Update on Chemotherapy for Advanced Colorectal Cancer

Introduction

During the past decade, more changes in the management of colorectal cancer have come about than in the previous half-century of clinical research. Such changes include the establishment of adjuvant treatment for patients with high-risk stage II and III colorectal cancer, in addition to new approaches to managing advanced disease. Previously, there was much nihilism in the management of these patients. This translated into low expectations of benefit from systemic chemotherapy or multimodality approaches, which could possibly extend the life of a patient with metastatic disease and also possibly cure some patients.

The past decade of clinical research in colorectal cancer has also sparked discussion about establishing appropriate end points of clinical benefit from chemotherapy. The gold standard for regulatory approval in the United States is an overall survival advantage with treatment. Previously, only the addition of leucovorin to fluorouracil(Drug information on fluorouracil) (5-FU) was approved on this basis. In addition to overall survival, many investigators think that progression-free survival—if properly measured—could provide a surrogate of treatment effect in clinical trials and also a measure of clinical benefit for patients.

This has not been a universally accepted end point, however, and is not currently used for approval of oncologic drugs in the United States. Although clinical investigators have depended on response rates to establish interest in a treatment program, this measure is associated with wide variability and thus may not be dependable for establishing patient benefit, particularly in retrospective analyses. Furthermore, measures of quality of life have generally fallen short of establishing clinical benefit of treatment. It is in the setting of this controversy that new treatments are being assessed, at least one of which has achieved the gold standard for approval in the United States, namely the addition of irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) to fluorouracil (5-FU) and leucovorin for first-line therapy of patients with metastatic colorectal cancer.

Fluoropyrimidine Therapy

Until recently, various methodologies of systemic 5-FU administration have represented not only the standard of practice but also the standard of care in clinical trials for patients with metastatic disease. The development of optimal treatment programs has been both arduous and long. Ansfield and colleagues reported a phase III trial comparing four different 5-FU regimens in 1977.[1] Results of this early trial suggested that loading course (ie, repetitive daily dosing) 5-FU, with moderate toxicity, was superior to a weekly intravenous (IV) schedule, a nontoxic IV schedule, and an oral schedule. In the latter part of the 20th century, countless patients participated in clinical trials comparing various doses and schedules of 5-FU, with and without new drugs.

Perhaps the most significant change in 5-FU use for metastatic colon cancer was the development of biochemically modulated regimens with leucovorin. Leucovorin stabilizes the ternary complex with fluorodeoxyuridine monophosphate (FdUMP) and the enzyme thymidylate synthase. The combination of 5-FU and leucovorin has been compared with bolus 5-FU alone. A meta-analysis of the randomized trials demonstrated a significantly improved response rate with 5-FU and leucovorin but no significant improvement in overall survival.[2]

A standard regimen for the treatment of metastatic colorectal cancer has been the Mayo Clinic regimen, in which 5-FU and leucovorin are administered for 5 consecutive days every 4 weeks for two cycles, followed by the same regimen every 5 weeks. Results from the first two trials conducted at the Mayo Clinic and the North Central Cancer Treatment Group (NCCTG) showed response rates of 43% and 35%, and median survival times of 12.7 and 9.3 months, respectively.[3,4] With further study, response rates with the Mayo Clinic regimen have ranged from 11% to 19%, and median survival times from 9.2 to 13.1 months.[5-7]

Continuous-Infusion vs Bolus 5-FU

Both the efficacy and toxicity of 5-FU depend—to some degree—on the drug dose and schedule and whether leucovorin is administered concurrently. Early in the use of 5-FU, it was observed that the toxicity profile of continuously infused 5-FU was different from that of bolus regimens, eg, decreased myelosuppression and mucositis but increased dermatologic toxicities, including hand-foot syndrome. An early clinical trial by Seifert et al comparing continuously infused 5-FU with bolus injection demonstrated this toxicity difference and also suggested an improved clinical benefit with infusional 5-FU in terms of response and survival rates.[8]

A subsequent meta-analysis of six randomized trials of continuously infused 5-FU was published in 1998.[9] Results were similar to those obtained with the addition of leucovorin to 5-FU, with an improvement in response rate from 14% to 22% (P = .0002), but only a marginal improvement in overall survival from 11.3 to 12.1 months (P = .04). The incidence of hematologic toxicity significantly decreased and hand-foot syndrome increased with infusional 5-FU.

Many infusional 5-FU regimens are currently in use. One of the first regimens developed is a true continuous-infusion program, in which 5-FU at 300 mg/m² is administered for more than 4 weeks or until significant toxicity occurs.[10] Alternative regimens have also been developed, including a high-dose 24-hour regimen known as the AIO regimen or Andolan regimen, with 5-FU doses ranging from 2,000 to 2,600 mg/m².[11] This regimen has also been combined with leucovorin.

Results of a large trial comparing the 24-hour infusional regimen, with and without leucovorin, to the Mayo Clinic regimen were recently reported.[12] The findings suggested that the infusional approach improved response rate and time to treatment failure, with an increase in toxicity when leucovorin was added, but with no significant improvement in survival.

Another commonly used regimen combines bolus and infusional administration, as devised by de Gramont and colleagues.[5] Bolus 5-FU and leucovorin are administered on the first and second days of a 2-week cycle, with 22-hour 5-FU infusions after each bolus dose. This regimen has been compared directly with a Mayo Clinic-type regimen in which bolus therapy was administered every 4 weeks.[5] A significantly better response rate (32.6% vs 14.4%) and improvement in progression-free survival resulted from the infusion approach; however, overall survival was similar with the two regimens (14.3 vs 13.1 months, P = .067).

Infusional approaches, therefore, have not consistently improved overall survival but have been associated with higher response rates, longer time to tumor progression, and a toxicity profile more suitable than that of bolus regimens for combination with myelosuppressive drugs. An open question, which will be addressed in another paper in these proceedings, is whether oral fluoropyrimidines will offer the clinical benefit of infusional 5-FU while also improving patient acceptance.

Based on an overview of either biochemically modulated fluorouracil with leucovorin or methotrexate(Drug information on methotrexate) or continuous-infusion 5-FU, there is a consistent trend toward improved response rate with newer regimens using other than bolus 5-FU alone.[2,9] However, the impact on overall survival from these changes has been modest, with an overall survival hazard ratio of 0.90 (0.84, 0.97) compared with bolus 5-FU alone. These data strongly suggest that further studies of fluoropyrimidine therapy alone are unlikely to show the clinical benefit desired for optimal management of metastatic disease.

Irinotecan

Irinotecan is a topoisomerase I inhibitor that has a mechanism of action different from that of fluoropyrimidines. In previously treated colorectal cancer patients, irinotecan at 125 mg/m² weekly or 350 mg/m² every 3 weeks resulted in response rates of 15.0% and 12.1%, respectively.[13] This single-agent activity is comparable to that observed in patients treated with fluoropyrimidines. In early phase II trials, the toxicity of single-agent irinotecan included manageable myelosuppression and diarrhea. Although diarrhea may be dose-limiting, in the clinic it is usually quite manageable with aggressive loperamide(Drug information on loperamide) use.

Single-Agent Activity

Based on the early phase II data and on the anticipated results of second-line trials of irinotecan in 5-FU-refractory patients, irinotecan was approved in the United States in 1996 for the treatment of colorectal cancer. Approval was initially limited to 5-FU-refractory disease, but results of two further landmark studies led to its approval as for second-line therapy in 1998.

In the first of these trials, patients who had failed bolus 5-FU therapy were randomly assigned to receive irinotecan plus best supportive care or best supportive care alone.[14] The study end point was improvement in overall survival, which was achieved. Median survival was 9.2 months in the irinotecan-treated group and 6.5 months in the best supportive care alone group (P = .00001). Quality-of-life measures suggested that this improvement in survival was achieved without increasing toxicities significantly.

In the second trial, patients who had failed bolus 5-FU were randomly assigned to receive irinotecan or one of three infusional 5-FU regimens.[15] Median survival was 10.8 months in irinotecan-treated patients compared with 8.5 months in fluorouracil-treated patients (P = .035). Based on the known modest activity of infusional 5-FU in patients who have failed bolus therapy, it was not surprising that the overall survival advantage of irinotecan was somewhat less than in the previous study. Nevertheless, both achieved the clinical trial objective for patients with advanced disease, which was improvement in overall survival. Since 1998, irinotecan has been the standard second-line therapy for 5-FU refractory patients with advanced colorectal cancer in the United States and much of the world.

Combination Chemotherapy

Given irinotecan’s single-agent activity and its different mechanism of action compared to 5-FU, combinations of these agents, typically also with leucovorin, were assessed in phase I and II trials. Of several regimens that were developed, one used bolus 5-FU and leucovorin for 4 weeks out of 6, with irinotecan also administered on the same days.[16] In another regimen, infusional 5-FU was administered with biweekly irinotecan treatment.[17] Using these regimens, two phase III prospective randomized controlled trials evaluated the combination of 5-FU, leucovorin, and irinotecan vs 5-FU and leucovorin alone. The first of these pivotal trials compared bolus 5-FU, leucovorin, and irinotecan with bolus 5-FU and leucovorin alone.[18] A third arm of irinotecan alone was also included.

More than 200 patients were entered into each study arm. The primary end point was progression-free survival. Results showed that the combination was superior in terms of response rates, time to tumor progression, and overall survival rates.[18] Response rates were 39%, 21% , and 18% with combination treatment, 5-FU/leucovorin, or irinotecan, respectively; this was highly significant in favor of the combination. Time to tumor progression (7.0 vs 4.3 months; P = .004) and median survival (14.8 vs 12.6 months; P = .042) were also significantly improved with the combination, compared with 5-FU/leucovorin alone. Once again, the available data suggest that these improvements were achieved without a substantial decrement in overall quality of life or increased toxicity.[19]

The second pivotal trial of combination chemotherapy with irinotecan compared two different regimens of infusional 5-FU and leucovorin (either the AIO or the de Gramont regimen).[20] Irinotecan was administered weekly or biweekly according to the 5-FU schedule. This trial also demonstrated improved response rate, time to tumor progression, and median survival for patients receiving the irinotecan combination. Median survival, the most important end point, was 17.4 months with the combination vs 14.1 months with fluorouracil and leucovorin (P = .032).

A combined survival analysis of these two trials was recently presented at the American Society of Clinical Oncology (ASCO) meeting.[21] Combined survival for the irinotecan/5-FU/leucovorin regimen was 15.9 months, and for the nonirinotecan regimen, 13.3 months (P = .003; survival hazard ratio, 0.79). Notably, a significant proportion of patients in both trials who were assigned to 5-FU and leucovorin alone subsequently received second-line irinotecan. Despite this crossover, a survival advantage was maintained, suggesting that sequential chemotherapy for advanced colorectal cancer may not be as effective as combination first-line treatments.

Analyses have also been undertaken to determine which patients benefit most from combination chemotherapy.[22] Preliminary results suggest that all patients benefit, but that those with normal performance status and lactate dehydrogenase levels have the greatest improvement in overall survival compared with that achieved with 5-FU and leucovorin. Preliminary results of a cost-effectiveness analysis done in the United Kingdom also suggested that combination chemotherapy was more cost-effective than 5-FU and leucovorin.[23]

Taken together, these data suggest that combination chemotherapy represents a new standard of care for patients with advanced colorectal cancer. In the United States, the combination used is 5-FU, leucovorin, and irinotecan, as approved by the U.S. Food and Drug Administration (FDA) Oncology Drugs Advisory Committee (ODAC) in March 2000.[19]