Trial Information

Randomized Trial of Treatment Strategy for Chemotherapy in Colorectal Cancer, FFCD 2000-05

Background:

The addition of oxaliplatin and irinotecan to 5-FU improves tumor response rate and
progression-free survival in patients with advanced colorectal cancer compared with 5-FU
alone, but increases toxicity. It is not clear whether such combination therapies
(5-FU+oxaliplatin or 5-FU+irinotecan) should be systematically used as first line treatment
or as second line treatment after 5-FU failure.

Design: open-label, multicentric, randomized trial

Aim: The main objective of this multiline strategy trial was to compare two 5-FU based
regimens with or without the addition of oxaliplatin to 5-FU in the first line setting in
terms of progression-free survival after two lines of chemotherapy in patients with
metastatic colorectal cancer.

Treatment compared:

Control arm: first line, 2-hour infusion 400 mg/m² leucovorin (LV) followed by
5-fluorouracil 400 mg/m² and 46-hours 2,400 mg/m² every 2 weeks (LV5FU2), second line,
LV5FU2 + oxaliplatin 100 mg/m² as a 2-hour perfusion on day 1 (FOLFOX6), third line, LV5FU2
+ irinotecan 180 mg/m² (FOLFIRI)

Experimental arm: first line, FOLFOX6, second line, FOLFIRI, third line, 5-FU 250 mg/m²/day
in continuous perfusion 7 out of 8 weeks or capecitabine 2,500 mg/m² per oral 14 out of 21
days or inclusion in a phase I

Inclusion criteria:

- Histologically confirmed metastatic colorectal adenocarcinoma

- Unresectable metastasis

- Bidimensionally measurable disease (WHO criteria)

- WHO performance status of 2 or less

- Adequate hematologic, renal function and liver functions

- No previous chemotherapy other than previous adjuvant chemotherapy or concomitant
chemoradiotherapy with 5-fluorouracil and leucovorin for the treatment of the primary
tumor completed at least 6 months before inclusion

- Signed written inform consent

- Quality of life questionnaire (QLQ C-30) filled out

Exclusion criteria:

- Pregnant or breast-feeding women

- No possible regular follow-up for psychological, social or geographical reason

- Severe cardiac, respiratory, renal or hepatic failure

- Active coronary heart disease

- Central nervous system metastases

- Past history of second malignancies

- Another investigational drug

- Chronic inflammatory bowel disease

- Previous chemotherapy with irinotecan or oxaliplatin based regimens

Randomization:

Randomization is performed centrally using a minimization technique, stratifying patients
according to centre, previous adjuvant treatment, WHO performance status, and number of
metastatic sites

Outcomes:

Progression-free survival after two lines of chemotherapy, defined as the time duration from
randomization until progression after two lines of chemotherapy or death whatever the cause
in the absence of progression or last-follow-up.

Overall survival, secondary surgery, response rate, progression-free survival after the
first and the third line of chemotherapy, safety, quality of life and costs

Follow-up:

Tumor assessments is performed every 8 weeks, quality of live assessment every 8 weeks until
progression after 2 lines of chemotherapy or for one year if no progression. After the end
of the planned treatment, patients are followed up until death or the cut-off date.

Sample size and statistical analyses:

570 patients, 285 per arm will be needed to detect a difference in median of
progression-free survival after two lines of chemotherapy of 3 months from 10 months in the
control arm to 13 months in the experimental arm, for a type I error of 5% and a power of
80% (bilateral log rank test).

The analysis will be performed according to the intent-to treat principle. An interim
analysis is planned after the inclusion of 400 patients with 3 months follow-up or the
occurrence of 250 events and reviewed by an independent data monitoring committee.

Estimated duration of the trial: accrual period, 3 years, minimum follow-up, one year