Introduction of Colorectal Cancer 白禮源血液腫瘤科中國醫藥大學附設醫院 1
Outlines Introductions Screening Work-up and Staging Treatment Metastatic situation Adjuvant situation Neoadjuvant situation Conclusions 2
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Epidemiology Of Colorectal Cancer (CRC) CRC is the third most common form of cancer worldwide Over 1 million cases diagnosed worldwide each year; >50% develop advanced disease Mortality worldwide from CRC is 530,000/year 4
美國癌症死亡率與治療費用 1960-1990 5
臺灣地區男性主要癌症死亡率趨勢圖 每十萬男性人口死亡數 45 標準化每十萬男性人口死亡數 45 40 肝癌 40 35 35 30 肺癌 30 肝癌 25 25 肺癌 20 20 15 胃癌 15 10 結腸直腸癌 10 結腸直腸癌 胃癌 5 口腔癌 ( 含口咽及下咽 ) 5 口腔癌 ( 含口咽及下咽 ) 0 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 年 0 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 年 註 : 標準化死亡率係以民國七十年臺灣地區男性年中人口年齡結構為基準 6
臺灣地區女性主要癌症死亡率趨勢圖 每十萬女性人口死亡數 18 17 肺癌 16 15 14 肝癌 13 12 11 10 子宮頸癌 9 8 7 結腸直腸癌 6 5 女性乳癌 4 3 2 1 0 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 年 標準化每十萬女性人口死亡數 18 17 16 15 14 13 12 11 肺癌 10 子宮頸癌 9 肝癌 8 7 6 結腸直腸癌 5 女性乳癌 4 3 2 1 0 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 年 註 : 標準化死亡率係以民國七十年臺灣地區女性年中人口年齡結構為基準 7
危險因子 遺傳 基因突變 環境 飲食 生活作息 息肉 年齡 8
高度危險性 中度危險性 一般危險 性 比率 5-10% 15-20% 70-80% 年齡 Any Any 50 Y/O Past history Chron s disease Ulcerative colitis Adenomatous polyp Colorectal cancer None Family history Familiar polyposis coli (FAP) Hereditary nonpolyposis colorectal cancer (HNPCC) Ovarian One first-degree Ca relative<60 Y/O or 2 any age have adenomatous polyp or CRC None 9
Screening Digital rectal examination Fecal occult blood testing Sigmoidoscopy Colonoscopy Air-contrast barium enema Virtual CT colonography 10
Screening Recommendations-Normal Risks Test or Procedure Fecal occult-blood testing (FOBT) American Cancer Society Annually, FOBT or fecal immunochemical test (FIT), startinga t age 50 Sigmoidoscopy Every 5 years, starting at age 50 Flexible sigmoidoscopy Flexible sigmoidoscopy every 5 years, starting at age 50 Double contrast barium enema Every 5 years, starting at age 50 CT colonography Every 5 years, starting at age 50 Digital rectal examination (DRE) No recommendation Colonoscopy Every 10 years, starting at age 50 11
Cancer Work Up 1. Pathology review 2. Hemogram 3. Chemistry profile 4. CEA level 5. Chest/abdominal/chest CT scan 6. PET scan is not routinely indicated 7. K-ras gene mutation study 12
Non-metastasis 13
Metastasis 14
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AJCC 7 16
AJCC 7 17
Therapy for Colorectal Cancer 1. Surgical interventionl - tumor resection +/- metastatectomy 2. Radiotherapy - CCRT or local radiotherapy 3. Chemotherapy - neoadjuvant, adjuvant, salvage or palliation 4. Targeted therapy - combination with systemic cytotoxic chemotherapy 18
化學治療理論 一般細胞的成長以及死亡皆處於正常控制下, 相對的, 癌細胞則是處於異常增生狀態而不受正常生理衡定所節制 所以, 化學治療是經由停止癌細胞的生長或直接破壞癌細胞等手段來達成抑制癌症的目的 19
Major advances in Systemic Treatment New chemotherapy - Irinotecan ( ex FOLFIRI, CapeIri ) - Oxaliplatin (FOLFOX) - Capecitabine (XELOX, CapeIri ) Antibodies - EGFR antibodies ( cetuximab, panitumumab ) --VEGF antibodies ( bevacizumab ) 20
5-FU, UFUR, Xeloda Anti-metabolite 抗代謝物 21
Alkylating agent 螯合劑 Oxaliplatin 22
Topoisomerase Inhibitor 拓樸酶抑制劑 Irinotecan= CPT11 23
不同藥物?? IFL regimen CapeIRI regimen FOLFOX regimen FOLFIRI regimen FOLFIRI versus FOLFOX?? 24
IFL versus FOLFIRI 39% 20 % 49% 50.7% 7.0 6.7 9.0 14.8 17.4 16.2 12 months 25
FOLFOX4 FOLFOX6 mfolfox6 FOLFOX7 mfolfox7 相同藥品 不同劑量 不同時間 26
FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study 不同順序, 相同結果 FOLFIRI/FOLFOX6 14.2 months FOLFOX6/FOLFIRI 10.9 months Phase III Randomized Trial N= 226 patients Untreated metastatic colorectal cancer FOLFIRI/FOLFOX6 21.5 months FOLFOX6/FOLFIRI 20.6 months 27 J Clin Oncol 2004; 22: 229--237
Fluouracil Capecitabine Oxaliplatin Irinotecan FOLFOX XELOX FOLFIRI CapeIri Cetuximab Bevacizumab 28
Conclusions Efficacy is equivalent for - FOLFOX, XELOX -FOLFIRI Predominant toxicity -Irinotecan: diarrhea, alopecia - Oxaliplatin: neurotoxicity - XELOX: hand-foot syndrome 29
Metastatic CRC 30
Fluouracil Capecitabine Oxaliplatin Irinotecan FOLFOX XELOX FOLFIRI CapeIri Cetuximab Bevacizumab 31
Chemotherapy plus Targeted Agents in the First-line Treatment of Metastatic Colorectal Cancer Chemotherapy + Bevacizumab ( AVF 2107; NO16966; BICC-C ) Chemotherapy + Cetuximab ( Crystal, OPUS, COIN) 32
Angiogenesis is involved throughout tumour formation, growth and metastasis Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumour progression Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207 25 33
Tumour vasculature is abnormal Normal blood vessels Tumour blood vessels Maturation factors Growth factors (VEGF) No growth factors Tight Support cells Integrins Leaky Fewer supporting cells Jain R. Nat Med 2003;9:685 93 34 Carmeliet P. Nat Med 2003;9:653 60
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Avastin in mcrc (AVF2107) PFS OS Hurwitz H. N Engl J Med 2004;350:2335 42. 36
EGFR expression in solid tumors Colorectal EGFR is expressed in a variety of solid tumors Lung (NSCLC) Head and neck (SCCHN) Tumor Target % Colorectal cancer 72 89 Head and neck cancer 95 100 Lung cancer (NSCLC) 40 80 Breast cancer 14 91 Ovarian cancer 35 70 Renal cell cancer 50 90 Pancreatic cancer 30-95 Cunningham et al. N Engl J Med 2004;351:337 345; Grandis et al. Cancer 1996;78:1284 1292; Salomon et al. Crit Rev Oncol Hematol 1995;19:183 232; Walker & Dearing. Breast Cancer Res Treat 1999;53:167 176; Folprecht et al. ASCO 2004 (Abstract #283). 37
Cetuximab EGF EGFR IgG1 monoclonal antibody Binds to EGFR ERBITUX Overexpression is observed in various cancers. Activation is Blocks signal transduction PI3K STAT RAS upon ligands binding. AKT RAF MEK mtor ERK Gene transcription Cell cycle progression Angiogenesis Metastasis Survival 38 Proliferation
Chemotherapy + Cetuximab Crystal Trial - FOLFIRI +/- Cetuximab OPUS Trial - FOLFOX +/- Cetuximab COIN Trial - FOLFOX or XELOX + Cetuximab 39
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Metastatic CRC 42
Adjuvant Chemotherapy in CRC Oxaliplatin-base chemotherapy 1.MOSAIC trial ( FOLFOX4 versus FU5LV2) 2.NO 16968 ( XELOX versus FU5LV2 ) Irinotecan-base chemotherapy 1. CALGB 89803 ( FOLFIRI versus FU5LV2 ) 2. PETACC-3 ( FOLFIRI versus FU5LV2 ) 43
Adjuvant Chemotherapy in CRC P=0.258 P=0.005 P=0.648 P=0.023 72.9 68.7 Disease -free survival Overall Survival 44
Conclusions 1. FOLFOX regimen improved 5-year DFS and 6-year OS in the adjuvant treatment in stage III colon cancer 2. According to the result of NO16968, XELOX regimen is an another option in stage III colon cancer 3. Irinotecan-based chemotherapy is not superior to FU5LV2 alone in adjuvant colon cancer ( both DFS and OS ) 4. The addition of bevacizumab to FOLFOX6 did not result in an overall statisticaly significant prolongation in DFS 5. Cetuximab does not improved DFS and OS in resected stage III adjuvant chemotherapy 45
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Rescue Surgery for Unresectable Colorectal Liver Metastases Downstage by Chemotherapy Ann Surg 2004; 240:644-658 48
Ann Surg 2004; 240:644 658 49
Neoadjuvant chemotherapy in unresectable metastatic colorectal cancer CELIM study FOLFOX/ Cetuximab FOLFIRI/ Cetuximab ORR, % R0 resection, % 70 34 BOXER study XELOX/Bevacizumab 78 35 50
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Conclusions Introductions Screening Work-up and Staging Treatment Metastatic situation: Chemotherapy, Targeted therapy Adjuvant situation Neoadjuvant situation 52
Thank You for Your Attention 53