Irinotecan in the First-Line Treatment of Colorectal Cancer

Introduction

Irinotecan(Drug information on irinotecan) (CPT-11 [Camptosar]) is a semisynthetic, water-soluble derivative of the plant alkaloid camptothecin. Based on the results of extensive clinical evaluations,[1] irinotecan received FDA approval for use in fluorouracil(Drug information on fluorouracil)-refractory stage IV colorectal cancer. Other potential uses of irinotecan, both in colorectal cancer and in other types of malignancies, are currently under active investigation.

This review will focus on the potential use of irinotecan, either alone or in combination, in the first-line treatment of colorectal cancer. It should be emphasized that these first-line strategies are, at the time of this writing, being actively investigated and are not presently recommended for routine clinical use.

Irinotecan

Irinotecan (CPT-11) is one of several derivatives of camptothecin entering the clinical arena. (The "CPT" in CPT-11 is an abbreviation for camptothecin.) Camptothecin is the active isolate from the stem wood of Camptotheca acuminata, a tree that grows throughout most parts of Asia.[2]

Initial clinical trials of irinotecan in the 1970s reported encouraging evidence of antitumor activity; however, substantial and unpredictable toxicities were also encountered.[3-5] This unfavorable toxicity profile caused a loss of clinical interest in the camptothecins until more than a decade later, when the mechanism of action of camptothecin was demonstrated to be the inhibition of the nuclear enzyme topoisomerase I.[6-10]

Knowledge of the target of camptothecin rekindled activity in the development of soluble analogs that could be more practically applied clinically.

One such series of investigations led to the identification of 7-ethyl-10[4-(1-piperidino)-1-piperidino]-1-carbonyloxy-camptothecin as an agent with good aqueous solubility and a favorable preclinical activity profile.[11-13] Phase I testing of this agent, called CPT-11 at that time, was initiated in Japan[14,15] and subsequently in the United States[16,17] and France.[18] These early phase I trials demonstrated evidence of antitumor activity of irinotecan in advanced, treatment-refractory colorectal cancer patients, leading to an extensive worldwide development program of the drug in this disease.

Treatment of Refractory Colorectal Cancer

Shimada et al published the first phase II study of irinotecan in patients with metastatic colorectal cancer, 81% of whom had fluorouracil-refractory disease.[19] A major objective response rate of 27% was reported in the 63 evaluable patients treated, with a 22% response rate in those who had been treated previously with fluorouracil.

In a subsequent trial conducted in the United States, 43 patients with fluorouracil-refractory colorectal cancer were treated with irinotecan by 90-minute infusion weekly for 4 weeks followed by a 2-week rest period. This trial reported similar results, with a major objective response rate of 23%.[20] Furthermore, an additional 31% of patients who did not achieve a major response demonstrated either stable disease or a minor clinical regression, increasing the percentage of patients who derived some demonstrable antitumor activity to 54%.

These data were later analyzed in combination with data from two other trials of irinotecan in fluorouracil-refractory colorectal cancer involving a total of 304 patients.[1] The major objective response rate was 13%, with an additional 49% of patients achieving clinical benefit in the form of either a minor response or disease stabilization.

Treatment of Chemotherapy-Naïve Colorectal Cancer

Antitumor activity of irinotecan in patients with previously untreated colorectal cancer had been noted in a small population of such patients treated in the initial phase II study by Shimada et al.[19] To more thoroughly investigate this issue, our group at Memorial Sloan-Kettering Cancer Center in New York performed a formal phase II trial of irinotecan in chemotherapy-naïve patients with measurable metastatic colorectal cancer.[21] In this trial, 41 patients received a starting dose of 125 mg/m2 of irinotecan weekly for 4 weeks, followed by a 2-week break. We observed a major objective response in 13 patients (32%; 95% confidence interval [CI], 18% to 46%). In addition, 44% of patients demonstrated a lesser degree of antitumor activity, in the form of either a minor response or stable disease. Treatment was reasonably well tolerated, with diarrhea and neutropenia being the major dose-limiting toxicities encountered.

At the time of initiation of the trial, our group was unaware of the work of Abigerges et al demonstrating the utility of an intensive loperamide(Drug information on loperamide)-based antidiarrheal regimen for the management of irinotecan-induced late-onset diarrhea.[22] Of the first 18 patients treated in our study, 10 (56%) required a dose reduction during therapy. After we became aware of the above-referenced antidiarrheal regimen, we began applying it assiduously. In the remaining 23 patients subsequently started on the trial, this decreased the proportion of those requiring a dose reduction to 9%.

Concurrent with our investigations, a cohort of chemotherapy-naïve colorectal cancer patients received irinotecan in a clinical trial conducted at the Mayo Clinic, using the same starting dose and schedule.[23] This trial reported major objective responses in 8 of 31 patients (26%; 95% CI, 12% to 45%).

European development of irinotecan has focused primarily on the use of a brief infusion given once every 3 weeks. Rougier et al conducted a trial of this once every-3-week schedule in colorectal cancer patients, utilizing a 350 mg/m² starting dose. Of the 213 patients in this trial, 48 had received no prior cytotoxic chemotherapy and 165 patients had progressed after one fluorouracil-based chemotherapy regimen.[24] The response rate to irinotecan in this trial was 18%, with activity rates essentially the same in both chemotherapy-naïve and fluorouracil-refractory patients.

Thus, three independent phase II trials have confirmed the substantial single-agent activity of irinotecan in the first-line treatment of colorectal cancer patients.

Toxicity

A consideration of the pros and cons of the use of irinotecan in the first-line treatment of colorectal cancer requires serious consideration of the toxicity profile of irinotecan, and a comparison of this toxicity with that of the fluorouracil-based chemotherapy regimens that are now routinely used in first-line therapy. The two major dose-limiting toxicities of irinotecan are diarrhea and neutropenia.

Diarrhea

Diarrhea due to irinotecan can be divided into two distinct syndromes: early-onset diarrhea, which occurs during or shortly after irinotecan administration, and late-onset diarrhea, occurring more than 24 hours after irinotecan administration.

Early-onset diarrhea is the most common manifestation of a cholinergic syndrome that can occur with irinotecan administration. This syndrome is characterized by rapid-onset diarrhea and may also include abdominal cramping and diaphoresis.[25] The syndrome is relatively unusual, however, and, if encountered, is easily managed with atropine(Drug information on atropine). The incidence of previously treated patients reporting grade 3 or 4 diarrhea within 24 hours of irinotecan administration in the pivotal phase II US trials was 8%.[1]

Late-onset diarrhea, while representing a much more serious problem, has become far more manageable now than it was in the earlier irinotecan trials. Late-onset diarrhea was the major dose-limiting toxicity encountered in initial phase I and II trials. This late-onset diarrhea most commonly occurred on approximately day 10 of the treatment cycle.

Two major changes have occurred that have greatly reduced the incidence of late-onset diarrhea. First, investigators and clinicians have become more familiar with irinotecan and its toxicity profile. As doctors become more adept at discerning the early signs of gastrointestinal toxicity and adjusting the irinotecan dose accordingly, the incidence of severe diarrhea has declined.

Perhaps more importantly, based on work initially reported by Abigerges et al,[22] use of an intensive regimen of loperamide has become standard practice in patients treated with irinotecan. The loperamide must be started at the first sign of diarrhea, and taken at a dose of 2 mg every 2 hours (or 4 mg every 4 hours during the night) until the patient has been free of diarrhea for 12 hours. Failure to adhere strictly to this schedule appears to be associated with less successful treatment of the diarrhea.

The overall incidence of dose-limiting diarrhea in the 41 chemotherapy-naïve patients in the trial reported from Memorial Sloan-Kettering was 29%.[21] Of 193 fluorouracil-refractory patients who received the 125 mg/m² starting dose of irinotecan, 65 (34%) developed grade 3 or 4 diarrhea.[1]

To properly assess the importance of late-onset diarrhea with irinotecan, one needs to compare its incidence with that of severe diarrhea in similar patient populations treated with fluorouracil-based regimens. The North Central Cancer Treatment Group (NCCTG) reported a large, multicenter, phase III trial of the two most widely used schedules (in the United States) of fluorouracil plus leucovorin in chemotherapy-naïve colorectal cancer patients.[26] In this trial, dose-limiting diarrhea occurred in 32% of patients receiving weekly fluorouracil plus high-dose leucovorin and in 20% of patients receiving daily × 5 low-dose leucovorin.