asco ‘04 in perspective gi highlights
DESCRIPTION
ASCO ‘04 in Perspective GI Highlights. George A. Fisher M.D. Ph.D. Stanford University School of Medicine. ASCO ‘03 GI Highlights A Tough Act to Follow. First (+) adjuvant colon trial in >10 years Mosaic Trial: LV5FU2 vs. FOLFOX4 “Targeted” therapies in metastatic colon - PowerPoint PPT PresentationTRANSCRIPT
ASCO ‘04 in PerspectiveGI Highlights
George A. Fisher M.D. Ph.D.Stanford University School of Medicine
ASCO ‘03 GI HighlightsA Tough Act to Follow
• First (+) adjuvant colon trial in >10 years– Mosaic Trial: LV5FU2 vs. FOLFOX4
• “Targeted” therapies in metastatic colon– First line: IFL + Bevacizumab– Second line: Cetuximab + Irinotecan
• Encouraging early results Phase III pancreas– GemOx vs Gem: response and DFS improvements
GEM vs GEMOX (Louvet et al #4008)
The GERCOR Pancreatic Trial
RANDOMIZATION
Gemcitabine 1000 mg/m2 over 30 minWeekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1Oxaliplatin 100 mg/m2 2 hour infusion day 2Every 2 weeks
GEM vs GEMOX EfficacyGEM GEMOX p value
Response rate 17.3% 26.8% .044 Locally adv. 14.9% 27.4% Metastatic 18.3 26.4%Prog. Free Surv. 3.7 mos 5.8 mos .038Clinical Benefit 26.9% 38.2% .03Overall Survival 7.1 mos 9.0 mos ns1-yr survival 27.8% 34.7% ns
Current ECOG TrialMetastatic Pancreas Cancer
RANDOMIZATION
Gemcitabine 1000 mg/m2 over 30 minWeekly x 7, then 3 weeks of 4
Gemcitabine 1000 mg/m2 (10 mg/m2/min) day 1Oxaliplatin 100 mg/m2 2 hour infusion day 2Every 2 weeks
Gemcitabine 1000 mg/m2 (10 mg/m2/min)
Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial
RANDOMIZATION
T3NxRectal
50.4 GyCI 5-FU Surgery 5-FU x 4
Surgery 50.4 Gy 5-FU x 4 CI 5-FU
Rectal Cancer ASTRO ‘03The German pre-op vs. post-op trial
Saur et al ASTRO ‘03
Post-opN= 394
Pre-opN= 405
p value
5 yr Local Failure 12% 6% .006
5 yr survival 74% 74% ns
Acute Toxicity 40% 28% .005
Chronic Toxicity 23% 10% .04
Sphincter Preservation
20%(17/85)
39%(43/109)
.004
Capecitabine vs. Infusional 5-FU Concurrent with Neoadjuvant XRT
[Randomized Phase III NSABP R-04]
T3-4orN1
Rectal
Capecitabine (825/m2 bid)+ radiation
5-FU infusion (225/m2 daily)+ radiation
SURGERY
Endpoints:-path response-local relapse- down staging- sphincter sparing- quality of life- biomarkers
RANDOMIZATION
Preoperative Chemoradiotherapy: A Phase I/II Rectal Trial
Kuo et al. Stanford University
US T3/4or N1RectalCancer
BiopsyDay 8
BiopsyDay 0
Radiation therapyCetuximab q weekCapecitabine M-FOxaliplatin q 2wks
SURGERY
PET PET
Endpoints:-toxicity-op morbidity-path response-downstaging-sphincter-molecular, imaging and circulating cell correlates
Origin of FOLFOX
600600FOLFOX4(1995)
200
Bolus 400Bolus 400
85 200
Bolus 400Bolus 400
600600LV5FU2(1984) 200
Bolus 400Bolus 400
200
Bolus 400Bolus 400
1997 (De Gramont et al. JCO): Better response rate with less toxicity than bolus 5-FU (Mayo regimen)
2000 (De Gramont et al. JCO):Better response rate and DFS than LV5FU2
2004 (Goldberg et al. JCO): Better response rate / DFS / OS with less toxicity than IFL (Saltz regimen)
600600FOLFOX4(1995)
Doses mg/mDoses mg/m22: 5-FU,: 5-FU, oxaliplatinoxaliplatin,, leucovorinleucovorin
Bolus 400Bolus 400
FOLFOX6(1997)
2400FOLFOX7(1998)
Evolution of FOLFOX Regimens
200
Bolus 400Bolus 400
85200
400100
2400-3000
400130
Bolus 400Bolus 400
48 hr24 hr
FOLFOX4Reasons for Discontinuation
• Reanalysis of Intergroup Study N9741– 43% patients off study due to progressive disease– 57% for “other” reasons”
• 23% neurotoxicity• 23% myelosuppression• 7% hypersensitivity• 9% Complete response or secondary resection of
mets• 29% Patient refusal: unspecified• 9% Other
Axel Grothey et al
Optimox I [De Gramont #3525]Optimizing Oxaliplatin:
Concept of Intermittent Therapy
RANDOMIZATION
FOLFOX4 to progressive disease or intolerance
FOLFOX7 x 6 LV5FU2 to PD FOLFOX7
600600200
Bolus 400Bolus 400
85200
Bolus 400Bolus 400
2400400130
FOLFOX4 FOLFOX7Response rate 58.5% 58.3%PFS (mos) 9.0 9.2OS (mos) 20.0 21.6G3/4 N-Tox 18.7% 13.3%
Optimox 1 [De Gramont #3525]Optimizing Oxaliplatin
Concept of Intermittent Therapy
-more acute thrombocytopenia, N / V, cold sensitivity with FOLFOX 7 vs. FOLFOX 4
-variable adherence to protocol by center (resuming FOLFOX7)
-protocol adherence correlated with improved survival
Optimox 2 Trial [using mFOLFOX7]
2400FOLFOX7 400130
3000mFOLFOX7100400
RANDOMIZATION
mFOLFOX7 x 6 no rx until PD mFOLFOX7
mFOLFOX7 x 6 LV5FU2 mFOLFOX7
Oxaliplatin NeuropathyPossible Protection by Ca/Mg
• Ca2+ gluconate + Mg2+ sulfate 1 gram each before and after oxaliplatin
• Post-hoc analysis of 161 patients– Gamelin et al, Clin Cancer Research 2004– % pts stopping due to neurotoxicity
• 35% controls vs 5% for Ca / Mg treated• No decrement in response rate
CONcePT: Optimization of FOLFOX + Bevacizumab
2 x 2 randomization: 532 patients
mFOLFOX7 + Bevacizumab Continued until treatment failure + placebo
mFOLFOX7 + Bevacizumab Intermittent oxali therapy + placebo
mFOLFOX7 + Bevacizumab Intermittent oxali therapy + Ca/Mg
mFOLFOX7 + Bevacizumab Continued until treatment failure + Ca/Mg
3000 (5-FU)*mFOLFOX7 85 (Ox)400 (LV)
5 (Bev)
Integrating Parallel Successes Bevacizumab: Role in first line
FOLFOX >> IFL IFL + Bevacizumab > IFL
??FOLFOX + Bev > FOLFOX
FOLFOX ~ FOLFIRI
??FOLFIRI + Bev > FOLFIRI
Bevacizumab: CurrentCooperative Group Trials
Second Line ECOG Trial completed; results ASCO ‘05FOLFOX4 + BevResults expected fall/winter ‘04; ASCO ‘05
First Line SWOG Trial: (underway)[mFOLFOX6 vs. CAPOX] + Bevacizumab
Adjuvant NSABP Trial: (activation 10/04?)Stage II / III colon cancermFOLFOX6 + Bevacizumab
EGFR Inhibition with First Line EGFR Inhibition with First Line FOLFOX ChemotherapyFOLFOX Chemotherapy
ASCO‘04
Treatment Number ofPatients
ResponseRate
Fisher et al#3514
*Gefitinib +FOLFOX 4
36 78%
Taberneroet al #3512
**Cetuximab + FOLFOX 4
42 81%
*Gefitinib at 500 mg; higher GI toxicity c/w FOLFOX**Eligibility required EGFR(+) tumors
Proposed Intergroup Trial
RANDOMIZATION
Investigator’s Choice:
mFOLFOX6
CAPOX
FOLFIRI
[CAPIRI]
+ Bevacizumab
+ Cetuximab
+ Bevacizumab + Cetuximab
“Reasonable” Options for Metastatic Disease
• First line therapy– Good performance status
• FOLFOX (n) vs CAPOX + Bevacizumab• FOLFIRI vs CAPIRI + Bevacizumab
– Poor KPS• Capecitabine or 5-FU
+ Bevacizumab– Liver mets only
• Consider resection of responders
• Second line therapy– If first line irinotecan
• Capecitabine• CAPOX or FOLFOX• Cetuximab (if EGFR +)• Cetuximab + irinotecan
– If first line oxaliplatin• Irinotecan• Irinotecan + cetuximab
ALWAYS CONSIDER CLINICAL TRIALS
Recently Completed Adjuvant Trials for Colon Cancer
• Intergroup Stage III:– IFL vs Roswell Park 5-FU/LV (Saltz #3500)
• NSABP Stage II/III:– *Bolus 5-FU/oxali vs Roswell Park 5-FU/LV
• European Trials Stage II/III– *FOLFIRI vs LV5-FU2– UK Study: Continuous infusion 5-FU x 3 mos vs bolus
5-FU/LV x 6 months– FOLFOX vs LV5-FU2
• Capecitabine vs bolus 5-FU Stage III (Cassidy #3509)
*no efficacy data available to date
Bolus 5-FU (Mayo) vs Capecitabine for Stage III
X-ACT Trial (Cassidy # 3509)
Standard Mayo Clinic bolus 5-FU regimen x 6 versusCapecitabine (1250 mg/m2 bid x 14 d q 3wks) x 8
Median follow-up 3.8 years• Significantly decreased gr 3/4 diarrhea, stomatitis and
neutropenia• 3 year DSF [HR = 0.87; p = 0.0526]• 3 year Overall survival [HR = 0.84; NS]
“Reasonable” Options for Adjuvant Therapy
• Stage II– Assess risk
• Clinical parameters• Molecular markers
– High risk• FOLFOX vs CAPOX
vs. Capecitabine
– Low risk• Observation vs.
capecitabine
• Stage III– Good performance
status• FOLFOX vs. CAPOX
– Poor performance status
• Capecitabine vs. observation
ALWAYS CONSIDER CLINICAL TRIALS
ASCO ‘03-04: Implications• No role for IFL / Vanishing role for bolus 5-FU• “Acceptable”, even “recommended” options include
regimens with no Phase II data– FOLFOX or FOLFIRI + Bevacizumab first line colon– Irinotecan + cetuximab after FOLFOX failure
• Consistently high activity with EGFR inhibitors and fluoropyrimidine /oxali regimens– Three phase II studies with > 75% response rates 1st line
• The Stage II dilemma continues– Less toxic adjuvant options may shift risk-benefit
• Back to the drawing board:– pancreas, gastric, esophageal and hepatocellular