioperative morbidity and mortality, suggesting the necessity of a better selection of patients [17-19]. Some authors have suggested that the ALPPS procedure should be performed only as a rescue, that is in case of insufficient liver hypertrophy after PVE [15,20-22]. Yet, 352 August 10, 2017 Volume 8 Issue 4

55 Maulat C et al. Rescue ALPPS: Experience and literature review very few data relative specifically to the rescue ALPPS have been published [21-24] as most of the existing articles do not focus on this particular indication. The aim of our study was to report the outcomes of patients with primary and secondary liver tumors undergoing a rescue ALPPS procedure in our center, after failure of previous portal embolization. We also performed a literature review. MATERIALS AND METHODS Patients and data collection Between January 2014 and December 2015, every patient who underwent a rescue ALPPS procedure in Toulouse Rangueil University Hospital, France, was included. We evaluated the patients who could benefit from this strategy at our regional multidisciplinary team meeting, attended by senior hepatobiliary surgeons, hepatologists, oncologists, and radiologists. The criteria for a rescue ALPPS procedure in our center were: A project of major hepatectomy, a previous PVE with insufficient liver hypertrophy after the procedure, age above 18, an absence of contraindication to surgery, and the approval of the patient after thorough information regarding the risks of the procedure. In our center, a FLR-BWR < 0.5% was considered as a contraindication to perform major liver surgery. In case of fibrotic liver, previous chemotherapy, previous hepatectomy or multiple comorbidities, our center had higher ratio objectives. FLR-BWR around 1 was considered as optimal for major hepatic surgery. Patients who were eligible for a rescue ALPPS but did not complete the procedure were excluded from our study. All data were retrospectively collected in our local database, including patient characteristics, volumetric measurements, surgical characteristics and complications. PVE procedure PVE was performed in an interventional X-ray room or in an operating theater. For all patients, we used a floor-mounted image-guided system (Innova IGS 520, General Electric Healthcare, United Kingdom) to perform ultrasound-guided puncture of a portal branch of the left liver lobe, usually segment Ⅲ. After a complete portography, we performed a contralateral embolization, using a mixture of 50% Lipiodol (Guerbet, Vilepinte, France) and 50% Glubran2 (GEM SRL, Viareggio, Italy). We injected it selectively in each branch of the right portal tree, in order to occlude it. If occlusion of segment IV portal veins was necessary, it was performed after selective catheterization of the portal branches. Then, we administered 100, 250 and 400 μm microspheres (Embozene TM, Boston scientifics, Marlborough, MA, United States). This step was generally completed by 0.35 inch coils (Tornado, Cook Medical, Bloomington, IN, United States). After each PVE, we confirmed the complete occlusion of the right portal veins and the integrity of the left remaining ones by a final portography. CT scans examinations Before inclusion, each patient had a classical multi-slice computed tomography (MSCT) examination, including a portal phase. A control CT scan examination was done 3 to 6 wk after the PVE procedure and 6 to 8 d after ALPPS-1. These examinations were performed using a 16-detector row CT scanner (Innova 411, General Electric Healthcare, United Kingdom). The acquisition parameters were: Voltage 120 KVp, intensity 650 mas, and slice thickness 2 mm, collimation 1mm. Hepatic volumetry was evaluated on the portal phase of the MSCT examination using a semi-automatic method (Terarecon software, Frankfort, Germany). Surgical procedure The ALPPS procedure was performed in two steps (ALPPS-1 and ALPPS-2), separated by an interval phase. The surgical technique during ALPPS-1 was the following: Exploration of the abdominal cavity to look for signs of extra-hepatic metastases, which would be a contraindication to surgical resection. In case of cholangiocarcinoma, intra-hepatic metastases were also considered a contraindication; Ultrasonographic examination of the liver; Cholecystectomy; Introduction of a transcystic catheter, left in place after the first step (except for one patient who had a radiological biliary drainage); Hanging maneuver [25] ; Splitting of the hepatic parenchyma for extended right hepatectomy, under intermittent clamping. We performed a complete parenchymal split; in case of metastases located in the FLR, wedge resections or thermoablations were performed during ALPPS-1. Parenchymal transection was performed using Erbejet (Erbejet, RBE Elektromedizin GmbH, Waldhornlestrasse, Tubingen, Germany, ESM2 model, ref ) or ultrasonic dissector (Dissectron, Satelec Medical, ref DP ). The right hepatic artery, the bile duct and the hepatic veins were identified and surrounded with vessel loops to allow better identification during ALPPS-2. After in situ splitting, the two slices of the liver were covered using sheets of Tachosil with hemostatic aim. Instead of a bag, we placed COVA membranes (COVA+, Biom Up, France) around the liver, the hepatic pedicle and between the two hepatic slices. Silicone drainage was placed between the resection surfaces. ALPPS-2 was performed within 7 to 9 d after the first step. After identifying the vascular and biliary structures, we performed the dissection and ligation of the remaining artery, the bile duct and the hepatic veins. Then the right liver was removed. For hilar cholangiocarcinoma, a Roux-en-Y hepaticojejunostomy was performed. Silicone drainage was placed near the resection surface. Interval phase Patients were hospitalized into intensive care unit during 353 August 10, 2017 Volume 8 Issue 4

56 Maulat C et al. Rescue ALPPS: Experience and literature review Table 1 Preoperative characteristics of patients Variable Rescue ALPPS (n = 7) Male/female gender 4/3 Age, yr (range) 61 (53-70) Body mass index (range) 23 (21-27) ASA ASA 3 1 Colorectal liver metastases 4 Number of liver metastases (range) 5 (2-7) Size of the largest metastases, mm (range) 45 (20-65) Tumor location Right lobe ± segment Ⅳ 3 Right lobe + segment Ⅳ + left lateral 1 segment Previous colorectal resection 3 Previous hepatic resection or thermoablation 3 Preoperative chemotherapy 4 Oxaliplatin based 4 Irinotecan based 3 Angiogenesis inhibitor 1 Intra-arterial chemotherapy 1 Number of preoperative chemotherapy 16 (8-25) cycles (range) Cholangiocarcinoma 3 Perihilar/intrahepatic 2/1 Preoperative chemotherapy 1 Gemcitabine and oxaliplatin 1 No. of preoperative chemotherapy cycles 3 Portal vein embolization 7 Right lobe 5 Right lobe + segment Ⅳ 2 Comorbidity Cardiovascular 2 Pulmonary 0 Diabetes 0 Prior history of cancer 2 ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy. the first few days, and the transcystic stent (or the radiological biliary drain) remained opened during the interval phase, in order to avoid biliary complications. We encouraged enhanced recovery by early removal of catheter, mobilization and transfer into standard care unit. Variables Postoperative liver failure was defined using the criteria [26], which associates prothrombin time (PT) < 50% and serum bilirubin (SB) > 50 μmol/l at day 5. Postoperative complications were assessed according to the Dindo-Clavien Classification [27]. Literature review Literature review was performed using PubMed, Google Scholar and the Cochrane Library Central. Articles reported were written in English and ALPPS procedures were limited to humans. The mesh terms were: ALPPS, Associating liver partition and portal vein ligation for staged hepatectomy, Portal vein embolization, rescue ALPPS, salvage ALPPS. FLR volume (cc) RESULTS Future liver remnant (cc) Before PVE Before ALPPS-1 Before ALPPS-2 Figure 1 Future liver remnant volume increase among different steps of rescue associating liver partition and portal vein ligation for staged hepatectomy. FLR: Future liver remnant; PVE: Portal vein embolization; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy. From January 2014 to December 2015, 10 patients were initially selected to undergo a rescue ALPPS procedure. Two patients had only an explorative laparotomy because their tumor was found unresectable during ALPPS-1. The third patient had more metastases in the left lobe than expected; therefore, the surgeon changed strategy during ALPPS-1 and performed a classical two-stage hepatectomy. These 3 patients were excluded from our analysis. The characteristics of the 7 patients who underwent the rescue ALPPS procedure are detailed in Table 1. In our cohort, 4 patients had colorectal liver metastases (CRLM), and the others had cholangiocarcinoma. The 2 patients with a Bismuth-Corlette type Ⅲa perihilar cholangiocarcinoma (pcca) had had a radiological biliary drainage prior to surgery. Among our 7 patients, one had a previous history of left lobectomy. FLR and FLR/BWR volume increase among the different steps of rescue ALPPS are reported in Figures 1 and 2. Median FLR before PVE, ALPPS-1 and ALPPS-2 were respectively 263 cc ( ), 450 cc ( ), and 660 cc ( ) (Figure 1). Median FLR/BWR before PVE, ALPPS-1 and ALPPS-2 were respectively 0.4% (0.3%-0.5%), 0.6% (0.5%-0.8%), and 1% (0.8%-1.2%) (Figure 2). Median volume growth of FLR was 69% (18%-92%) after PVE, and 45% (36%-82%) after ALPPS-1. The combination of PVE and ALPPS induced a median growth of initial FLR of +408 cc ( ), leading to a median increase of +149% (68%-199%). Intermittent hilar or portal clamping was performed in all patients during ALPPS-1, with a median total duration of 20 min (15-35). ALPPS-1 had a median surgical duration of 240 min ( ), and median blood losses were 750 ml ( ). ALPPS-2 median surgical duration was 90 min (60-120) and median blood losses were 300 ml (0-800). Six patients required 354 August 10, 2017 Volume 8 Issue 4

57 Maulat C et al. Rescue ALPPS: Experience and literature review Table 2 Clinical outcomes and complications Variable Rescue ALPPS (n = 7) Surgery Right trisegmentectomy extended to segment I 4/7 Right lobectomy 1/7 Right lobectomy combined with thermoablation 2/7 Days between ALPPS-1 and ALPPS-2 (range) 7 (7-9) ALPPS-1 Surgery duration ALPPS-1, min (range) 240 ( ) Blood loss during ALPPS-1, ml (range) 750 ( ) Prothrombin ratio day 5, % (range) 76 (70-85) Bilirubin day 5, µmol/l (range) 24 (15-70) MELD score day 5 (range) 10 (8-15) ALPPS-2 Surgery duration ALPPS-2, min (range) 90 (60-120) Blood loss during ALPPS-2, ml (range) 300 (0-800) Prothrombin ratio day 5, % (range) 60 (41-73) Bilirubin day 5, µmol/l (range) 43 (10-182) MELD score day 5 (range) 14 (9-21) Complications Liver failure after ALPPS-1 0/7 Liver failure after ALPPS-2 2/7 Complications after ALPPS-1 and before ALPPS-2 0/7 Complications after ALPPS-2 7/7 Clavien Ⅰ-Ⅱ 4/7 Clavien Ⅲ 1/7 Clavien Ⅳ 1/7 Clavien Ⅴ 1/7 30 d mortality 1/7 90 d mortality 1/7 R0 resection 6/7 ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy; ALPPS-1: First stage ALPPS; ALPPS-2: Second stage ALPPS. blood transfusions during ALPPS-1 and 4 patients during ALPPS-2. One patient required platelet transfusion during ALPPS-2. R0 resection was completed in 6 patients. One patient with CLRM had a R1 resection (surgical margin in contact with one metastasis) (Table 2). Complications The postoperative outcomes are detailed in Tables 2 and 3. There was no per-operative incident reported during ALPPS-1 or ALPPS-2 surgical steps, and we did not experience any complication, including biliary complications, during the interval phase between ALPPS-1 and ALPPS-2. After ALPPS-2, postoperative complications occurred among all of our patients. Four patients had stage Ⅰ- Ⅱ complications: Ascites (n = 3), urinary infection (n = 1) or intraoperative blood transfusion (n = 6). Three patients had more serious complications. One had intra-abdominal abscess requiring radiological drainage (patient 4). Patient 6 developed a hemorrhage two hours after ALPPS-2, requiring an emergency revision surgery. A surgical clip on an arterial branch had slipped, causing massive internal bleeding. Six days later, she had septic shock, leading to another emergency revision surgery, but we could not find the cause of the septic FLR-BWR (%) shock. A radiological drainage was performed a few days later to drain an abdominal abscess. Afterwards, she progressively enhanced total recovery. We report one postoperative death 10 d after ALPPS-2, due to a peritonitis caused by bowel perforation (patient 1). Two patients suffered from postoperative liver failure according to the 50/50 criteria. None of our patients developed any biliary complication. DISCUSSION Future liver remnant to body weight ratio Before PVE Before ALPPS-1 Before ALPPS-2 Figure 2 Future liver remnant to body weight ratio increase among different steps of rescue associating liver partition and portal vein ligation for staged hepatectomy. PVE: Portal vein embolization; FLR-BWR: Future liver remnant to body weight ratio; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy. In this study, we report 7 cases of rescue ALPPS that illustrate how such a procedure can be used successfully after failure of PVE. In our cohort, FLR volume increased despite a previously insufficient hypertrophy after PVE. The causes of insufficient volume growth of FLR after PVE are known: Technical failure during the procedure (impossibility of cannulating the portal system due to altered portal anatomy), portal vein recanalization, portal collateral development and poor quality of hepatic parenchyma [7,28,29]. In our study, 5 patients had chemotherapy before PVE, which induced histopathological damages (steatosis, sinusoidal obstruction syndrome, cholestasis, etc.), and affected the regenerative capacities of the liver after PVE. It allowed 7 patients to reach surgery, while they were considered unresectable after PVE. Among them, 6 had R0 resection. Without the rescue ALPPS technique, they would have been considered unresectable despite PVE, and offered only palliative measures. Nonresection following PVE has been described by Abulkhir et al [7] in Their study focused on a cohort of 1088 patients undergoing PVE and showed a 15% failure rate, including inadequate hypertrophy of remnant liver in 2% of cases. These results show that while the inadequate hypertrophy of FLR after PVE must be feared, it remains infrequent. It explains the low number of patients in our study, and it also explains 355 August 10, 2017 Volume 8 Issue 4

58 Maulat C et al. Rescue ALPPS: Experience and literature review Table 3 Patient characteristics Patient number Gender Age Tumor Underlying FLR/BWR liver function before PVE, % FLR/BWR before ALPPS-1, % FLR/BWR before ALPPS-2, % ALPPS-2 day 5 Bilirubin, μmol/l ALPPS-2 day 5 PT, % Dindo- Clavien classification Complications(by order of appearance) 1 M 68 pcca Cholestasis Ⅴ Intraoperative blood transfusion, intraabdominal abscess, pleural effusion, death due to peritonitis caused by bowel perforation 2 M 70 icca Ⅱ Intraoperative blood transfusion, transitory ascites 3 M 55 CRLM FNH Ⅱ Intraoperative blood transfusion 4 F 66 pcca Cholestasis Ⅲ Transitory ascites and intra-abdominal abscess 5 F 59 CRLM SOS and steatosis Ⅱ Intraoperative blood transfusion, urinary infection 6 F 53 CRLM Dystrophy Ⅳ Intraoperative blood transfusion, internal hemorrhage, transitory hepatic insufficiency, infected ascites, septic choc, and intra-abdominal abscess 7 M 61 CRLM Ⅱ Intraoperative blood transfusion, transitory chylous ascites pcca: Perihilar cholangiocarcinoma; icca: Intrahepatic cholangiocarcinoma; CRLM: Colorectal liver metastases; FNH: Focal nodular hyperplasia; SOS: Sinusoidal obstruction syndrome; M: Male; F: Female; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy. the scarcity of literature about rescue ALPPS performed after PVO, as is shown in our literature review (Table 4). However, the rate of insufficient FLR after PVE will probably increase in the years to come, due to more and more intensive chemotherapies, which greatly alter hepatic parenchyma. Most papers describe series of 1 to 3 cases and only 4 studies report small cohorts (9 to 11 patients) (Table 4). Therefore, the size of our cohort (7 patients) is consistent with the number of cases developed in literature. We decided to perform ALPPS procedure for 2 patients who had a median FLR/BWR before PVE of 0.8% due to a high risk of liver failure after major hepatectomy: One patient had previous left lobectomy, wedge resections, thermoablation and neoadjuvant chemotherapy, inducing steatosis and sinusoidal obstruction syndrome. The second patient had multiple neoadjuvant chemotherapy cycles, suggesting that it was necessary to optimize its FLR volume to avoid postoperative liver failure. In our cohort, median FLR growth between ALPPS-1 and ALPPS-2 was 45% (36%-82%), which might appear less than in the literature (70%-80% [14,18] ). The impact of PVE before ALPPS might be an explanation to this result. Compared to the original ALPPS procedure, liver hypertrophy is developed in two steps: With PVE first, and then with the rescue ALPPS procedure. Therefore, it is more adequate to compare the FLR growth of the original ALPPS with the overall FLR growth of the complete rescue ALPPS procedure (from PVE to ALPPS). In our study, the median overall FLR growth of the complete rescue ALPPS procedure is 149%, which is far greater than the FLR growth induced by the original ALPPS described in the literature. Another factor which might explain our results regarding FLR growth between ALPPS-1 and ALPPS-2 is that the interval phase was shorter (7 d) than reported in literature: An average of 14 d was reported from 320 cases in the International ALPPS Registry by Schadde et al [30] in Among our 7 patients, we report 43% of major complications (Clavien-Dindo > Ⅲ), including one death after ALPPS-2, due to bowel perforation, which is consistent with the literature of original ALPPS [31,32]. It is important to note that rescue ALPPS after PVE does not induce more major complication than the original ALPPS. It suggests that PVE does not have any impact on the rate of complications. Surgical complications after ALPPS procedure are partly linked to inflammatory adhesions around the liver and the hepatic pedicle, inducing many dissection difficulties during ALPPS August 10, 2017 Volume 8 Issue 4

59 Maulat C et al. Rescue ALPPS: Experience and literature review Table 4 Literature review of rescue associating liver partition and portal vein ligation for staged hepatectomy Rescue ALPPS after PVO (PVE/ PVL/PVE + PVL) Tumor Days between ALPPS-1 and ALPPS-2 FLR/BWR before PV0, % FLR/BWR before ALPPS-1, % FLR/BWR before ALPPS-2, % Growth of FLR between PVO and ALPPS-1, % (range) Growth of FLR between ALPPS-1 and ALPPS-2, % (range) Clavien Dindo > III 30-d mortality Conrad et al [37], 2012 Gauzolino et al [15], 2013 Knoefel et al [21], 2013 Björnsson et al [20], 2013 Tschuor et al [22], 2013 Vyas et al [38], 2014 Nadalin et al [39], 2014 Fard-Aghaie et al [40], 2015 Alavrez et al [41], 2015 Croome et al [42], 2015 Truant et al [23], 2015 Björnsson et al [43], 2016 Sparrelid et al [24], 2016 Ulmer et al [44], (1/0/0) CRLM 9 NC NC NC /1 0/1 1 (1/0/0) CRLM 7 NC NC 0.4 NC 26 0/1 0/1 3 (3/0/0) NC 6 NC NC NC /2 1/2 2 (2/0/0) CRLM (n = 1) 9 NC NC NC NC NC 0/2 NC HCC (n = 1) 3 (1/1/1) CRLM 8 NC NC NC /3 0/3 1 (1/0/0) Neuroendocrine metastases /1 0/1 2 (2/0/0) CRLM (n = 1) 13 NC NC NC NC 1/2 1/2 Pancreatic metastases (n = 1) 1 (1/0/0) CRLM 26 NC NC NC /1 1/1 1 (0/0/1) CRLM 7 NC NC NC /1 0/1 2 (2/0/0) CRLM 8 NC NC NC NC NC NC NC 9 (9/0/0) NC 8 NC NC NC NC NC NC NC 10 (NC) CRLM 8 NC NC NC NC NC NC 0/10 11 (7/4/2) CRLM (7-67) 62 1 (19-120) 4/11 0/11 9 (9/0/0) CRLM (n = 6), CCA (n = 2), others liver metastases (n = 1) Maulat, (7/0/0) CRLM (n = 4), CCA (n = 3) 9 NC NC NC /9 1/ /7 1/7 1 Median; 2 Mean. PVE: Portal vein embolization; PVL: Portal vein ligation; PVE + PVL: Portal vein embolization associated with portal vein ligation; CRLM: Colorectal liver metastases; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; NC: Not communicated; ALPPS: Associating liver partition and portal vein ligation for staged hepatectomy. Using absorbable collagen membranes (COVA membranes) instead of bags at the end of ALPPS-1 helped prevent these inflammatory adhesions. We also performed ALPPS-2 within 7 to 9 d after ALPPS-1, which is shorter than the interval phase duration described in literature [30]. These two factors explain why we did not experience major inflammatory adhesions during ALPPS-2. It is interesting to note that we did not have any biliary complication in our cohort. In 2015, Truant et al [23] reported that among a series of 62 patients who underwent ALPPS procedure, 25 patients (40%) had biliary fistula: 19 (31%) after ALPPS-1 and 16 (27%) after ALPPS-2. Other studies are reporting bile leakage in up to 20% of patients after ALPPS procedure [14,18,33-35]. Biliary complications are the main cause of morbidity after ALPPS, and they are much more frequent than with ordinary hepatectomies (5%). It is even one of the main criticisms of this technique, as biliary fistula is known to alter the liver regeneration capacities, increase the risk for sepsis, extend the time of hospital stay, and increase postoperative mortality [36]. Therefore, it is of great importance to prevent biliary complication. Our results suggest that the use of biliary drainage during the interval phase (with transcystic catheter or radiological biliary drainage) is a promising technique to prevent biliary complications. To our knowledge, this is the first publication describing the use of a systematic biliary drainage between ALPPS-1 and ALPPS-2. In conclusion, our study suggests that rescue ALPPS may be an alternative after unsuccessful PVE and could allow previously unresectable patients to reach surgery. It provides an opportunity for complete resection in cases otherwise eligible only to palliative treatments. Although the rate of complications is high, the use of PVE prior to the ALPPS procedure does not seem to increase morbidity. The use of a biliary drainage during the interval phase seems a promising technique to reduce biliary complications, although further studies should be performed to confirm these results. 357 August 10, 2017 Volume 8 Issue 4

60 Maulat C et al. Rescue ALPPS: Experience and literature review COMMENTS Background Hepatic surgery appears as the best curative option for patients with primary or secondary malignant tumors of the liver. The main complication after major hepatectomy is liver failure. Several studies have shown that the size of the future liver remnant (FLR) is a key element as it is directly correlated to the postoperative liver function. Several strategies have been developed to lower the risk of postoperative liver failure, such as portal vein embolization (PVE). The aim of this technique is to decrease the portal blood flow to the ipsilateral liver, inducing atrophy of the ipsilateral liver and hypertrophy of the contralateral liver. In 2012, a new surgical technique has been developed, Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This procedure induces rapid and extensive hypertrophy of the FLR in two steps. Several studies have described high perioperative morbidity and mortality. Therefore, some authors have suggested that ALPPS should be performed only as a rescue, after failed PVE. Research frontiers Considering the high perioperative morbidity and mortality of ALPPS procedure, the current hotspots in this research field is the necessity of a better selection of patients and the necessity to minimize complications, and more specifically biliary complications. Innovations and breakthroughs Yet, very few data relative specifically to the rescue ALPPS have been published as most of the existing articles do not focus on this particular indication. Most papers describe series of 1 to 3 cases and only 4 studies report small cohorts (9 to 11 patients). Therefore, the size of the cohort (7 patients) is consistent with the number of cases developed in literature. Moreover, biliary complications are the main cause of morbidity after ALPPS, and they are much more frequent than with ordinary hepatectomies (5%). This study suggests that the use of a biliary drainage during the interval phase seems a promising technique to reduce biliary complications. To our knowledge, this is the first publication describing the use of a systematic biliary drainage between ALPPS-1 and ALPPS-2. Applications The results of the study suggest that in the future, ALPPS procedure should be performed only as a rescue, in case of insufficient liver hypertrophy after PVE. Rescue ALPPS could allow previously unresectable patients to reach surgery. It provides an opportunity for complete resection in cases otherwise eligible only to palliative treatments. Terminology ALPPS: (Associating liver partition and portal vein ligation for staged hepatectomy) procedure was performed in two steps (ALPPS-1 and ALPPS-2), separated by an interval phase. During ALPPS-1, the surgeon performs a transection of the hepatic parenchyma. In this study, ALPPS-2 was performed within 7 to 9 d after ALPPS-1. During ALPPS-2, the right liver is removed, after having ligated the remaining artery, bile duct and hepatic veins. Peer-review The authors present a study on the interesting subject of rescue ALPPS. REFERENCES 1 Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 1990; 77: [PMID: DOI: /bjs ] 2 Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013; 145: [PMID: DOI: /j.gastro ] 3 Shirabe K, Shimada M, Gion T, Hasegawa H, Takenaka K, Utsunomiya T, Sugimachi K. Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume. J Am Coll Surg 1999; 188: [PMID: DOI: /S (98) ] 4 Shoup M, Gonen M, D Angelica M, Jarnagin WR, DeMatteo RP, Schwartz LH, Tuorto S, Blumgart LH, Fong Y. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg 2003; 7: [PMID: DOI: /S X(02) ] 5 Kishi Y, Abdalla EK, Chun YS, Zorzi D, Madoff DC, Wallace MJ, Curley SA, Vauthey JN. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 2009; 250: [PMID: DOI: /SLA.0b013e3181b674df] 6 Azoulay D, Castaing D, Krissat J, Smail A, Hargreaves GM, Lemoine A, Emile JF, Bismuth H. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg 2000; 232: [PMID: DOI: / ] 7 Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, Habib N, Jiao LR. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg 2008; 247: [PMID: DOI: /SLA.0b013e31815f6e5b] 8 Adams RB, Aloia TA, Loyer E, Pawlik TM, Taouli B, Vauthey JN. Selection for hepatic resection of colorectal liver metastases: expert consensus statement. HPB (Oxford) 2013; 15: [PMID: DOI: /j x] 9 Truant S, Oberlin O, Sergent G, Lebuffe G, Gambiez L, Ernst O, Pruvot FR. Remnant liver volume to body weight ratio & gt; or =0.5%: A new cut-off to estimate postoperative risks after extended resection in noncirrhotic liver. J Am Coll Surg 2007; 204: [PMID: DOI: /j.jamcollsurg ] 10 Truant S, Boleslawski E, Sergent G, Leteurtre E, Duhamel A, Hebbar M, Pruvot FR. Liver function following extended hepatectomy can be accurately predicted using remnant liver volume to body weight ratio. World J Surg 2015; 39: [PMID: DOI: / s ] 11 Madoff DC, Gaba RC, Weber CN, Clark TW, Saad WE. Portal Venous Interventions: State of the Art. Radiology 2016; 278: [PMID: DOI: /radiol ] 12 Hemming AW, Reed AI, Howard RJ, Fujita S, Hochwald SN, Caridi JG, Hawkins IF, Vauthey JN. Preoperative portal vein embolization for extended hepatectomy. Ann Surg 2003; 237: ; discussion [PMID: DOI: /01.SLA C0] 13 Farges O, Belghiti J, Kianmanesh R, Regimbeau JM, Santoro R, Vilgrain V, Denys A, Sauvanet A. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003; 237: [PMID: DOI: /01.SLA B] 14 Schnitzbauer AA, Lang SA, Goessmann H, Nadalin S, Baumgart J, Farkas SA, Fichtner-Feigl S, Lorf T, Goralcyk A, Hörbelt R, Kroemer A, Loss M, Rümmele P, Scherer MN, Padberg W, Königsrainer A, Lang H, Obed A, Schlitt HJ. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012; 255: [PMID: DOI: /SLA.0b013e f5] 15 Gauzolino R, Castagnet M, Blanleuil ML, Richer JP. The ALPPS technique for bilateral colorectal metastases: three variations on a theme. Updates Surg 2013; 65: [PMID: DOI: /s ] 16 Vivarelli M, Vincenzi P, Montalti R, Fava G, Tavio M, Coletta M, Vecchi A, Nicolini D, Agostini A, Ahmed EA, Giovagnoni A, Mocchegiani F. ALPPS Procedure for Extended Liver Resections: A Single Centre Experience and a Systematic Review. PLoS One 2015; 10: e [PMID: DOI: /journal.pone ] 17 Kokudo N, Shindoh J. How can we safely climb the ALPPS? Updates Surg 2013; 65: [PMID: DOI: / s ] 18 Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R, Soubrane O, Schnitzbauer AA, Raptis D, Tschuor C, Petrowsky H, De Santibanes E, Clavien PA. Early survival 358 August 10, 2017 Volume 8 Issue 4

61 Maulat C et al. Rescue ALPPS: Experience and literature review and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014; 260: ; discussion [PMID: DOI: /SLA ] 19 Dokmak S, Belghiti J. Which limits to the ALPPS approach? Ann Surg 2012; 256: e6; author reply e16-e17 [PMID: DOI: /SLA.0b013e318265fd64] 20 Björnsson B, Gasslander T, Sandström P. In situ split of the liver when portal venous embolization fails to induce hypertrophy: a report of two cases. Case Rep Surg 2013; 2013: [PMID: DOI: /2013/238675] 21 Knoefel WT, Gabor I, Rehders A, Alexander A, Krausch M, Schulte am Esch J, Fürst G, Topp SA. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013; 100: [PMID: DOI: /bjs.8955] 22 Tschuor Ch, Croome KP, Sergeant G, Cano V, Schadde E, Ardiles V, Slankamenac K, Clariá RS, de Santibaňes E, Hernandez-Alejandro R, Clavien PA. Salvage parenchymal liver transection for patients with insufficient volume increase after portal vein occlusion -- an extension of the ALPPS approach. Eur J Surg Oncol 2013; 39: [PMID: DOI: /j.ejso ] 23 Truant S, Scatton O, Dokmak S, Regimbeau JM, Lucidi V, Laurent A, Gauzolino R, Castro Benitez C, Pequignot A, Donckier V, Lim C, Blanleuil ML, Brustia R, Le Treut YP, Soubrane O, Azoulay D, Farges O, Adam R, Pruvot FR. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): impact of the inter-stages course on morbi-mortality and implications for management. Eur J Surg Oncol 2015; 41: [PMID: DOI: / j.ejso ] 24 Sparrelid E, Gilg S, Brismar TB, Lundell L, Isaksson B. Rescue ALPPS is efficient and safe after failed portal vein occlusion in patients with colorectal liver metastases. Langenbecks Arch Surg 2017; 402: [PMID: DOI: /s y] 25 Belghiti J, Guevara OA, Noun R, Saldinger PF, Kianmanesh R. Liver hanging maneuver: a safe approach to right hepatectomy without liver mobilization. J Am Coll Surg 2001; 193: [PMID: DOI: /S (01) ] 26 Balzan S, Belghiti J, Farges O, Ogata S, Sauvanet A, Delefosse D, Durand F. The criteria on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg 2005; 242: , discussion [PMID: DOI: /01.sla e] 27 Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: [PMID: DOI: /01.sla ae] 28 van Lienden KP, van den Esschert JW, de Graaf W, Bipat S, Lameris JS, van Gulik TM, van Delden OM. Portal vein embolization before liver resection: a systematic review. Cardiovasc Intervent Radiol 2013; 36: [PMID: DOI: /s y] 29 Brouquet A, Belghiti J. Chemotherapy and its effect on liver hypertrophy: implications for portal vein embolization and resection. Semin Intervent Radiol 2008; 25: [PMID: DOI: /s ] 30 Schadde E, Raptis DA, Schnitzbauer AA, Ardiles V, Tschuor C, Lesurtel M, Abdalla EK, Hernandez-Alejandro R, Jovine E, Machado M, Malago M, Robles-Campos R, Petrowsky H, Santibanes ED, Clavien PA. Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry. Ann Surg 2015; 262: ; discussion [PMID: DOI: /SLA ] 31 Schadde E, Schnitzbauer AA, Tschuor C, Raptis DA, Bechstein WO, Clavien PA. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. Ann Surg Oncol 2015; 22: [PMID: DOI: /s ] 32 Adam R, Imai K, Castro Benitez C, Allard MA, Vibert E, Sa Cunha A, Cherqui D, Baba H, Castaing D. Outcome after associating liver partition and portal vein ligation for staged hepatectomy and conventional two-stage hepatectomy for colorectal liver metastases. Br J Surg 2016; 103: [PMID: DOI: / bjs.10256] 33 Cai YL, Song PP, Tang W, Cheng NS. An updated systematic review of the evolution of ALPPS and evaluation of its advantages and disadvantages in accordance with current evidence. Medicine (Baltimore) 2016; 95: e3941 [PMID: DOI: / MD ] 34 Takamoto T, Sugawara Y, Hashimoto T, Makuuchi M. Associating liver partition and portal vein ligation (ALPPS): Taking a view of trails. Biosci Trends 2015; 9: [PMID: DOI: /bst ] 35 Zhang GQ, Zhang ZW, Lau WY, Chen XP. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): a new strategy to increase resectability in liver surgery. Int J Surg 2014; 12: [PMID: DOI: /j.ijsu ] 36 Yamashita Y, Hamatsu T, Rikimaru T, Tanaka S, Shirabe K, Shimada M, Sugimachi K. Bile leakage after hepatic resection. Ann Surg 2001; 233: [PMID: DOI: / ] 37 Conrad C, Shivathirthan N, Camerlo A, Strauss C, Gayet B. Laparoscopic portal vein ligation with in situ liver split for failed portal vein embolization. Ann Surg 2012; 256: e14-e15; author reply e14-e15 [PMID: DOI: /SLA.0b013e318265ff44] 38 Vyas SJ, Davies N, Grant L, Imber CJ, Sharma D, Davidson BR, Malago M, Fusai G. Failure of portal venous embolization. ALPPS as salvage enabling successful resection of bilobar liver metastases. J Gastrointest Cancer 2014; 45 Suppl 1: [PMID: DOI: /s ] 39 Nadalin S, Capobianco I, Li J, Girotti P, Königsrainer I, Königsrainer A. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons Learned from 15 cases at a single centre. Z Gastroenterol 2014; 52: [PMID: DOI: /s ] 40 Fard-Aghaie MH, Stavrou GA, Schuetze KC, Papalampros A, Donati M, Oldhafer KJ. ALPPS and simultaneous right hemicolectomy - step one and resection of the primary colon cancer. World J Surg Oncol 2015; 13: 124 [PMID: DOI: /s ] 41 Alvarez FA, Ardiles V, de Santibañes M, Pekolj J, de Santibañes E. Associating liver partition and portal vein ligation for staged hepatectomy offers high oncological feasibility with adequate patient safety: a prospective study at a single center. Ann Surg 2015; 261: [PMID: DOI: /SLA ] 42 Croome KP, Hernandez-Alejandro R, Parker M, Heimbach J, Rosen C, Nagorney DM. Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. HPB (Oxford) 2015; 17: [PMID: DOI: /hpb.12386] 43 Björnsson B, Sparrelid E, Røsok B, Pomianowska E, Hasselgren K, Gasslander T, Bjørnbeth BA, Isaksson B, Sandström P. Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases--intermediate oncological results. Eur J Surg Oncol 2016; 42: [PMID: DOI: /j.ejso ] 44 Ulmer TF, de Jong C, Andert A, Bruners P, Heidenhain CM, Schoening W, Schmeding M, Neumann UP. ALPPS Procedure in Insufficient Hypertrophy After Portal Vein Embolization (PVE). World J Surg 2017; 41: [PMID: DOI: / s ] P- Reviewer: Sandri JBL, Sturesson C, Tarazov PG S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 359 August 10, 2017 Volume 8 Issue 4

62 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.360 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) CASE REPORT BRAF V600Q-mutated lung adenocarcinoma with duodenal metastasis and extreme leukocytosis Ayman Qasrawi, Addison Tolentino, Mouhanna Abu Ghanimeh, Omar Abughanimeh, Sakher Albadarin Ayman Qasrawi, Mouhanna Abu Ghanimeh, Omar Abughanimeh, Department of Internal Medicine, University of Missouri - Kansas City School of Medicine, Kansas City, MO 64108, United States Addison Tolentino, Saint Luke s Cancer Specialists, Saint Luke s Hospital of Kansas City, Kansas City, MO 64111, United States Sakher Albadarin, Division of Gastroenterology, University of Missouri - Kansas City School of Medicine, Kansas City, MO 64108, United States Author contributions: Qasrawi A wrote the manuscript; Tolentino A reviewed, modified and edited the manuscript; Abu Ghanimeh M and Abughanimeh O contributed to the literature review; Albadarin S performed the endoscopy, provided the images and wrote up the endoscopic findings. Institutional review board statement: This case report was exempt from the Internal Review Board standards of University of Missouri - Kansas City School of Medicine and Saint Luke s Hospital of Kansas City. Informed consent statement: The patient provided verbal informed consent for the publication of the contents of the manuscript before her death, authorizing use and disclosure of her protected health information. Personal details have been anonymized to protect her identity. Conflict-of-interest statement: The authors have no competing interests to declare. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Unsolicited manuscript Correspondence to: Ayman Qasrawi, MD, Department of Internal Medicine, University of Missouri - Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108, United States. qasrawia@umkc.edu Telephone: Fax: Received: April 8, 2017 Peer-review started: April 17, 2017 First decision: May 22, 2017 Revised: June 11, 2017 Accepted: June 30, 2017 Article in press: July 3, 2017 Published online: August 10, 2017 Abstract Driver mutations in patients with non-small cell lung cancer (NSCLC) can lead to distinct behaviors and patterns of metastasis. Mutations in the proto-oncogene B-raf (BRAF ) occur in approximately 3% of NSCLC cases. In the literature, reports of patients with lung adenocarcinomas metastasizing to the duodenum are rare, and most of the only 21 cases reported were from before the advent of next-generation sequencing. We present here a case involving a 57-year-old female who had a lytic lesion in her lesser trochanter. Biopsy showed metastatic adenocarcinoma of lung origin. Chest X-ray showed a large left upper lobe mass. Next-generation sequencing analysis confirmed the presence of BRAF V600Q mutation. The patient presented with persistent anemia and melena. Esophagogastroduodenoscopy confirmed the presence of duodenal metastasis. She also had suspected paraneoplastic leukemoid reaction. To our knowledge, this is only the second well-documented case of gastrointestinal metastasis from BRAF -mutated lung cancer. Key words: BRAF; Lung adenocarcinoma; Duodenum; Metastasis; Gastrointestinal bleeding; Endoscopy; Leukocytosis 360 August 10, 2017 Volume 8 Issue 4

63 Qasrawi A et al. BRAF V600Q-mutated lung adenocarcinoma The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: We report a rare and interesting case of BRAFmutated lung adenocarcinoma with metastases to the bone and duodenum, and extreme leukocytosis. We found next-generation sequencing to be helpful in prognostication and determination of some of the unique clinical behaviors of lung adenocarcinoma. This is only the second case of BRAF-mutated lung adenocarcinoma with well documented metastases to the gastrointestinal tract. The addition of this case to the literature should prompt interest in studying the propensity of BRAF -mutated malignancies to metastasize to the gastrointestinal tract. Qasrawi A, Tolentino A, Abu Ghanimeh M, Abughanimeh O, Albadarin S. BRAF V600Q-mutated lung adenocarcinoma with duodenal metastasis and extreme leukocytosis. World J Clin Oncol 2017; 8(4): Available from: URL: wjgnet.com/ /full/v8/i4/360.htm DOI: org/ /wjco.v8.i4.360 INTRODUCTION Non-small cell lung cancer (NSCLC) has been traditionally classified and treated as a single disease. However, recent research has helped us to better understand the molecular pathogenesis of lung cancers in general. For example, mutations in the epidermal growth factor receptor (EGFR) and rearrangements of the anaplastic lymphoma kinase (ALK) gene were discovered in 2004 and 2007, respectively [1]. These mutations, often called driver mutations, have been shown to drive NSCLC tumorigenesis and are now being exploited as a targeted strategy for treatment-the application of which consisting mostly of tyrosine kinase inhibitors. Tumors with different driver mutations have been shown to have different clinical backgrounds, pathological features and prognoses [2]. In addition, different driver mutations can lead to distinct patterns of metastatic spread [3]. Generally, however, small bowel metastases from lung cancer is very uncommon, and duodenal metastases are particularly rare [4,5]. It is unknown if certain driver mutations can lead to an increased predisposition to gastrointestinal spread in patients with lung cancer. In this report, we present a case of a metastatic lung adenocarcinoma with a V600Q mutation in the proto-oncogene B-raf (BRAF) and which had an atypical course of duodenal metastasis and extreme leukocytosis. Because this represents such a rare case, we also provide a review of the literature regarding BRAF-mutated lung cancers and of previous reports of duodenal metastasis originating from lung cancer. Finally, we also provide reasoned hypotheses as to the causes of the accompanying leukocytosis. CASE REPORT Our patient was a 57-year-old female with a known history of metastatic lung adenocarcinoma. Her history dated back to December 2015, when she developed left hip pain. It was initially treated conservatively and imaging examination was not performed. However, over the ensuing 4 mo, the pain worsened and became gnawing and constant. She was afebrile. Results from laboratory work-up revealed leukocytosis ( /L; reference range: /L) with 84% neutrophils, microcytic anemia (7.1 g/dl; reference range: g/dl) with mean corpuscular volume (MCV) of 71 fl, and thrombocytosis ( /L; reference range: /L). At 4 mo prior, her hemoglobin had been 13.0 g/dl (reference range: g/dl). A computed tomography (CT) scan of the left hip was obtained, and showed marked irregularity of the lesser trochanter with cortical bone destruction. A soft tissue mass was also seen in the region of the cortex. A plain chest film revealed a large left lung mass. Iron studies revealed a ferritin level of 86 ng/ml, iron of < 10 µg/dl (reference range: µg/dl) and totaliron binding capacity of 353 µg/dl (reference range: µg/dl). Other causes of anemia were ruled out. A peripheral smear showed microcytic hypochromic anemia and granulocytosis without left-shift. The patient was transfused with a unit of packed red blood cells (PRBCs) and taken to the operating room. She underwent intralesional curettage, partial excision of the lesser trochanter, and open arthotomy of the left hip with extraction of the mass. Pathological examination of the extracted bone and soft-tissue mass revealed poorly differentiated metastatic adenocarcinoma cells. Immunohistochemical staining revealed strong reactivity for cytokeratin 7 (CK7) and thyroid transcription factor-1 (TTF-1) and negative reactivity for cytokeratin 20 (CK20) and GATA binding protein 3 (GATA3); these findings are most consistent with lung origin. CT scans revealed a large left upper lobe mass, measuring 8.5 cm 6.7 cm 10.7 cm, with extensive local invasion. In addition, there was a left adrenal mass indicative of metastatic disease. Genetic testing of the tumor was carried out using Caris Molecular Intelligence (Caris Life Sciences, Irving, TX, United States). The next-generation sequencing (NGS) analysis revealed exon 15 BRAF V600Q and exon 7 TP53 G215V mutations. No mutations or rearrangements were found in the genes for Kirsten ras viral oncogene (KRAS), neuroblastoma ras viral oncogene (NRAS), anaplastic lymphoma receptor tyrosine kinase (ALK), tyrosine-protein kinase Met (cmet), EGFR, ROS1, retinoblastoma-1 (RB1), phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), or ret proto-oncogene (RET). The patient received palliative radiotherapy to the left femur. Her anemia was considered likely multifactorial, given the active malignancy with possible iron deficiency. Ferrous sulfate supplementation was initiated (oral; 325 mg regular-release twice daily), but only minimal improvement in her anemia was observed. Of note, her leucocyte count remained elevated after the surgery ( /L). She had no signs of 361 August 10, 2017 Volume 8 Issue 4

64 Qasrawi A et al. BRAF V600Q-mutated lung adenocarcinoma A B Figure 1 Computed tomography scan of the chest showing the left lung mass. A: At the time of diagnosis; B: Explosive growth of the tumor after two cycles of chemotherapy. Figure 2 Esophagogastroduodenoscopy showing the malignant-appearing 1-cm mass in the second part of the duodenum. The scope could not traverse the lesion and the exam could not be finished. Cold forceps biopsies were taken for histology. infection or inflammation. After the radiotherapy, two cycles of carboplatin and pemetrexed were administered. However, shortly after the second cycle, the patient presented to the emergency room with increasing shortness of breath and weakness. She also reported intermittent melanotic stool for the past few days. Physical exam revealed pallor and almost no air entry into the left part of the chest on auscultation. She was afebrile. Laboratory investigations showed a leucocyte count of /L with 92% neutrophils, 6% monocytes and 2% lymphocytes, hemoglobin of 6.0 g/dl, and platelet count of /L. Guaiac fecal occult blood test was positive. CT scan showed extensive growth of the upper lobe mass (to 14.5 cm 10.0 cm 17.4 cm) with progressive mediastinal invasion (Figure 1). The patient was admitted to the hospital and transfused with 1 U of PRBCs. Esophagogastroduodenoscopy was performed, and an ulcerated bleeding 1-cm mass with malignant appearance was found in the second part of the duodenum (Figure 2). The scope could not traverse the lesion, and the exam could not be finished. Cold forceps biopsies were taken. On pathological exam, poorly differentiated adenocarcinoma was determined. The morphological and immunohistochemical characteristics of the tumor were similar to the findings on the original bone biopsy, being consistent with lung origin. The patient s leukocytosis worsened (up to /L, with 92% neutrophils, 3% monocytes, 2% myelocytes, 1% metamyelocytes, 1% promyelocytes and 1% lymphocytes). She did not have fever or other signs of infection. She did not receive any granulocytestimulating agent with her chemotherapy and did not receive steroids. A peripheral smear showed absolute neutrophilia with coarse toxic granulation and Döhle bodies in numerous neutrophils and with occasional metamyelocytes and myelocytes. In addition, rare nucleated red blood cells were observed. Peripheral flow cytometry did not show any increase in blast count. Mutational analysis showed no mutation in the genes for Janus kinase-2 (JAK-2), calreticulin (CALR) and colonystimulating factor 3 receptor (CSF3R). In addition, reverse-transcriptase polymerase chain reaction assay of peripheral blood gave negative results for BCR- ABL b2a2, b3a2, and e1a2 fusion gene transcripts. This finding lessened the likelihood of chronic myeloid leukemia as well as of chronic myeloproliferative disorders. Given the patient s very poor prognosis, bone marrow examination was not performed. Considering the patient s rapid course of progression and development of resistance to frontline chemotherapy, she was started on the off-label combination of dabrafenib with trametinib, which has Federal Drug Administration approval for use in BRAFmutated melanoma. Unfortunately, her clinical condition deteriorated quickly and she died around 2 wk after her presentation. 362 August 10, 2017 Volume 8 Issue 4

65 Qasrawi A et al. BRAF V600Q-mutated lung adenocarcinoma DISCUSSION The BRAF gene on chromosome 7 (7q34) is a protooncogene that encodes the serine/threonine specific protein kinase family member BRAF [6]. The BRAF protein participates in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, which is also known as the Ras-Rafmitogen-activated protein kinase kinase (MEK)-ERK pathway [1]. It is a chain of proteins that functions in the signaling from cell surface to the nucleus [1]. Activation of this pathway leads to synthesis of transcription factors that are important in cell cycle regulation [7]. Mutations in MAPK/ERK can lead to uncontrolled growth and neoplastic transformation. BRAF mutations were first described in 2002 and occur in varying frequencies in melanoma, colorectal carcinomas, and lung, thyroid and other types of malignancies [8]. BRAF is mutated in approximately 3% of patients with NSCLC (mainly of adenocarcinoma type) [9]. The most commonly observed mutation in BRAF is the valine (V) to glutamic acid (E) substitution at codon 600 (BRAF V600E) on exon 15 [10]. BRAF V600E accounts for about 50% of the BRAF mutations in NSCLC cases [11]. A large meta-analysis found that the BRAF V600E mutation was more frequent in women and was closely related a history of never-smoking [9]. In addition, one study showed that V600E-mutated tumors had an aggressive histotype and were significantly associated with shorter disease-free and overall survival rates [12]. Two other studies showed that V600E-mutated tumors responded less favorably to platinum-based chemotherapy, although the finding did not reach statistical significance [13,14]. In contrast, other studies have shown that overall survival was not statistically different between patients with wild-type BRAF and those with V600E or non-v600e BRAF mutations [10,11,15]. Our patient had metastasis to the duodenum. The immunohistochemical pattern of her bone and duodenal biopsies was suggestive of adenocarcinoma originating in the lung. In general, positive staining for TTF-1 and CK7, in addition to negative CK20 staining (i.e., TTF1 + / CK7 + /CK20 - pattern) strongly supports a lung origin, as opposed to a gastrointestinal origin [16]. Metastases to the small bowel from lung cancer are very rare and usually asymptomatic [4]. According to a literature review by Hillenbrand et al [4] published in 2005, clinicallymanifested small bowel metastasis was documented in 58 reports between 1961 and The most common symptoms were perforation and/or obstruction, or less commonly, bleeding. Duodenal metastasis from lung cancer is exceedingly rare. AlSaeed et al [5] reported a case of duodenal metastasis from lung adenocarcinoma and cited another 11 previous reports. In addition, we found 9 more cases of lung cancer with duodenal metastasis [17-23]. Out of the 21 total cases reported, 9 showed adenocarcinoma histology, 7 showed squamous cell histology, 2 showed large cell histology, 2 showed small cell histology, and 1 was deemed unspecified NSCLC. Symptoms of gastrointestinal bleeding and/or iron deficiency occurred in 13 cases. Other reported clinical features include obstructive jaundice, abdominal pain, obstruction, and perforation. None of the reported cases had accompanying molecular analyses data for driver mutations. We have previously reported a case of BRAF V600Emutated lung adenocarcinoma, which had an aggressive clinical course and gastric metastases [24]. Herein, we present another case with a similar aggressive course and duodenal metastasis. Previous reports and studies have not indicated the association between certain genetic mutations in lung cancer and the predilection to gastrointestinal metastasis. In addition, gastric or intestinal metastases are rare and difficult to diagnose on imaging, and most of the reported cases of gastrointestinal metastases from lung cancer occurred before the discovery of driver mutations. Therefore, it cannot be proven that the BRAF mutation contributed to the gastric or duodenal metastasis in the previously reported cases. We suggest that in cases of lung cancer with BRAF V600E mutations, an aggressive behavior must be expected. In addition, gastrointestinal tract involvement must be kept in mind. Clinical research on a larger scale (rather than relying on the rare case reports) will be imperative to understand the incidence of gastrointestinal involvement. In addition to mutated BRAF, our patient had a missense mutation in codon 245 of exon 7 of the TP53 gene (G245V). This mutation occurred in the DNA-binding site of the protein and was previously reported in lung cancer [25]. A previous, large meta-analysis found that TP53 mutations conferred worse clinical outcomes in patients with NSCLC, especially in those with adenocarcinoma histology [26]. It is possible that the TP53 mutation in our patient contributed to the aggressive clinical course and resistance to chemotherapy. Another interesting feature of our case was the extreme neutrophilia. Infections and myeloproliferative disorders were unlikely in the absence of fever or signs of infection, JAK-2 mutations, or BCR-ABL rearrangements. Bone marrow infiltration from adenocarcinoma cells was a possibility, given the presence of rare nucleated red blood cells in the peripheral smear. Unfortunately, the patient s bone marrow was not examined. It is also possible that her poor outcome was related to a paraneoplastic leukemoid reaction. Interestingly, neutrophilic leukemoid reaction was reported in a patient with BRAF V600E-mutated metastatic melanoma [27]. In another report, a case of squamous cell carcinoma with peritoneal carcinomatosis and an eosinophilic leukemoid reaction showed coexistence of the BRAF V600E and oncogenic KRAS G12A mutations [28]. Up-regulation of granulocyte colony-stimulating factor (G-CSF) through RAS/RAF/MEK pathway activation can lead to a paraneoplastic leukemoid reaction [29]. Finally, dabrafenib and trametinib are small molecule 363 August 10, 2017 Volume 8 Issue 4

66 Qasrawi A et al. BRAF V600Q-mutated lung adenocarcinoma inhibitors of BRAF and MEK1/MEK2, respectively. Their oral administration combination is approved for treatment of BRAF V600E-mutated melanoma and is currently being investigated for lung cancer harboring the mutation [30]. In that trial, the overall response rate was 63%, with the median duration of response being 9 mo. We started our patient on dabrafenib and trametinib. Unfortunately, she died of her disease before any response was observed. In conclusion, certain molecular mutations in NSCLC might lead to unique clinical behaviors. We have described a case of lung adenocarcinoma which had an atypical and aggressive clinical course, with duodenal metastasis and extreme leukocytosis. We have performed molecular analysis using NGS, which showed the mutations of exon 15 BRAF V600Q and exon 7 TP53 G245V. To the best of our knowledge, this is only the second reported case of well-documented BRAF-mutated lung adenocarcinoma with metastases to the gastrointestinal tract. Indeed, the continued use of modern molecular methods, such as NGS, will allow us to explore possible correlations between certain mutations and clinical behaviors. COMMENTS Case characteristics A 57-year-old female with metastatic lung adenocarcinoma mutation in the proto-oncogene B-raf (BRAF) gene with presentation of fatigue, increasing shortness of breath and melena. Clinical diagnosis Pallor and almost no air entry into the left part of the chest on auscultation. Differential diagnosis Peptic ulcer disease, esophagitis, gastritis, duodenitis, vascular lesions or tumors. Laboratory diagnosis Anemia, extreme leukocytosis, and positive hemoccult stool test. Imaging diagnosis Computed tomography chest scan showing rapid progression of the cancer. Esophagogastroduodenoscopy with duodenal mass demonstrating a metastatic deposit of lung origin. Pathological diagnosis The morphological and immunohistochemical characteristics of the tumor were similar to the findings on the original biopsy, being consistent with lung origin. Treatment Dabrafenib and trametinib were started, but the patient died before any response could be measured. Related reports This is only the second well-documented case of gastrointestinal metastasis from BRAF-mutated lung cancer. Term explanation The BRAF gene is a proto-oncogene that encodes the serine/threonine specific protein kinase family member BRAF. The BRAF protein participates in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Experiences and lessons BRAF-mutated lung adenocarcinoma can be aggressive. Further studies are needed to explore possible correlations between BRAF mutations and clinical behaviors. Furthermore, treatment with dabrafenib and trametinib has promising results. Peer-review The object is interesting and the manuscript clearly reported. This is the second well-documented case of gastrointestinal metastasis from BRAF-mutated lung cancer. REFERENCES 1 de Langen AJ, Smit EF. Therapeutic approach to treating patients with BRAF-mutant lung cancer: latest evidence and clinical implications. Ther Adv Med Oncol 2017; 9: [PMID: DOI: / ] 2 Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev 2010; 29: [PMID: DOI: /s ] 3 Doebele RC, Lu X, Sumey C, Maxson DA, Weickhardt AJ, Oton AB, Bunn PA Jr, Barón AE, Franklin WA, Aisner DL, Varella-Garcia M, Camidge DR. Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 2012; 118: [PMID: DOI: /cncr.27409] 4 Hillenbrand A, Sträter J, Henne-Bruns D. Frequency, symptoms and outcome of intestinal metastases of bronchopulmonary cancer. Case report and review of the literature. Int Semin Surg Oncol 2005; 2: 13 [PMID: DOI: / ] 5 AlSaeed EF, Tunio MA, AlSayari K, AlDandan S, Riaz K. Duodenal metastasis from lung adenocarcinoma: A rare cause of melena. Int J Surg Case Rep 2015; 13: [PMID: DOI: / j.ijscr ] 6 Hussain MR, Baig M, Mohamoud HS, Ulhaq Z, Hoessli DC, Khogeer GS, Al-Sayed RR, Al-Aama JY. BRAF gene: From human cancers to developmental syndromes. Saudi J Biol Sci 2015; 22: [PMID: DOI: /j.sjbs ] 7 Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006; 24: [PMID: DOI: / ] 8 Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature 2002; 417: [PMID: DOI: /nature00766] 9 Chen D, Zhang LQ, Huang JF, Liu K, Chuai ZR, Yang Z, Wang YX, Shi DC, Liu Q, Huang Q, Fu WL. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 2014; 9: e [PMID: DOI: /journal. pone ] 10 Villaruz LC, Socinski MA, Abberbock S, Berry LD, Johnson BE, Kwiatkowski DJ, Iafrate AJ, Varella-Garcia M, Franklin WA, Camidge DR, Sequist LV, Haura EB, Ladanyi M, Kurland BF, Kugler K, Minna JD, Bunn PA, Kris MG. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer 2015; 121: [PMID: DOI: /cncr.29042] 11 Tissot C, Couraud S, Tanguy R, Bringuier PP, Girard N, Souquet PJ. Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. Lung Cancer 2016; 91: [PMID: 364 August 10, 2017 Volume 8 Issue 4

67 Qasrawi A et al. BRAF V600Q-mutated lung adenocarcinoma DOI: /j.lungcan ] 12 Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, Viola P, Pullara C, Mucilli F, Buttitta F. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011; 29: [PMID: DOI: /JCO ] 13 Ding X, Zhang Z, Jiang T, Li X, Zhao C, Su B, Zhou C. Clinicopathologic characteristics and outcomes of Chinese patients with non-small-cell lung cancer and BRAF mutation. Cancer Med 2017; 6: [PMID: DOI: /cam4.1014] 14 Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, Yeap BY, Sholl LM, Johnson BE, Jänne PA. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer.clin Cancer Res 2013; 19: [PMID: DOI: / CCR ] 15 Kinno T, Tsuta K, Shiraishi K, Mizukami T, Suzuki M, Yoshida A, Suzuki K, Asamura H, Furuta K, Kohno T, Kushima R. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol 2014; 25: [PMID: DOI: /annonc/mdt495] 16 Su YC, Hsu YC, Chai CY. Role of TTF-1, CK20, and CK7 immunohistochemistry for diagnosis of primary and secondary lung adenocarcinoma. Kaohsiung J Med Sci 2006; 22: [PMID: DOI: /S X(09) ] 17 Jeba J, Backianathan S, Ishitha G, Singh A. Oral and gastrointestinal symptomatic metastases as initial presentation of lung cancer. BMJ Case Rep 2016; 2016: bcr [PMID: DOI: /bcr ] 18 Iwamuro M, Uetsuka H, Makihata K, Yamamoto K. Metastatic tumors in the duodenum: A report of two cases. J Cancer Res Ther 2015; 11: 648 [PMID: DOI: / ] 19 Linsen PV, Linsen VM, Buunk G, Arnold DE, Aerts JG. Iron deficiency anemia as initial presentation of a non-small cell lung carcinoma: A case report. Respir Med Case Rep 2015; 16: [PMID: DOI: /j.rmcr ] 20 Lee KA, Lee SK, Seo DW, Kim MH. Duodenal metastasis from lung cancer presenting as obstructive jaundice. Gastrointest Endosc 2001; 54: 228 [PMID: ] 21 Nakamura H, Mizokami Y, Iwaki Y, Shiraishi T, Ohtsubo T, Miura S, Narasaka T, Matsuoka T. Lung cancer with metastases to the stomach and duodenum: report of three cases. Digest Endosc 2003; 15: Raijman I. Duodenal metastases from lung cancer. Endoscopy 1994; 26: [PMID: DOI: /s ] 23 Goh BK, Teo MC, Chng SP, Tan HW, Koong HN. Upper gastrointestinal bleed secondary to duodenal metastasis: a rare complication of primary lung cancer. J Gastroenterol Hepatol 2006; 21: [PMID: DOI: /j ] 24 Qasrawi A, Abu Ghanimeh M, Albadarin S, Yousef O. Gastric Metastases from Lung Adenocarcinoma Causing Gastrointestinal Bleeding. ACG Case Rep J 2017; 4: e25 [PMID: DOI: /crj ] 25 Feng H, Wang X, Zhang Z, Tang C, Ye H, Jones L, Lou F, Zhang D, Jiang S, Sun H, Dong H, Zhang G, Liu Z, Dong Z, Guo B, Yan H, Yan C, Wang L, Su Z, Li Y, Nandakumar V, Huang XF, Chen SY, Liu D. Identification of Genetic Mutations in Human Lung Cancer by Targeted Sequencing. Cancer Inform 2015; 14: [PMID: DOI: /CIN.S22941] 26 Gu J, Zhou Y, Huang L, Ou W, Wu J, Li S, Xu J, Feng J, Liu B. TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis. Mol Clin Oncol 2016; 5: [PMID: DOI: /mco ] 27 Gouveia E, Sousa M, Passos MJ, Moreira A. Paraneoplastic leukemoid reaction in a patient with BRAF V600E-mutated metastatic malignant melanoma. BMJ Case Rep 2015; 2015: bcr [PMID: DOI: /bcr ] 28 Li B, Lu JC, He D, Wang J, Zhou H, Shen L, Zhang C, Duan C. Rapid onset lung squamous cell carcinoma with prominent peritoneal carcinomatosis and an eosinophilic leukemoid reaction, with coexistence of the BRAF V600E and oncogenic KRAS G12A mutations: A case report. Oncol Lett 2014; 8: [PMID: DOI: /ol ] 29 McCoach CE, Rogers JG, Dwyre DM, Jonas BA. Paraneoplastic Leukemoid Reaction as a Marker of Tumor Progression in Non-Small Cell Lung Cancer. Cancer Treat Commun 2015; 4: [PMID: DOI: /j.ctrc ] 30 Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S, Rigas JR, Upalawanna A, D Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)- mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016; 17: [PMID: DOI: /S (16) ] P- Reviewer: Tontini GE, Velayos B S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 365 August 10, 2017 Volume 8 Issue 4

68 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.366 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) CASE REPORT Intimal sarcoma of the pulmonary artery with multiple lung metastases: Long-term survival case Sonia García-Cabezas, Macarena Centeno-Haro, Simona Espejo-Pérez, Elvira Carmona-Asenjo, Alberto L Moreno-Vega, Rosa Ortega-Salas, Amalia Palacios-Eito Sonia García-Cabezas, Amalia Palacios-Eito, Department of Radiation Oncology, Reina Sofia University Hospital, Cordoba, Spain Macarena Centeno-Haro, Rosa Ortega-Salas, Department of Pathological Anatomy, Reina Sofia University Hospital, Cordoba, Spain Simona Espejo-Pérez, Department of Radiology, Reina Sofia University Hospital, Cordoba, Spain Elvira Carmona-Asenjo, Department of Nuclear Medicine, Reina Sofia University Hospital, Cordoba, Spain Alberto L Moreno-Vega, Department of Medical Oncology, Reina Sofia University Hospital, Cordoba, Spain Author contributions: All authors contributed to the acquisition of patient s clinical data, writing and revision of this manuscript. Institutional review board statement: This publication has been approved by the Institutional Review Board. Informed consent statement: The patient provided informed written consent prior to publication. Conflict-of-interest statement: All authors declare that there are no conflicts of interest. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Amalia Palacios-Eito, PhD, Department of Radiation Oncology, Reina Sofia University Hospital, Avda. Menéndez Pidal, s/n, Cordoba, Spain. amalia.palacios.sspa@juntadeandalucia.es Telephone: Fax: Received: November 30, 2016 Peer-review started: December 1, 2016 First decision: February 17, 2017 Revised: June 12, 2017 Accepted: July 21, 2017 Article in press: July 24, 2017 Published online: August 10, 2017 Abstract Pulmonary artery intimal sarcoma (PAIS) is a rare tumor with a very poor prognosis. Clinical and radiological findings usually mimic thromboembolic disease, leading to diagnostic delays. The treatment of choice is surgery, and adjuvant chemotherapy and radiotherapy have limited results. We report the case of a 48-year-old male patient, initially suspected with pulmonary thromboembolism. The angio-ct revealed a filling defect in the pulmonary artery trunk. The patient underwent surgery, resulting in with complete resection of the mass with a diagnosis of PAIS. The tumor progressed rapidly in the lung, requiring surgery of multiple lung metastases. The patient was treated with stereotactic body radiation therapy (SBRT) on two occasions for new pulmonary lesions. In the last follow up (4 years after initial diagnosis), the patient was disease-free. In conclusion, SBRT proved to be an alternative treatment to metastasectomy, allowing palliative chemotherapy to be delayed or omitted, which may result in improved quality of life. Key words: Intimal sarcoma of the pulmonary artery; Lung metastases; Metastasectomy; Stereotactic body radiation therapy; Treatment The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. 366 August 10, 2017 Volume 8 Issue 4

69 García-Cabezas S et al. Long-term survival case of metastatic PAIS Core tip: Intimal sarcoma of the pulmonary artery is a rare tumor with a very poor prognosis. It has been described in a limited number of reports. This case is a uncommon patient with long-term survival despite having rapid metastatic progression, who maintains a complete remission after initial surgical treatment, completed after occurrence of progression with stereotactic body radiotherapy. García-Cabezas S, Centeno-Haro M, Espejo-Pérez S, Carmona- Asenjo E, Moreno-Vega AL, Ortega-Salas R, Palacios-Eito A. Intimal sarcoma of the pulmonary artery with multiple lung metastases: Long-term survival case. World J Clin Oncol 2017; 8(4): Available from: URL: full/v8/i4/366.htm DOI: INTRODUCTION Pulmonary artery intimal sarcoma (PAIS) is a rare tumor first described by Mandelstamm [1] in Since then, about 300 cases have been reported in the literature [2,3]. The prognosis is generally poor, with a median overall survival of approximately 17 mo [2-4]. Clinical and radiological findings usually mimic thromboembolic disease, leading to diagnostic delays [5]. Surgical resection of the primary tumor is the best therapeutic option to prolong survival and adjuvant chemotherapy and radiotherapy have limited results [2,3]. The treatment of choice is surgery, as adjuvant chemotherapy and radiotherapy have limited results. When metastases occur, they may be resected in specific patients [6,7]. Otherwise, treatment is generally systemic and palliative in nature. In recent years, stereotactic body radiation therapy (SBRT) for lung metastases, a highprecision external radiotherapy technique, alternative to metastasectomy, has undergone significant development. Prospective phase Ⅰ/Ⅱ studies have shown that SBRT is safe and effective as treatment of lung metastases in oligometastatic patients who are not candidates for surgery [8,9]. SBRT of inoperable lung metastases is today considered routine in many centers. We report the case of a rapidly metastatic PAIS, with sustained complete remission following surgical resection and SBRT. CASE REPORT A 48-year-old male patient presenting with suddenonset symptoms of sweating, dizziness and falling to the ground, with loss of consciousness, and spontaneous recovery. After observing electrocardiographic changes, he was hospitalized with suspected acute coronary syndrome. An angio-computed tomography (CT) was performed, resulting in a diagnosis of pulmonary thromboembolism, with no improvement after anticoagulant therapy. The patient was transferred to our hospital, where a repeat angio-ct was performed, revealing a filling defect in the pulmonary artery trunk, extending from the subvalvular area to the origin of the right pulmonary artery, with no change in size with respect to the previous angio-ct (Figure 1). The patient was operated on for a suspected primary tumor of the pulmonary artery, resulting in with complete resection of the mass, whose pathological result was an intermediategrade malignant tumor suggestive of PAIS (Figure 2). Following an extension study, CT showed only a nonspecific pulmonary nodule of 4 mm in diameter in the right upper lobe. No adjuvant treatment was given. Three months later, a positron emission tomography-computed tomography (PET-CT) found that the previously mentioned nodule measured 6 mm, suggestive of metastasis. Another 4 mm de novo nodule was found and two more of 2-3 mm in size, possibly granulomas, all without an increase in metabolic activity. The patient underwent surgery where 4 bilateral pulmonary lesions, compatible with metastasis, were resected. Fifteen months later, a new PET-CT reveals a subpleural nodule in the left upper lobe, again suspicious of metastasis (Figure 3A), as well as several millimeter-size nodules reported in the previous CT, not metabolically characterizable. After discussion in a multidisciplinary committee, the patient was given treatment with SBRT (12 Gy 5 fractions), with excellent control. Six months later, growth of the two new pulmonary lesions noted in the previous CT was observed (Figure 3B and C). Chemotherapy was prescribed, which was rejected by the patient, and a second course of SBRT was given on both pulmonary lesions. Nine months after SBRT, the patient is diseasefree by PET-CT. DISCUSSION PAIS is characterized by insidious growth, causing extensive local invasion and hematogeneous metastases. Because it is a rare tumor, only case reports and small case series have been published, most of them focused on the histopathological findings and surgical aspects of its management [3,4,10-12]. Few patients achieve long-term survival and they are those without disease dissemination. The largest analysis of outcomes of this tumor reported better median survival of patients who received multimodality treatment with respect those who had single treatment (median survival of 24.7 and 8.0 mo, respectively). However, single treatment was defined as either surgery, chemotherapy or radiotherapy alone, instead of surgery without postoperative treatment [2]. Mussot et al [3] described a surgical series of 31 patients. They concluded that there appeared to be no statistical survival benefit in those who received adjuvant treatment compared to those who did not. A recent study [4] analyzed 20 patients diagnosed with PAIS obtaining a median overall survival of 17 mo: Patients who received postoperative chemo and radiotherapy showed a trend towards better survival compared to those who had surgery alone (24 mo vs 8 mo, P = ). Successful 367 August 10, 2017 Volume 8 Issue 4

70 García-Cabezas S et al. Long-term survival case of metastatic PAIS Figure 1 Angio-computed tomography: Filling defect in pulmonary artery trunk measuring 58 mm 32 mm 44 mm, extending from the subvalvular area to the origin of the right pulmonary artery. A C D B E F Figure 2 The patient was operated on for a suspected primary tumor of the pulmonary artery, resulting in with complete resection of the mass, whose pathological result was an intermediate-grade malignant tumor suggestive of Pulmonary artery intimal sarcoma. A: Macro: View of the pulmonary artery transversal section with infiltrating sarcoma on the lumen; B: High power of the tumor. Note the variable atypia 200. Immunohistochemical stainings 100 ; C: Smooth muscle actin: Focal tumor cell reaction 100 ; D: Desmine: Negative 100 ; E: CD31: Reaction of the endothelium surrounded by negative tumor cells 100 ; F: Ki-67: Variable proliferation index in tumor cells 100. cases reported in metastatic patients are anecdotal. Thus, Said et al [13] reported a case of pulmonary artery angiosarcoma, with a follow-up of 5 years and multiple repeat lung metastasectomies, which has a disease-free interval of 1 year. Choi et al [14] published a case of PAIS with metastases in the thyroid and adrenal glands, 4.7 and 6.3 years, respectively, after initial surgery. Both metastases were surgically resected, with an unusual 368 August 10, 2017 Volume 8 Issue 4

71 García-Cabezas S et al. Long-term survival case of metastatic PAIS A B C Figure 3 Positron emission tomography computed tomography, three months later. A: Subpleural hypermetabolic nodular lesion in left upper lobe (SUV max 3.8) measuring 27 mm 30 mm, suggestive of tumor activity; B and C: Computed tomography, a 38-mm nodule in right upper lobe and another 20-mm nodule in left upper lobe, compatible with metastasis. survival of 12.5 years up to the last follow-up. In our case, dissemination occurred much earlier, as the patient was operated on for lung metastases 5 mo after the initial surgery, though it is likely that patient was already metastatic at diagnosis. He is currently disease-free, 4 years after diagnosis. To our knowledge, this is the first published case of metastatic PAIS with long-term survival treated with surgery and SBRT. In conclusion, SBRT proved to be an alternative treatment to metastasectomy, allowing palliative chemotherapy to be delayed or omitted, which may result in improved quality of life. COMMENTS Case characteristics A 48-year-old male presenting sudden-onset symptoms of sweating, dizziness and fall, with momentary loss of consciousness. Clinical diagnosis Acute coronary syndrome. Differential diagnosis Thromboembolic disease. Imaging diagnosis Angio-computed tomography: Filling defect in the pulmonary artery trunk, extending from the subvalvular area to the origin of the right pulmonary artery. Pathological diagnosis Intermediate-grade malignant tumor suggestive of pulmonary artery intimal sarcoma. Treatment The patient underwent surgery. The tumor progressed rapidly in the lung, requiring surgery of multiple lung metastases. Finally, he was treated with stereotactic body radiation therapy on two occasions for new pulmonary lesions. Experiences and lessons This case report describes a uncommon patient with exceptional long-term survival despite having rapid metastatic progression. This case teaches us that SBRT is an alternative treatment to metastasectomy, allowing palliative chemotherapy to be delayed or omitted. Peer-review The article presents an unusual case of intimal sarcoma of the pulmonary artery. There are a small number of cases reported. This is a rare sarcoma with very good response to treatment with radiotherapy. REFERENCES 1 Mandelstamm M. Über primäre Neubildungen des Herzens. Virchows Arch Pathol Anat 1923; 245: Blackmon SH, Rice DC, Correa AM, Mehran R, Putnam JB, Smythe WR, Walkes JC, Walsh GL, Moran C, Singh H, Vaporciyan AA, Reardon M. Management of primary pulmonary artery sarcomas. Ann Thorac Surg 2009; 87: [PMID: DOI: / j.athoracsur ] 3 Mussot S, Ghigna MR, Mercier O, Fabre D, Fadel E, Le Cesne A, Simonneau G, Dartevelle P. Retrospective institutional study of 31 patients treated for pulmonary artery sarcoma. Eur J Cardiothorac Surg 2013; 43: [PMID: DOI: /ejcts/ezs387] 4 Wong HH, Gounaris I, McCormack A, Berman M, Davidson D, Horan G, Pepke-Zaba J, Jenkins D, Earl HM, Hatcher HM. Presentation and management of pulmonary artery sarcoma. Clin Sarcoma Res 2015; 5: 3 [PMID: DOI: / s ] 5 Jiang S, Li J, Zeng Q, Liang J. Pulmonary artery intimal sarcoma misdiagnosed as pulmonary embolism: A case report. Oncol Lett 2017; 13: [PMID: DOI: /ol ] 6 Digesu CS, Wiesel O, Vaporciyan AA, Colson YL. Management of Sarcoma Metastases to the Lung. Surg Oncol Clin N Am 2016; 25: [PMID: DOI: /j.soc ] 7 Chudgar NP, Brennan MF, Munhoz RR, Bucciarelli PR, Tan KS, D Angelo SP, Bains MS, Bott M, Huang J, Park BJ, Rusch VW, Adusumilli PS, Tap WD, Singer S, Jones DR. Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma. J Thorac Cardiovasc Surg 2017; 154: e1 [PMID: DOI: /j.jtcvs ] 8 Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, Schell MC. Stereotactic Body Radiation Therapy (SBRT) for lung metastases. Acta Oncol 2006; 45: [PMID: DOI: / ] 9 Rusthoven KE, Kavanagh BD, Burri SH, Chen C, Cardenes H, Chidel MA, Pugh TJ, Kane M, Gaspar LE, Schefter TE. Multiinstitutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J Clin Oncol 2009; 27: [PMID: DOI: /JCO ] 10 Grazioli V, Vistarini N, Morsolini M, Klersy C, Orlandoni G, Dore R, D Armini AM. Surgical treatment of primary pulmonary artery sarcoma. J Thorac Cardiovasc Surg 2014; 148: [PMID: DOI: /j.jtcvs ] 11 Huo L, Moran CA, Fuller GN, Gladish G, Suster S. Pulmonary artery sarcoma: a clinicopathologic and immunohistochemical study of August 10, 2017 Volume 8 Issue 4

72 García-Cabezas S et al. Long-term survival case of metastatic PAIS cases. Am J Clin Pathol 2006; 125: [PMID: ] 12 Tavora F, Miettinen M, Fanburg-Smith J, Franks TJ, Burke A. Pulmonary artery sarcoma: a histologic and follow-up study with emphasis on a subset of low-grade myofibroblastic sarcomas with a good long-term follow-up. Am J Surg Pathol 2008; 32: [PMID: DOI: /PAS.0b013e31817d7fd0] 13 Said SM, Sundt TM 3rd, Garces YI, Wigle DA. 5-year survival after multiple repeat metastasectomy for pulmonary artery angiosarcoma. Ann Thorac Surg 2011; 91: e49-e51 [PMID: DOI: / j.athoracsur ] 14 Choi YM, Jang EK, Ahn SH, Jeon MJ, Han JM, Kim SC, Han DJ, Gong G, Kim TY, Shong YK, Kim WB. Long-term survival of a patient with pulmonary artery intimal sarcoma after sequential metastasectomies of the thyroid and adrenal glands. Endocrinol Metab (Seoul) 2013; 28: [PMID: DOI: / EnM ] P- Reviewer: Bramhall S, Cerwenka HR S- Editor: Kong JX L- Editor: A E- Editor: Lu YJ 370 August 10, 2017 Volume 8 Issue 4

73 W J C O World Journal of Clinical Oncology Submit a Manuscript: DOI: /wjco.v8.i4.371 World J Clin Oncol 2017 August 10; 8(4): ISSN (online) Long-term stabilization of metastatic melanoma with sodium dichloroacetate CASE REPORT Akbar Khan, Doug Andrews, Jill Shainhouse, Anneke C Blackburn Akbar Khan, Doug Andrews, Medicor Cancer Centres Inc, Toronto, ON M2N 6N4, Canada Jill Shainhouse, Insight Naturopathic Clinic, Toronto, ON M4P 1N9, Canada Anneke C Blackburn, the John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia Author contributions: Khan A treated the patient and wrote most of the case report; Andrews D assisted in development of the natural medication protocol for reduction of DCA side effects, and wrote a portion of the case report; Shainhouse J treated the patient with natural therapy; Blackburn AC interpreted the case report in the context of the literature on in vitro and in vivo DCA research, wrote parts of the introduction and discussion, and reviewed the manuscript overall. Informed consent statement: The patient described in this manuscript has given consent to publish his case anonymously. Conflict-of-interest statement: One of the authors (Khan) administers dichloroacetate therapy for cancer patients through Medicor Cancer Centres at a cost, and without profit. The clinic is owned by a family member of this author. The other authors have nothing to disclose. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Manuscript source: Invited manuscript Correspondence to: Akbar Khan, MD, Medical Director, Medicor Cancer Centres Inc, 4576 Yonge St., Suite 301, Toronto, ON M2N 6N4, Canada. akhan@medicorcancer.com Telephone: Fax: Received: January 30, 2017 Peer-review started: February 12, 2017 First decision: March 28, 2017 Revised: May 5, 2017 Accepted: May 30, 2017 Article in press: May 31, 2017 Published online: August 10, 2017 Abstract Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define response by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain longterm stability in patients with advanced melanoma. Key words: Dichloroacetate; Cancer; BRAF; Melanoma; Cytostatic The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since It has been shown that DCA therapy can result in a classic response which is measured by reduction or disappearance of 371 August 10, 2017 Volume 8 Issue 4

74 Khan A et al. Dichloroacetate therapy in metastatic melanoma tumours on imaging. However, DCA can also halt cancer cell growth without causing apoptosis (cytostatic effect). This can result in long-term stabilization of metastatic cancer. We present a case of oral DCA therapy resulting in reduction and stabilization of metastatic melanoma in a 32-year-old male for over 4 years, with only minor side effects. Khan A, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017; 8(4): Available from: URL: DOI: INTRODUCTION Sodium dichloroacetate (DCA) caught the attention of the medical community in 2007, when Bonnet et al [1] published the first in vitro and in vivo study illustrating the value of DCA as a metabolic cancer therapy, through its inhibitory action on the mitochondrial enzyme pyruvate dehydrogenase kinase. Previously, Stacpoole et al [2-4] had published several studies of DCA for the treatment of congenital lactic acidosis in mitochondrial diseases [2-5]. These studies demonstrated that oral DCA is a safe drug for human use. DCA was noted to have an absence of renal, pulmonary, bone marrow and cardiac toxicity [4]. Most DCA side effects were modest, with the most serious one being reversible peripheral neuropathy [6]. Reversible delirium has also been reported [7]. Elevation of liver enzymes (asymptomatic and reversible) has been noted in a small percentage of patients [3]. The prior human research in mitochondrial disorders has enabled the rapid translation of DCA into human use as an off-label cancer therapy. Several reports of clinical trials using DCA as cancer therapy have now been published, confirming its safety profile, and indicating an increasing recognition of the potential usefulness of DCA in the cancer clinic [8-11]. One limitation of these studies involving late stage patients is that they have only reported on treatment for short periods of time. In Bonnet s 2007 publication [1], DCA treatment was shown to reduce mitochondrial membrane potential which promoted apoptosis selectively in human cancer cells. Aerobic glycolysis inhibition (the Warburg effect) and mitochondrial potassium ion channel activation were identified as the mechanisms of action of DCA. Further investigations of DCA in vitro have confirmed the anti-cancer activity against a wide range of cancer types, which have been reviewed recently by Kankotia and Stacpoole [12]. In addition, DCA is also able to enhance apoptosis when combined with other agents [13-15]. Other anticancer actions of DCA have also been suggested, including angiogenesis inhibition [16], alteration of HIF1-α expression [17], alteration of cell ph regulators V-ATPase and MCT1, and other cell survival regulators such as p53 and PUMA [18]. However, many in vitro studies use unreasonably high concentrations of DCA that are not clinically achievable, in an effort to show cytotoxic activity [12]. In other studies, more modest DCA concentrations were used, demonstrating that DCA could be cytostatic. The second report in 2010 of its in vivo anti-cancer activity found DCA alone to be cytostatic in a metastatic model of breast cancer [19], inhibiting proliferation without triggering apoptosis. This suggests a role for DCA as a cancer stabilizer, similar to angiogenesis inhibitors. In response to the 2007 report of the anti-cancer actions of DCA, Khan began using DCA for the treatment of cancer patients with short prognosis or who had stopped responding to conventional cancer therapies. A natural medication protocol was developed in collaboration with a naturopathic physician (Andrews) to address the dose-limiting neurologic toxicity of DCA. This consisted of 3 medicines: Acetyl L-carnitine [20-22], R-alpha lipoic acid [23-25] and benfotiamine [26-28], for neuropathy and encephalopathy prevention. In over 300 advanced stage cancer patients, observational data revealed that DCA therapy benefitted 60%-70% of cases. The neuropathy risk when natural neuroprotective medicines were combined with DCA was approximately 20% using mg/kg per day dosing on a 2 wk on/1 wk off cycle (clinic observational data published online at Here, a patient case report illustrating both the apoptotic and anti-proliferative effects of chronic DCA treatment over a period of over four years is presented. CASE REPORT A 32 years old previously healthy fair-skinned male originally noted that a mole on his left calf began to change in He consulted a doctor and the mole was excised. A pathologic diagnosis of melanoma was made. A sentinel node dissection was carried out, and was negative for metastatic disease. In 2007, the patient noted enlargement of left inguinal lymph nodes, and small melanocytic lesions on the skin of his left leg. He was treated with interferon alpha under a clinical trial at a regional cancer hospital, with reduction of the nodes and resolution of the skin metastases. Interferon was stopped after 9 mo due to side effects. The patient remained well until 2010, when a new left leg skin metastasis appeared. This was surgically excised. In late 2011, another new cutaneous metastasis was identified on the left leg, within the scar from the original melanoma surgery. This was biopsied and a diagnosis of recurrent melanoma was confirmed. He was then treated with wide excision and skin graft. In March 2012, the patient was diagnosed with a recurrence within the left leg skin graft. This was excised and a new skin graft procedure was performed. Pathology revealed positive margins of the excised 372 August 10, 2017 Volume 8 Issue 4

75 Khan A et al. Dichloroacetate therapy in metastatic melanoma Figure 1 Computed tomography scan from March 2012 prior to natural therapies and prior to dichloroacetate therapy. Largest node measured 8 mm in diameter. Figure 2 Computed tomography scan from July 2012 after 3 mo of natural therapy alone, just prior to the start of dichloroacetate therapy. Largest node measured 22 mm 20 mm. metastasis, so a re-excision was performed, again with positive margins. At the same time, needle biopsy of a left inguinal lymph node confirmed the presence of BRAF-positive metastatic melanoma. A Computed tomography (CT) scan performed in Mar 2012 revealed no evidence of distant metastases. The largest left inguinal node was 8mm in diameter, which was reported as insignificant by size criteria (Figure 1). In April 2012, the patient consulted a naturopathic doctor (Shainhouse) and began therapy with the following oral natural anti-cancer agents: Active hexose correlated compound or AHCC (mushroom extract) [29], dandelion root [30], curcumin [31], and astragalus root [32]. Parenteral therapy was also started, which consisted of intravenous vitamin C twice weekly [33] and subcutaneous European mistletoe extract [34]. The patient also changed to a vegan diet. In May 2012, the patient attended the author s clinic (Khan) looking to pursue additional non-traditional therapies. DCA therapy was discussed, but the patient decided to give the natural anti-cancer therapies (prescribed by Shainhouse) an adequate trial first. CT scan was performed again in May 2012 (after only 1 mo of natural therapy) and indicated mild growth of multiple inguinal and external iliac nodes, with sizes ranging from 10 mm 11 mm to 14 mm 15 mm. In July 2012, CT scan was repeated to assess the patient s natural anti-cancer therapies. At that time, the left inguinal and external iliac nodes had enlarged again, and ranged in size from 13 mm 16 mm to 22 mm 20 mm (Figure 2). PET scan was also performed in preparation for entering a clinical trial in Boston, MA (United States), and confirmed increased glucose uptake in the left inguinal nodes. There was new low intensity (2/10) aching pain in the left inguinal region. Examination revealed a 20 mm non-tender left inguinal lymph node, and two small skin metastases within the left calf skin graft. The patient was thus diagnosed with disease progression. At that point he decided to initiate DCA therapy. He began oral DCA 500 mg 3 times per day, which was equivalent to 17 mg/kg per day (manufacturer: Tokyo Chemical Industry, United States) in addition to maintaining the other natural therapies. The DCA treatment cycle was 2 wk on and 1 wk off. To minimize the occurrence of DCA side effects, 3 additional natural medications were prescribed: Oral acetyl L-carnitine 500 mg 3 times a day, oral benfotiamine 80 mg twice a day and oral R-alpha lipoic acid 150 mg 3 times a day. These supplements were taken daily (no cycle). Routine baseline blood tests were performed (Table 1). These were all normal, except for low creatinine which was felt to be insignificant. In November 2012, 4 mo after the addition of DCA to his original natural anti-cancer therapies, the patient was re-assessed. He felt generally well. Two new symptoms were reported to have begun only after initiation of DCA therapy: Slightly reduced sensation of the finger tips and toes, and slightly reduced ability to concentrate during the 2 wk periods in which he was taking DCA. The mild sensory loss was not worsening and was felt to be mild DCA-related neuropathy. Both the numbness and reduced concentration were reported to resolve during the weeks when the patient was off DCA. Blood panel from October 2012 showed no significant changes (Table 1). August 2012 and November 2012 CT scans revealed significant regression of all previously enlarged lymph nodes. The largest node was 10 mm, and there was no evidence of intra-thoracic or intra-abdominal disease, and no bone metastases (Figure 3). The patient continued to feel well on DCA therapy, and did not notice any new skin metastases or new enlargement of inguinal nodes. He continued to have frequent clinical monitoring with his naturopathic doctor (Shainhouse), and annual follow-up with his medical doctor (Khan). The listed natural anti-cancer therapies (prescribed by Shainhouse) and DCA therapy were maintained into Blood panel results in June 2016 continued to be normal (Table 1). CT scan was repeated in August 2016, showing no evidence of metastatic melanoma, after a full 4 years of ongoing DCA therapy, combined with natural anti-cancer therapy (Figure 4). By December 2016, the patient reported an increase in work-related stress and a reduction in compliance 373 August 10, 2017 Volume 8 Issue 4

76 Khan A et al. Dichloroacetate therapy in metastatic melanoma Table 1 Blood panel prior to and during dichloroacetate therapy Blood test July 12 pre-dca October 12 3 mo DCA June 16 4 yr DCA Units Normal range Hemoglobin g/l White cell count /L Platelets /L Glucose mmol/l Urea mmol/l Creatinine µmol/l Calcium mmol/l Albumin g/l Bilirubin µmol/l < 22 Sodium mmol/l Potassium mmol/l Chloride mmol/l Alkaline Phosphatase U/L LDH U/L GGT U/L AST U/L 7-37 ALT U/L Indicates abnormal value. DCA: Dichloroacetate; LDH: Lactate dehydrogenase; GGT: Gamma-glutamyltransferase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase. Figure 3 Computed tomography scan from November 2012 after 4 mo of dichloroacetate therapy. Largest node measured 10 mm. with his medications. At the time, he noted a new left inguinal mass. Ultrasound imaging was obtained, which revealed a new conglomerate of enlarged lymph nodes measuring 40 mm 25 mm 23 mm, with colour Doppler showing blood flow within the mass. This was interpreted as re-growth of melanoma, after approximately four and a half years of continuous DCA therapy. Further workup was performed including a PET/CT scan, which confirmed disease recurrence in 3 left inguinal nodes (SUVmax ranging from 13 to 17.8). In summary, the patient received conventional therapy for recurrent stage 3 melanoma over a period of 6 years, consisting of primary surgical excision with lymph node dissection, interferon alpha and surgical excisions for recurrent cutaneous metastases on 5 occasions. The patient then received natural anticancer therapy alone (prescribed by Shainhouse) for 3 mo with no response, evidenced by steady disease progression on serial CT scans. Finally the patient added oral DCA therapy to the natural anti-cancer therapy, with 3 concurrent neuroprotective medicines Figure 4 Computed tomography scan after 4 years of dichloroacetate therapy without any concurrent conventional cancer therapies. Scan demonstrates absence of cancer re-growth. All nodes measure less than 10 mm. (lipoic acid, acetyl L-carnitine and benfotiamine) and no concurrent conventional cancer therapies. The result was a complete radiological remission lasting for over 4 years, followed by recurrence. During the course of DCA therapy, the patient experienced trivial side effects consisting of slight neuropathy and slight reduction of concentration. The patient maintained ECOG level 0 function, and he was able to work full time. DISCUSSION The use of oral DCA in the metastatic melanoma patient described herein demonstrates tumour shrinkage and long-term disease stability according to clinical status and CT imaging. Disease stability was maintained for over 4 years while taking DCA in the absence of any concurrent conventional therapy, with a survival time since the initial diagnosis of 10 years. According to the National Cancer Institute s SEER cancer statistics, the survival of this patient who showed no evidence of distant metastases is 374 August 10, 2017 Volume 8 Issue 4

77 Khan A et al. Dichloroacetate therapy in metastatic melanoma not remarkable (62.9% 5-year survival rate for melanoma with spread to regional lymph nodes, gov/statfacts/html/melan.html). What is remarkable is that in a situation where involved lymph nodes were clearly enlarging, the addition of oral DCA therapy was efficacious in shrinking the enlarging nodes (Figures 2 and 3), and in achieving a remission lasting over 4 years. It is possible that the natural anti-cancer therapies the patient received synergized with DCA, but it is also clear that these natural therapies alone cannot account for the disease regression. DCA has been reported to have both apoptotic and cytostatic effects [14,17,19,35,36], which is consistent with this patient s clinical course of regression (apoptotic) and prolonged remission (cytostatic). The recurrence after 4 years coincided with reduced compliance, suggesting that this method of cancer management with DCA requires the metabolic pressure to be maintained continuously. Despite recurrence, the patient remained clinically well and planned to start new immunotherapy medications. It remains to be seen if a change in therapy can once again achieve disease regression or stability. In addition to the maintenance of remission for over 4 years, this case illustrates that DCA can be well-tolerated in a cancer patient for a prolonged time period, as compared to all published DCA cancer clinical trials. Notably, this patient was able to tolerate 17 mg/kg per day in a regime of 2 wk on/1 wk off for 4 years with minimal side effects. This is similar to our previous case report of chronic DCA usage in colon cancer [37], where the patient was able to tolerate 16 mg/kg per day (but not 25 mg/kg per day) in the same regime, but contrasts with the clinical trials for DCA, which recommend a lower dose of mg/kg per day given continuously [9,11]. The 1 wk break or the neuroprotective supplements may both contribute to the ability of the patients in the case reports to tolerate the higher dose. Genetic polymorphisms in GSTZ1, the liver enzyme that metabolises DCA, may also contribute to the dose of DCA that can be tolerated [9,38]. Variable drug levels have been reported in the trials, but not all of them have considered this pharmacogenetic aspect of DCA therapy [9,11], and further studies are needed to clarify if this is a significant contributor to DCA tolerance. As of this writing, a DCA multiple myeloma human trial is ongoing, which is examining both GSTZ1 genotypes and drug levels to contribute to our understanding of these issues (Australia New Zealand Clinical Trials Register #ACTRN , org.au). This case report shows that chronic DCA therapy can be used without reducing quality of life, as compared to conventional melanoma therapies such as interferon. To determine the optimal protocol for maximum tolerable acute or chronic treatment with DCA, human trials are needed. But more importantly, it still remains to be clarified what dose is required for on-target effects that will be efficacious against cancer. This information is necessary before investing in larger, long term studies on patient outcomes. DCA deserves further investigation in clinical trials as a non-toxic cancer therapy due to its modest cost and low toxicity, and deserves consideration as an off-label cancer therapy. ACKNOWLEDGMENTS The authors wish to thank Dr. Humaira Khan for her assistance, and also the patient for his support and consent to publish his case. COMMENTS Case characteristics The 32-year-old male patient presented with a pigmented lesion on his leg. Clinical diagnosis The patient was diagnosed with a melanoma. Laboratory diagnosis Melanoma confirmed by excisional biopsy. Imaging diagnosis Enlarged inguinal node confirmed to be involved with melanoma (needle biopsy). Pathological diagnosis Melanoma, BRAF positive. Treatment Excision of primary lesion with skin graft, sentinel node dissection, multiple excisions of recurrent cutaneous metastases. Traditional therapy stopped and natural anti-cancer therapies started (AHCC, dandelion root, curcumin, astragalus root, i.v. vitamin C, s.c. European mistletoe). Progression after 3 mo, dichloroacetate (DCA) added. Regression and remission following addition of DCA lasting for over 4 years. Related reports Computed tomography scan reports demonstrate the course of the disease and response to therapies. Term explanation DCA: Dichloroacetate sodium; RECIST: Response Evaluation Criteria for Solid Tumours; ECOG: Eastern Cooperative Oncology Group. Experiences and lessons DCA can act as a pro-apoptotic and cytostatic drug, and can thus achieve regression as well as long-term stabilization of metastatic cancer without serious side effects, as illustrated by this melanoma case. Peer-review Dr. Khan described a 32-year-old man received DCA therapy, with other medications from natural therapists and maintained in a stabilization state (metastatic melanoma) for over 4 years. It is an interesting case. REFERENCES 1 Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-k+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007; 11: [PMID: DOI: / j.ccr ] 375 August 10, 2017 Volume 8 Issue 4

78 Khan A et al. Dichloroacetate therapy in metastatic melanoma 2 Stacpoole PW, Kurtz TL, Han Z, Langaee T. Role of dichloroacetate in the treatment of genetic mitochondrial diseases. Adv Drug Deliv Rev 2008; 60: [PMID: DOI: / j.addr ] 3 Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW, Shuster JJ. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 2008; 121: e1223-e1228 [PMID: DOI: / peds ] 4 Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW, Valenstein E. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 2006; 117: [PMID: DOI: /peds ] 5 Berendzen K, Theriaque DW, Shuster J, Stacpoole PW. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion 2006; 6: [PMID: DOI: /j.mito ] 6 Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006; 66: [PMID: DOI: /01. wnl ] 7 Brandsma D, Dorlo TP, Haanen JH, Beijnen JH, Boogerd W. Severe encephalopathy and polyneuropathy induced by dichloroacetate. J Neurol 2010; 257: [PMID: DOI: / s ] 8 Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010; 2: 31ra34 [PMID: DOI: /scitranslmed ] 9 Dunbar EM, Coats BS, Shroads AL, Langaee T, Lew A, Forder JR, Shuster JJ, Wagner DA, Stacpoole PW. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs2014; 32: [PMID: DOI: / s ] 10 Garon EB, Christofk HR, Hosmer W, Britten CD, Bahng A, Crabtree MJ, Hong CS, Kamranpour N, Pitts S, Kabbinavar F, Patel C, von Euw E, Black A, Michelakis ED, Dubinett SM, Slamon DJ. Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer. J Cancer Res Clin Oncol 2014; 140: [PMID: DOI: /s ] 11 Chu QS, Sangha R, Spratlin J, Vos LJ, Mackey JR, McEwan AJ, Venner P, Michelakis ED. A phase I open-labeled, single-arm, doseescalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest New Drugs 2015; 33: [PMID: DOI: /s y] 12 Kankotia S, Stacpoole PW. Dichloroacetate and cancer: new home for an orphan drug? Biochim Biophys Acta 2014; 1846: [PMID: DOI: /j.bbcan ] 13 Sun RC, Board PG, Blackburn AC. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells. Mol Cancer 2011; 10: 142 [PMID: DOI: / ] 14 Stockwin LH, Yu SX, Borgel S, Hancock C, Wolfe TL, Phillips LR, Hollingshead MG, Newton DL. Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 2010; 127: [PMID: DOI: /ijc.25499] 15 Gang BP, Dilda PJ, Hogg PJ, Blackburn AC. Targeting of two aspects of metabolism in breast cancer treatment. Cancer Biol Ther 2014; 15: [PMID: DOI: / ] 16 Sutendra G, Dromparis P, Kinnaird A, Stenson TH, Haromy A, Parker JM, McMurtry MS, Michelakis ED. Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer.oncogene 2013; 32: [PMID: DOI: /onc ] 17 Cairns RA, Bennewith KL, Graves EE, Giaccia AJ, Chang DT, Denko NC. Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104. Clin Cancer Res 2009; 15: [PMID: DOI: / CCR ] 18 Anderson KM, Jajeh J, Guinan P, Rubenstein M. In vitro effects of dichloroacetate and CO2 on hypoxic HeLa cells. Anticancer Res 2009; 29: [PMID: ] 19 Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 2010; 120: [PMID: DOI: / s ] 20 De Grandis D. Acetyl-L-carnitine for the treatment of chemotherapyinduced peripheral neuropathy: a short review. CNS Drugs 2007; 21 Suppl 1: 39-43; discussion [PMID: ] 21 Maestri A, De Pasquale Ceratti A, Cundari S, Zanna C, Cortesi E, Crinò L. A pilot study on the effect of acetyl-l-carnitine in paclitaxeland cisplatin-induced peripheral neuropathy. Tumori 2005; 91: [PMID: ] 22 Evans JD, Jacobs TF, Evans EW. Role of acetyl-l-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacother 2008; 42: [PMID: DOI: /aph.1L201] 23 Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol 2012; 2012: [PMID: DOI: /2012/456279] 24 Liu F, Zhang Y, Yang M, Liu B, Shen YD, Jia WP, Xiang KS. [Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study]. Zhonghua Yixue Zazhi 2007; 87: [PMID: ] 25 Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995; 38: [PMID: ] 26 Winkler G, Kempler P. [Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy]. Orv Hetil 2010; 151: [PMID: DOI: /OH ] 27 Ang CD, Alviar MJ, Dans AL, Bautista-Velez GG, Villaruz-Sulit MV, Tan JJ, Co HU, Bautista MR, Roxas AA. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev 2008; (3): CD [PMID: DOI: / CD pub3] 28 Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung 1999; 49: [PMID: DOI: /s ] 29 Ignacio RM, Kim CS, Kim YD, Lee HM, Qi XF, Kim SK. Therapeutic effect of Active Hexose-Correlated Compound (AHCC) combined with CpG-ODN (oligodeoxynucleotide) in B16 melanoma murine model. Cytokine 2015; 76: [PMID: DOI: /j.cyto ] 30 Chatterjee SJ, Ovadje P, Mousa M, Hamm C, Pandey S. The efficacy of dandelion root extract in inducing apoptosis in drug-resistant human melanoma cells. Evid Based Complement Alternat Med 2011; 2011: [PMID: DOI: /2011/129045] 31 Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei HR, Salehi H, Peyvandi M, Pawelek JM, Sahebkar A. Curcumin: A new candidate for melanoma therapy? Int J Cancer 2016; 139: [PMID: DOI: /ijc.30224] 32 Huang XY, Zhang SZ, Wang WX. Enhanced antitumor efficacy with combined administration of astragalus and pterostilbene for melanoma. Asian Pac J Cancer Prev 2014; 15: [PMID: ] 33 Wagner SC, Markosian B, Ajili N, Dolan BR, Kim AJ, Alexandrescu DT, Dasanu CA, Minev B, Koropatnick J, Marincola FM, Riordan NH. Intravenous ascorbic acid as an adjuvant to interleukin-2 immunotherapy. J Transl Med 2014; 12: 127 [PMID: DOI: 376 August 10, 2017 Volume 8 Issue 4

79 Khan A et al. Dichloroacetate therapy in metastatic melanoma / ] 34 Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev 2008; (2): CD [PMID: DOI: / CD pub2] 35 Delaney LM, Ho N, Morrison J, Farias NR, Mosser DD, Coomber BL. Dichloroacetate affects proliferation but not survival of human colorectal cancer cells. Apoptosis 2015; 20: [PMID: DOI: /s ] 36 Abildgaard C, Dahl C, Basse AL, Ma T, Guldberg P. Bioenergetic modulation with dichloroacetate reduces the growth of melanoma cells and potentiates their response to BRAFV600E inhibition. J Transl Med 2014; 12: 247 [PMID: DOI: /s ] 37 Khan A, Andrews D, Blackburn AC. Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy. World J Clin Cases 2016; 4: [PMID: ] 38 Tzeng HF, Blackburn AC, Board PG, Anders MW. Polymorphismand species-dependent inactivation of glutathione transferase zeta by dichloroacetate. Chem Res Toxicol 2000; 13: [PMID: ] P- Reviewer: Su CC S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ 377 August 10, 2017 Volume 8 Issue 4

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