CHEMOTHERAPY FOR COLON CANCER OUTLINE OF TODAY S TALK. Colon Cancer Epidemiology 11/6/2012 GATRA/GCCR FALL CONFERENCE NOVEMBER 14 16, 2012

Transcription

1 CHEMOTHERAPY FOR COLON CANCER JONATHAN C. BENDER,MD MEDICAL DIRECTOR OF PIEDMONT FAYETTE CANCER CENTER OUTLINE OF TODAY S TALK 1. Overview of Colon Cancer in the US 2. Colon Cancer staging and risks of relapse 3. Standards of care and NCCN guidelines 4. Chemotherapy regimens and biologics 5. Case discussions 6. Questions Colon Cancer Epidemiology 3 rd most common cause of cancer 143,460 new cases in the US per year 103,170 Colon 40,290 Rectal 51,690 deaths in the US per year 9% of all cancer related deaths 2 3% decline over the past 15 years 1

2 Colon cancer epidemiology 5% average life time risk 90% occurs after age 50 Shift to right sided colon cancer especially cecal primaries function of screening? US has best survival rates of colon cancer 2

3 What is survival of colon cancer? A. 90% at 5 years B. 60% at 5 years C. 35% at 5 years Colon cancer diagnosis by age Colon cancer diagnosis by country 3

4 Risk factors genetic Familial adenomatous polyposis (FAP) mutation in APC gene hundreds of colon polyps Lynch Syndrome ( HNPCC) mutation in DNA repair genes few polyps endometrial, ovarian, brain, gastric Ca Risk factors genetic Risk factors genetic Family history in first degree relative up 10% Personal history of colon cancer 3% History of adenomatous polyps 6% Genetic account of 10% of all cases Inflammatory bowel disease 4

5 Risk factors environmental Obesity Diabetes mellitus Constant alcohol consumption Diet high in red meats/saturated fat Smoking Physical activity Protective factors Diet high in fruits/vegetables, fiber Calcium and vitamin D supplements? Aspirin and NSAIDS (Sulindac, Celebryx) NCCN Colon cancer screening Average risk person 50 to 75 yrs of age Colonoscopy every 10 years Alternatives annual stool test for blood flex sigmoidoscopy every 5 years +/ stool test for blood 5

6 NCCN Colon cancer high risk History of colon cancer within 1 year of then every 3 5 years History of polyps every 3 5 years Genetic syndrome (FAP,Lynch) age 25, every 1 2 years 1 st degree relative with colon cancer start age 40, every 3 5 years Clinical staging colon cancer Colonoscopy biopsy with pathologic review CBC Liver function testing CEA especially prior to surgery CT chest/abdomen/pelvis Consider Pelvic MRI PET scan optional NCCN treatment options STAGE I (T1 T2, N0) II (T2 T4,N0) T4 III (T1 4,N1 2) IV (T1 4,N1 2,M1) TREATMENT SURGERY ALONE SURGERY /+ CHEMO SURGERY + CHEMO CHEMO /+ SURGERY 6

7 Colon cancer staging 5 year Survival by Stage Stage I (T1 2,N0) Stage IIA (T3N0) Stage IIB (T4,N0) Stage IIIA (T1 2,N1) Stage IIIB (T3 4,N1) Stage IIIC (anyt,n2) 93% 85% 72% 83% 64% 44% 5 year survival by stage 7

8 Adverse prognostic indicators by CAP Depth of tumor invasion ( T ) Number of lymph nodes (N ) Number of lymph nodes removed Satellite tumor deposits (N1c) Vascular invasion Preoperative CEA Residual cancer (R1 or R2 resection) Chemotherapy drugs cytotoxics 5 Fluorouracil (5FU) and Leucovorin Capecitabine (Xeloda) Irinotecan/CPT 11 (Camptosar) Oxaliplatin (Eloxatin) Biologics stage IV only Anti angiogenic inhibitors Bevacizumab (Avastin) Aflibercept (Zaltrap) Regorafenib ib(sti (Stivarga) Anti epidermal growth factor receptors Cetuximab (Erbitux) Panitumumub (Vectibix) 8

9 Are they expensive? year old male diagnosed with metastatic colon cancer, stage IV 2. He has a recommendation of chemotherapy 3. Average life span with ihthis diagnosis i is 2 years 4. He weighs 170lb and is 5ft 8in tall High cost of chemotherapy single infusion every 2 weeks Irinotecan $3,404 Oxaliplatin $6,494 Avastin $3,850 Erbitux $7,163 Vectibix $9,240 5FU $230 (generic) Does not include anti nausea meds or administration costs 5FU 1. Developed in only active colon cancer drug for decades 3. Inhibits DNA synthesis 4. Synergy with Leucovorin (folinic acid) 5. Side effects diarrhea, mucositis, myelosuppression, 6. Still back bone of many regimens 7. Oral form capecitabine 9

10 Adjuvant 5FU stage II/III colon cancer 38% proportional RR Chemotherapy regimens with 5FU Infusional 5FU (de Gramont) Mayo Clinic regimen Roswell Park regimen FOLFOX4 FOLFOX6 FOLFOX7 FOLFOX with Avastin XELOX/CAPOX FLOX FOLFIRI FOLFOXIRI IFL (toxic) FOLFIRI with Erbitux FOLFIRI with Avastin FOLFIRI with Vectibix FOLFIRI with Zaltrap XELIRI (toxic) Oxaliplatin Discovered 1978 and FDA approved in 2002 Attaches to DNA and inhibits its replication Always used with 5FU/Leucovorin FOLFOX regimen Approved as adjuvant and metastatic setting Side effecst: neuropathy, nausea/vomiting, low counts, cold intolerance 10

11 MOSIAC trial MOSIAC DFS curves NCCN guidelines stage II/III Chemotherapy FOLFOX or 5FU/Xeloda Stage III patients do better with FOLFOX Stage II patients Stage II patients consider 5FU/Xeloda or FOLFOX no survival benefit seen in Stage II FOLFOX high risk: T4, bowel obstruction, vascular invasion, <12 lymph nodes, perforation 11

12 Chemotherapy for stage II Assess for mismatch repair MSI high pts do not benefit from chemo Consider Oncotype assay on stage II prognostic but not predictive most clinicians do not get this test Oncotype Dx colon cancer assay Irinotecan FDA approved in 1996 Prevents DNA unwinding by topoisomerase 1 inhibition d f l i Used for only stage IV patients No better than F5U in stage II/III patients Side effects: diarrhea, neutropenia, hair loss Toxic to pts with UGT1A1 liver enzyme variant 12

13 FOLFIRI regimen Irinotecan 180mg/m2 IV day 1 F5U bolus 400mg/m2 IV day 1 Leucovorin 400mg/m2 IV day 1 Infusional 5FU 2400mg/m2 over 46 hours via CADD pump Infusional 5FU via CADD Vascular endothelial growth factor VEGF made by the tumor to recruit blood supply Allows tumor growth and metastasis G f il G G G G VEGF family VEGF A,VEGF B,VEGF C,VEGF D High levels predicts poor prognosis Main target of angiogenesis inhibitor Two approved Avastinand Zaltrap 13

14 Bevacizumab/Avastin Monoclonal antibody that inhibits VEGF A Avastin/Bevacizumab FDA approved for stage IV colon cancer 2004 Used in conjunction with FOLFOX and FOLFIRI Used to treat brain, breast, kidney, lung, ovarian and colon cancer, macular degeneration Side effects: impaired wound healing, hypertension, bowel perforation, thrombosis, and bleeding NCCN guidelines: stage IV only 14

15 Aflibercept/Zaltrap Fusion protein acts as receptor decoy for VEGF A and VEGF B FDA approved 2012 as 2 nd line for stage IV colon cancer with FOLFIRI Extends survival from 12.1mos to 13.5 mos Regorafenib/Stivarga Oral agent 160mg daily for 21 out of 28 days Binds to VEGF receptors and turns them off FDA approved 2012 as last resort Extends survival from 5mos to 6.4mos No objective shrinkage of the tumor Side effects: HTN, hand/foot syndrome, fatigue, mouth sores, diarrhea Epidermal growth factor receptor EGFR are family of receptors ErbB 1, HER 2, ErbB 3 and ErB 4 Tumor associated EGF binds to EGFR to stimulate cell growth 3 inhibitors approved: Erbitux, Vectibix, and Tarceva 15

16 Cetuximab/Erbitux Monoclonal antibody binds and inhibits EGFR Given every 1 2 weeks IV FDA approved for stage IV pts alone or with chemotherapy h (Irinotecan or FOLFIRI) Does not work in KRAS mutation pts SIDE EFFECTS: rash, diarrhea, allergy reactions, diarrhea, N/V Erbitux Rash 16

17 Cetuximab benefit NCCN approved stage IV regimens FOLFOX +/ Avastin CapeO +/ Avastin FOLFIRI +/ Avastin 5FU or Xeloda +/ Avastin FOLFIRI +/ Erbitux or Vectibix Erbitux or Vectibix FOLFOXIRI NCCN approved 2 nd line agents after FOLFOX FOLFIRI +/ Avastin FOLFIRI +/ Erbitux or Vectibix Irinotecan +/ Avastin or Erbitux/Vectibix FOLFIRI + Zaltrap 3 rd line: Stivarga or Erbitux or Vectix +/ Irinotecan 17

18 Alternative management for stage IV CRC patients Chemo emoblization Radioactive bead embolization Stereotactic radiation Surgical resection of selected metastatic disease Case presentation 64 y/o male complaining of progressive fatigue over the past 3 4 months He saw his PCP who ran CBC and chemistries. i He was noted to have anemia (9.8g/dL) and iron deficiency Referred for a colonoscopy Colonoscopy results 18

19 Case presentation Tumor seen in the colon and biopsy done which revealed adenocarcinoma Preoperative CEA was 13.4 Referred to general surgery for a colectomy Chest xray and CT abdomen/pelvis ordered CT abdomen shows liver lesion Case presentation Case presented at tumor conference Recommendations 1. Biopsy liver lesion cycles of chemotherapy 3. Rescan if response is seen, proceed with surgery 4. Complete total of 12 cycles post operatively 19

20 Summary Best treatment screening colonoscopy Prevention: diet, exercise, ASA Most patients are cured >60% Selected stage IV patients are also cured Increase in new options over past 20 years Biologics now integral part of mangement Survival in stage IV pts > 2 years 20