5-fluorouracil (5FU) has been the cornerstone of therapy for the treatment of colorectal cancer for more than 50 years. Within the past six years, two other cytotoxic drugs, irinotecan and oxaliplatin, and two monoclonal antibodies that target specific cancer-related proteins, bevacizumab and cetuximab, have proven efficacious in the treatment of colorectal cancer. Recent results of randomized clinical trials have changed the approach to the treatment of colorectal cancer.
Irinotecan was first shown as a single agent to improve survival and quality of life for patients who progressed on 5FU-based therapy.2,3 Subsequently, two pivotal studies demonstrated a survival benefit of the combination of 5FU and leucovorin with irinotecan compared with 5FU and leucovorin alone. Different approaches in North America and Europe were pursued; in the North American study, 5FU, leucovorin, and irinotecan were administered on a weekly bolus schedule (IFL) and compared with bolus 5FU and leucovorin.4 A median survival benefit was demonstrated (14.8 months compared with 12.6 months, p=0.04) and established IFL as the standard of care in the US. The European study gave an infusion schedule of 5FU with leucovorin and irinotecan and also showed a survival advantage when compared with an infusion schedule of 5FU and leucovorin (17.4 months compared with 14.1 months, p=0.031).5 Subsequently, oxaliplatin with infusion 5FU and leucovorin (FOLFOX) was compared with infusion 5FU and leucovorin as first line treatment in a European study6 and as second line therapy in a North American study after progression on IFL.7 The European study again demonstrated an advantage to combination chemotherapy in the first line setting with an improvement in median progression-free survival (9.0 months versus 6.2 months, p=0.0003). The North American study demonstrated an advantage of the FOLFOX regimen compared with either infusion 5FU or single agent oxaliplatin in the second line setting in terms of response rate (9.9% versus 0% and 1.3%, respectively), time to tumor progression (4.6 months versus 2.7 months and 1.6 months, respectively), and improvement in tumor-related symptoms (33% versus 12% and 12%, respectively).
The randomized US Gastrointestinal Intergroup study was designed to determine the most effective therapy for the first-line treatment of advanced disease.8 At the time this study was designed, bolus 5FU and leucovorin were the standard arm and oxaliplatin was not available commercially. The study was amended to reflect increased toxicity in some of the bolus combination schedules and the inferiority of 5FU and leucovorin as first-line therapy. It ultimately compared IFL with FOLFOX and a combination of irinotecan and oxaliplatin (IrOx).The final results demonstrated an improved survival for FOLFOX compared with either IFL or IrOx. There are three major factors that may have contributed to these results. Patients who were randomized to receive oxaliplatin in a first-line regimen had an active second-line agent available to them at the time of progression – either irinotecan or 5FU. This was not the case for patients randomized to receive IFL, as oxaliplatin was not available except in the setting of a second-line clinical trial. The role of infusion 5FU used in the FOLFOX regimen compared with bolus 5FU in the IFL regimen may have contributed to the difference in two ways: 5FU, when given as an infusion, has shown an increase in response rate compared with 5FU as a bolus injection, although no survival benefit has previously been demonstrated.9,10 Furthermore, the incidence of treatment-related deaths was higher in the IFL regimen and is thought to be related to the use of bolus 5FU with irinotecan. This increase in mortality is not seen in infusion 5FU and irinotecan combinations.5 Finally, the use of oxaliplatin compared with irinotecan in the first-line setting may actually account for the difference. This has not been proven, however, as subsequent studies using 5FU, leucovorin, oxaliplatin, and irinotecan have led to a median survival of 20–21 months for patients who have received all agents, regardless of the sequence.8,11–13
The bolus IFL regimen has fallen out of favor as a result of associated toxicity demonstrated in two large randomized studies. In the Intergroup study for advanced disease, 14 patients died within 60 days of starting therapy compared with five patients on the FOLFOX arm and five patients on the IrOx arm.14 Meanwhile, an adjuvant study for patients with stage III colon cancer randomized patients to receive the bolus IFL regimen or the standard weekly bolus 5FU and leucovorin regimen following surgical resection. Again, an increased and unacceptable rate of treatment-related deaths was demonstrated in the IFL arm (14 compared with five).15 Subsequently, this regimen was not shown to offer a survival advantage compared with the standard 5FU and leucovorin in the final analysis recently reported.16
Prior to this toxicity being recognized, enrollment was progressing in a randomized study comparing IFL with IFL with the monoclonal antibody bevacizumab. Bevacizumab inhibits circulating vascular endothelial growth factor (VEGF), preventing its binding to the VEGF receptor tyrosine kinase. A median survival benefit was demonstrated for the combination of IFL with bevacizumab, compared with IFL (20.3 months compared with 15.6 months, p value less than 0.001).17 When added to 5FU and leucovorin alone, the addition of bevacizumab was also shown to improve survival.18 This led to the approval of bevacizumab for the firstline treatment of advanced colorectal cancer with 5FU-based chemotherapy.The actual median survival of IFL with bevacizumab was comparable with the median survival demonstrated in the Intergroup study for FOLFOX.8,17 Whether the addition of bevacizumab to FOLFOX will result in further prolongation of survival remains to be seen when the results of the Eastern Cooperative Oncology Group study of FOLFOX compared with FOFLOX with bevacizumab as second-line therapy becomes available. In these first studies demonstrating activity of one of the angiogenesis inhibitors, some unique toxicities were shown. The patients randomized to receive bevacizumab had a higher incidence of hypertension, asymptomatic proteinuria, and minor bleeding.Although infrequent, of greater concern was the increased incidence of arterial thrombosis and bowel perforation.With widespread use of this agent, the significance of these serious complications will become apparent.