NANTES, France-European researchers are moving beyond colorectal cancer regimens based on infusional fluorouracil (5-FU) to comparing combinations and to examining the effects of scheduling on response and time to progression, according to Jean-Yves Douillard, MD, PhD. Professor Douillard, who developed a widely-used regimen for colorectal cancer, is professor of medical oncology and head of the department of medical oncology, Centre Rene Gauducheau, at the University of Nantes in France.
NANTES, FranceEuropean researchers are moving beyond colorectal cancer regimens based on infusional fluorouracil (5-FU) to comparing combinations and to examining the effects of scheduling on response and time to progression, according to Jean-Yves Douillard, MD, PhD. Professor Douillard, who developed a widely-used regimen for colorectal cancer, is professor of medical oncology and head of the department of medical oncology, Centre Rene Gauducheau, at the University of Nantes in France.
European clinicians view the value of chemotherapy for colorectal cancer as well established and favor infusional over bolus 5-FU, according to Professor Douillard. "A combination of fluorouracil, leucovorin, and irinotecan (CPT-11, Camptosar) or oxaliplatin (Eloxatin) is now becoming standard therapy," he said. "Most use a simplified de Gramont regimen, with a 5-FU bolus of 400 mg/m2 followed by 5-FU at 2.4 to 3.6 g/m2 over 46 hours, repeating every 2 weeks" (see Table 1).
Ongoing European studies in advanced colorectal cancer include comparisons between single agent 5-FU/leucovorin and various combinations and comparisons of combinations. European researchers are also experimenting with variations in drug scheduling, either in exclusive chemotherapy or in combination with surgery for resectable patients.
Ongoing Trials Summarized
Professor Douillard summarized these ongoing trials.
A German trial is comparing the German AIO regimen (2,600 mg/m2 5-FU given as a 24-hour infusion plus 500 mg/m2 leucovorin weekly x 6 with 1 week rest, continuing for 18 weeks to the same regimen plus irinotecan at 80 mg/m2/week, but with the 5-FU dose reduced to 2,000 mg/m2. Preliminary results of this 430-patient trial, which were presented at the 2002 American Society of Clinical Oncology meeting (Kohne et al, ASCO abstract 532) showed a median progression-free survival of 8.5 months for the irinotecan arm vs 6.5 months for the 5-FU/leucovorin arm (P < .0001). "This is one of the longest time to progression periods reported so far in this population of patients," Professor Douillard said.
An ongoing UK study (FOCUS) in 2,100 patients is comparing five regimens:
1. 5-FU/leucovorin followed by irinotecan given every 3 weeks;
2. 5-FU/leucovorin followed by FOLFIRI, another regimen containing fluorouracil, leucovorin, and irinotecan;
3. FOLFIRI alone;
4. 5-FU/leucovorin followed by FOLFOX6 (fluorouracil, leucovorin, oxaliplatin); and
5. FOLFOX6 alone.
Several US trials on the drawing board include the older FOLFOX4 regimen, but FOLFOX has continued to evolve in the European trials. "The FOLFOXes are moving fast, and you have to keep up with them. FOLFOX7 is presently in clinical trials and other FOLFOXs8 and 9may soon be proposed," Professor Douillard said.
The objectives of this trial are to compare efficacy of a 5-FU/leucovorin-based combination vs sequential 5-FU/leucovorin followed by irinotecan, to determine if the combination is best used as first-line treatment or reserved for use after 5-FU/leucovorin failure, to compare the efficacy of FOLFIRI vs FOLFOX6, and to compare toxicity, overall survival, progression-free survival, and quality of life among the five regimens. "This trial should provide us with very important information," Professor Douillard said.
Six hundred of a planned 700 patients have been accrued for the "Optimox" phase III trial comparing FOLFOX4 (fluorouracil/leucovorin plus oxaliplatin 85 mg/m2 every 2 weeks until progression) to 6 cycles of FOLFOX7 (fluorouracil/leucovorin plus oxaliplatin 130 mg/m2, then 12 cycles of 5-FU/leucovorin). The primary endpoint is time to treatment failure.
Several trials are investigating chemotherapy/surgery combinations. An Aventis-sponsored study is testing triple chemotherapy with irinotecan/oxaliplatin, and 5-FU/leucovorin in patients with marginally resectable liver metastases. "The major problem here is determining marginal resectabilty. If you show the same patient to three surgeons, one will say the cancer is completely resectable, a second will say it is not resectable, and the third will say it is partly resectable," Professor Douillard said. The European Organization for Research and Treatment of Cancer (EORTC) is conducting a randomized phase III trial (EORTC-40983) comparing surgery alone to surgery preceded and followed by FOLFOX4 for patients with resectable liver metastases (see Table 2).
"My feeling is that chemotherapy should be integrated with a surgical approach, even for patients who have advanced metastases. With the improved response rates that are achieved with modern chemotherapy, the surgical opportunity should be evaluated more often all along the evaluation period," Professor Douillard said.
The integration of biological targeted therapy is being studied in a Merck-sponsored randomized phase trial in 300 irinotecan-resistant patients with colorectal tumors that overexpress the epidermal growth factor receptor. Patients will be randomized to irinotecan plus cetuximab (Erbitux) or to cetuximab alone.
"As a conclusion, it is to be emphasized that major progress has been made in the treatment of advanced colorectal cancer and median survival above 20 months may be expected," Professor Douillard stated. "It is reasonable to hope that concerted integration of chemotherapy, surgery, and hopefully soon, targeted biological therapies, will still improve these results and also might translate into a better cure rate for less advanced diseases."