The treatment of colorectal carcinoma presents many challenges to the clinician. Among those are the presence of intrinsic or the development of acquired drug resistance, the aggressive nature of the disease, and (most notably) the limited number of treatment options.[1-3] Although fluorouracil(Drug information on fluorouracil) (5-FU) has been the mainstay of treatment for colorectal cancer for 4 decades, as a single agent it is associated with only a 10% to 15% objective response rate. Patients treated with 5-FU can expect to achieve a median survival of about 10 months.[4-6]
The addition of folinic acid, also known as leucovorin, increases the response rate, but does not improve the overall median survival regardless of delivery as bolus 5-FU/leucovorin or as a continuous or short-term (24- to 48-hour) infusion.[7-11] While regimens consisting of short-term infusions of 5-FU with high-dose leucovorin have acceptable tolerability and are widely used for the treatment of colorectal cancer, especially in Europe, the fact that the median survival reported in most trials using these regimens is in the range of 9 to 14 months has prompted the search for alternative approaches to treatment.[7,9-11]
One of the more promising new treatment options for patients with metastatic colorectal cancer is oxaliplatin(Drug information on oxaliplatin) (Eloxatin), a third-generation platinum derivative with a unique mechanism of action.[3,12,13] Oxaliplatin is among the few drugs that have activity against human colorectal cancers. In vitro, human tumor xenograft, and clinical studies indicate that it is synergistic with 5-FU and leucovorin.[3,12,13]
Phase II and III clinical trials conducted in Europe show that the combination of oxaliplatin with 5-FU/leucovorin is effective as first- or second-line treatment for patients with metastatic colorectal cancer. Objective response rates as first-line treatment were > 50% and as second-line treatment, ranged between 20% and 45%. However, the trials comparing triple- drug therapy to 5-FU/leucovorin did not show a significant advantage in terms of mean duration of survival compared to 5-FU/leucovorin alone. These trials did, however, meet their original goals of demonstrating a significant improvement in response rate and progression-free survival. Thus, a number of studies are currently underway in North America that are exploring various oxaliplatin combination regimens to help determine the optimal dosage and administration schedule of combination therapy (Table 1).
Rationale and Design
Because of the discovery and development of a number of active new agents, the treatment of colon and rectal cancer is at a crossroads. 5-FU/leucovorin regimens have been the standard treatment for decades, and a multitude of regimens using differing doses, sequences, and lengths of drug delivery (ranging from bolus to continuous administration) have been studied. In addition, several combination regimens of 5-FU/leucovorin plus irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) have shown promise, including the weekly schedule of administration widely known as the Saltz regimen (named after the physician who developed and initially tested this regimen).
Based on a randomized study comparing 5-FU/leucovorin with irinotecan plus 5-FU/leucovorin and irinotecan alone, the Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) approved the three-drug regimen as first-line therapy of advanced colorectal cancer in March 2000. The approval was based on an improvement in response rate (from 21% to 39%) in the two- vs three-drug regimen, and a commensurate improvement in median survival of 2.2 months (from 12.6 to 14.8 months). When asked if the Saltz regimen should henceforth be considered the new regimen to which other agents or multidrug regimens should be compared, ODAC answered in the affirmative. This had major consequences for ongoing and future trial designs.
The Redesign Process
The North Central Cancer Treatment Group (NCCTG) N9741 study has undergone several metamorphoses since it first opened in November 1998. It was originally designed as a four-arm trial comparing three regimens of 5-FU/leucovorin plus irinotecan vs the Mayo/NCCTG regimen control arm: 5-FU at 425 mg/m2 plus leucovorin at 20 mg/m2.
The rationale for using the 5-FU at 425 mg/m2 plus leucovorin at 20 mg/m2 regimen as the control arm was based on a meta-analysis published in 1992 that showed a 23% response rate and a 12-month median survival for the regimen. This was still the expectation for the overall success rate in the control group when trial NCCTG N9741 began.
However, one 5-FU/leucovorin regimena 2-g/24-hour infusion of 5-FUwas dropped because of toxicity issues. Shortly after the study opened, and oxaliplatin became available for US trials, the study was amended (June 1999) to include three oxaliplatin arms. Thus, the NCCTG N9741 trial temporarily became a six-arm study in which patients were randomized to one of six treatment regimens: (1) 5-FU/leucovorin (Mayo/NCCTG), (2) 5-FU/leucovorin plus irinotecan (Saltz simultaneous), (3) 5-FU/leucovorin plus irinotecan (Mayo sequential), (4) irinotecan plus oxaliplatin (combination), (5) 5-FU/leucovorin plus oxaliplatin (bolus), or (6) 5-FU/leucovorin plus oxaliplatin (infusion).
In June 2000, the study was finally amended because of two issues. First, the ODAC’s suggestion that the Saltz regimen should be the new comparator arm in future trials made it necessary to delete the old comparator arm of 5-FU/leucovorin (Mayo/NCCTG regimenarm 1) from the study. Second, the third and fifth arms of the study were noted to be associated with excessive toxicity, including several treatment-related patient deaths. In addition, the investigators participating in the trial and the leaders of the gastrointestinal committees from the cooperative groups participating in the trial now felt that a simpler three-arm trial was a better design. By comparing arms 2, 4, and 6, the most important variations of these three active agents could be examined side by side, and results would be available much sooner than would have been possible with the six-arm trial (Figure 1).
Mayo Sequential Regimen: Mullany and coworkers first described sequence-dependent synergy in colon cancer xenografts when they noted that the optimal interval between administration of irinotecan and 5-FU was about 24 hours. Consequently, a three-drug regimen was developed on the basis of laboratory studies performed by Fonseca et al at the Mayo Clinic.
This phase I study in 56 patients began initially with the administration of a very low dose of irinotecan plus 5-FU due to concerns about synergistic diarrhea. Although most of the patients were refractory to previous therapy, there were 10 partial or minor responses. Toxicity consisted of the usual diarrhea, neutropenia, and vomiting. Doses recommended for further testing were irinotecan at 275 mg/m2 administered on day 1, and 5-FU at 400 mg/m2 plus leucovorin at 20 mg/m2 administered on days 2 to 5.
Because this regimen is repeated every 3 weeks, the dose intensity of 5-FU and leucovorin is similar to that of the standard Mayo regimen described by Poon and coworkers, which is given every 4 or 5 weeks. However, 5 of the first 60 patients accrued to this arm died, possibly of treatment-related causes. Therefore, it appeared unlikely that this regimen would prove to be superior to the one developed by Saltz and colleagues, and it was certainly more toxic. Thus, rather than reduce the doses prescribed by this regimen, the arm was dropped from the trial.
Oxaliplatin Bolus Regimen: In the United States, many members of the Gastrointestinal (GI) Intergroup and others regarded bolus 5-FU dosing as the most familiar method by which to administer 5-FU and leucovorin. Therefore, an oxaliplatin regimen given in concert with bolus 5-FU was included in this trial. This regimen was based on a European trial in 115 patients who progressed after being treated with a regimen of 5-FU plus leucovorin (unpublished data on file, Sanofi-Synthelabo). Oxaliplatin at 130 mg/m2 was administered on day 1, followed by 5-FU at 320 mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. (This regimen was repeated every 3 weeks.)
Although the response rate in the original report was 13%, this was a second-line regimen and therefore, was felt to have demonstrated sufficient activity to merit further testing. Both the median time to progression (4.3 months) and median survival (10.1 months) were similar to the rates reported with other second-line regimens. The main toxicities included nausea, neutropenia, and neuropathy.
Early in the NCCTG N9741 trial, after about 25 patients had received this regimen, three deaths occurred due to toxicity. All the patients developed fatigue, neutropenia, and dehydration, and died within 1 or 2 weeks following treatment. Representatives of the National Cancer Institute (NCI), the cooperative groups participating in the trial, and patient representatives held a meeting to discuss these reports. As a result, the doses of both oxaliplatin and 5-FU were reduced.
Patients in the oxaliplatin bolus regimen arm of the N9741 trial then began to receive oxaliplatin at 100 mg/m2 on day 1, followed by 5-FU at 280 mg/m2 plus leucovorin at 20 mg/m2 on days 1 to 5. When two additional treatment-related deaths were observed at the reduced dose level, this arm of the trial was dropped.