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Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer Axel Grothey, MD Senior Associate Consultant Division of Medical.

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Presentation on theme: "Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer Axel Grothey, MD Senior Associate Consultant Division of Medical."— Presentation transcript:

1 Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer Axel Grothey, MD Senior Associate Consultant Division of Medical Oncology Mayo Clinic College of Medicine Rochester, MN Neoadjuvant Colorectal Cancer

2 Case 1: Neoadjuvant Therapy 54-year-old male with 6-months of weight loss and fatigue Sees PCP and physical exam significant for liver edge palpable 2 cm below RCM Hb 9.7 g/dL with MCV 75 µm³ (previously 90 µm³) Stool guaiac positive

3 Case 1: Neoadjuvant Therapy Referred to gastroenterologist for evaluation CEA 25 ng/mL Colonoscopy shows sigmoid mass Biopsy adenocarcinoma with signet ring features CT scan shows – 5 hepatic lesions up to 4 cm in diameter (2 in left, 3 in right liver lobe) – Thickening of sigmoid colon with local node enlargement

4 Case 1: Neoadjuvant Therapy Which treatment option would you recommend?  Surgery for primary, followed by chemotherapy  Surgery for primary and metastatic disease  Primary (neoadjuvant) chemotherapy followed by surgery

5 Case 1: Neoadjuvant Therapy Which treatment option would you recommend?  Surgery for primary, followed by chemotherapy  Surgery for primary and metastatic disease  Primary (neoadjuvant) chemotherapy followed by surgery Recommended approach – Primary (neoadjuvant) chemotherapy followed by surgery

6 Pertinent Issues for Case 1 Optimal management of liver metastases – Primarily resectable metastases Role of neoadjuvant therapy – Unresectable metastases Optimal therapy to downsize metastases (“conversion” therapy) – Role of postoperative, adjuvant therapy

7 Liver Resection – New Perspective Old: Resectability determined by “what comes out” New: Resectability determined by “what stays in”

8 Future Liver Remnant Volume (FLR) Abdalla EK. Arch Surg 2002; 137: Complications (%) 6/12 4/30 % FLR ≤ 20% % FLR > 20% P <.05

9 Multimodality Management of CRC Liver Metastases Neoadjuvant chemotherapy – Resectable liver metastases Facilitate surgery Obtain predictive and prognostic information Early systemic therapy for poor-prognosis pts Conversion chemotherapy – Unresectable liver metastases Allow R0 resection via downsizing Postoperative (adjuvant) chemotherapy – Hepatic arterial infusion (HAI) – Systemic treatment

10 Importance of Response to Neoadjuvant Therapy of Liver Metastases Prior to Resection 131 (of 441) patients with CRC and > 4 liver metastases underwent (mostly) FOLFOX-based neoadjuvant therapy Survival outcome by response to chemotherapy ResponseStabilizationProgressionP No. of patients58 (44%)39 (30%)34 (26%) Nodules (mean) Hepatic recurrence55%77%82% 1-yr survival95%92%63% 5-yr survival37%30%8%< Adam et al., Ann Surg 2004

11 54% Survival After Primary or Secondary Resection of Liver Metastases Proportion Surviving Survival Time (years) % 34% 50% 34% 19% 27% Resectable (N = 425) Initially non-resectable (N = 95) Bismuth et al., 1996

12 Studies with neoadj. focus Phase III trials Phase II trials Folprecht et al., Ann Oncol 2005 Resectability Correlates with RR

13 Hepatic Arterial Infusion of Chemotherapy After Hepatic Metastasis 5-FU/LV + HAI FUDR 5-FU/LV Randomized After Hepatic Resection N=156 HAI FUDR = hepatic arterial infusion with floxuridine and dexamethasone. Combination Therapy 5-FU/LVP 2-yr OS (%) mOS (mo) NS 2-yr recurrence-free survival (%) < yr risk of death1.02.3x.027 Median OS update 2005 (mo) Kemeny et al. N Engl J Med. 1999;341:2039 Kemeny et al. N Engl J Med 2005;352:734

14 EORTC Perioperative FOLFOX in Resectable Liver Mets R A N D O M IZ E SurgeryFOLFOX4 Surgery 6 cycles (3 months) N = 364 patients (09/00-07/04) 6 cycles (3 months) Aim: To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone Primary endpoint: PFS (40% increase in median PFS (HR = 0.71) with 80% power and 2-sided significance level 5%) Secondary endpoints: OS, resectability, response, safety Nordlinger et al., ASCO 2007 Abstract LBA5

15 Complications of Surgery Peri-op CTSurgery Postoperative complications* 40/159 (25.2%) 27/170 (15.9%) Cardio-pulmonary failure32 Bleeding33 Biliary Fistula125 (Incl output > 100 ml/d, >10d)(9)(2) Hepatic Failure118 (Incl. bilirubin>10 mg/dl, >3d)(10)(5) Wound infection44 Intra-abdominal infection82 Need for reoperation53 Other2516 Incl. postoperative death1 patient2 patients *P = 0.04 Nordlinger et al., ASCO 2007 Abstract LBA5

16 Patient Flow Informed consent Randomized: 364 Pre & Postop CT 182 Surgery 182 Ineligible 11 Started pre-op CT 171 Resected 152 Resected 151 Started postop CT 115 Resectable on imaging Resectable at surgery Preop cycles 1-6: 78.6% Start postop CT: 63.2% Postop cycles 1-6: 43.9% Nordlinger et al., ASCO 2007 Abstract LBA5

17 Results EORTC N pts CT N pts Surgery % absolute difference in 3-year PFS Hazard Ratio (Confidence Interval) P-value All patients % (28.1% to 35.4%) 0.79 ( ) All eligible Patients % (28.1% to 36.2%) 0.77 ( ) All resected Patients % (33.2% to 42.4%) 0.73 ( ) MOSAIC: 3-yr DFS for stage III: +7.2% Nordlinger et al., ASCO 2007 Abstract LBA5

18 Progression-free Survival in Eligible Patients HR = 0.77; CI: , P = Periop CT 28.1% 36.2% +8.1% At 3 years years ONNumber of patients at risk: Surgery only Nordlinger et al., ASCO 2007 Abstract LBA5

19 Take-Home Messages EORTC Perioperative therapy with FOLFOX4 improves PFS (DFS) in patients with resectable liver metastases With preoperative FOLFOX4 higher incidence of postoperative complications, but same operative mortality Study never intended to answer question if ALL patients with resectable liver metastases should receive pre- operative chemo  Trial provides first evidence in a prospective trial that chemotherapy in the context of resected stage IV disease provides PFS benefit

20 Case 2: Stage III Colorectal Cancer 62-year-old woman – History of hypertension, but otherwise healthy Presents with GI bleeding, adenocarcinoma of descending colon identified Patient undergoes laparoscopic colectomy Pathology demonstrates T3N1 (2/15) M0 colon cancer, moderately differentiated and no evidence of lymphovascular invasion Patient has healed well, discharged from the hospital in 5 days

21 Case 2: Stage III Colorectal Cancer Which treatment option would you recommend?  5-FU/LV  Capecitabine  FOLFIRI  FOLFOX  Bolus 5-FU/LV and oxaliplatin (FLOX)  CAPOX (XELOX)  Other

22 Case 2: Stage III Colorectal Cancer Which treatment option would you recommend?  5-FU/LV  Capecitabine  FOLFIRI  FOLFOX  Bolus 5-FU/LV and oxaliplatin (FLOX)  CAPOX (XELOX)  Other Recommended approach – FOLFOX

23 Case 2: Stage III Colorectal Cancer Would you add a targeted agent to adjuvant chemotherapy?  No  Yes, bevacizumab  Yes, cetuximab (or panitumumab)

24 Case 2: Stage III Colorectal Cancer Would you add a targeted agent to adjuvant chemotherapy?  No  Yes, bevacizumab  Yes, cetuximab (or panitumumab) Recommended approach – No – Remains investigational in adjuvant setting

25 Pertinent Issues for Case 2 Relatively young patient, no serious comorbidities Stage IIIB colon cancer T3 N1 (2/15) Standard adjuvant therapy for stage III colon cancer? Addition of biologics of any benefit?

26 5-FU/lev superior to surgery alone 5-FU/LV superior to surgery alone 5-FU/LV superior to 5- FU/lev 6- and 12-month treatment cycles equivalent Lev unnecessary High-dose and low-dose LV equivalent Monthly and weekly treatment equivalent LV5-FU2 and monthly bolus equivalent Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;106:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract O’Connell et al. J Clin Oncol. 1998;16:295. Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982. Andre et al. Proc Am Soc Clin Oncol Abstract 529. History of Adjuvant Therapy for Colon Cancer

27 3-Year DFS vs. 5-Year OS Sargent, et al. J Clin Oncol 2005;23:8664– r = Year DFS 5-Year OS May 05, 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer

28 MOSAIC: Study Design Primary end-point: disease-free survival Secondary end-points: safety, overall survival N = 2246 Enrollment: Oct 1998=Jan 2001 (146 centers; 20 countries) Completely resected colon cancer Stage II, 40%; Stage III, 60% Age years KPS ≥ 60 No prior chemotherapy R LV5-FU2 FOLFOX4 (LV5-FU2 + oxaliplatin 85 mg/m²) (N = 1,123) LV5-FU2: Leucovorin 200 mg/m 2 iv over 2 hours followed by 5-FUl 400 mg/m 2 bolus and 5-FU 600 mg/m 2 iv over 22 hours on Days 1 and 2, every 14 days FOLFOX4: LV5-FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1 André, et al. N Engl J Med 2004

29 MOSIAC: Disease-free Survival Stage II and Stage III Patients (ITT) Data cut-off: June 2006 Disease-free Survival (months) Probability Events FOLFOX4 304/1123 (27.1%) LV5-FU2 360/1123 (32.1%) HR [95% CI]: 0.80 [0.68–0.93] 5.9% P = de Gramont A, et al. ASCO Abstract #4007

30 MOSIAC: Disease-free Survival Stage II and Stage III Patients Data cut-off: June 2006 Months HR [95% CI] P-value Stage II 0.84 [0.62–1.14] Stage III 0.78 [0.65–0.93] FOLFOX4 stage II LV5-FU2 stage II FOLFOX4 stage III LV5-FU2 stage III Probability % 7.5% P = P = de Gramont A, et al. ASCO Abstract #4007

31 MOSAIC - ASCO 2007: Disease-free Survival - Final Update 5-year DFS % HR [95% CI]P-value FOLFOX4LV5-FU2 ITT (overall population) [0.68 – 0.93] Stage III [0.65 – 0.93] Stage II [0.62 – 1.14] High-risk stage II N = [0.52 – 1.06] — Low-risk stage II N = [0.66–2.26] — Data cut-off: June 2006 de Gramont A, et al. ASCO Abstract #4007

32 “High-risk” Stage II Colon Cancer Clinico-pathological parameters (MOSAIC) – T4 tumors – Obstruction/perforation – Lymphatic or vascular invasion – Undifferentiated histology – Less than 10 (12) Ln examined Molecular parameters – LOH 18q – MSS – Other?

33 MOSIAC: Long-Term Safety FOLFOX 5.3% LV5-FU2 5.7% Data cut-off: January 2007 Second CancerPeripheral Sensory Neuropathy Evaluable Patients (N = 811) Grade 084.3% Grade 112.0% Grade 22.8% Grade 30.7% de Gramont A, et al. ASCO Abstract #4007.

34 MOSIAC: Overall Survival Stage II and Stage III (ITT) Data cut-off: January 2007 Overall Survival (months) Probability Events FOLFOX4 243/1123 (21.6%) LV5-FU2 279/1123 (24.8%) HR [95% CI]: 0.85 [0.72–1.01] 2.6% P = de Gramont A, et al. ASCO Abstract #4007.

35 MOSIAC: Overall Survival Stage II and Stage III Data cut-off: January 2007 FOLFOX4 stage II LV5-FU2 stage II FOLFOX4 stage III LV5-FU2 stage III Overall Survival (months) Probability HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.1% 4.4% P = P = de Gramont A, et al. ASCO Abstract #4007.

36 Take Home Messages: MOSAIC DFS benefit for FOLFOX is maintained over 5 years Significant OS benefit for stage III, but NOT for unselected stage II patients – “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear No increased rate of secondary cancers, but more deaths from cancer in FOLFOX group (21 vs.11) Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)  FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

37 FU Rest LV500 FU500 Rest LV500 OHP 852hr 500 Week R x3 Kuebler et al. J Clin Oncol 2007 N = 2407 Endpoint 3-yr DFS 30% stage II RP FLOX NSABP C-07

38 Kuebler et al. J Clin Oncol 2007 NSABP C-07: DFS

39 Kuebler et al. J Clin Oncol 2007 NSABP C-07: HR DFS

40 Cross-Study Comparison Toxicity: MOSAIC/C-07 FOLFOX 4 (MOSAIC) FLOX (C-07) Gr 3-4 Neutropenia 41% (2% neut. fever) 4% (?) Gr 3-4 Diarrhea11%38% Gr 3-4 Neuro (cum oxali) 12.4% (1,020 mg/m 2 ) 8.4% (765 mg/m 2 ) All Cause Mortality0.5%1%

41 X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon Cancer 1° endpoint: disease-free survival (DFS) Chemo-naïve Dukes C, resection ≤ 8 weeks Capecitabine 1250 mg/m 2 twice daily, d 1-14, q21d N = Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20 mg/m 2, d 1-5, q28d N = weeks Twelves et al. NEJM 2005

42 X-ACT Trial: DFS Years Estimated probability Capecitabine (N = 1 004) 5-FU/LV (N = 983) Log-rank P = HR = 0.87 (95% CI: ) Absolute difference at 3-years: 4% Median follow-up 3.8 yrs Twelves et al. NEJM 2005

43 What is the Standard Adjuvant Therapy for Colon Cancer ? FOLFOX is standard adjuvant therapy for stage III and can be considered in high-risk stage II colon cancer FLOX validates adjuvant oxaliplatin, but too toxic (diarrhea) Capecitabine for those patients who are not considered candidates for oxaliplatin Irinotecan-based combinations are NOT options in the adjuvant setting XELOX data eagerly awaited (ASCO 2008?) Bevacizumab and cetuximab are under investigation

44 Ongoing U.S. Cooperative Group Trials Adjuvant Therapy of Colon Cancer Stage III colon cancer (N = 2,300) Stage II/III colon cancer (N = 2,400) mFOLFOX6 6m mFOLFOX6 6m + bevacizumab 12m Intergroup N0147 NSABP C-08 mFOLFOX6 6m mFOLFOX6 6m + cetuximab 6m Revised 5/05

45 ASCO 2007 – Colorectal Cancer Commentary


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