Topics:

Options Explored for Treating Patients With Recurrent Colorectal Cancer Following IFL Therapy

Options Explored for Treating Patients With Recurrent Colorectal Cancer Following IFL Therapy

NASHVILLE, Tennessee-"The need to find effective treatment for patients with recurrent colorectal cancer following treatment with IFL" (irinotecan [CPT-11, Camptosar], fluorouracil [5- FU], and leucovorin) was the driving force leading to a recent three-arm trial conducted at institutions in Canada and in the United States. Data from the trial were presented by Mace L. Rothenberg, MD, Ingram Professor of Cancer Research at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee (ASCO abstract 1011). For the past 3 years, IFL "has been widely used in North America as first-line chemotherapy in patients with metastatic colorectal cancer," Dr. Rothenberg pointed out in his presentation. Therapeutic Options for Progressive Disease "However, in the United States and Canada no standard therapy has been available for patients with progressive disease following this first-line therapy. Because there are no data in this setting, we extrapolated from phase II trials performed in patients with progressive disease following 5-FU and leucovorin. This suggested potential activity for three therapeutic options." Dr. Rothenberg listed those options as:

  • infusional 5-FU plus leucovorin;
  • single-agent oxaliplatin (Eloxatin); or
  • the combination of 5-FU, leucovorin, and oxaliplatin (FOLFOX4).
"Given the similarity of results between these three alternatives in terms of objective response rate, time to tumor progression, and immediate survival, and the need to find effective treatment for patients with recurrent colorectal cancer following IFL treatment, we designed this three-armed trial," he explained. Eligibility criteria for this trial included a diagnosis of metastatic colorectal adenocarcinoma, progressive disease during or within 6 months following IFL, and the ability to complete a tumor-related questionnaire. Patients were randomized to the three arms as outlined above. Patients receiving 5-FU/leucovorin were considered the control group and those experiencing progressive disease while receiving 5-FU/leucovorin were later given the opportunity to participate in the oxaliplatin treatment-access program. Study Design The trial was designed to accrue 786 patients and have a primary end point of overall survival, and secondary end points of objective response rate, time to tumor progression, safety, and time to tumor symptom worsening. Baseline patient characteristics were well-balanced between all three arms in terms of median age (approximately 60 years old), gender (55% to 60% of patients being male), and race. There was also equivalent distribution of baseline stratification factors between treatment arms. Karnofsky performance status (KPS) was 70 to 100 in about 95% of patients. Approximately 65% had two or more sites of metastases and onethird of patients had elevated LDH. About 70% of patients had tumors arising in the colon and 20% in the rectum. By independent radiologic review, the objective response rate was 0.7% for patients treated with 5-FU and leucovorin and 9.6% for patients treated with FOLFOX4. The difference was significant with a P value of less than .0001. Single-agent oxaliplatin was associated with a response rate of 1.1% which was not significantly different from the control arm. Similar results were obtained from using investigator- assessed responses. Determination of time to tumor progression by the independent radiologic review panel was based entirely on radiographic data. In this analysis, time to tumor progression was 2.6 months for the 5-FU/leucovorin control arm and 5.6 months for FOLFOX4, a difference that again was statistically significant with a P value less than .0001. Interestingly, patients treated with single-agent oxaliplatin did not fare as well, with a median time to tumor progression of 1.9 months. This difference was significant in favor of the control arm with a P value less than .008. Time to tumor progression determined by investigators included not only radiographic events of progressive disease but also clinical parameters of disease progression such as death or clinical worsening due to tumor-related symptoms. Median time to tumor progression was 1.9 months for the single-agent oxaliplatin, 2.6 months for 5-FU/leucovorin, and 5.6 months for FOLFOX4. Approximately two-thirds of patients had tumor-related symptoms at baseline. To meet the criteria for relief of tumorrelated symptoms, patients had to have at least one of the following: an improvement in KPS by at least 20 points, a decrease in pain intensity by at least 20 millimeters on a 100 millimeter scale, decrease in analgesic consumption by at least 50%, or weight gain of at least 5%. The proportion that had improvement in at least one of these parameters lasting for at least 4 weeks was 15% of patients treated with 5-FU/leucovorin, and 28% for patients treated with FOLFOX4. The difference was significant with a P value of less than .002, once again in favor of FOLFOX4. Patients treated with single-agent oxaliplatin had a 10% rate of relief from tumor-related symptoms, which was not significantly different from the control arm. Survival Median survival in patients treated with 5-FU/leucovorin was 8.7 months, and patients treated with FOLFOX4 had a median survival of 9.8 months. This difference did not reach statistical significance with a two-sided stratified log-rank value of 0.07. Although patients treated with FOLFOX4 had an overall 16% reduction in death hazard ratio compared to patients in the control arm, the 95% confidence intervals overlap, indicating that improved survival may not be one of the advantages conferred by this therapy in this second-line setting. Median survival in patients treated with single-agent oxaliplatin was 8.1 months. Dr. Rothenberg posited three possible explanations for the similarities in survival. "First, the survival of the control group was better than expected while survival of the FOLFOX4 group was not as great as expected. Second, salvage treatment with oxaliplatin could have affected the survival in the 5-FU/leucovorin control group. About 42% of patients randomized to the control group received oxaliplatin through the treatment access program. However the exact impact of this salvage therapy on survival is difficult to assess accurately. Finally it is possible that the additive effect of FOLFOX4 on survival is brief when used in a second-line setting and not detected by the log rank method, which gives greatest weight to late events." Safety and Toxicity Data Compared to the control arm, patients who received FOLFOX4 had a greater incidence of grade 3/4 diarrhea (12% vs 2%), nausea (11% vs 3%), and vomiting (9% vs 2%). Grade 3/4 neutropenia occurred more commonly in patients treated with FOLFOX4 (48%) than in those patients treated with 5-FU/leucovorin (6%). The clinical manifestations of neutropenia, mainly neutropenic fever, were relatively uncommon, occurring in 5% of patients treated with FOLFOX4 and 1% treated with 5-FU/leucovorin. Grade 3/4 thrombocytopenia was also more common with FOLFOX4 (5% vs 0), but there were no episodes of severe bleeding in any patients. Preliminary results from this trial were used as the basis for accelerated FDA approval of oxaliplatin in August 2002.
 
Loading comments...
Please Wait 20 seconds or click here to close