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攝護癌化學治療之副作用管理與衛教注意事項林口長庚血液腫瘤科沈雯琪醫師 2014-10-4

Natural History of Prostate Cancer Typical patient presentation as they move through different stages Local therapy Androgen deprivation Therapies after LHRH agonists and antiandrogens Burden of disease First-line therapy Salvage therapy Death Asymptomatic Nonmetastatic Under the care of Symptomatic ONCOLOGIST Metastatic Castrate sensitive Castrate resistant Higano C, et al. In: Figg WD, et al. Drug management of prostate cancer; 2010.

Treatment Options for Prostate Cancer Have Snowballed After a 6-Yr Hiatus Sipuleucel-T* [8] Cabazitaxel* [7] Denosumab LHRH agonists* [1,2] Zoledronic Acid [4] [9] Abiraterone* [10] Mitoxantrone [3] Docetaxel* [5,6] MDV3100 [11] Radium-223 [12] 1984-1989 1996 2002 2004... 2010 2011 * Approved agent for PCa Reversible AR blockers [1,2] However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy 1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1. 12. Parker C, et al. ASCO GU 2012. Abstract 8.

Interactive Decision Support Tool: 1 Tool; 5 Expert Recommendations In the IDST (Available at: http://clinicaloptions.com/crpctool), the above 5 variables were used to make treatment decisions.

Expert Guidance in Defining and Treating CRPC When Is Chemotherapy Appropriate in the CRPC Patient? Yes, this patient should receive chemotherapy Nodal spread with no evidence of bone or visceral (liver, lung) disease Bone disease without nodal disease or visceral spread Visceral metastases with or without other metastatic sites No, this patient should not receive chemotherapy Locally progressing tumor without metastatic disease Rising PSA and no detectable metastatic disease (rising PSAcastrate) clinicaloptions.com/oncology

Evolving Role of Chemotherapy in the Management of Castration- Resistant Metastatic Prostate Cancer

The trial showed improved pain control with chemotherapy but no difference in survival (it was not powered to show a survival difference) The FDA approved mitoxantrone and prednisone as palliative treatment for men with symptomatic HRPC the first time a chemo drug had been approved based on a symptom control endpoint SOGUG, Madrid

Main results of the Canadian trial of mitoxantrone + prednisone vs prednisone alone Prednisone (N=81) Mitoxantrone + Prednisone (N=80) p Primary endpoint ( pain) 12% 29% 0.01 Total response ( pain and/or pain medication) 21% 38% 0.025 There was no improvement in survival but the trial was too small to detect such differences Mitoxantrone was approved by FDA the first chemo agent to be approved for prostate cancer Mitoxantrone is well tolerated and remains an option for treatment SOGUG, Madrid

Mitoxantrone and prednisone became the comparator for later trials of chemotherapy SOGUG, Madrid

SOGUG, Madrid More toxicity with docetaxel/estramustine compared to mitoxantrone (and with docetaxel/prednisone in TAX-327)

Docetaxel and prednisone became the standard first line palliative chemotherapy for CRPC

Docetaxel HRPC Trials<br />Toxicity Data Presented By Daniel Petrylak at 2014 ASCO Annual Meeting

Taxotere Management of Select Adverse Events

副作用及注意事項 (1) 嗜中性白血球減少症 Neutropenia 嗜中性白血球減少症的發生迅速 ( 最低點的中數在第 8 天 ) 且恢復快速 ( 通常在 1 週內 ) 建議經常性監測血球數目,直到嗜中性白血球數目恢復至大於 1.5 x 10 9 /L 才能再投與剋癌易 Taxotere 嗜中性白血球減少症可能發生在病患回家以後因此,病患應該被告知發生感染的可能性,若病患感覺不適即應該監測體溫若體溫高於 38,則應該告知其治療中心當病患服用類固醇和處在嗜中性白血球減少症的危機中,更應該特別注意口腔衛生

副作用及注意事項 (2) 過敏反應雖然使用口服類固醇前處理藥物可降低過敏反應的頻率及嚴重程度,護理人員仍應該警覺可能發生的過敏反應輸注期間若觀察到嚴重過敏反應,應該立即停止給藥,並即時給予適當治療下列急診用藥在治療過敏反應發生時應能隨時取用 diphenhydramine, 50 mg, IV noradrenaline, 1 ml, 1/1000, IV methylprednisolone, 125 mg, IV dexamethasone, 10 mg, IV salbutamol nebules and nebulizer 為了降低過敏反應的發生率,建議輸注的前 5 分鐘輸注速度變慢,然後持續依照既定速度輸注 1 小時

副作用及注意事項 (3) 體液滯留 Fluid retention 體液滯留並非是危及生命的不良反應它與剋癌易 Taxotere 累積劑量有關通常發生在數個治療周期之後 ( 發生之累積劑量中數為 797 mg/m 2 ),類固醇前處理藥物明顯降低體液滯留的發生率嚴重程度並延後症狀之發生體液滯留可觀察到病患有水腫體重增加,少數病患會有胸肋膜滲出液水或心包膜滲出液若有體液滯留情況發生時,根據體液滯留嚴重情況加上 furosemide 或 spironolactone 長期使用利尿劑應該小心

副作用及注意事項 (4) 皮膚神經學及胃腸方面的反應若有皮膚乾燥或潮濕脫皮現象,病患應被建議採取溫水浴,採用無香水的香皂,並在乾燥皮膚區域敷上水性乳霜若有皮膚癢的情況,可用抗組織胺作症狀處理曾有報告顯示 pyridoxine(vit B6), 口服, 50 mg,每天三次,可減輕改善剋癌易 Taxotere 所致之感覺遲鈍觸痛等現象胃腸方面的副作用,確定病患出院時有開立適當的止吐劑,止瀉劑勸導病患密切注意口腔衛生,使用軟質牙刷及處方的牙膏製品若口腔有傷口,勸導病患避免太辣太鹹的食物

副作用及注意事項 (5) 禿髮使用剋癌易 Taxotere 治療時常發生,禿髮的可能性須在事前告知病患並與之討論,給與準備假髮適當帽子等建議預期想法有助於病患之心理狀態輸注藥物期間使用冰帽可降低禿髮狀況無力關節痛及肌肉痛無力感發在三分之二的病患,約有 12 % 的案例為程度嚴重關節痛及肌肉痛一般為輕度至中度病患應被告知使用剋癌易 Taxotere 治療時,因為這些症狀病患的生活品質可能會有所影響使用輕度止痛劑便可有效減輕關節痛及肌肉痛建議適度運動可改善無力現象

副作用及注意事項 (6) 血管外滲不會引起全身性毒性徵候 / 症狀包括腫脹及 / 或輕微疼痛紅斑靜脈輸注部位無血液回流外滲 (extravasation) 的處理立即停止剋癌易 Taxotere 給藥, 抽吸 IV 注射針, 移除 IV 注射針, 在輸注部位冰敷 15~20 分鐘,並告知病患回家後接下來的 72 小時,每 4~6 小時重複一次或依照一般原則立即處理及告知病患回家後處理方式

Frozen cap & gloves use in the prevention of Docetaxel-induced alopecia & onycholysis reaction

Effectiveness of cold cap in the prevention of docetaxel-induced alopecia M. Lemenager, S. Lecomte, M. E. Bonneterre, E. Bessa, J. Dauba and J. Bonneterre France group European Journal of Cancer Volume 33, Issue 2, February 1997, Pages 297-300

Hypothesis of Mechanism

Study & Results Patients: 98 Method: using a cold cap Drug: 100 mg/m 2 docetaxel l h i.v. Q 3 wks Results: 83 patients (86%) were evaluated as a success to the cold cap, as they presented WHO grade alopecia 2 and no need to wear a wig. 14 patients (14%) had to wear a wig; among them, 7 patients withdrew before the evaluation at three cycles One patient was lost to follow-up. Conclusion: The cold cap is a very effective technique with minimal sideeffects

Assessment of frozen glove use in the prevention of Docetaxel-induced onycholysis reaction: results of a multicenter case-control study Nail toxicity: Dyschromia Onycholysis Beau s line Pain * Lemenager et al, Eur J Cancer, 1997

THE GLOVE Elasto-Gel (glycerin) Cold cap principle * - 20 F (- 30 C) Direct contact protected Frozen 3 hours before use

Drug: STUDY PLAN Docetaxel 75 mg/m² Q3wk, 1 hour IV Single agent or combination Method: Right hand protected with glove, left hand not protected (control) Glove protection started 15 min before and concluded 15 min after infusion Glove changed after 45 minutes Photo and clinical assessment before each cycle

STUDY OBJECTIVE Primary endpoint: Efficacy on onycholysis prevention Secondary endpoints: Efficacy on skin toxicity prevention Median time to nail and skin toxicity occurrence Patient s comfort assessment Nail and skin toxicity incidence

PATIENTS CHARACTERISTICS N=45 (August 2002 September 2003) Median age (range): 65 (41-80) Male 35 (78%) Female 10 (22%) Tumor Type: Prostate 26 (58%) Lung (non small cell) 11 (24%) Breast 5 (11%) Others 3 (6%)

NAIL TOXICITY RESULTS Grade Hand Control (45 patients) Protected Hand (45 patients) 0 49 % 89 % 1 29 % 11 % 2 22 % 0 % p=0.0001 (Wilcoxon test) MEDIAN TIME FOR TOXICITY OCCURRENCE Control (days), CI 95% Protected hand (days), CI 95% Nail 58 (43 73) 105 (64 146)

Nail Toxicity Grade 1 (Dyschromia)

Nail Toxicity Grade 2 (Onycholysis)

PATIENT S COMFORT Global Comfort (n=43) Cold Tolerance (n=43) Satisfied Unsatisfied 86 % 14 % (6 pts) 93 % 7 % (3 pts) N=43 evaluable patients for glove safety (2 pts received Docetaxel but refused the glove)

CONCLUSION Frozen glove significantly prevents (vs control) occurrence of: nail toxicity 11 vs 51 % No onycholysis (grade 2) with glove protection Increased median time until nail toxicity occurrence New tool for supportive care in cancer

Malik Z et al. J Clin Oncol 32, 2014 (suppl 4; abstr 109)

Ongoing Cabazitaxel Trials Presented By Daniel Petrylak at 2014 ASCO Annual Meeting

Cabazitaxel Dosing 給藥劑量乃根據個人的體表面積 BSA 來計算, 其劑量為 25 mg/m2, 每 3 週靜脈輸注一次, 每次輸注時間 1 小時治療期間必須每天口服 prednisone 或 prednisolone 10 mg 製備及投與 cabazitaxel 輸注溶液時, 不可使用聚氯乙稀 PVC 之輸注容器及聚氨酯 polyurethane 之注射用輸液管 1. Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010. 1. Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Cabazitaxel 製備方法 (I) Cabazitaxel 包裝含注射劑及溶劑小瓶注射劑 60 mg/1.5 ml:1.5 ml 的 polysorbate 80 中含有 60 mg 的 cabazitaxel, 稀釋溶劑 : 含有 13%(w/w) 乙醇的注射用水, 大約 5.7 ml Cabazitaxel 注射劑在適當的儲存下呈現清澈濃稠黃至棕黃色溶液 Cabazitaxel 注射前必需進行 2 次稀釋第一次稀釋必須先和所提供之稀釋溶劑的所有內容物完全混合 Both items are in a blister pack inside 1 carton¹ 1. Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Cabazitaxel 製備方法 (II) 第二次最終稀釋將步驟 1 製備而得的 Cabazitaxel 10 mg/ml 溶液以校準之注射器抽取建議之劑量, 將其注入含有 0.9% 氯化鈉溶液 ( 生理氯化鈉注射液 ) 或 5% 葡萄糖溶液 ( 注射液 ) 的無菌非 PVC 材質之 250 ml 容器中, 以進一步稀釋成輸注液 1. Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Cabazitaxel 製備方法 (III) Cabazitaxel 的最終輸注液 0.9% 氯化鈉溶液 ( 生理氯化鈉注射液 ) 或 5% 葡萄糖溶液 ( 注射液 ) 應於常溫下 8 小時內包括 1 小時的輸注時間用完, 若為冷藏, 則必須在 24 小時內包括 1 小時的輸注時間用完因為最終輸注液為過度飽和溶液, 在一段時間後可能會有結晶析出若有這種情況發生, 應丟棄不用使用前應以肉眼檢查是否有顆粒產生任何結晶或變色的情況若 Cabazitaxel 的第一次稀釋溶液或第二次最終稀釋的輸注液不清澈或出現沉澱物, 則應予以丟棄

Cabazitaxel Premedication 每次給藥前至少 30 分鐘應先給予下列靜脈注射的前驅藥物, 以降低過敏反應的危險及 / 或嚴重度 Antihistamine: dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent antihistamine Corticosteroid: dexamethasone 8 mg or equivalent steroid H 2 antagonist: ranitidine 50 mg or equivalent H 2 antagonist Anti-emetic prophylaxis (oral or IV) is recommended if needed Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Jevtana Management of Select Adverse Events

Hypersensitivity May occur in patients sensitive to Polysorbate 80 ( 注射劑 60 mg/1.5 ml:1.5 ml 的 polysorbate 80 中含有 60 mg 的 cabazitaxel) All patients should be premedicated before infusion of Cabazitaxel Patients should be observed closely during the first 2 infusions of Cabazitaxel for hypersensitivity reactions Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Management of Severe Hypersensitivity Reactions TIME MOST LIKELY TO OCCUR First few minutes of infusion, especially during the first or second course of Cabazitaxel INTERVENTION Stop infusion; maintain IV access with normal saline during the first or second course of Cabazitaxel Treat with diphenhydramine 50 mg IV and/or dexamethasone 10 mg IV and/or epinephrine DO NOT RECHALLENGE 1) Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010; 2) Ignoffo R, et al. Preventing chemotherapy toxicities and other issues on drugs used in oncology. Updated 2010. Available at http://www.cancersupportivecare.com/chemotherapy.html; 3) ASCO. J Clin Oncol. 2004;22:4613-4615.

Management of Neutropenia* TIME MOST LIKELY TO OCCUR Median time to nadir (12 days) 1 GENERAL RECOMMENDATIONS Weekly CBC with ANC required with first dose, then before each subsequent cycle Cabazitaxel should not be administered if the neutrophil count is 1500 cell/mm 3 *Febrile neutropenia, or documented infection with neutropenia, or neutropenia > 7 days. Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010 1 Mita A C, etal. Clin Cancer Res. 2009;15:723-730

Growth Factor Support Primary prophylaxis Therapeutic use and secondary prophylaxis Should be considered in patients with high risk features Age > 65 years Poor performance status Previous episodes of febrile neutropenia Extensive prior radiation ports Poor nutritional status Other serious comorbidities Should be considered in all patients considered to be at increased risk for neutropenic complications Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010.

Management of Diarrhea TIME MOST LIKELY TO OCCUR After each infusion GENERAL RECOMMENDATIONS First episode: loperamide 4 mg PO, then 2 mg PO after each episode until resolution (no more than 16 mg/day) Assess patient s diet Adequate fluid intake Avoid insoluble fiber, alcohol, caffeine, lactose, fried foods Include soluble fiber: rice, noodles, white toast, bananas If grade 3 diarrhea still occurs after loperamide and fluid and electrolyte replacement Delay treatment until improvement or resolution Reduce Cabazitaxel dose to 20 mg/m 2 Important: Discontinue Cabazitaxel treatment if a patient continues to experience any of these reactions at 20mg/m 2 Cabazitaxel Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010; ONS. Putting Evidence into Practice. Available at http://www.ons.org.

NCCN 2014 guideline(i)

NCCN 2014 guideline(ii)

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