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Despite concerns about neurotoxicity, 5-year data from MOSAIC confirm that the FOLFOX4 regimen improves disease-free survival in the adjuvant setting for patients with stage II and III colorectal cancer.
"Disease-free survival seen at 3 years was maintained at 5 years in all subgroups, especially in stage III and high-risk stage II disease," Dr. Aimery de Gramont reported in an update.
The Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), compared conventional treatment with leucovorin and 5-fluorouracil (LV5FU2) to FOLFOX4, an updated regimen adding oxaliplatin (Eloxatin) to LV5FU2.
The population comprised 2,246 patients who had completely resected stage II (40%) or III (60%) colorectal cancer. None had prior chemotherapy, radiotherapy, or immunotherapy. The patients were randomly assigned in equal numbers to receive LV5FU2 or FOLFOX4 every 2 weeks for 12 cycles for 6 months.
The initial report, published in 2004, showed a significant benefit in response rate and the primary end point of disease-free survival for FOLFOX4 (N. Engl. J. Med. 2004;350:2343-51).
In his update, Dr. de Gramont reported 5-year disease-free survival was 73% in the FOLFOX4 arm and 67% in the LV5FU2 arm, a difference that was statistically significant (hazard ratio 0.80, P = .003). FOLFOX4 also was superior in the patient subgroups with stage III and high-risk stage II disease.
In addition, these longer-term gains were achieved without increases in secondary cancers among the 811 patients evaluable at the beginning of 2007, he said. Secondary malignancies were diagnosed in between 5% and 6% of both arms.
Although the investigators observed recovery from peripheral sensory neuropathy over the 6 years, Dr. de Gramont reported grade 3 neuropathy occurred in 12% of the FOLFOX4 patients vs. 0% of those on LV5FU2.
The FOLFOX4 arm also had more neutropenia: 41% vs. 5% in the LV5FU2 arm.
At 6 years, 21.6% of patients in the FOLFOX4 arm had died, compared with 25% in the LV5FU2 arm. Relapse was the cause of death in 17% and 22%, respectively. The probability of surviving 6 years was 79% and 76% in the respective arms, a difference that fell short of statistical significance, said Dr. Gramont, a professor of oncology at the Hôpital Saint Antoine in Paris.
Only stage III patients gained disease-free and overall survival advantages with FOLFOX4.
At a median follow-up of 6 years, the study demonstrated a significant overall survival advantage of 4.4% for FOLFOX4, compared with LV5FU among stage III colon cancer patients (P = .029). No such advantage was seen among stage II patients.
"These results support the use of FOLFOX4 as adjuvant therapy in patients with stage III colorectal cancer," Dr. de Gramont said, adding that the FOLFOX4 regimen cannot be recommended in low-risk stage II patients. "There will still be a debate about high-risk stage II patients until we learn more about this population," he concluded.
Discussant Dr. Alberto F. Sobrero likened MOSAIC to wine that gets better every year. "Although for the combined analysis the P value is not quite significant, I think we're getting there, said Dr. Sobrero of San Martino Hospital, Genoa, Italy.
The MOSAIC trial results are consistent with data from the National Surgical Adjuvant Breast and Bowel Project C-07 trial supporting a plausible benefit in overall survival, he noted. "However, the finding of 15% neurotoxicity at 4 years, including 3% with severe grade 2-3 neurotoxicity, is important and that doesn't seem to decrease substantially," Dr. Sobrero noted, asking whether adjuvant chemotherapy in this setting is worth the toxicity.
The future of adjuvant FOLFOX lies in combined therapy with biologics such as bevacizumab and cetuximab, with the goal of reducing neurotoxicity by reducing the duration of treatment from 6 months to perhaps 3 months, Dr. Sobrero said, adding that the MOSAIC study does have implications for clinical practice.
"I will walk out of this room reinforced to prescribe FOLFOX4 in both stage III and stage II high-risk patients, whereas I'll be discouraged from prescribing the regimen in stage II colorectal cancer patients."n
de Gramont A. et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. Abstract 4007.
Commentary |
Previously reported results for the primary end point of the study show a significant benefit in disease-free survival for the FOLFOX4-treated patients at a median follow-up of 3 years. Now at 5 years' follow-up, final disease-free survival is consistent with the earlier results (hazard ratio of 0.80, P = .003). In addition, at a median follow-up of 6 years, the study demonstrates a significant benefit in overall survival for the stage III patients. For high-risk stage II patients, progression-free survival increased in the FOLFOX arm, but overall survival did not improve in stage II patients. It is important that the benefit of FOLFOX has been maintained for node-positive patients. If the regimen is to be used in node-negative patients, it must be limited to the high-risk group—and then with the realization that overall survival may not be improved. This has to be weighed against the known toxicity issues. — Stuart M. Lichtman, M.D.
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