Study Supports Safety & Efficacy of FOLFOX4 in Older Pts

April 1, 2006

Age alone should not be a contraindication to FOLFOX4 chemotherapy in older adults with colorectal cancer.

SAN FRANCISCO—Age alone should not be a contraindication to FOLFOX4 chemotherapy in older adults with colorectal cancer, researchers reported at the 2006 Gastrointestinal Cancers Symposium (abstract 228). Data from a pooled analysis of trials showed that, compared with their younger counterparts, patients aged 70 years or older had similar improvements in clinical outcomes with FOLFOX4—fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (Eloxatin)—without clinically meaningful increases in toxicity.

"The average patient with colorectal cancer in the United States is 68 years of age when diagnosed," said lead author Richard M. Goldberg, MD, chief of the Division of Hematology/Oncology, University of North Carolina at Chapel Hill. This fact, he said, as well as the increasing addition of more drugs to combination chemotherapy for colorectal cancer, highlights the need to determine if such regimens are as safe and efficacious in older patients as in younger ones.

Dr. Goldberg's research team conducted a pooled analysis of four trials that tested the FOLFOX4 regimen against other regimens in various populations with colorectal cancer: These trials were:

MOSAIC (Andre et al, N Engl J Med 2004), conducted in the adjuvant setting and using 5-FU/LV as the control.

N9741 (Goldberg et al, J Clin Oncol 2004), conducted in the first-line advanced-disease setting and using IFL—5-FU/LV/irinotecan [Camptosar]—as the control.

A trial by de Gramont and colleagues (J Clin Oncol 2004), conducted in the first-line advanced-disease setting and using 5-FU/LV as the control.

A trial by Rothenberg and colleagues (J Clin Oncol 2003), conducted in the second-line advanced- disease setting and using 5-FU/LV as the control.

Together, the trials included 3,743 patients. Only 16% of the patients were aged 70 years or older, the cutoff used in the analysis for the older age group. "One might have expected 45% of patients, had all patients been enrolled in this trial regardless of age," Dr. Goldberg noted.

Study Results Similar

FOLFOX4 was as efficacious in patients aged 70 years or older as in younger patients, regardless of the setting and the endpoint evaluated, Dr. Goldberg said.

In the MOSAIC adjuvant therapy trial, FOLFOX4 yielded similar hazard ratios relative to the control for disease-free survival in older patients and in younger patients (0.71 and 0.78, respectively).

In the two first-line trials, relative to the control treatment, FOLFOX4 was associated with comparable hazard ratios in older and younger groups for both progression-free survival (0.60 and 0.72) and overall survival (0.67 and 0.73). Likewise, in the single second-line trial, compared with the control, FOLFOX4 led to similar hazard ratios in the older and younger age-groups for both progression-free survival (0.69 and 0.61) and overall survival (1.08 and 0.82).

In analyses of response rates, the odds ratios for a response with FOLFOX4 relative to the control did not differ between patients aged 70 years or older and their younger counterparts in the adjuvant trial (1.6 and 1.7, respectively), in the de Gramont first-line trial (2.9 and 3.6), and in the second-line trial (2.3 and 9.2).

With respect to adverse events, patients aged 70 years or older had a significantly higher incidence of grade 3 or higher neutropenia and thrombocytopenia, and a marginally higher incidence of grade 3 fatigue relative to their younger counterparts. These differences, Dr. Goldberg noted, "often are not clinically meaningful differences and would not necessarily affect patient tolerance, although they might affect dose reductions in future cycles."

Moreover, he added, "for the sorts of toxicity that cause patients symptoms, there were no significant differences." Specifically, incidences of grade 3 or higher neurotoxicity, diarrhea, and nausea and vomiting were similar for younger and older patients; furthermore, the 60-day incidence of death did not differ significantly between age groups.

In analyses of the dose intensity delivered, which focused on cycle 3 and cycle 6 of chemotherapy, patients aged 70 or older received a dose intensity similar to that in their younger counterparts in each of the four trials studied.

When the outcomes assessed were the percentages of patients who received chemotherapy in cycle 3 and in cycle 6, the findings were similar, although in the second-line trial, there was a trend toward a lower proportion of patients aged 70 or older than of younger patients receiving chemotherapy in cycle 6.

"Care must be used in extrapolating [these findings] to the entire population of elderly patients, and obviously, good clinical judgment is important in making these decisions," Dr. Goldberg commented. In particular, he noted, the

findings were based on patients who were fit enough to enroll in clinical trials and who chose to do so. Moreover, three of the trials limited enrollment to patients aged 75 years or younger. "So there is very little data to tell you what to do with the octogenarian patient you see in the clinic," he remarked.

Dr. Goldberg concluded that age alone should not exclude an otherwise healthy elderly patient with colorectal cancer from receiving the FOLFOX4 chemotherapy regimen. "I believe that this analysis represents an experience you can use in making your clinical decisions," he said, "and that we likely ought to be treating more older patients with doublet chemotherapy and particularly FOLFOX, as illustrated by this analysis, than perhaps is being done as a matter of general practice."