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1 肺癌手術與合併治療新進展陳晉興 a,b 李元麒 a a 臺大醫學院外科及臺大醫院胸腔外科 b 台大雲林分院外科部

2 綱要肺癌手術及麻醉新進展胸腔鏡肺葉切除術胸腔鏡肺節切除術免插氣管內管之胸腔鏡手術合併治療新進展合併化學治療合併標靶治療

3 肺癌 : 近五年來台灣癌症死亡原因之第一名 10,000 8,000 7,153 7,302 7,479 7,993 7,777 死亡人數 6,000 4,000 2,000 肺癌肝癌結腸直腸癌資料來源 : 行政院衛生署

4 非小細胞肺癌 : Consisting 80% of lung cancer Surgery: Curative resection: the best hope for cure, particularly for those with early disease

5 Standard Posterolateral Thoracotomy: 傷口大, 恢復慢, 長期疼痛比例高

6 胸腔鏡手術器械配置圖及傷口器械入口器械入口內視鏡

7 胸腔鏡手術 : 優點胸腔鏡肺葉切除術後之肺功能影響較小胸腔鏡手術引發較少之發炎反應, 對免疫功能較好胸腔鏡肺葉切除術後長期生活品質較好 1. Kaseda S. Ann Thoracic Surg, Leaver HA. Eur J Clin Investi, Sugiura H. Surg Laparo Endo, 1999

8 肺葉切除術 : 胸腔鏡或開胸手術? 目前胸腔鏡肺葉切除術已經有許多醫學中心使用於肺癌之手術治療. 安全性 : 與開胸手術類似, 甚至更好腫瘤學方面考量 (JCO 2009 metaanalysis): 局部復發率沒有差別遠處轉移率較低 5 年死亡率較低 Yan TD. J Clin Oncol 2009.

9 VATS versus Thoracotomy for Lung cancer: NTUH experience Retrospective study: patients with lung cancer undergoing curative resection at NTUH 344 patients were excluded stage III and IV tumor size > 5 cm, undergoing wedge resection, sleeve lobectomy or pneumonectomy. Only 424 patients undergoing lobectomy or bilobectomy were included for analysis.

10 65y/o female, RLL lung adenocarcinoma

11 RLL VATS Lobectomy

12 Table 1. Demographic data ( ) VATS Thoracotomy (n=121) (n=303) p value Sex (male) 47 (39%) 167(55%) Age (years) Tumor size (cm) Cell type Adenocarcinoma 99 (82%) 215 (71%) Squamous carcinoma 15 (12%) 72 (24%) Others 7 (6%) 16 (5%) Clinical staging Ia 67 (55%) 116 (38%) Ib 42 (35%) 137 (45%) IIa 3 (3%) 15 (5%) IIb 9 (7%) 35 (12%) Procedure Lobectomy 120 (99%) 280 (92%) Bilobectomy 1 (1%) 23 (8%) Operation Mortality 0 (0%) 3 (1%) VATS = video-assisted thoracic surgery

13 VATS (n=121) Disease-free Survival (%) VATS (n=121) Thoracotomy (n=303) Overall Survival (%) Thoracotomy (n=303) P = P = Days Days Disease-free survival Overall survival

14 Multivariate analysis of factors affecting disease-free survival (424 patients) Relative Risk Confidence Interval p value Sex (female vs male) Age (<65y vs >65y) Cell type (Adenoca vs others) Clinical staging (I vs II) Operation (lobectomy vs bilobectomy) Approach (thoracotomy vs VATS) < Old age, adenocarcinoma, and advanced stage are associated with poor disease-free survival. 2. Operation method and approach method: not correlated with disease-free survival.

15 Conclusion and Discussion VATS lobectomy is a safe alternative to posterolateral thoracotomy in treating lung cancer patients Comparable complication and mortality rates Long-term survival: unclear by multivariate analysis Further prospective studies are required

16 62 歲女性, 胸部電腦斷層發現 0.7 公分結節, 是否一定要接受肺葉切除?

17 52 歲女性, right lung small nodule Needle localization with a hook-wire system

18 Needle localization

19 VATS sublobar resection for lung cancer Including wedge resection or segmentectomy Similar overall and disease-free survival in large retrospective studies Indications: Tumor size < 2cm, especially for BAC With prior resection Old patients with poor pulmonary reserve Bilfinger TV. Curr Opin Pulm Med 2008

20 VATS segmentectomy 80 歲男性 CAD 心導管支架置放術後須最近二月體重減輕 8 公斤

21 免氣管插管之胸腔鏡手術 Non-intubated thoracoscopic surgery

22 傳統胸腔手術之麻醉 General anesthesia with muscle paralysis Endotracheal intubation with one lung ventilation -> 醫師輕鬆, 病患危險增加 : Increased risk of pneumonia Impaired cardiac performance Barotrauma by ventilator Pulmonary atelectasis Intubation-related complication

23 Double lumen endotracheal tube 胸腔手術之麻醉及插管

24 Advantages of non-intubated thoracic surgery with epidural anesthesia Effect on cardiovascular system Improved myocardial blood flow Improved LV function Reduced heart rate and arrhythmia Effect on lung function Intact cough ability immediate after op Improved post-op lung function Effect in patients with COPD Decreased bronchospasm Decreased respiratory complications Mineo TC. Eur J Cardiothorac Surg. 2007

25 Non-intubated (Awake) thoracoscopic surgery

26 手術錄影帶 :

27 免氣管插管之迷你胸腔鏡切除肺腫瘤 76 歲女性, 大腸癌術後左下肺 1 公分腫瘤 81 歲男性, COPD 雙側肺腫瘤, 無診斷

28 胸椎硬腦膜外麻醉 + 傷口局部麻醉 ( 沒有氣管插管 )

29 病人術後恢復良好術後病患可以自行移床, 可馬上進食術後第一天拔除胸管術後第二天出院術後 2-3 天可恢復正常生活作息

30 Non-intubated thoracoscopic surgery: NTUH experience VATS wedge resection: 18 cases VATS lobectomy: 9 cases VATS segmentectomy: 1 cases No major complications, no mortality

31 免氣管插管胸腔鏡手術總結未來的世界是老年人的世界體力不好心臟不好呼吸功能不好手術併發症比例高不僅開刀方式要微創, 麻醉方式也要微創 General anesthesia with endotracheal intubation 決不是每一台胸腔手術的必然選擇未來主流 :Target anesthesia and minimal invasive approach: Non-intubated thoracoscopic surgery

32 Multimodality Approach in Patients with Stage-III Resectable Non-Small Cell Lung Cancer: Literature Review and the Experience of National Taiwan University Hospital

33 Stage III Resectable Disease: Disappointing long-term outcome by surgery only" approach Pre-op positive mediastinal nodes: 5% 5-y survival Intra-operative multilevel nodal involvement: 11% 5-y survival Distant metastasis in 80% of cases with relapse Systemic treatment with combined modality for better control of both local and disseminated diseases is indicated Andre F, JCO 2000;18:2981

34 Multimodality Approach for Stage III Resectable NSCLC Neoadjuvant Adjuvant Chemotherapy Chemotherapy Diagnosis & Staging Radiotherapy Surgery Radiotherapy Target therapy Target therapy Increase resectability Eradicate distant micromets Decrease the residual tumor Eradicate distant micromets

35 Theoretical Advantage of Neo- adjuvant Chemotherapy Better compliance & all patients eligible (many don't receive adjuvant CT after surgery) Reduce tumor burden Downstages: Mediastinal lymph node clearance More complete resection Earliest treatment of micro-metastatic disease

36 Randomized Trials of Neoadjuvant Therapy in IIIA NSCLC Stage No. of patients Regimen MS (months) 5-yr SR (%) Hazard P value Pass et al. (1992) Roth et al. (1994) Rosell et al. (1994) Depeirre et al. (2002) IIIA 14 Surgery CT+surgery NS IIIA 32 Surgery CT+surgery <0.05 IIIA 30 Surgery CT+surgery <0.05 IB-IIIA 119 Surgery 26 NA CT+surgery 37 NA 0.15 Concerns: 1. Positive results: only small patient numbers 2. Most trials stop earlier because positive results of adjuvant C/T

37 Neoadjuvant Chemotherapy with Docetaxel-Cisplatin in N2 NSCLC: Results of a Prospective Study in NTUH Jin-Hsing Chen, Muzo Wu, Chih-Hsin Yang, Fu-Chang Hu, Jin- Yuan Shih, Kuan-Yuh Chen, CC Ho MD, ZZ Lin, Chong-Jen Yu, Yuan-Chi Lee

38 Study Protocol ( ): 2005): Inclusion criteria: Patients with resectable N2 NSCLC (stage IIIA or IIIB) Histological Dx of Mediastinal Nodes Neoadjuvant C/T 2-3 Cycles Doc + CDDP* Surgery Adjuvant C/T 2-4 Cycles Doc + CDDP* VATS or Mediastinoscopy *Doc (36 mg/m2, d1,8,15,29,36,43), CDDP (70 mg/m2, d15,43) before and after surgery

39 57y/o M, SqCC, T2N2M0 Before chemotherapy 2003/12/ /3/28

40 Before neoadjuvant C/T After neoadjuvant C/T

41 78 y/o man, T3-4N2M0. FEV1 1.02L, FEV1% 48.6%

42 After 3 cycles of Doc/Cis. Surgeon hesitates. Give 3 more cycles

43 Complete 6 cycles of Doc/Cis. FEV1 1.30L, FEV1% 55.8%

44 Neoadjuvant C/T + Surgery + Adjuvant C/T with Docetaxel+Cisplatin,, NTUH ( ) 2005) Results (39 patients) Overall response rate: 69.3% Surgery performed in 35 patients (89.7%) No operation mortality or major morbidity Median follow-up: 49 months Recurrence: 62.9% 3 year overall survival: 75.9% univariate analysis: early recurrences were correlated with female gender (p=0.024), age < 60 years (p=0.044), adenocarcinomas (p=0.005), and increased number of residual metastatic lymph nodes (p=0.022). Multivariate analysis: adenocarcinoma was the strongest factor for early recurrences over squamous cell carcinoma (p=0.0242).

45 Conclusions ( ) 2005) : Combination of neoadjuvant C/T + surgery +/- adjuvant C/T with Doc+CDDP provides a safe and feasible alternative for stage III NSCLC patients 3-year overall survival: satisfactory Adenocarcinoma was an independent factor for early recurrences over squamous cell carcinoma

46 Adjuvant Chemotherapy for Lung Cancer

47 (1867 patients): IALT Trial (1867 patients): Cisplatin-based adjuvant C/T improves survival with completely resected NSCLC Especially for stage III patients (IALT. NEJM 2004;350:351)

48 結論 :Cisplatin: Cisplatin-based adjuvant C/T is suggested for stage II and III disease Goodgame B. J Thorac Oncol 2009.

49 The role of target therapy in neoadjuvant or adjuvant for lung ca: unclear TARGETS EGFR family Angiogenesis Farnesyltransferase Histone deacetylase mtor COX2. TARGETED AGENTS Erlotinib, gefitinib Bevacizumab, ZD2171 Ionafrmib LAQ824, CI994 RAD001, AP23573 Celecoxib

50 Neoadjuvant (Induction) Erlotinib Response in Stage IIIA Non Small-Cell Lung Cancer 67 y/o female Adenocarcinoma Stage IIIA (T1N2M0) EGFR mutation analysis: Exon 19 deletion OP: LLL B6 segmentectomy + LN dissection Before Erlotibib After Erlotibib J Clin Oncol 2008

96L, 55% of prediction Adenocarcinoma occupyting the right hilum, pneumonectomy is

51 Neoadjuvant (Induction) Gefitinib Response in Locally advanced Lung Cancer 70 y/o female, COPD, FEV1 = 0.96L, 55% of prediction Adenocarcinoma occupyting the right hilum, pneumonectomy is indicated for complete resection EGFR mutation analysis: Exon 21 mutation OP: Right middle lobectomy + LN dissection Before Gefitinib After Gefitinib

Right middle wedge resection + RLL lobectomy + LN dissection Pathology:

52 Adjuvant Erlotinib in Advanced Non Small-Cell Lung Cancer 54 y/o male, RCC s/p right nephrectomy Adenocarcinoma with BAC pattern occupying the RML and RLL OP: Right middle wedge resection + RLL lobectomy + LN dissection Pathology: Mediastinal LN metastasis, T2N2M1, stage IV No recurrence for 14 months after operation

53 肺癌手術與合併治療趨勢 Minimally invasive surgical approaches and procedures Minimally invasive anesthesia Adjuvant therapy if > stage II Personalized treatment 考量身體狀況年齡肺功能 (balance between radicality and life quality) 基因檢測及對藥物之反應

54 臺大雲林分院肺癌國際學術研討會 2010 年 3 月 27 日竭誠歡迎您的參與

聖馬爾定醫院正子中心健保開單診療指引（guideline）

聖馬爾定醫院正子中心健保開單診療指引（guideline）聖馬爾定醫院正子中心健保開單診療指引 (guideline) 2011.10.27 全身癌症掃描檢查 (2010 年 6 月 1 日起健保開始對下列正子掃描之適應症給付 ): 1. 乳癌淋巴癌之分期治療及懷疑復發或再分期 2. 大腸癌直腸癌食道癌頭頸部癌 (