Improved Treatment for Metastatic Colorectal Cancer
ABSTRACT & COMMENTARY
Synopsis: A prospective, randomized study involving 683 patients with metastatic colorectal cancer was performed to compare combination chemotherapy with irinotecan (125 mg/m2), fluorouracil (500 mg/m2), and leucovorin (20 mg/m2) weekly for four weeks every six weeks (231 patients) with fluorouracil (425 mg/m2) and leucovorin (20 mg/m2) daily for five consecutive days every four weeks (226 patients). A third group of patients received irinotecan alone (125 mg/m2) weekly for four weeks every six weeks (226 patients). The weekly treatment with irinotecan plus fluorouracil and leucovorin was shown to be superior to the regimen of fluorouracil and leucovorin in terms of progression-free and overall survival, and did not compromise the quality of life.
Source: Saltz LB, et al. N Engl J Med 2000;343:905-914.
Metastatic colorectal cancer remains an important public health problem in the United States and is estimated to account for 10% of cancer deaths in men and 11% of cancer deaths in women in the year 2000.1 The primary, initial treatment for patients with this disease has included the antimetabolite fluorouracil (5-FU), which works as an inhibitor of the enzyme thymidylate synthase. Several strategies for biochemical modulation of 5-FU have been evaluated, including administration of 5-FU in combination with leucovorin, a reduced folate (tetrahydrofolate) to increase the affinity of 5-FU for thymidylate synthase.2,3 Various schedules of 5-FU and leucovorin have been evaluated, and this treatment combination is frequently administered as an initial therapy for patients with metastatic colorectal cancer. Other agents, such as irinotecan, have also been evaluated for patients with metastatic colorectal cancer. Irinotecan works as a potent inhibitor of topoisomerse I, and has been shown to have activity for patients with metastatic colorectal cancer.4-6 In addition, clinical investigations have identified dose and schedules for combination therapies involving irinotecan in combination with 5-FU and lecovorin for patients with metastatic colorectal cancer, and efficacy of this treatment has been suggested.7,8
Saltz and colleagues performed a phase-3 trial to compare combination chemotherapy with irinotecan, 5-FU, and leucovorin with a commonly used regimen of 5-FU and leucovorin as initial treatment for patients with metastatic colorectal cancer. A third group of patients was assigned to receive irinotecan alone. A total of 683 patients were enrolled into this prospective, randomized, multi-center trial. The intent-to-treat patient distribution included 231 patients in the group assigned irinotecan, 5-FU, and leucovorin, 226 patients in the group assigned 5-FU and leucovorin, and 226 patients in the group assigned irinotecan alone. Baseline patient characteristics were similar in treatment groups except for an increased percentage of men in the three-drug group vs. the two-drug group (65% vs 54%; P = 0.02). The primary study end point was progression-free survival, and this was significantly longer in the patients assigned to receive irinotecan, 5-FU, and leucovorin than in the patients assigned to receive 5-FU and leucovorin (median of 7.0 months vs 4.3 months; P = 0.004). The median progression-free survival in the patients assigned to receive irinotecan alone was 4.2 months and was similar to patients receiving 5-FU and leucovorin. Objective response rates were also greater in patients assigned irinotecan, 5-FU, and leucovorin than in patients assigned 5-FU and leucovorin (50% vs 28%; P < 0.001). The objective response rate in patients assigned irinotecan alone was 29% and was similar to patients assigned 5-FU and leucovorin. Finally, overall survival was also increased in patients assigned irinotecan, 5-FU, and leucovorin in comparison with 5-FU and leucovorin (median survival of 14.8 months compared to 12.6 months; P = 0.04). The median survival of patients assigned irinotecan alone was 12.0 months and was similar to the 12.6 months of patients assigned to 5-FU and leucovorin.
An analysis of adverse effects was performed for patients who received each of the three treatments. The adverse effects of grade-3 diarrhea and grade-3 or 4 vomiting were greater in the irinotecan, 5-FU, and leucovorin group compared with the 5-FU and leucovorin group. The adverse effects of grade-3 or 4 mucositis, grade-4 neutropenia, and neutropenic complications were greater in the 5-FU and leucovorin group compared with the irinotecan, 5-FU, and leucovorin group. Grade 4 diarrhea was similar in both the 3-drug and 2-drug groups. Overall quality of life analyses showed no significant differences between the treatment groups given irinotecan, 5-FU, and leucovorin or 5-FU and leucovorin. Saltz et al conclude that the treatment combination of irinotecan, 5-FU, and leucovorin, when compared with a commonly used regimen of 5-FU and leucovorin, is associated with higher rates of tumor regression, progression-free survival, and overall survival without compromising quality of life.
Comment by Mark R. Albertini, MD
Treatment options are improving for patients with metastatic colorectal cancer. The use of biochemical modulation of 5-FU with leucovorin provided a recent advance, and has been widely used as first-line treatment for patients with metastatic colorectal cancer. Additional agents with distinct mechanisms of anti-tumor activity, such as the topoisomerase I inhibitor irinotecan, have been shown to have activity against metastatic colorectal cancer. The current study by Saltz et al provides a prospective, randomized evaluation of combination chemotherapy with irinotecan, 5-FU, and leucovorin in comparison with 5-FU and leucovorin. A control arm of irinotecan alone is also evaluated. Saltz et al confirm the importance of prognostic factors including good performance status, fewer metastatic sites, normal lactate dehydrogenase and bilirubin levels, normal white-cell count, and a hemoglobin level more than 11 g/dL with better outcomes. The demonstration of improved tumor regression, increased progression-free and overall survival, and no compromise in quality of life with irinotecan, 5-FU, and leucovorin represents an important advance for the treatment of patients with metastatic colorectal cancer. This overall survival benefit is especially noteworthy as Saltz et al report that more than half of patients initially randomized to 5-FU and leucovorin received irinotecan as second-line therapy upon subsequent disease progression. Thus, concurrent first-line treatment with irinotecan, 5-FU, and lecovorin appears better than sequential administration of irinotecan following failure of first-line treatment with 5-FU and leucovorin.
The current report describes an advance for our treatment of patients with metastatic colorectal cancer. Further treatment advances for patients with metastatic colorectal cancer are certainly needed and, perhaps, will be identified as additional agents receive clinical investigation. However, an even greater effect for the current regimen of irinotecan, 5-FU, and leucovorin may be possible as adjuvant therapy for patients with resected stage-3 disease. Saltz et al report that a clinical trial evaluating this combination treatment for patients with resected stage-3 disease is now in progress, and results from that study are eagerly awaited.
References
1. Greenlee RT, et al. CA Cancer J Clin 2000;50:7-33.
2. Buroker TR, et al. J Clin Oncol 1994;12:14-20.
3. Leichman CG, et al. J Clin Oncol 1995;13:1303-1311.
4. Conti JA, et al. J Clin Oncol 1993;11:909-913.
5. Rougier P, et al. J Clin Oncol 1997;15:251-260.
6. Cunningham D, et al. Lancet 1998;352:1413-1418.
7. Saltz LB, et al. J Clin Oncol 1996;14:2959-2967.
8. Douillard JY, et al. Lancet 2000;355:1041-1047.
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