肺癌 完成日期:20120618

學習目標 肺癌篩檢與預防 小細胞肺癌(small cell lung cancer, SCLC)與非小細 胞肺癌(non small cell lung cancer, NSCLC)的治療與 監測 臨床治療準則 治療相關的預期療效

流行病學 資料來源: 國民健康局

流行病學(續) 資料來源: 國民健康局

流行病學(續) 資料來源: 國民健康局

吸菸率與肺癌死亡率 資料來源:國民健康局

肺癌病理學 小細胞肺癌(~13%) 非小細胞肺癌(~87%) 通常病程進展迅速 與吸菸相關 腺癌(37-47%) 發生率逐漸下降 非小細胞肺癌(~87%) 腺癌(37-47%) 常見於非吸菸者 鱗狀上皮細胞癌(25-32%) 生長較緩慢 巨細胞癌(large cell carcinoma, 10-18%, 發生率漸降)

轉移 淋巴結 骨頭 肝臟 腎上腺 腦部

小細胞肺癌

病例一 林OO，59歲已婚男性。職業為快炒店老闆，習慣每天抽 兩包菸。因乾咳、吞嚥困難、飲水時易嗆到、爬四層樓後 便呼吸困難、持續聲音沙啞。於是至外院就診，在外院進 行胸部X光及電腦斷層檢查，發現肺部有不正常顯影。 過去病史: 20年前曾進行過皮下脂肪瘤摘除手術 家族病史: 無 用藥史: 無

身體檢查 (Physical Examination) BP 151/92 P 97 T 36.6℃ Wt 85.1 kg HT 162.0 cm BSA 1.78m2 General Well-nourish and developed man without respiratory distress HEENT Head- no mass or other lesion Neck No palpable mass Breath sounds Clear, no wheezing Heart Regular heart beats, no murmur Abdomen Ovoid Extremities Free movable, no pitting edema

Lab 檢驗名稱 結果值 單位 參考值 Na 143 mmol/L 135 - 148 K 3.9 3.7 - 5.3 Cl 107 96 - 110 Ca 9.6 mg/dl 8.0 - 9.9 BUN 13 8.0 - 23.0 Cr 0.88 0.60 - 1.30 INR 1.02 Index < 1.3 W.B.C 6.74 10^3/ul 3.6 - 10.0 SEG 60.4 % 40.0 - 75.0 LYMPH 30.7 20.0 - 50.0 MONO 5.5 2 - 10 HGB 15.6 g/dl 13.5 - 17.5 PLT 253.0 150 - 400

Lab 檢驗名稱 結果值 單位 參考值 BASO 0.3 % 0.0 - 1.0 Bilirubin Total 0.46 mg/dl 0.20 - 1.20 Bilirubin Direct 0.16 0.00-0.40 ALP 88 U/L 40-129 AST / GOT 17 10 - 27 ALT / GPT 23 5 - 33 LDH 382 106 - 211

Work-up 胸部X光: 在左上葉(LUL)有腫塊，縱膈腔兩側及左 邊胸門淋巴結膨大。 細針抽吸: 小細胞肺癌。 骨骼掃描: L5 spine 有不正常顯影，推斷是退化性 病變，無骨骼轉移。 腦部電腦斷層: 無腦部轉移

小細胞肺癌的分期 局限期(Limited stage) : 病變局限在半側胸腔和 同側淋巴結 擴散期(Extensive stage) : 病變範圍超越了局限 期的界線，即出現了遠端轉移的病灶或另一側 的胸腔

問題 在limited stage之小細胞肺癌的治療為何? 這位病人的預後為何? 這位病人最有可能遇見的副作用為何?

治療- Limited stage SCLC 治療目標: 治癒 同步放射線及化學治療(45-70 Gy total) 需進行4-6個療程 在18-24個月時的存活率為40-50% 同步放射線及化學治療(45-70 Gy total) 含Cisplatin 之化學治療 Cisplatin 60 mg/m 2 IV D1, etoposide 120 mg/m 2 IV D1-3 Q21days 需進行4-6個療程 Response rate: ORR 65-95%, CR 45-75% 達到完全緩解(CR)後的病人，需進行預防性的腦部放 射線治療 Meta-analysis: 3年存活率15% vs. 21%

治療- Extensive stage SCLC 治療目標: 緩和治療 化學治療 PS 0-1: Cisplatin ˙75 mg/m 2 IV D1, etoposide 100 mg/m 2 IV D1-3 Q21days * 4-6 cycles PS 2: 降低起始劑量及/或以carboplatin替換 不同的劑量或頻率給與cisplatin + etoposide有相似的療效 Initial response rate: ORR 60-80%, CR 15-20% 存活率: 經化學治療後，平均存活期為9-11個月 給4-6次化療後，再次評估病情 增加化學治療次數並無好處

治療- Extensive stage SCLC (續) 年紀太大或身體狀況較差的病人的預後相當差- 應提 早考慮安寧醫療! 腦部放射線治療 已有腦部轉移 有症狀: 化學治療前便先執行腦部放射線治療 無症狀: 化學治療後再執行腦部放射線治療 無腦部轉移 若在化療後，胸部的病灶已有緩解，則需進行腦部放射線治療。 此舉可將一年存活率由13%提高至27%

病例一 - 治療 以cisplatin/etoposide + RT治療 施打cisplatin前先給與1.5 L的生理食鹽水，施打 cisplatin後給與2 L 生理食鹽水+20 mEq KCl 止吐藥: aprepitant, 5-HT3 antagonist, 及 dexamethasone 因劇烈嘔吐，故第2-4次化療便改以70%的劑量施打 因CT顯示胸腔內的腫塊縮小，但右邊腎上腺有腫大的現 象，第5次化療改以80%的劑量，第6次化療更以90%的 劑量施打 RT(共60 Gy)已全部結束，醫師計畫再多做2-4次化療， 若腫瘤持續增大，則改以第二線化學治療。

治療- Extensive stage SCLC (續) 對第二線化學治療的反應 ＞6個月才復發-可考慮再次進行同樣的化學治療 3-6個月內復發: ORR 20-30% ＜3個月內便復發: ＜10% 單一藥物的療效 藥物 ORR Topotecan 17-25% Irinotecan 16-24% Vinorelbine 14% Gemcitabine Paclitaxel 29% Docetaxel 25%

第二線化學治療-topotecan Topotecan 1.5 mg/m2 IV daily *5 days, Q21 days = Topotecan 2.3 mg/m2 PO daily *5 days, Q21 days 常見副作用: 白血球數下降、中性球數下降、血小板減少、 貧血、噁心、嘔吐、掉髮 依腎功能調整劑量: Clcr＞50 ml/min : 75% Clcr=10-50 ml/min : 50% Clcr＜10 ml/min : 25%

非小細胞肺癌

篩檢-NSCLC National lung cancer screening trial (NLST) 2002-2004- 將53,454個受試者隨機分配至每年照射胸部 X光或低劑量電腦斷層兩組，執行至2009年底。這些受試 者為55-74歲，並具有高度危險因子(≧30 pack year 抽菸 史) 主要終點(primary endpoint): 整體存活期(overall survival)

篩檢-NSCLC 結果: 討論: 在CT組，每檢測320個人才能防止1人死於肺癌 因肺癌而死亡: CT 247/100,000 person-year vs. CXR 309/100,000 person-year. Rate ratio: 1.13; 95% 信賴區 間: 1.03- 1.23 死亡率(不論死因為何)在低劑量電腦斷層組下降了6.7% 檢出率(positive screens): CT 24.2% vs. CXR 6.9% 討論: 偽陽性發生率: CT 96.4% vs. CXR 94.5% 經濟效率? 在CT組，每檢測320個人才能防止1人死於肺癌 NEJM 2011 ;365:395-409

預後-NSCLC 可手術切除 5年存活率 ⅠA ＞70% ⅠB 60% ⅡA 50% ⅡB 30-40% ⅢA 10-30% 不可手術切除 平均存活期 ⅢB 10-14個月 Ⅳ 19-37週

7th Edition of TNM Staging 6th Edition Descriptor 7th Edition N0 N1 N2 N3 T1 (≤ 2 cm) T1a IA IIA IIIA IIIB T1 (> 2-3 cm) T1b T2 (> 3 to ≤ 5 cm) T2a IB T2 (> 5-7) T2b IIB T2 (> 7 cm) T3 T3 invasion T4 (same lobe nodules) T4 (extension) T4 M1 (ipsilateral lung) T4 (pleural effusion) M1a IV M1 (contralateral lung) M1 (distant) M1b Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

NSCLC Stage

輔助性化療-NSCLC Stage Ⅱ-ⅢA: Cisplatin 為主的化學治療, 可增加5年存活率 Vinorelbine + cisplatin 的組合在研究論文中最常被使用 4 cycles 存活危險比(survival hazard Ratio): 有接受輔助性化療:沒接受輔助性化療=0.69 (0.52-0.91) Grade toxicity ¾=33%-75% Age consideration 65-75: no difference VS <65 >75, few studies J Clin Oncol 2007;25:5506-5518

治療-stage ⅢB NSCLC 治療目標: 縮小腫瘤，以期手術。 治療方式: 同步放射線及化學治療的療效會比接續式放射線及化學治 療(sequential chemoradiotherapy)來得好，但毒性也比 較大。 Cisplatin 50 mg/m2 IV D1,8,29,36 Cisplatin 100 mg/m2 IV D1,29 Etoposide 50 mg/m2 IV D1-5, 29-33 Vinblastine 5 mg/m2 IV weekly * 5 RT= 61Gy total RT= 60 Gy total 2 cycles

晚期非小細胞肺癌 第ⅢB期: 第四期轉移至腦、骨、腎上腺、肝、不同肺葉 有心包膜積水 轉移至鎖骨上淋巴結 緩和性化學治療(PS 0-1): 1. 增進生活品質 2. 延長存活期 3. 減少症狀 4. 適當的投報率 第四期轉移至腦、骨、腎上腺、肝、不同肺葉 第ⅢB期: 有心包膜積水 轉移至鎖骨上淋巴結

組織學- NSCLC 這些病人有相同的診斷及臨床症狀 (第四期非小細胞肺癌) 65歲男性吸菸者 鱗狀上皮細胞癌 KRAS Mt Mt, mutation; NSCLC, non-small-cell lung cancer.   The question that we just posed and what is shown on this slide emphasizes the first point of differentiation between patients with non-small-cell lung cancer, and that is recognition of great interpatient heterogeneity in the molecular characteristics. These are the differences between one patient and the next. In this cartoon, all the figures appear to be the same, but if we look at 3 patients individually, you will see this first patient is a 65-year-old male smoker, who has squamous cell carcinoma. His cancer is characterized by a KRAS mutation.

組織學- NSCLC (續) 這些病人有相同的診斷跟臨床症狀 (第四期非小細胞肺癌) 65歲男性 39歲女性 吸菸者 非吸菸者 鱗狀上皮細胞癌 39歲女性 非吸菸者 腺癌 KRAS Mt EGFR Mt Mt, mutation; NSCLC, non-small-cell lung cancer.   Our third patient, shown here, is a 54-year-old male never-smoker with adenocarcinoma. His cancer is molecularly defined by an ALK fusion. Why is this important? I think it is obvious to everyone in the year 2012 that these patients are very different. Most oncologists would agree that these patients had different malignancies; most oncologists would also agree that these patients should receive different therapy.

組織學- NSCLC (續) 這些病人有相同的診斷跟臨床症狀 (第四期非小細胞肺癌) 65歲男性 39歲女性 吸菸者 非吸菸者 鱗狀上皮細胞癌 39歲女性 非吸菸者 腺癌 KRAS Mt EGFR Mt Mt, mutation; NSCLC, non-small-cell lung cancer.   Our third patient, shown here, is a 54-year-old male never-smoker with adenocarcinoma. His cancer is molecularly defined by an ALK fusion. Why is this important? I think it is obvious to everyone in the year 2012 that these patients are very different. Most oncologists would agree that these patients had different malignancies; most oncologists would also agree that these patients should receive different therapy. 54歲男性 非吸菸者 腺癌 ALK fusion

在所有病人群中，擁有”有潛力可接受目前已有或正在研究中的藥物治療”的驅動變異(Driver mutation)占有多少比例? 2% 10% 25% 50% 75% So, the answer here is actually 50%, and I was surprised when I heard these data. So, let me show you why 50% is an appropriate answer, and why it really opens a great deal of promise for the future.

Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas No Mutation Detected KRAS 22% AKT1 EGFR 17% NRAS MEK1 ELM4-ALK 7% MET AMP HER2 Now, this is being done by other groups as well, and this is data that was presented at the World Conference by Bruce Johnson and his colleagues from the Lung Cancer Molecular Consortium. And it shows that in 54% of lung adenocarcinomas that were analyzed, an actionable driver mutation or abnormality was found, so this is the answer to the question I asked you earlier about in what percentage of cases would you find some actionable abnormality?   And in this study they referred patients to appropriate biomarker driven clinical trials, based on the specific analysis. PIK3CA 2% BRAF 2% Double Mutants 3% Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%) Referral to appropriate biomarker-driven clinical trial based on patient-specific analysis Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01

晚期 NSCLC 治療 Advanced-Stage NSCLC & PS 0-1 Erlotinib or gefitinib EGFR mutation positive ELM4-ALK positive EFGR mutation and ALK negative and nonsquamous histology EFGR (-) squamous histology Bevacizumab appropriate Bevacizumab inappropriate Erlotinib or gefitinib first line NSCLC, non-small-cell lung cancer; PS, performance score.   So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy. Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed ± bevacizumab Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

結論-晚期 NSCLC 治療 Proposed treatment algorithm Molecular Poor PS Good PS EGFR mutation positive or ALK fusion positive Molecular Poor PS Good PS Clinical (PS) Single-agent chemotherapy Erlotinib or Crizotinib Nonsquamous Histologic Squamous Bevacizumab eligible Clinical Bevacizumab ineligible First line Platinum/pemetrexed (or D,P,V,G*) ± bevacizumab Platinum/pemetrexed (or D,P,V,G*) Platinum/gemcitabine (or D,P,V*) Now, in this next slide this algorithm has been modernized to 2011, and your first question may be, “Gee, it looks almost exactly the same.” And it does, and in fact there is only 1 significant difference, and that is I have updated it to include testing for ALK fusion in these patients. But you can see everything else is disappointingly the same: clinical, histologic, clinical. End of first-line chemotherapy Bevacizumab or erlotinib or pemetrexed Based on prior therapy Pemetrexed or erlotinib Erlotinib Maintenance Progression Second line Chemotherapy by algorithm Based on prior therapy Based on prior therapy Based on prior therapy *D: Docetaxel, P: Paclitaxel, V: Vinorelbine, G:Gemcitabine Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394. 38

提問時間

非小細胞肺癌-第一線化療

History of Therapy in Advanced NSCLC: FDA Approval Dates Docetaxel 2002 Gefitinib 2003 Standard therapies First line Second line Third line Maintenance Not approved Erlotinib Pemetrexed 2004 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Bevacizumab 2006 *Label does not include NSCLC-specific indication Pemetrexed 2008/2009 Vinorelbine 1994 Carboplatin* 1989 12+ Median OS (mos) Cisplatin* 1978 BSC, best supportive care; C, carboplatin; P, paclitaxel ~ 8-10 ~ 6 ~ 2-4 1970 1980 1990 2000 Bevacizumab + PC BSC Single-agent platinum Doublets Histology-directed therapy 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

Agents With Activity in Advanced NSCLC Older Agents* Newer Agents* Carboplatin Cisplatin Etoposide Ifosfamide Mitomycin C Vinblastine Vindesine Docetaxel Gemcitabine Irinotecan Paclitaxel Topotecan Vinorelbine Pemetrexed Gefitinib Erlotinib Bevacizumab Cetuximab Crizotinib *Not all drugs listed have FDA approval.

第一 線化療-晚期 NSCLC 含白金類的化療組合為首選 Overall response rate (ORR): 25-35% Time to progression (TTP): 4-6個月 平均存活期: 8-10個月 一年存活率: 30-40%　 NCCN practice guideline: Non-small cell lung cancer v.2012

History of Therapy in Advanced NSCLC: FDA Approval Dates Docetaxel 2002 Gefitinib 2003 Standard therapies First line Second line Third line Maintenance Not approved Erlotinib Pemetrexed 2004 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Bevacizumab 2006 *Label does not include NSCLC-specific indication Pemetrexed 2008/2009 Vinorelbine 1994 Carboplatin* 1989 12+ Median OS (mos) Cisplatin* 1978 BSC, best supportive care; C, carboplatin; P, paclitaxel ~ 8-10 ~ 6 ~ 2-4 1970 1980 1990 2000 Bevacizumab + PC BSC Single-agent platinum Doublets Histology-directed therapy 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

First-line Treatment: 2 Agents Are More Effective Than 1 Meta-analysis: 65 trials (N = 13,601) between 1980-2001 Compared efficacy of Doublet vs single-agent regimens Triplet vs doublet regimens Survival Outcome Doublet vs Single-Agent Regimens Triplet vs Doublet Regimens 1-yr OS Doublet > single-agent OR: 0.80; 95% CI: 0.70-0.91; P < .001 5% absolute benefit Triplet = doublet OR: 1.01; 95% CI: 0.85-1.21; P = .88 Median OS MR: 0.83; 95% CI: 0.79-0.89; MR: 1.00; 95% CI: 0.94-1.06; P = .97 MR, median survival ratio; OR, odds ratio Delbaldo C, et al. JAMA. 2004;292:470-484.

臨床試驗 ECOG 1594: 4組白金類化療組合比較 ECOG 4599: Carbo/Pac 該不該加Bevacizumab? JMDB: Cis + Pemetrexed vs. Cis + Gemcitabine

ECOG 1594: Comparison of 4 First-line Doublet Regimens in Advanced NSCLC Reference Arm Paclitaxel 135 mg/m2 over 24 hrs on Day 1 Cisplatin 75 mg/m2 on Day 2 3-wk cycle Gemcitabine 1000 mg/m2 on Days 1, 8, 15 Cisplatin 100 mg/m2 on Day 1 4-wk cycle Advanced-stage, previously untreated NSCLC patients (N = 1207) Docetaxel 75 mg/m2 on Day 1 Cisplatin 75 mg/m2 on Day 1 3-wk cycle Stratified by: ECOG PS (0/1 vs 2) Weight loss in previous 6 mos (< 5% vs ≥ 5%) Disease stage (IIIB vs IV or recurrent) Brain metastases (yes vs no) Paclitaxel 225 mg/m2 over 3 hrs on Day 1 Carboplatin AUC 6.0 mg/mL/min on Day 1 3-wk cycle Schiller JH, et al. N Engl J Med. 2002;346:92-98.

ECOG 1594-platinum doublets

ECOG 1594- 比較白金類的組合(續) 毒性/級別 Cis/Pac Cis/Gem Cis/Doc Carbo/Pac 中性球數下降(4) 57% 39% 48% 43% 血小板數下降(4) 2 28 1 中性球數下降發燒(4) 14 3 10 4 噁心(3) 25 37 24 9 神經損傷(3) 5 所有(4) 68 61 53 Schiller JH et al. N Engl J Med. 2002；346:92-98.

ECOG 1594- 比較白金類的組合(續) 總結 就存活率而言，這4個組合並無差異 Carbo/Pac的毒性最小 Schiller JH et al. N Engl J Med. 2002；346:92-98.

ECOG 4599 總結 符合以下條件者，使用Cis + Pac + Bevacizumab 可 增加存活率: 非鱗狀上皮細胞癌之非小細胞肺癌病人 ECOG PS =0-1 Sandler A, et al. N Engl J Med. 2006；355:2542-2550.

JMDB：Cisplatin/Gemcitabine VS Cisplatin/Alimta (Phase 3) Scagliotti GV, et al. J Clin Oncol 2008；26:3543-3551.

JMDB 3-4級副作用, % Peme/Cis (N=839) Gem/Cis (N=830) P value 中性球數下降 15.1 26.7 ＜0.001 貧血 5.6 9.9 0.001 血小板數下降 4.1 12.7 中性球數下降發燒 1.3 3.7 0.002 噁心 7.2 3.9 0.004 嘔吐 6.1 1.000 Scagliotti GV, et al. J Clin Oncol 2008；26:3543-3551.

JMDB 總結 整體存活率: Cis + Peme = Cis + Gem 鱗狀上皮細胞癌: :Cis + Peme ＜ Cis + Gem Scagliotti GV, et al. J Clin Oncol 2008；26:3543-3551.

Chemotherapy Today and the Need for Targeted Therapies Doublet chemotherapy for 4-6 cycles is standard Select chemotherapy based on histology Future selection by other markers (ie, ERCC1) There is a need for “targeted” chemotherapy and other agents Antiangiogenesis: VEGF targeted (bevacizumab, etc) EGFR-targeted antibody (cetuximab), TKI (erlotinib, etc) Newer targets (ALK and others) Recent identification of “driver mutations” in 50% of NSCLC adenocarcinomas TKI, tyrosine kinase inhibitor

非小細胞肺癌-維持化療，只換湯還是得換藥?

維持化療(Maintenance Therapy) Cisplatin + “A” * 4次 Continuation maintenance 打 “C” ，直到病情惡化或毒性發生 PD, progressive disease.   The next slide shows the scenarios for the maintenance therapy trials that have been done. These considered giving platinum-based doublet chemotherapy plus an additional agent, so it is either cisplatin or carboplatin plus an additional agent. After 4 cycles, they either continued the drug that was given, which we will call continuation maintenance, or in other trials, switched to a different agent, which is switch maintenance. Switch maintenance

Main Grade 3/4 Toxicities 臨床試驗- Continuation Maintenance 1. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506. 3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510. Study Yr Induction Therapy Maintenance Therapy Median PFS, Mos Median OS, Mos Main Grade 3/4 Toxicities Brodowicz[1] 2006 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4 Gemcitabine 1250 mg/m2 on Days 1,8 BSC 6.6 5.0 (P < .001) 13.0 11.0 Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC Belani[2] 2010 Gemcitabine 1000 mg/m2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4 Gemcitabine 1000 mg/m2 on Days 1,8 7.4 7.7 (P = .575) 8.0 9.3 (P = .838) ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC Perol[3] Gemcitabine 1000 mg/m2 on Days 1,8 3.8 1.9 (P < .0001) NR At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares[4] 2011 Pemetrexed 500 mg/m2 on Day 1 + cisplatin 75 mg/m2 on Days 1 x 4 Pemetrexed 500 mg/m2 on Day 1 4.1 2.8 (P = .00006) Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC AE, adverse event; ANC, absolute neutrophil count; AUC, area under the concentration curve; BSC, best supportive care; HR, hazard ratio; NR, not reported; OS, overall survival; PFS, progression-free survival; Plts, platelets.   The next slide shows the same sort of analysis for continuation maintenance trials. Again, the drugs in question are gemcitabine or pemetrexed. As you can see, there is evidence of potential benefit in at least some of these studies, sometimes only in progression-free survival, and sometimes in overall survival as well.

臨床試驗-Switch Maintenance Agent/Control Arm N PFS Salvage Treatment, % OS Fidias[1] Docetaxel Delayed docetaxel 309 5.7 mos HR: 0.63 2.7 mos P = .001 63 12.3 HR: 0.80 9.7 P = .085 Ciuleanu[2] Pemetrexed Placebo 663 4.0 mos HR: 0.50 2.6 mos P < .0001 67 13.4 HR: 0.79 10.6 P = .012 Cappuzzo[3] Erlotinib 889 12.3 wks HR: 0.71 11.1 wks P < .0001 72 12.0 HR: 0.81 11.0 P = .0088 Miller[4] Erlotinib + bevacizumab Placebo + bevacizumab 768 4.8 mos HR: 0.72 3.8 mos P = .001 55.5 15.9 HR: 0.90 13.9 P = .2686 Perol[5] Observation 310 2.9 mos HR: 0.82 1.9 mos P = .002 81.9 NA HR: .91 NA Zhang[6] Gefitinib 296 4.8 mos HR: 0.42 58.8 18.7 HR: .84 16.9 P = .2608 HR, hazard ratio; NA, not available; OS, overall survival; PFS, progression-free survival.   The next slide shows the results of a variety of studies that have been done looking at switch maintenance, either by comparison with delayed therapy, as in the first study by Fidias, or by comparison with a placebo, or observation. As you can see, for docetaxel, pemetrexed, erlotinib, erlotinib plus bevacizumab, and gefitinib, there is some evidence, at least in progression-free survival, that there is benefit to a switch maintenance approach. 1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511.

總結-維持化療(Maintenance Therapy) 非鱗狀上皮細胞+EGFR (-) or 不明 Continuation maintenance : Bevacizumab (category 1) or cetuximab (category 1) Pemetrexed or gemcitabine Switch maintenance: Pemetrexed or erlotinib 鱗狀上皮細胞 Continuation maintenance: Cetuximab (category 1) or gemcitabine Switch mainyenance: Docetaxel (category 2B) or erlotinib NCCN guidelines version 2.2012 Non-small cell lung cancer

維持化療(Maintenance Therapy)? 誰該進行?何時進行? 該如何運用這些臨床試驗數據在臨床工作上? 如果病人已先接受6次第一線化療，他還需要接受維持 化療嗎? 如果病人經過第一線化療後，呈現Stable disease及持 續有症狀，那他該進行維持化療還是提早進入第二線化 療? 如果病人經過第一線化療後，呈現CR或PR，並且症狀 都消失了，維持化療真的有比持續觀察好嗎? 不同的病人有不同的分子生物表現 Gandara DR. Best of ASCO 2011.

非小細胞肺癌-救援化療

救援治療(Salvage therapy) 第2線治療: 單獨使用docetaxel, pemetrexed, erlotinib 或gefitinib Docetaxel 比支持療法、vinorelbine或ifosphamide 都 來得佳 (Fossella FV, et al. J Clin Oncol 2000；18:2354-2362, Shepherd FA, et al. J Clin Oncol 2000；18:2095-2103) Docetaxel 與pemetrexed的療效一致(HR=0.99)，但 docetaxel的毒性要比後者明顯得多 (Hanna N, et al. J Clin Oncol 2004；22:1589-1597) 第3線治療: Erlotinib 或 Gefitinib

結論- 晚期 NSCLC 治療 Advanced-Stage NSCLC & PS 0-1 Erlotinib or gefitinib EGFR mutation positive ELM4-ALK positive EFGR mutation and ALK negative and nonsquamous histology EFGR (-) squamous histology Bevacizumab appropriate Bevacizumab inappropriate Erlotinib or gefitinib first line NSCLC, non-small-cell lung cancer; PS, performance score.   So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy. Consider crizotinib first or second line Consider carboplatin/paclitaxel + bevacizumab or cisplatin/pemetrexed ± bevacizumab Consider cisplatin or carboplatin combined with pemetrexed, docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Consider cisplatin or carboplatin combined with docetaxel or gemcitabine or paclitaxel or cisplatin/vinorelbine ± cetuximab Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

結論-晚期 NSCLC 治療 Proposed treatment algorithm Molecular Poor PS Good PS EGFR mutation positive or ALK fusion positive Molecular Poor PS Good PS Clinical (PS) Single-agent chemotherapy Erlotinib or Crizotinib Nonsquamous Histologic Squamous Bevacizumab eligible Clinical Bevacizumab ineligible First line Platinum/pemetrexed (or D,P,V,G*) ± bevacizumab Platinum/pemetrexed (or D,P,V,G*) Platinum/gemcitabine (or D,P,V*) Now, in this next slide this algorithm has been modernized to 2011, and your first question may be, “Gee, it looks almost exactly the same.” And it does, and in fact there is only 1 significant difference, and that is I have updated it to include testing for ALK fusion in these patients. But you can see everything else is disappointingly the same: clinical, histologic, clinical. End of first-line chemotherapy Bevacizumab or erlotinib or pemetrexed Based on prior therapy Pemetrexed or erlotinib Erlotinib Maintenance Progression Second line Chemotherapy by algorithm Based on prior therapy Based on prior therapy Based on prior therapy *D: Docetaxel, P: Paclitaxel, V: Vinorelbine, G:Gemcitabine Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394. 68

病例二 胡OO， 48歲已婚男性，職業為台鐵員工，曾在青少 年時期抽過菸，但已有30年以上不曾抽菸了。 目前疾病病程: 過去病史: 最近一個月有間歇性咳嗽，有少量帶血絲痰。 過去病史: 高血壓，正在用藥控制。 左腎萎縮 在1969年因尿路結石開刀 在1984年因十二指腸潰瘍開刀

病例二 (續) 家族病史: 無 用藥史: Diltiazem 90 mg daily Dipyridamole 25 mg tid Physical exam BP 160/75 P 77 T 37.2℃ Wt 59.2 kg HT 159.1 cm BSA 1.64m2 General Well-nourish, thin man without respiratory distress HEENT Head- no mass or other lesion Neck No palpable mass Breath sounds Clear, no wheezing Heart Regular heart beats, no murmur Abdomen Flat, surgical scar in midline Extremities Free movable, no pitting edema 家族病史: 無 用藥史: Diltiazem 90 mg daily Dipyridamole 25 mg tid Calcium carbonate 500 mg tid Hi-beston 50 mg daily Transamine 250 mg tid Dextromethorphan 15 mg tid

病例二 (續) 檢驗名稱 結果值 單位 參考值 Na 141 mmol/L 135 - 148 K 4.5 3.7 - 5.3 Cl 108 96 - 110 Ca 9.5 mg/dl 8.0 - 9.9 BUN 32 8.0 - 23.0 Cr 3.37 0.60 - 1.30 INR 1.04 Index < 1.3 W.B.C 10.13 10^3/ul 3.6 - 10.0 SEG 78.0 % 40.0 - 75.0 LYMPH 9.0 20.0 - 50.0 MONO 7.0 2 - 10 HGB 13.6 g/dl 13.5 - 17.5 PLT 398.0 150 - 400

病例二 (續) 檢驗名稱 結果值 單位 參考值 BASO 0.0 % 0.0 - 1.0 Bilirubin Total 0.43 mg/dl 0.20 - 1.20 Bilirubin Direct 0.15 0.00-0.40 ALP 112 U/L 40-129 AST / GOT 43 10 - 27 ALT / GPT 67 5 - 33 LDH 187 106 - 211

病例二 (續) Work-up 胸部X光: 在right upper lobe(RUL)有腫塊，右邊肺門淋 巴結膨大。 電腦斷層:在right upper lobe(RUL)有32*33 mm腫塊， 右邊肺門淋巴結膨大；左側腎臟萎縮，並有鈣化。 粗針抽吸: 中等分化(moderately differentiated)之腺癌。 正子掃描: 在RUL、右側肺門及肝臟有較高的代謝。 粗針+細針抽吸: 肝臟有轉移病灶。 EGFR mutation (+)

病例二- 治療 Docetaxel + carboplatin * 6次 (2010/12/27-2011/4/18) 第4期NSCLC Docetaxel + carboplatin * 6次 (2010/12/27-2011/4/18) Docetaxel (2011/5/5-2011/6/20) 2011/6/14 CT顯示腫瘤增大 Gefitinib (2011/7/4-2012/2/27) EGFR mutation positive 2012/2/14 腦部MRI 發現有腦部轉移 Erlotinib (2012/3/12- 2012/8/9) 緩和性腦部放射線治療 3600 cGy，分13次照射(2012/2/16- 2012/3/6)

練習題 65歲女性，非吸菸者，症狀有呼吸急促及間歇性咳嗽 ，無咳血。病人無體重減輕，活動力正常。 過去病史: 無高血壓、糖尿病、呼吸或心血管疾病。 家族病史: 無肺癌家族病史。 過敏史: 無。 身體檢查: 正常 抽血檢查: 正常，無感染。

練習題 (續) 診斷: 電腦斷層: 右上肺葉有3公分腫塊，肺門及縱膈腔淋巴結膨 大 ，脊柱T5有病變。 細針抽吸: 較少分化的腺癌。 腦部核磁共振: 正常。 診斷: 晚期非小細胞肺癌，腺癌，疑似第四期。

練習題(續) 以下哪項化療方式最適合這位病人? Paclitaxel/carboplatin Bevacizumab/pemetrexed/carboplatin Gemcitabine/carboplatin 答案 : B

練習題 (續) 經過兩次化療(bevacizumab/pemetrexed/carboplatin) ， 化療前一周開始IM vitamin B12 (1000 mEq，每9 周一次) 及每日口服葉酸。再次檢查發現病情符合部 分有效(partial response)，病人也沒有發生出血、高 血壓、血液毒性或蛋白尿。再施行兩次化療後，發現 病情穩定。請問以下哪項維持治療適合此位病人? Single-agent bevacizumab Single-agent pemetrexed Single-agent erlotinib 答案: A

練習題 (續) 病人對維持治療耐受良好，但有呼吸急促及疲憊的症 狀。做了電腦斷層檢查後發現肺部腫瘤及縱膈腔淋巴 結都皆變大。接下來，您會給這個病人哪項治療? 開始使用docetaxel做為第二線治療 開始使用erlotinib做為第二線治療 以細(粗)針抽吸檢驗肺部腫瘤的分子生物標記(molecular biomarker) 答案: C

練習題 (續) 細針抽吸後發現病人有EGFR突變(在exon 19)。於是病 人接受每日口服erlotinib 150 mg的治療，治療反應很 好， 但是病人抱怨每天都會腹瀉3-4次，臉及軀幹上 有青春痘伴有輕微疲倦，請問您會如何處理? 持續使用相同劑量及頻率的erlotinib治療 降為每日口服erlotinib 100 mg 停止使用erlotinib 答案: B

練習題 (續) 故事盡頭 病人調降劑量，改為每日服用erlotinib 100 mg，副作用大 為減輕，病人活動力提升。直到1.5年後，病情一直處於 緩解(remission)的狀態。

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