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A trio of phase III trials have concluded that the XELOX regimen of capecitabine plus oxaliplatin is equivalent to the FOLFOX regimen, the current standard for the treatment of metastatic colorectal cancer.
XELOX and FOLFOX produce virtually identical treatment responses and survival rates at expected toxicities, according to separate posters presented by the investigators.
A French trial reported by Dr. Michel Ducreux evenly randomized 306 patients (median age 65 years) receiving front-line treatment for metastatic disease.
Patients received either 3-week cycles of XELOX (1,000 mg/m² of capecitabine [Xeloda] twice a day and 130 mg/m² oxaliplatin [Eloxatin]) for a maximum of 8 cycles, or 2-week cycles of FOLFOX6 (100 mg/m² of oxaliplatin, 400 mg/m² of folinic acid, and 5-fluorouracil in a 400-mg/m² intravenous bolus on day 1 followed by 2,400-3,000 mg/m² for 46 hours) for a maximum of 12 cycles.
"We wanted to see if we could replace 5-FU infusion with capecitabine, which is a very convenient adjuvant drug. Patients were able to receive intensive chemotherapy plus capecitabine, which has similar activity to the FOLFOX regimen but is given less frequently," explained Dr. Ducreux of the Institut Gustave-Roussy in Villejuif, France.
This noninferiority trial found no differences in progression-free survival or overall survival, which in both arms were about 9 and 20 months, respectively.
Grade 3/4 neuropathy, neutropenia, and febrile neutropenia were significantly more common in the FOLFOX6 arm, while patients on XELOX experienced more thrombocytopenia.
The second study, an update of an international trial, compared the same XELOX regimen with FOLFOX4 with and without bevacizumab in a front-line metastatic setting as well. The original two-arm study recruited 634 patients and subsequently was enlarged with the addition of 1,400 patients (median age 61 years) to create a 2x2 partially blinded study assessing the addition of placebo and bevacizumab.
In the two-arm study, 317 patients on FOLFOX4 received oxaliplatin (85 mg/m²) administered as a 2-hour infusion on day 1, and leucovorin (200 mg/m²) administered as a 2-hour infusion on day 1 and day 2, which was followed by a loading dose of 5-FU (400 mg/m²) in an intravenous bolus after which 5-FU (600 mg/m²) was administered via ambulatory pump.
The data showed that XELOX with or without bevacizumab is noninferior to FOLFOX4 with or without bevacizumab with respect to both progression-free (about 8 months) and overall survival (about 20 months), according to lead investigator Dr. James Cassidy.
Although grade 3/4 diarrhea was significantly more common with XELOX, neutropenia was significantly more common in the FOLFOX arm, said Dr. Cassidy, a professor of oncology at the University of Glasgow in Scotland.
"As far as side effects are concerned, I could not pick a winner between the two, but XELOX is better overall due to the fact that patients can take capecitabine orally at home, and that improves their quality of life," Dr. Cassidy said.
He added in an interview that these data have prompted him and his colleagues to switch from FOLFOX to XELOX.
The third study, also an international trial, compared XELOX and FOLFOX4 in metastatic colorectal cancer patients who had failed first-line therapy with an irinotecan-based regimen.
It included 627 patients (median age 60 years), who were well balanced between the two standard dose regimens, according to the report by Dr. Mace L. Rothenberg, a professor of medicine and Ingram professor of cancer research at the Vanderbilt-Ingram Cancer Center in Nashville.
Both arms of this second-line study showed progression-free survival of 5 months and overall survival of 1 year. Response rates were equivalent in the two arms, and there were no unexpected toxicities.
After a brief review of the three poster abstracts, the discussant, Dr. Richard Goldberg, concluded that "we don't need another XELOX-FOLFOX study to prove equivalence in metastatic colorectal cancer."
These studies have put the lid on any doubts that XELOX is equivalent to FOLFOX as the current standard in the treatment of metastatic colorectal cancer, according to Dr. Goldberg, chief of the division of hematology-oncology at the University of North Carolina in Chapel Hill.
Ducreux M. et al. Efficacy and safety findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5-FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC). Abstract 4029.
Cassidy J. et al. XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC). Abstract 4030.
Rothenberg M.L. et al. Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC). Abstract 4031.
Commentary |
The French study by Dr. Michel Ducreux and associates was a non-inferiority trial comparing XELOX with FOLFOX6 in the front-line treatment of metastatic colorectal cancer. Of note, the toxicity profiles showed that XELOX patients had more grade 3/4 hand-foot syndrome (3% vs. 0%, P = .21), thrombocytopenia (12% vs. 5%, P = .052), and diarrhea (12% vs. 7%, P = .1), but less grade 3/4 febrile neutropenia (0% vs. 6%, P = .001), and neuropathy (8% vs. 19%, P = .003) than those on FOLFOX6. Treatment discontinuation for toxicity was 19% and 23% in the XELOX and FOLFOX6 arms, respectively. Response rates were statistically identical in the 42%-46% range. Progression-free survival was approximately 9 months, and overall survival was 20 months in both arms. The investigators concluded that the primary end point has been met and that XELOX is noninferior to FOLFOX6, with a good safety profile in first-line therapy. This study seems to confirm the belief that in metastatic disease these regimens are very similar in response and survival. Any differences are due to issues such as drug toxicity, side effects of continuous infusions, compliance with oral regimens, and drug interactions. Dr. James Cassidy and associates also demonstrated that overall XELOX is similar to FOLFOX4 in terms of efficacy when measured by progression-free and overall survival in the front-line treatment of metastatic disease. The differences in toxicity were what one would expect, with XELOX increasing hand-foot syndrome and FOLFOX4 showing more myelosuppression. Neurosensory toxicity was equivalent. Dr. Mace Rothenberg and colleagues conducted a similar trial in the second-line setting. Again overall survival and progression-free survival were similar. Therefore, in both the first- and second-line settings, XELOX and FOLFOX4 are clinically equivalent in terms of benefit with known differences in toxicity. Either regimen is an acceptable choice. The differences in toxicity can help the clinician decide the appropriate regimen for the individual patient. — Stuart M. Lichtman, M.D.
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