Carcinoma of the colon and rectum remains one of the most common malignant diseases afflicting people living in industrialized countries. The estimated number of new cases of colorectal cancer in the United States in 1998 will exceed 131,000. During the same year, colorectal carcinoma will result in an estimated 55,000 deaths, remaining the second most common cause of cancer-related deaths in the United States. The US populations lifetime risk of ever developing invasive colorectal cancer is approximately 1 in 17.
Five-year relative survival rates for colorectal cancer have improved modestly over the last 2 decades, and death rates for men with this disease have decreased about 1.9% per year from 1990 to 1994. Despite these results, 19% to 25% of patients will be diagnosed with advanced colorectal cancer, for which systemic chemotherapy is the mainstay of treatment.
Fluorouracil(Drug information on fluorouracil) (5-FU) has been used in the treatment of cancer for nearly 40 years. The rates of regression in advanced colorectal cancer patients treated with the same dose and schedule of 5-FU have ranged from 8% to 85%. A recent meta-analysis reported an 11% overall response rate to single-agent 5-FU among patients with previously untreated metastatic disease.
Modulation of 5-FU has been pursued using several agents, including leucovorin, methotrexate(Drug information on methotrexate), interferon-alfa (Intron A, Roferon-A), and N-(phosphonacetyl)-L-aspartate (PALA), as a means to increase antitumor activity. In the meta-analysis, the combination of 5-FU and leucovorin showed an increase in response rate (23%) but not an improvement in overall survival. Randomized trials of 5-FU vs 5-FU and leucovorin have demonstrated prolongation of median survival with the biochemically modulated regimens.[5,6]
A phase II study by the Southwest Oncology Group (SWOG) assessed the efficacy and toxicity of seven different regimens of 5-FU in patients with untreated advanced colorectal carcinoma. The median survival for the entire patient cohort was 14 months, and no regimen was superior relative to single-agent 5-FU (bolus or continuous infusion) therapy in terms of response or survival. For patients treated with bolus 5-FU or continuous-infusion 5-FU, the overall objective response rate (confirmed and unconfirmed) was 29%, although the continuous infusion produced a more favorable toxicity profile.
A recent meta-analysis demonstrated a higher tumor response rate in patients treated with continuous-infusion 5-FU than in those given bolus 5-FU (23% vs 14%), as well as a slight increase in overall survival. With the limited advantages of prolonged infusion of 5-FU or modulation of 5-FU, development of alternative agents for treatment of patients with metastatic colorectal carcinoma remains of great interest.
Camptothecin is a natural alkaloid product first extracted from the stem wood of the Chinese tree Camptotheca acuminata. Preclinical studies of the purified drug demonstrated activity in mouse L1210 leukemia and rat Walker carcinosarcoma.[9,10] The original preparation (camptothecin sodium) was evaluated in clinical trials in the late 1960s and early 1970s. A preliminary trial by Gottlieb and colleagues was encouraging, with 11 of 18 patients showing evidence of response or improvement (> 50% decrease in tumor mass in 5 patients).
Subsequent phase II trials in advanced gastrointestinal cancer and malignant melanoma failed to demonstrate significant clinical activity of camptothecin sodium.[12,13] The toxic effects encountered in both studies included gastrointestinal and hematologic effects and hemorrhagic cystitis. Based on these data, Moertel et al concluded in 1972 that "camptothecin is a drug of protean and unpredictable toxicity that has no clinical value in the management of gastrointestinal cancer."
Clinical drug development from 1970 to 1985 yielded few agents of merit for patients with advanced colorectal cancer. Marsoni et al reviewed 42 investigational agents evaluated during this period and determined 41 to be inactive against colon cancer. The only drug with potential activity, tegafur(Drug information on tegafur), did not demonstrate significant activity in a confirmatory trial when compared to 5-FU.
Investigators began to search for analogs of camptothecin with an improved toxicity profile, better water solubility, and enhanced therapeutic efficacy. Work by Kunimoto and colleagues led to the synthesis of a more water-soluble, semisynthetic derivative of camptothecin. Irinotecan(Drug information on irinotecan) hydrochloride (CPT-11 [Camptosar]) was found to have greater in vitro and in vivo activity than its parent compound while demonstrating less severe, more predictable toxicity. Interest in the camptothecins increased with the discovery of the novel mechanism of action of this class of chemotherapeutic agents in preclinical studies.
Many anticancer agents are known to act as topoisomerase inhibitors. Hsiang et al, while evaluating compounds for topoisomerase II inhibitory activity, demonstrated that camptothecins blocked the enzymatic action of topoisomerase I. Several authors have reviewed the action of camptothecins on topoisomerase I activity.[19,20] The topoisomerase I enzyme transiently cleaves and reseals one DNA strand through a transesterification reaction. This allows the other DNA strand to pass through the transient break and changes the DNA topology. The resulting topoisomerase I/DNA complex, also known as the cleavable complex, is the target for camptothecin and its derivatives. Irinotecan binds to the cleavable complex and inhibits resealing of the parent DNA, thereby halting nucleic acid synthesis. Collision between the replication fork and the stable cleavable complex results in double-strand DNA breaks and ultimately cellular death through apoptosis.
Irinotecan is rapidly converted in vivo by cellular carboxylesterases to its active metabolite, SN-38, which is 250 to 1,000 times more potent an inhibitor of topoisomerase I than the parent compound. It has also been shown that the antitumor effectiveness of irinotecan can be accounted for by the intracellular concentrations of SN-38.
Topoisomerase I activity is present in all cells, but Giovanella and colleagues have shown that levels of the enzyme in colon cancers are 30-fold higher than in normal colonic mucosa. Several colon cancer xenografts that have been studied also expressed significantly higher levels of topoisomerase I. In these experiments, the xenografts were highly resistant to multiple chemotherapeutic agents; however, several camptothecin analogs demonstrated significant activity. Giovanella et al found 9-amino-camptothecin to be highly effective in this xenograft model, inducing disease-free remissions in several established tumors.
Houghton et al have also studied camptothecin analogs in chemotherapy-resistant colon cancer xenografts. These analogs demonstrated impressive in vivo activity, which was strongly schedule dependent. The optimal schedule was equivalent to a low-dose continuous administration of the camptothecin analog. As a result of these preclinical findings and the development of more soluble analogs, camptothecin derivatives once again moved into the clinical arena.
Multiple phase I studies of irinotecan have been performed using many different schedules. Initial phase I studies of irinotecan began in Japan in 1986. The common dose-limiting toxicities (DLTs) encountered in these studies were hematologic (primarily leukopenia/neutropenia) and gastrointestinal (primarily diarrhea). The schedules currently used in Japan include 100 mg/m² of irinotecan weekly or 150 mg/m² every 2 weeks.[24,25]
European phase I studies have concentrated on three different schedules; the most widely used of these involves a single irinotecan infusion every 3 weeks. Abigerges and colleagues encountered a DLT of delayed diarrhea with a dosage of 350 mg/m² every 3 weeks. Subsequent incorporation of high-dose loperamide(Drug information on loperamide) allowed for further dose escalation. At the highest dose of 750 mg/m², grade 4 granulocytopenia was the DLT.
Initial phase I trials in the United States used two different dose schedules. Rowinsky and colleagues evaluated a single 90-minute infusion of irinotecan every 3 weeks, with doses ranging from 100 to 345 mg/m². At the highest dose levels of 290 and 345 mg/m², the investigators encountered a spectrum of gastrointestinal side effects, including diarrhea, nausea, vomiting, abdominal cramps, and anorexia. They suggested a phase II starting dose of 240 mg/m².
Rothenberg et al at the University of Texas Health Science Center in San Antonio developed another schedule consisting of weekly treatments for 4 weeks, followed by 2 weeks rest, with courses repeated every 6 weeks. With this regimen, the DLT was diarrhea at the 180 mg/m² dose level, and the recommended starting dose for phase II trials was 150 mg/m². The definition of maximum tolerated dose (MTD) differed between these two US phase I trials, as did the supportive measures, which likely accounts for the differences in recommended phase II starting doses.
Other investigators have used granulocyte colony-stimulating factor (G-CSF [Neupogen]) support in an attempt to escalate the irinotecan dose on the weekly × 4 schedule while minimally increasing the MTD. The MTD for an every-other-week schedule also is under investigation.
Based on the phase I schedule developed in San Antonio and initial encouraging results from Japan, further phase II trials were developed to assess the efficacy and toxicity of CPT-11 in patients with advanced colorectal carcinoma.