Current Chemotherapy Regimens Prolong Colorectal Cancer Survival

September 26, 2007 — Newer chemotherapy regimens are providing patients with advanced colorectal cancer clear, incremental benefits in delaying disease progression and prolonging survival, researchers say. However, the benefits of multidrug combinations come at a cost, researchers warn in the September 20 Online First issue of The Lancet Oncology. Among the drawbacks are increased toxicities.
"More data are needed to balance the benefits of the best newer regimens against their potential toxicity," senior author John Ioannidis, MD, from the University of Ioannina School of Medicine in Greece told Medscape Oncology. "Our meta analysis identifies which regimens are currently the best and which comparisons lack sufficient data," he added. "It can therefore be used in guiding the design of future trials."
Dr. Ioannidis said his research team had expected to see progress in the field and had sought to quantify these advances. "Our results can be used for building recommendations for the treatment of advanced colorectal cancer with a more accurate understanding of how much benefit can be attained with each regimen," he said.
For years, fluorouracil had been the mainstay of systemic treatment of colorectal cancer, though the overall benefit in survival was reportedly small. Attempts to improve survival led to the biochemical modulation of fluorouracil, mainly by leucovorin, which offered an added modest survival advantage. Newer chemotherapy drugs, such as irinotecan and oxaliplatin, and molecular-targeted agents, such as bevacizumab and cetuximab, have also shown effectiveness in trials of patients with advanced colorectal cancer.
Newer Regimens Providing Incremental Benefits
The investigators studied 242 randomized trials to compare systemic treatment regimens conducted during the last 40 years. The team categorized treatment by fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab.
The research team used multiple-treatment meta-analysis methodology to combine information from direct comparisons such as treatments compared within a randomized trial and indirect comparisons such as treatments compared between trials.
The primary endpoint for the study was death, and the secondary endpoint was progression of disease. The researchers used Monte Carlo simulations to establish what regimen offered the most benefit for these endpoints. They conducted analyzes of all trials and studied trials separately that looked at first-line treatments and non–first-line treatments.
The trials included a total of 56,677 patients and involved 137 different chemotherapy regimens. The researchers found that irinotecan, oxaliplatin, and molecular-targeted treatments prolong survival for patients with advanced colorectal cancer by several months vs a few years ago when these treatments were unavailable.
The investigators report that for patients who would be expected to live for 1 year while taking fluorouracil and leucovorin, the estimated absolute survival benefit of additional treatment with irinotecan and bevacizumab was 8 months. Benefits of survival were also noted for the addition of oxaliplatin and bevacizumab or irinotecan and oxaliplatin; they observed a prolongation of 4.7 months for each regimen.
Improving Survival but Increasing Dangerous Adverse Events as Well
The regimen of fluorouracil, leucovorin, irinotecan, and bevacizumab, which has the highest probability to be the best in improving survival according to the analysis, might be complicated by up to 84.9% of grade 3 or 4 adverse events, the study authors warn, including a 1.5% chance of perforation of the gastrointestinal tract.
Dr. Ioannidis pointed out a number of limitations to the study. "The analysis depends on results that have been publicly available," he told Medscape Oncology. "It may therefore be affected by publication bias against negative results for specific regimens."
New drugs are currently being tested, and another limitation of the analysis involves gaps in available data. For example, the study authors include considerable information on bevacizumab, but less on cetuximab. However, they anticipate that additional evidence will become available during the next few years.
Dr. Ioannidis and his team note that at least 2 other trials have presented preliminary data on the combination of cetuximab with oxaliplatin and fluorouracil with leucovorin in abstracts, but no mature survival or progression data are currently available.
They add that a phase 3 trial for panitumumab has shown encouraging results as a second-line treatment against best supportive care, but it was also not eligible for the present meta-analysis, and more evidence for this drug will likely be published soon.
"Our meta-analysis concludes that progress has definitely been made in this area of research," the study authors write, "but the existing uncertainties suggest that more data are needed especially for the newest regimens."
The study authors have disclosed no relevant financial relationships.
Lancet Oncol. Published online September 20, 2007.