|
An effort to reduce oxaliplatin toxicity by giving advanced colon cancer patients chemotherapy-free intervals failed to reduce neuropathy or improve disease control in the OPTIMOX2 trial.
Indeed, patients who continued on a maintenance therapy lived longer than those who stopped chemotherapy after completing a FOLFOX regimen. Median overall survival was 26 months vs. 19 months (P = .05), said Dr. Frédérique Maindrault-Goebel of Hôpital Saint Antoine in Paris. Median progression-free survival was 8.3 months in the continuous arm and 6.7 months in the stop-and-go arm (P= .04).
"Despite the quality of life advantages for the patients, a full break in therapy cannot be recommended based on the results of this study," Dr. Maindrault-Goebel said. She recommended that a shorter break or intermittent chemotherapy be evaluated.
The study's rationale was that, while new combination therapies improve survival, they can increase toxicities such as the sensory neuropathy associated with oxaliplatin (Eloxatin) that often prompts cessation of treatment.
The French Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) sponsored the multicenter Optimized Leucovorin (LV)-5-fluouracil (5-FU)-Oxaliplatin Strategy in Metastatic Colorectal Cancer (OPTIMOX2), study. It was an outgrowth of the OPTIMOX1 trial of intermittent treatment based on FOLFOX7, a simplified LV 5-FU2 regimen with high-dose oxaliplatin (J. Clin. Oncol. 2006;24:394-400).
In OPTIMOX1, 620 previously untreated patients with metastatic colorectal cancer were randomly assigned to FOLFOX4 administered every 2 weeks until progression or to FOLFOX7 for 6 cycles followed by maintenance with LV 5-FU2 but not oxaliplatin for 12 cycles, after which FOLFOX7 was reintroduced. It found metastatic colorectal cancer patients with good tolerance could achieve a median overall survival of 26 months without oxaliplatin.
OPTIMOX2 was designed to enroll 600 patients in a phase III trial, but was downgraded to a phase II study with 202 patients after bevacizumab was approved in France. From 2004 to 2006, it randomized participants as follows:
• OPTIMOX1 (99 patients): Six cycles of FOLFOX7 followed by LV 5-FU2 until progression at which point FOLFOX7 was reintroduced.
• OPTIMOX2 (103 patients): Six cycles of FOLFOX7, complete stoppage of chemotherapy, and reintroduction of FOLFOX7 before tumor progression could reach baseline measures.
Median duration of the chemotherapy-free interval (CFI) was 4.6 months in the OPTIMOX2 arm and 4 months in patients who did not have surgery. Patients with poor prognosis had a significantly shorter median CFI, Dr. Maindrault-Goebel reported, while those with poor prognosis derived the most benefit from maintenance therapy. Combined partial/complete response rates were about 62% in both arms,.
Modified FOLFOX7 was well tolerated, with grade 3/4 neuropathy seen in 12%-19% of patients, grade 3/4 thrombocytopenia in 4%-12%, and gastrointestinal toxicity in fewer than 7%.
Maindrault-Goebel F. et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study. Abstract 4013.
Commentary |
OPTIMOX1 demonstrated that efficacy was maintained with decreased toxicity in patients with metastatic colorectal cancer who received a regimen containing oxaliplatin and then had an oxaliplatin-free interval using maintenance leuvovorin/5-fluorouracil. OPTIMOX2 evaluated an interval in which patients did not receive any chemotherapy, and FOLFOX was reintroduced on progression. It showed this strategy may be detrimental to disease control and overall survival. The maintenance therapy in OPTIMOX1 may be a critical component. Therefore, based on this trial, the OPTIMOX1 strategy can be considered a standard therapy. There are patients for whom a true treatment-free interval may be beneficial in terms of quality of life. This was not evaluated in the current trial, however. If a true treatment-free interval is contemplated, the data from these trials need to be discussed with patients. — Stuart M. Lichtman, M.D.
|