RADIOTHERAPY FOR HEAD AND NECK CANCER

Transcription

1 Topics Introduction of head and neck cancer. The role of chemotherapy in head and neck cancer. Recent advances of chemotherapy in head and neck cancer.

2 頭頸癌 鼻咽癌 口腔癌 : 唇, 舌, 頰, 牙齦, 硬顎.. 等等 口咽癌 : 扁頭腺, 舌根, 軟顎.. 等等 下咽癌 喉癌 其他 : 鼻腔癌, 唾液腺癌, 副鼻竇癌 等等

3 臺灣地區癌症十大死因, 2009 癌症類死亡人數死亡率 (/10 5 ) 百分比 總死亡數 肺癌 肝癌 大腸直腸癌 女性乳癌 胃癌 口腔口咽下咽癌 攝護腺癌 食道癌 胰臟癌 子宮頸癌 鼻咽癌

4 男女性十大癌症發生率, 民國 94 年 (7159 人 ) 肝 (5566 人 ) 肺 (5497 人 ) 結腸及直腸 (4310 人 ) 口腔 (2704 人 ) 攝護腺 (2288 人 ) 胃 (1403 人 ) 食道 (1363 人 ) 膀胱 (1138 人 ) 皮膚 (1123 人 ) 鼻咽 (6879 人 ) 其他癌症男性共 人 乳房 (6594 人 ) 結腸及直腸 (4107 人 ) 肝 (2757 人 ) 肺 (2746 人 ) 子宮頸 (1977 人 ) 胃 (1292 人 ) 甲狀腺 (1146 人 ) 皮膚 (1039 人 ) 子宮體 (987 人 ) 卵巢 (894 人 ) 其他癌症 (5938 人 ) 女性共 人

5 臺灣地區男性癌症十大死因, 2009 癌症類死亡人數死亡率 (/10 5 ) 百分比 總死亡數 肝癌 肺癌 大腸直腸癌 口腔口咽下咽癌 胃癌 食道癌 攝護腺癌 胰臟癌 白血病 非何杰金淋巴癌 鼻咽癌

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8 95-97 年台東縣十大惡性腫瘤排名一覽表

9 97 年台東縣與鄰近縣市之十大惡性腫瘤排名比較表

10 頭頸部癌症 台灣地區每 10 名新癌症病患中, 就有 1 位是頭頸癌患者 好發機率依序為口腔癌 鼻咽癌 喉癌 下咽癌 但台灣一半以上的口腔癌病人發現時, 都已第三期 第四期

11 頭頸部癌症發生原因 抽菸 :18 倍酒 : 10 倍檳榔 : 28 倍 煙 + 酒 + 檳榔 : 123 倍

12 頭頸部癌症發生原因 病毒 : EBV 病毒 => 鼻咽癌人類乳突狀病毒 => 口咽癌 遺傳 : 一等親內如果有人罹患鼻咽癌, 此人發生鼻咽癌的機率唯一般人的 16.3 倍 食物 : 鹽醃製品 環境汙染物 : 含硫酸的強無機酸霧 => 喉癌

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14 Topics Introduction of head and neck cancer. The role of chemotherapy in head and neck cancer. Recent advances of chemotherapy in head and neck cancer.

15 化學治療於頭頸癌的運用 前導性化療 (Neoadjuvant chemotherapy) : 在局部性治療 ( 手術及放射線治療 ) 以前所做的化療就是前導性化療 目的為減少局部腫瘤體積, 使開刀較容易, 減少遠處轉移以及評估腫瘤對化學治療的反應 併行性放射線化學治療 (Concurrent chemoradiation) : 同時進行放射線治療及化學治療 目的在增強放射線效果同時有細胞毒殺的功用 輔助性化療 (Adjuvant chemotherapy) : 施行於外科手術或放射線治療後, 用以殺死肉眼看不見之殘餘癌細胞 目的在減少局部復發及減少遠處轉移的機率 救援性化療 (Salvage chemotherapy) : 當第一線治療失敗時, 所進行之第二線治療 目的仍以腫瘤為治療目標, 積極地朝治癒方向進行 緩和性化療 (Palliative chemotherapy) : 針對轉移性疾病, 保守地不以治癒為目標, 使用化療藥物減輕癌症引起的症狀, 提高病人的生活品質, 即使無法延長生命

16 固態腫瘤 (solid tumor) 的化學治療 1. 治癒性 前導性化學治療 Induction chemotherapy 輔助性化學治療 Adjuvant chemothrapy 主要治療 : 手術 / 放射治療 完全緩解 同步放射與化學治療 Concurrent chemoradiotherapy 2. 姑息性 : 姑息性化學治療 (Palliative chemotherapy) : 復發或遠處轉移病患

17 化學治療在頭頸癌治療 過去化學治療在頭頸癌多半是擔任 症狀緩解治療 的角色, 對於復發 轉移之病患以化療減輕症狀, 延長生命 現在化學治療在頭頸癌的地位, 已由過去 救援投手 的角色升任為第一線 先發投手 : (-) EORTC, RTOG 9111 : 化學治療提升局部晚期頭頸部癌症的器官的保存率 ( 二 ) RTOG 9501, EORTC : 化學放射同步治療可提升頭頸癌治癒率

18 頭頸癌治療原則 鼻咽癌 : 放射線治療化學治療標靶治療 ( 自費 ) 口腔癌 : 手術切除放射線治療 +/- 化學治療標靶治療 ( 自費 ) 咽喉癌 : => 全喉切除 +/- 放射線治療 / 化學治療 => 放射線治療 + 化學治療或標靶治療, 若效果不佳再作全喉切除

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20 Topics Introduction of head and neck cancer. The role of chemotherapy in head and neck cancer. Recent advances of chemotherapy in head and neck cancer.

21 化學治療在頭頸癌治療 傳統以使用順鉑 (Cisplatin) 與 5-FU 兩種藥物為主 新一代的化學治療藥物 : Taxotere 標靶藥物 : Erbitux

22 Taxane 的作用方式 Taxane 類藥物會促進 Tubulin 的 polymerization 作用並抑制 Microtubule 的 depolymerization 而形成穩定但無功能之微小管束,在細胞分裂期間,妨礙兩套染色體被分離至 2 個子細胞中,細胞因此停滯於細胞分裂期,由於不正常的有絲分裂及細胞漿移動 (cytokinesis) 而死亡 簡單的說, 就是停止細胞內微小管的活動, 進而使癌細胞停止分裂進而死亡.

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24 TPF in locally advanced SCCHN: phase III study design Patients : unresectable SCC of the HN cancer. PF x 4 cycles -> RT (n=181) Cisplatin 100 mg/m2 D1 5-FU 1000 mg/m2 D1-D5 Stage III and IV non metastatic SCCHN (n=358) R TPF x 4 cycles -> RT (n=177) Taxotere 75 mg/m2 D1 Cisplatin 75 mg/m2 D1 5-FU 750 mg/m2 D1-D5 Primary endpoint: progression free survival Secondary endpoints: OS, TTF, duration of response, and safety

25 Outcome Median F/U : 32.5 mo Median PFS TPF => 11 mo PF => 8.2 mo Median OS TPF => 18.8 mo PF => 14.5 mo TPF reduces 28% in the risk of disease progression or death compared with PF

26 TAX 324 Phase III Trial of Induction Docetaxel-Cisplatin- 5FU (TPF) vs PF in Unresectable HNC: Study Design Patient Population Stage III or IV Inoperable SCCHN Stratification Center N status Primary site N = 501 R Endpoints Primary: OS Secondary: progression-free survival, response rates after induction, toxicity TPF 2 q3wk x 3 cycles PF 1 q3wk x 3 cycles RT+CT 3 Possible surgery Posner et al. N Engl J Med. 2007;357: Cisplatin: 100 mg/m² D1 5FU: 1000 mg/m² D1 - D5 2 Docetaxel: 75 mg/m² D1 - CDDP: 100 mg/m² D1 5FU: 1000 mg/m² D1 - D4 3 Weekly Carboplatin (AUC 1.5) x 7 - Conventional radiotherapy = 70 Gy

27 Probability (%) TAX 324: Overall Survival Median Follow-up: 42 Months TPF 67% PF 55% Time (months) Parameter TPF (n=255) PF (n=246) Median OS, mo (95% CI) TPF 62% PF 48% NR Died* 41% 53% HR TPF:PF [95% CI] 0.70 [ ] Log-rank p-value Posner et al. N Engl J Med. 2007;357:

28 TAX 324: Toxicity During Induction Chemotherapy Number of patients TPF (n=251) PF (n=243) NCIC-CTC Classification Grade 3/4 Grade 3/4 Anemia Thrombocytopenia Neutropenia Febrile neutropenia Nausea Alopecia Stomatitis Lethargy Vomiting Diarrhea Anorexia 12% 4% 83% 12% 14% 4% 21% 5% 8% 7% 12% 9% 11%* 56%* 7%* 14% 1% 27% 10%* 10% 3% 12% Posner et al. N Engl J Med. 2007;357: *Statistically significant (P <.05)

29 TAX 324 Phase III Trial of Induction TPF: Key Points TPF significantly improves survival versus PF 14% absolute improvement in 3-y survival 10% absolute improvement in 5-y survival 26% reduction in mortality (P = 0.014) Sequential therapy with TPF is tolerable and safe Toxicity of TPF arguably less than that of PF No significant difference in long-term toxicities (enteral feeding tube and tracheostomy) Sequential therapy with TPF followed by carboplatin-based chemoradiotherapy represents an acceptable standard of care for locally-advanced SCCHN

30 Phase III Trial of Induction (T)PF CT-RT vs CT-RT Alone in Unresectable Locally Advanced HNC: Study Design Primary endpoint: TTF in evaluable population (Time from randomization to progression, recurrence, surgery, death, withdrawal due to adverse events or no locoregional control) Secondary endpoints: locoregional control, TTP, OS, safety TTF R N=439 CRT (Cisplatin 100 mg/m 2 d1,22, 43) PF 3 cycles q3w CRT (Cisplatin 100 mg/m 2 d1,22, 43) Cisplatin 100 mg/m 2 d1, 5-FU 1000 mg/m 2 /d d1-5 (CIV). Neck dissection Surgery TPF 3 cycles q3w CRT (Cisplatin 100 mg/m 2 d1,22, 43) Hitt et al. ASCO Abstract Docetaxel 75 mg/m 2 d1, Cisplatin 75 mg/m 2 d1, 5-FU 750 mg/m 2 /d d1-5 (CIV) + primary G-CSF after protocol amendment.

31 Phase III Trial of Induction (T)PF CT-RT vs CT-RT: TTF (evaluable) HR = 0.57; 95% CI, p< ICT + CRT median 12.5 months CRT median 5.0 months 0.0 Number of patients at risk E N (Months) Hitt et al. ASCO Abstract 6009.

32 Phase III Trial of Induction (T)PF CT-RT vs CT-RT: Key Points Induction chemotherapy (ICT) prior to chemoradiotherapy is achievable, with manageable safety resulted in a doubling of time to treatment failure and significant benefit in locoregional control The outcomes suggest that ICT prior to CRT should now be considered as standard in patients with unresectable LAHNC Hitt et al. ASCO Abstract 6009.

33 Taxane in the treatment of HNC

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35 Target Therapy - Cetuximab Mechanisms of action - Erbitux (Cetuximab) - Erbitux is an IgG1 MAb targeting the EGFR Binding blocks EGFR signaling and inhibits proliferation, angiogenesis and metastasis, and stimulates apoptosis and differentiation Fc region may induce antibody-dependent cellmediated cytotoxicity (ADCC) (immune response) Courtesy of José Baselga (modified)

36 Cetuximab: IgG1-Induced Antibody-Dependent Cell Cytotoxicity (ADCC) IgG1 (cetuximab) Lysis of antibody-coated cell EGFR MEDIATED Anti-tumour Activity IgG1 MEDIATED ADCC MAXIMIZE ANTI-TUMOUR ACTIVITY Fan Z, et al. Cancer Res.1993;53: ;53:4322-8

37 EGFR expression in selected human tumors Colorectal EGFR is expressed in a variety of solid tumors Lung (NSCLC) Head & neck cancer Lung cancer (NSCLC) % 40 91% Colorectal cancer 72 84% Head & Neck (SCC) Breast cancer 14 91% Ovarian cancer 35 70% Renal cell cancer 50 90% Cunningham et al. N Engl J Med 2004;351: ; Grandis et al. Cancer 1996;78: ; Salomon et al. Crit Rev Oncol Hematol 1995;19: ; Walker & Dearing. Breast Cancer Res Treat 1999;53: ; Folprecht et al. ASCO 2004 (Abstract #283).

38 Alive (%) Failed (%) High EGFR expression in SCCHN is linked to lower survival and increased risk of 100 locoregional relapse Overall survival p= Locoregional relapse p= EGFR>median 50 EGFR median 50 EGFR median EGFR>median n= n= Years from randomization Years from randomization Ang K, et al. Cancer Res 2002;62:

39 ERBITUX + RT in locally advanced SCCHN: phase III study design Stratified by KPS Nodal involvement Tumor stage RT fractionation a Stage III and IV non metastatic SCCHN (n=424) R RT (n=213) Primary endpoint: duration of locoregional control Secondary endpoints: OS, PFS, RR, and safety ERBITUX + RT (n=211) ERBITUX initial dose (400 mg/m 2 ) 1 week before RT ERBITUX (250 mg/m 2 ) + RT (weeks 2 8) b Bonner J, et al. N Engl J Med 2006;354:

40 Locoregional control (%) Erbitux + RT: Locoregional control Erbitux + RT (n=211) RT (n=213) 47% (3-year control rate)a months 24.4 months Time (months) Hazard ratio=0.68 (95% CI: ); p= % (3-year control rate) Bonner J et al. N Engl J Med 2006;354:

41 Probability of overall survival Erbitux + RT: Overall survival 5-year update Erbitux + RT (n=211) RT (n=213) % (5-year survival rate) months Time (months) Hazard ratio=0.73 (95% CI: ); p= months 36.4% (5-year survival rate) Bonner J et al. Lancet Oncology published online Nov 2009

42 Erbitux + RT: Relevant grade 3 5 adverse events Mucositis/stomatitis Dysphagia Radiation dermatitis Xerostomia RT (n=212) Erbitux + RT (n=208) Fatigue/malaise Acne-like rash p<0.001 a Infusion reactions b p=0.01 a Patients (%) Median duration of any mucositis or dysphagia in the overall population was weeks and similar in both treatment groups a Fisher s exact test b Listed for its relationship to Erbitux Bonner J et al. N Engl J Med 2006;354:

43 Probability of survival (%) Erbitux + RT: Impact of skin rash grade on survival Development of skin rash is a strong predictive factor for prolonged survival Prominent rash group (n=127) Grade 2 4 Minimal rash group (n=81) Grade 0/1 51% reduction in the risk of death (p=0.002) months >68.8 months p=0.002, HR=0.49 ( ) Time (months) Bonner J et al. Int J Radiat Oncol Biol Phys 2008;72(Suppl):Abstract LB3

44 Global health status / QoL score Phase III study: change of QoL* as a function of time ERBITUX + RT significantly improves locoregional control and overall survival without adversely affecting QoL Visit Radiotherapy Radiotherapy / ERBITUX Baseline Week 4 Month 4 Month 8 Month 12 *Postbaseline scores for the QLQ-C30 Curran D, et al. J Clin Oncol 2007;25:

45 ERBITUX in locoregionally advanced SCCHN: efficacy summary ERBITUX + high-dose RT demonstrated significant efficacy benefits over high-dose RT alone RT + ERBITUX 20-month increase in median survival 10-month increase in median LR control Increase 10% absolute 5-year survival rate Almost 6 years survival in G2/4 skin rash group Bonner J, et al. N Engl J Med 2006;354:

46 ERBITUX in locoregionally advanced SCCHN: safety summary ERBITUX did not significantly increase acute RT-related side effects RT + ERBITUX 90% of all patients received the planned dose of ERBITUX ERBITUX did not affect RT-related QoL scores Main ERBITUX associated side effect was acne-like rash Bonner J, et al. N Engl J Med 2006;354: ; Curran D, et al. J Clin Oncol 2007;25:

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48 Compliance with ERBITUX or chemotherapy when administered with RT CRT arms of studies comparing CRT vs RT alone Patients receiving all planned doses (%) Bonner et al: Weekly doses (median 8 doses) ERBITUX 90% Huguenin et al: Cisplatin Full CT dose: 2 cycles on weeks 1 and 5 2nd cycle 71% Calais et al: Full CT dose: 3 cycles on weeks 1, 3, and 6 Carboplatin / 5FU 3rd cycle 66% / 67% Wendt et al: Cisplatin / 5FU / FA 3 cycles on weeks 1, 3, and 6 3rd cycle 46% / 47% / 59% Bonner J, et al. N Engl J Med 2006;354: ; Huguenin P, et al. J Clin Oncol 2004;22: Calais G, et al. J Natl Cancer Inst 1999;91: ; Wendt TG, et al. J Clin Oncol 1998;16:

49 Taxane in the treatment of HNC

50 Erbitux in Treatment of Recur / Meta SCCHN (EXTREME Study)

51 EXTREME: Study design Randomized Group A Either cisplatin (100 mg/m 2 IV, d1) or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m 2 IV, d1 4): 3-week cycles + ERBITUX 400 mg/m 2 initial dose then 250 mg/m 2 weekly Group B Either cisplatin (100 mg/m 2 IV, d1) or carboplatin (AUC 5, d1) + 5-FU (1000 mg/m 2 IV, d1 4): 3-week cycles 6 chemotherapy cycles maximum ERBITUX No treatment Progressive disease or unacceptable toxicity Vermorken JB et al. N Engl J Med 2008;359:

52 EXTREME study Cetuximab + platinum / 5-FU (n=222) Platinum / 5-FU (n=220) Median age (range) 56 years (37 80) 57 years (33 78) Men / women 89% / 11% 92% / 8% Recurrence/metastasis Locoregional recurrence Metastasis a 54% 46% 54% 46% Primary metastatic disease 8% 7% Vermorken JB, et al. N Engl J Med Sep 11;359(11):

53 Survival probability EXTREME: overall survival Cetuximab + CTX CTX only HR (95% CI): (0.644; 0.986) Strat. log-rank test: months 10.1 months Survival time (months) Patients at risk Vermorken JB, et al. N Engl J Med Sep 11;359(11):

54 Objective response rate (%) a Objective response rate (CR+PR) Vermorken JB, et al. N Engl J Med 2008;359: EXTREME: Objective Response Rates a P < % 20%

55 Most relevant Grade 3/4 Adverse Events (%) Modified from Vermorken JB, et al. N Engl J Med 2008;359: EXTREME: Most Relevant Grade 3/4 Adverse Events Platinum/5-FU (n=215) Platinum/5-FU + ERBITUX (n=219)

56 Erbitux in the treatment of Recur / Meta HNC

57 Erbitux 爾必得舒於 HNSCC 的使用 健保局 時機 限與放射線療法合併使用於局部晚期之口咽癌 下咽癌及喉癌患者, 且符合下列條件之一 : 1. 年齡 70 歲 ; 2. Ccr <50ml/min; 3. 聽力障礙者 ( 聽力障礙定義為 500Hz 1000Hz 2000Hz 平均聽力損失大於 25 分貝 ); 4. 無法耐受 platinum-based 化學治療

58 馬偕醫院頭頸癌化學治療準則

59 馬偕醫院頭頸癌化學治療準則

60 馬偕醫院頭頸癌化學治療準則