Combination and Sequential Chemotherapy of Metastatic Colorectal Cancer

D. Haller, CRC Symposium, 1.23.2001D. Haller, CRC Symposium, 1.23.2001OncologyOncology Spectrums Spectrums, NYC, NYC

Combination and Sequential Combination and Sequential Chemotherapy of Metastatic Chemotherapy of Metastatic

Colorectal CancerColorectal Cancer

Daniel G. Haller, MDDaniel G. Haller, MD

University of Pennsylvania Cancer CenterUniversity of Pennsylvania Cancer Center


Discussion topicsDiscussion topics

• What is the goal of administering What is the goal of administering combination vs sequential therapy?combination vs sequential therapy?

• What is the evidence for combination What is the evidence for combination versus sequential therapy?versus sequential therapy?

• What are the interim endpoints in What are the interim endpoints in studies of sequential therapy?studies of sequential therapy?

• How are new therapies incorporated How are new therapies incorporated into combination or sequential therapy?into combination or sequential therapy?


Chemotherapy for Metastatic Chemotherapy for Metastatic Colorectal CancerColorectal Cancer

What is the Goal of Combination What is the Goal of Combination vs Sequential Therapy?vs Sequential Therapy?

– Overall survivalOverall survival• The gold standard for regulatory approvalThe gold standard for regulatory approval

– Progression-free survivalProgression-free survival• Surrogate of activity for clinical trialsSurrogate of activity for clinical trials• Marker of clinical benefitMarker of clinical benefit

– Response rateResponse rate– Measures of quality of lifeMeasures of quality of life

• Time to symptom worseningTime to symptom worsening



Combination Chemotherapy (FU/LV With Combination Chemotherapy (FU/LV With CPT-11 or Oxaliplatin)CPT-11 or Oxaliplatin)

– RR: RR: range from 34–51%range from 34–51%– PFS: PFS: range from 6.7–9.3 mrange from 6.7–9.3 m– OS:OS: range from 14.8–19.4 mrange from 14.8–19.4 m

• Statistical superiority for FU/LV/CPT-11 Statistical superiority for FU/LV/CPT-11 compared to first-line FU/LVcompared to first-line FU/LV

• Incremental benefit achieved without marked Incremental benefit achieved without marked increase in toxicity or negative impact on QOLincrease in toxicity or negative impact on QOL

• Effects of crossover and surgical therapyEffects of crossover and surgical therapy



“There are only two tragedies in life: one is not getting what one wants, and the other is getting it.”

Oscar Wilde


NCCTG Trial N9741NCCTG Trial N9741

•FU/LV/CPT-11 (Saltz) weekly

•FU/LV (de Gramont) + oxaliplatin Q2W

•Oxaliplatin + CPT-11 Q3W

-Primary endpoint: Survival-No fixed crossover; no oxaliplatin available after progression on Saltz regimen

R




FRE-C97-3: FOLFIRI vs FOLFOX

• 113 patients/arm• Primary endpoint: PFS• No prior CT, >6mos from adjuvant Rx, no prior CPT-11 or oxaliplatin

Oxaliplatin + de Gramont FU/LVR

CPT-11 + de Gramont FU/LV

Proc ASCO, abstract 949, 2000


Duration of ChemotherapyDuration of Chemotherapy

MRC-CR06 TrialMRC-CR06 Trial

CIFUDe Gramont FU/LVTomudex

R

Patients are treated for 12 weeks; if stable or responding, a second randomization to 12 more weeks of therapy or discontinuation


Sequence of ChemotherapySequence of Chemotherapy

FOCUS TrialFOCUS Trial

Modified de Gramont FU/LV CPT-11Modified de Gramont FU/LV FU/LV+CPT-11FU/LV/CPT-11Modified de Gramont FU/LV FU/LV+oxaliplatinFU/LV/oxaliplatin

R

• 2100 patientsendpoints: PFS, OS, QOL



Pivotal Trial of Oxaliplatin: EFC 4584Pivotal Trial of Oxaliplatin: EFC 4584– Response rate in FU/LV and CPT-11 Response rate in FU/LV and CPT-11

failuresfailures– Survival advantage in patients who have Survival advantage in patients who have

failed FU/LV/irinotecanfailed FU/LV/irinotecan

infusional FU/LV(de Gramont)R oxaliplatin

infusional FU/LV+oxaliplatin



Oxaliplatin Trials in USOxaliplatin Trials in US– EFC 4584:EFC 4584: in FU/LV/CPT-11 (Saltz) in FU/LV/CPT-11 (Saltz)

failuresfailures

– EFC 4585: EFC 4585: CPT-11 alone vs CPT-11 + CPT-11 alone vs CPT-11 + oxaliplatin in FU/LV failuresoxaliplatin in FU/LV failures

– EFC 4759: EFC 4759: oxaliplatin in third-line therapyoxaliplatin in third-line therapy

– EFC 4760: EFC 4760: de Gramont FU/LV +de Gramont FU/LV +

oxaliplatin in third-line oxaliplatin in third-line therapytherapy

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Combination and Sequential Chemotherapy of Metastatic Colorectal Cancer