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Combination and Sequential Chemotherapy of Metastatic Colorectal Cancer. Daniel G. Haller, MD University of Pennsylvania Cancer Center. Discussion topics. What is the goal of administering combination vs sequential therapy? What is the evidence for combination versus sequential therapy?

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combination and sequential chemotherapy of metastatic colorectal cancer

Combination and Sequential Chemotherapy of Metastatic Colorectal Cancer

Daniel G. Haller, MD

University of Pennsylvania Cancer Center

discussion topics
Discussion topics
  • What is the goal of administering combination vs sequential therapy?
  • What is the evidence for combination versus sequential therapy?
  • What are the interim endpoints in studies of sequential therapy?
  • How are new therapies incorporated into combination or sequential therapy?
chemotherapy for metastatic colorectal cancer
Chemotherapy for Metastatic Colorectal Cancer

What is the Goal of Combination vs Sequential Therapy?

  • Overall survival
    • The gold standard for regulatory approval
  • Progression-free survival
    • Surrogate of activity for clinical trials
    • Marker of clinical benefit
  • Response rate
  • Measures of quality of life
    • Time to symptom worsening
chemotherapy for metastatic colorectal cancer1
Chemotherapy for Metastatic Colorectal Cancer

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

  • RR: range from 34–51%
  • PFS: range from 6.7–9.3 m
  • OS: range from 14.8–19.4 m
    • Statistical superiority for FU/LV/CPT-11 compared to first-line FU/LV
    • Incremental benefit achieved without marked increase in toxicity or negative impact on QOL
    • Effects of crossover and surgical therapy
chemotherapy for metastatic colorectal cancer2
Chemotherapy for Metastatic Colorectal Cancer

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

Oscar Wilde

chemotherapy for metastatic colorectal cancer3
Chemotherapy for Metastatic Colorectal Cancer

NCCTG Trial N9741

  • FU/LV/CPT-11(Saltz) weekly
  • •FU/LV(de Gramont) + oxaliplatin Q2W
  • Oxaliplatin + CPT-11Q3W
    • -Primary endpoint: Survival
    • -No fixed crossover; no oxaliplatin available
    • after progression on Saltz regimen

R

chemotherapy for metastatic colorectal cancer4
Chemotherapy for Metastatic Colorectal Cancer

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/LV

R

CPT-11 + de Gramont FU/LV

Proc ASCO, abstract 949, 2000

duration of chemotherapy
Duration of Chemotherapy

MRC-CR06 Trial

CIFU

De Gramont FU/LV

Tomudex

R

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

sequence of chemotherapy
Sequence of Chemotherapy

FOCUS Trial

Modified de Gramont FU/LV CPT-11

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

FU/LV/CPT-11

Modified de Gramont FU/LV FU/LV+oxaliplatin

FU/LV/oxaliplatin

R

• 2100 patients

endpoints: PFS, OS, QOL

chemotherapy for metastatic colorectal cancer5
Chemotherapy for Metastatic Colorectal Cancer

Pivotal Trial of Oxaliplatin: EFC 4584

  • Response rate in FU/LV and CPT-11 failures
  • Survival advantage in patients who have failed FU/LV/irinotecan

infusional FU/LV(de Gramont)

R oxaliplatin

infusional FU/LV+oxaliplatin

chemotherapy for metastatic colorectal cancer6
Chemotherapy for Metastatic Colorectal Cancer

Oxaliplatin Trials in US

  • EFC 4584: in FU/LV/CPT-11 (Saltz) failures
  • EFC 4585: CPT-11 alone vs CPT-11 + oxaliplatin in FU/LV failures
  • EFC 4759: oxaliplatin in third-line therapy
  • EFC 4760: de Gramont FU/LV +

oxaliplatin in third-line therapy