Presentation on theme: "Neoadjuvant Colorectal Cancer Axel Grothey, MD"— Presentation transcript:
1 Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer Neoadjuvant Colorectal CancerAxel Grothey, MDSenior Associate ConsultantDivision of Medical OncologyMayo Clinic College of MedicineRochester, MN
2 Case 1: Neoadjuvant Therapy 54-year-old male with 6-months of weight loss and fatigueSees PCP and physical exam significant for liver edge palpable 2 cm below RCMHb 9.7 g/dL with MCV 75 µm³ (previously 90 µm³)Stool guaiac positive
3 Case 1: Neoadjuvant Therapy Referred to gastroenterologist for evaluationCEA 25 ng/mLColonoscopy shows sigmoid massBiopsy adenocarcinoma with signet ring featuresCT scan shows5 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 chemotherapySurgery for primary and metastatic diseasePrimary (neoadjuvant) chemotherapy followed by surgery
5 Case 1: Neoadjuvant Therapy Which treatment option would you recommend?Surgery for primary, followed by chemotherapySurgery for primary and metastatic diseasePrimary (neoadjuvant) chemotherapy followed by surgeryRecommended approach
6 Pertinent Issues for Case 1 Optimal management of liver metastasesPrimarily resectable metastasesRole of neoadjuvant therapyUnresectable metastasesOptimal therapy to downsize metastases (“conversion” therapy)Role of postoperative, adjuvant therapy
7 Liver Resection – New Perspective Old:Resectability determinedby “what comes out”New:Resectability determinedby “what stays in”
9 Multimodality Management of CRC Liver Metastases Neoadjuvant chemotherapyResectable liver metastasesFacilitate surgeryObtain predictive and prognostic informationEarly systemic therapy for poor-prognosis ptsConversion chemotherapyUnresectable liver metastasesAllow R0 resection via downsizingPostoperative (adjuvant) chemotherapyHepatic 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 therapySurvival outcome by response to chemotherapyResponseStabilizationProgressionPNo. of patients58 (44%)39 (30%)34 (26%)Nodules (mean)6.25.7Hepatic recurrence55%77%82%1-yr survival95%92%63%5-yr survival37%30%8%<Adam et al., Ann Surg 2004
11 Survival After Primary or Secondary Resection of Liver Metastases Proportion Surviving1.9Resectable (N = 425)Initially non-resectable (N = 95).8.754%.6.550%34%.427%.334%.229%19%.112345678910Survival Time (years)Bismuth et al., 1996
12 Resectability Correlates with RR Response Rate0.9.8.7.126.96.36.199.188.8.131.52.0Resection RateStudies with neoadj. focusPhase III trialsPhase II trialsFolprecht et al., Ann Oncol 2005
13 Hepatic Arterial Infusion of Chemotherapy After Hepatic Metastasis 5-FU/LVRandomized After Hepatic ResectionN=1565-FU/LV + HAI FUDRCombination Therapy5-FU/LVP2-yr OS (%)86.072.0.03mOS (mo)72.259.3NS2-yr recurrence-free survival (%)90.060.0<.0012-yr risk of death1.02.3x.027Median OS update 2005 (mo)68.558.80.10HAI FUDR = hepatic arterial infusion with floxuridine and dexamethasone.Kemeny et al. N Engl J Med. 1999;341:2039Kemeny et al. N Engl J Med 2005;352:734
14 EORTC 40983 - Perioperative FOLFOX in Resectable Liver Mets RANDOMIZESurgeryFOLFOX46 cycles(3 months)N = 364 patients (09/00-07/04)Aim: To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alonePrimary endpoint: PFS (40% increase in median PFS (HR = 0.71) with 80% power and 2-sided significance level 5%)Secondary endpoints: OS, resectability, response, safetyNordlinger et al., ASCO 2007 Abstract LBA5
15 Complications of Surgery Peri-op CTSurgeryPostoperative complications*40/159 (25.2%)27/170 (15.9%)Cardio-pulmonary failure32BleedingBiliary Fistula125(Incl output > 100 ml/d, >10d)(9)(2)Hepatic Failure118(Incl. bilirubin>10 mg/dl, >3d)(10)(5)Wound infection4Intra-abdominal infectionNeed for reoperationOther2516Incl. postoperative death1 patient2 patients*P = 0.04Nordlinger et al., ASCO 2007 Abstract LBA5
17 % absolute difference in 3-year PFS (Confidence Interval) Results EORTC 40983N pts CTN pts Surgery% absolute difference in 3-year PFSHazard Ratio(Confidence Interval)P-valueAll patients182+7.2% (28.1% to 35.4%)0.79 ( )0.058All eligiblePatients171+8.1% (28.1% to 36.2%)0.77 ( )0.041All resected151152+9.2% (33.2% to 42.4%)0.73 ( )0.025MOSAIC: 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 = 0.041Periop CT28.1%36.2%+8.1% At 3 yearsyears123456102030405060708090100ONNumber of patients at risk:125171835737228115744321Surgery onlyNordlinger et al., ASCO 2007 Abstract LBA5
19 Take-Home Messages EORTC 40983 Perioperative therapy with FOLFOX4 improves PFS (DFS) in patients with resectable liver metastasesWith preoperative FOLFOX4 higher incidence of postoperative complications, but same operative mortalityStudy 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 womanHistory of hypertension, but otherwise healthyPresents with GI bleeding, adenocarcinoma of descending colon identifiedPatient undergoes laparoscopic colectomyPathology demonstrates T3N1 (2/15) M0 colon cancer, moderately differentiated and no evidence of lymphovascular invasionPatient 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/LVCapecitabineFOLFIRIFOLFOXBolus 5-FU/LV and oxaliplatin (FLOX)CAPOX (XELOX)Other
22 Case 2: Stage III Colorectal Cancer Which treatment option would you recommend?5-FU/LVCapecitabineFOLFIRIFOLFOXBolus 5-FU/LV and oxaliplatin (FLOX)CAPOX (XELOX)OtherRecommended approach
23 Case 2: Stage III Colorectal Cancer Would you add a targeted agent to adjuvant chemotherapy?NoYes, bevacizumabYes, cetuximab (or panitumumab)
24 Case 2: Stage III Colorectal Cancer Would you add a targeted agent to adjuvant chemotherapy?NoYes, bevacizumabYes, cetuximab (or panitumumab)Recommended approachNo – Remains investigational in adjuvant setting
25 Pertinent Issues for Case 2 Relatively young patient, no serious comorbiditiesStage IIIB colon cancer T3 N1 (2/15)Standard adjuvant therapy for stage III colon cancer?Addition of biologics of any benefit?
26 History of Adjuvant Therapy for Colon Cancer 5-FU/lev superior to surgery alone5-FU/LV superior to 5-FU/lev6- and 12-month treatment cycles equivalentLev unnecessaryHigh-dose and low-dose LV equivalentMonthly and weekly treatment equivalentLV5-FU2 and monthly bolus equivalent5-FU/LV superior to surgery alone1990199419982002Moertel 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. AbstractO’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.
27 3-Year DFS vs. 5-Year OSMay 05, 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer0.50.550.60.650.70.750.8r = 0.883-Year DFS5-Year OSSargent, et al. J Clin Oncol 2005;23:8664–8670.
28 MOSAIC: Study Design R FOLFOX4 LV5-FU2 N = 2246 Enrollment: Oct 1998=Jan 2001(146 centers; 20 countries)Completely resected colon cancerStage II, 40%; Stage III, 60%Age yearsKPS ≥ 60No prior chemotherapyFOLFOX4(LV5-FU2 + oxaliplatin 85 mg/m²)(N = 1,123)RLV5-FU2(N = 1,123)Primary end-point: disease-free survivalSecondary end-points: safety, overall survivalLV5-FU2: Leucovorin 200 mg/m2 iv over 2 hours followed by 5-FUl 400 mg/m2 bolus and 5-FU 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 daysFOLFOX4: LV5-FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1André, et al. N Engl J Med 2004
29 MOSIAC: Disease-free Survival Stage II and Stage III Patients (ITT) Disease-free Survival (months)Probability1.00.80.60.184.108.40.206.50.30.16121824603036424854EventsFOLFOX /1123 (27.1%)LV5-FU /1123 (32.1%)HR [95% CI]: [0.68–0.93]5.9%P = 0.003Data cut-off: June 2006de Gramont A, et al. ASCO Abstract #4007
30 MOSIAC: Disease-free Survival Stage II and Stage III Patients MonthsHR [95% CI] P-valueStage II [0.62–1.14]Stage III [0.65–0.93]FOLFOX4 stage IILV5-FU2 stage IIFOLFOX4 stage IIILV5-FU2 stage IIIProbability1.00.80.60.220.127.116.11.50.30.1612182460303642485466723.8%7.5%P = 0.258P = 0.005Data cut-off: June 2006de Gramont A, et al. ASCO Abstract #4007
31 MOSAIC - ASCO 2007: Disease-free Survival - Final Update 5-year DFS %HR [95% CI]P-valueFOLFOX4LV5-FU2ITT (overall population)73.367.40.80[0.68–0.93]0.003Stage III66.458.90.78[0.65–0.93]0.005Stage II83.779.90.84[0.62–1.14]0.258High-risk stage II N = 57618.104.22.168[0.52–1.06]—Low-risk stage II N = 32386.389.11.22[0.66–2.26]Data cut-off: June 2006de Gramont A, et al. ASCO Abstract #4007
32 “High-risk” Stage II Colon Cancer Clinico-pathological parameters (MOSAIC)T4 tumorsObstruction/perforationLymphatic or vascular invasionUndifferentiated histologyLess than 10 (12) Ln examinedMolecular parametersLOH 18qMSSOther?
33 MOSIAC: Long-Term Safety Peripheral Sensory NeuropathySecond CancerFOLFOX5.3%LV5-FU25.7%Evaluable Patients(N = 811)Grade 084.3%Grade 112.0%Grade 22.8%Grade 30.7%Data cut-off: January 2007de Gramont A, et al. ASCO Abstract #4007.
34 MOSIAC: Overall Survival Stage II and Stage III (ITT) Overall Survival (months)Probability1.00.80.60.22.214.171.124.50.30.16121824603036424854669672788490EventsFOLFOX /1123 (21.6%)LV5-FU /1123 (24.8%)HR [95% CI]: 0.85 [0.72–1.01]2.6%P = 0.057Data cut-off: January 2007de Gramont A, et al. ASCO Abstract #4007.
35 MOSIAC: Overall Survival Stage II and Stage III FOLFOX4 stage IILV5-FU2 stage IIFOLFOX4 stage IIILV5-FU2 stage IIIOverall Survival (months)Probability1.00.80.60.126.96.36.199.50.30.16121824603036424854669672788490HR [95% CI]Stage II [0.71–1.42]Stage III [0.66–0.98]0.1%4.4%P = 0.996P = 0.029Data cut-off: January 2007de Gramont A, et al. ASCO Abstract #4007.
36 Take Home Messages: MOSAIC DFS benefit for FOLFOX is maintained over 5 yearsSignificant 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 unclearNo 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 R NSABP C-07 x3 Rest Rest FU N = 2407 500 RP LV 500 FU 500 LV 500 FLOX Endpoint3-yr DFSOHP852hrWeek30% stage IIKuebler et al. J Clin Oncol 2007
38 NSABP C-07: DFSKuebler et al. J Clin Oncol 2007
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 cancerFLOX validates adjuvant oxaliplatin, but too toxic (diarrhea)Capecitabine for those patients who are not considered candidates for oxaliplatinIrinotecan-based combinations are NOT options in the adjuvant settingXELOX data eagerly awaited (ASCO 2008?)Bevacizumab and cetuximab are under investigation
44 Ongoing U.S. Cooperative Group Trials Adjuvant Therapy of Colon Cancer Intergroup N0147mFOLFOX6 6mStage III colon cancer (N = 2,300)Revised 5/05mFOLFOX6 6m + cetuximab 6mNSABP C-08mFOLFOX6 6mStage II/III colon cancer (N = 2,400)mFOLFOX6 6m + bevacizumab 12m