Irinotecan in Metastatic Colorectal Cancer
Irinotecan in Metastatic Colorectal Cancer
abstract & commentary
Of the 131,600 new cases of colorectal cancer that were expected in the United States during 1998, about half were curable with surgery or surgery plus adjuvant chemotherapy. In addition, adjuvant radiation therapy plays a role in the local control of rectal, but not colon primaries. However, the other half either present with or will develop metastatic disease. Primary therapy of metastatic colorectal cancer most often includes 5-fluorouracil plus folinic acid, but the doses and schedule of administration vary. No consensus has developed regarding the treatment of metastatic colorectal cancer that fails to respond to or progresses after first-line 5-fluorouracil-based therapy. In phase II studies, at least two agents have shown promising response rates in the setting of 5-fluorouracil-resistant disease: oxaloplatin1 and irinotecan.2,3 Irinotecan has recently been tested in two prospective randomized studies against infusional 5-fluorouracil in one and against best supportive care in another.
Rougier and colleagues randomly assigned 133 patients to irinotecan 300-350 mg/m2 by 90-minute infusion every three weeks and 134 patients to 5-fluorouracil given by one of three standard continuous infusion protocols (regimen 1-folinic acid 200 mg/m2 over 2 h followed by 400 mg/m2 5-fluorouracil by IV bolus, then 600 mg/m2/d continuous infusion for 2 days every 2 weeks; regimen 2-5-fluorouracil 250-300 mg/m2/d continuously until progression or toxicity; regimen 3-5-fluorouracil 2.6-3 g/m2/d for 24 hours with or without folinic acid 20-500 mg/m2 intravenously per day weekly for 6 weeks with 2-week rest periods between cycles). All patients had received first-line therapy with a 5-fluorouracil regimen and had either failed to respond or had progressive disease on therapy. Treatment with irinotecan or infusional 5-fluorouracil was given until disease progression, unacceptable toxicity, or patient refusal of further treatment. Overall survival was the primary end point, but progression-free survival, response rate, symptom-free survival, and quality of life were also assessed.
Patients treated with irinotecan lived significantly longer than those treated with infusional 5-fluorouracil. One-year survival was 45% among irinotecan-treated patients and 32% for 5-fluorouracil-treated patients (P = 0.035). Median survival was 10.8 months for the irinotecan group and 8.5 months for the 5-fluorouracil group. Median progression-free survival was 4.2 months with irinotecan and 2.9 months with 5-fluorouracil (P = 0.03). Median pain-free survival favored irinotecan, but not significantly. Toxicities were quantitatively similar on the two arms and quality-of-life assessments were comparable.
Cunningham and colleagues randomly assigned patients to irinotecan or to best supportive care in a 2:1 randomization; thus, 189 patients received irinotecan in the same dose and schedule as the Rougier et al study and 90 patients received symptomatic supportive care. Overall survival was significantly better in the irinotecan group—36.2% one-year survival vs. 13.8% one-year survival with best supportive care (P = 0.0001). Survival without weight loss, without pain, and without performance status deterioration were all significantly improved on the irinotecan arm. Diarrhea, a known dose-limiting toxicity from irinotecan, was the only symptom that was worse on irinotecan. All other significant differences in quality of life measures between the groups favored irinotecan.
Thus, these two prospective randomized clinical trials appear to establish irinotecan as a consensus choice for second-line therapy of metastatic colorectal cancer. (Rougier P, et al. Lancet 1998;352:1407-1412; Cunningham D, et al. Lancet 1998;352:1413-1418.)
COMMENTARY
Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor. Topoisomerase I is involved in the relaxation of supercoiled DNA. The enzyme cleaves one strand of the DNA and permits the double helix adjacent to the cut to unwind and then it reseals the single-stranded break. The inhibitors bind to the enzyme that is bound to DNA and interfere with the religation of the single-strand break. Thus, the enzyme results in the accumulation of single-strand DNA breaks. However, it is not completely clear how the topoisomerase I inhibitors ultimately kill the cell.
Irinotecan has two dose-limiting toxicities—myelosuppression (mainly neutropenia) and diarrhea. The diarrhea seems to be related to the concentration of SN-38, an active metabolite, converted in the intestine upon hepatic clearance and excretion of the drug. The diarrhea is of two types: one acute syndrome occurring within an hour after completing the infusion and the other delayed, occurring more than 12 hours after infusion and usually after the second or third weekly dose. The first or acute form is rarely dose limiting. The second form can be serious. High doses of loperamide are useful in controlling the diarrhea in most cases (4 mg initial dose followed by 2 mg every 2 hours or 4 mg every 4 hours until diarrhea has stopped for at least 12 hours); furthermore, octreotide also appears to be effective.
These clinical trials establish irinotecan as a standard second-line treatment for patients with metastatic colorectal cancer. These results somewhat complicate matters for those interested in drug development in colorectal cancer. In the first place, new drugs will be tested later in the course of the disease from now on. Only patients who have progressed on 5-fluorouracil and irinotecan will enter phase II studies of new agents. Furthermore, if phase II trials look promising, the next step is a phase III salvage study because it will now be necessary to compare every new active agent to irinotecan in patients who have progressed on 5-fluorouracil. This progress in treatment is slowing subsequent progress, which is not a happy outcome from these studies.
The magnitude of the survival advantage seen with irinotecan in these studies is small—2.3 months in one study and 2.7 months in the other. The influence of the drug on one-year survival was 13% in one study and 22.4% in the other. Thus, many patients are treated to extend the lives of a few. Although adjuvant therapy is similar in its "many are called, few are chosen" features, at least adjuvant therapy does not typically have a major adverse effect on quality of life. The diarrhea from irinotecan does have the potential to adversely affect quality of life. However, even in patients whose survival was not improved by the treatment, quality of life end points would seem to favor irinotecan as well.
Other agents of interest in colorectal cancer include oxaliplatin and capecitabine. Despite a long history of disappointment with "rational" drug combinations, it is at least possible that an empiric combination will improve upon single agent results. Although the progess is slow and incremental, it feels like solid tumors are finally beginning to respond to our newer therapies a bit more. And, with the apparent enhancement in antitumor effects being seen with antibodies plus chemotherapy in lymphoma and breast cancer, it may be that authentic progress in the treatment of common solid tumors is on the horizon.
References
1. Becouam Y, Rougier P. Semin Oncol 1998;25(suppl 5):23-31.
2. Van Cutsem E, et al. Proc Am Soc Clin Oncol 1997; 16:268a.
3. Rougier P, et al. J Clin Oncol 1997;15:251-260.
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