Newer Chemo Regimens Prolong Survival in Advanced Colorectal Cancer

IOANNINA, Greece, Sept. 24 -- Today's newer chemotherapy drugs add months to the lives of patients with advanced colorectal cancer, but at a high cost in toxicity and complications, a meta-analysis showed.

For patients expected to live for a year when treated with fluorouracil and leucovorin (Welcovorin), the estimated absolute survival benefit of additional treatment with irinotecan (Camptosar) plus bevacizumab (Avastin) was an added eight months, John P.A. Ioannidis, M.D., Ph.D., of the University of Ioannina here, and colleagues, reported online in the Sept. 20 issue of The Lancet Oncology.

Survival benefits of an added 4.7 months were also noted for the addition of oxaliplatin (Eloxatin) plus bevacizumab or for irinotecan plus oxaliplatin, the researchers said.

Newer chemotherapy drugs, such as irinotecan and oxaliplatin, and molecularly targeted agents such as bevacizumab and cetuzimab (Erbitux) have shown effectiveness in trials of patients with advanced colorectal cancer, but these drugs are highly toxic and the size of the benefits have not been measured, the researchers wrote.

For this purpose, the researchers systematically reviewed randomized trials comparing systemic treatment during the past 40 years. Treatment, both first-line and non-first-line was categorized by use of fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab.

Of 242 trials published from 1967 through 2007, including 56,677 patients and 137 different chemotherapy regimens, 37 of these trials were eligible for the meta-analysis.

Those trials provided 47 comparisons of mortality data for 13,875 patients and 48 comparisons of disease-progression data for 15,158 patients.

Compared with fluorouracil plus leucovorin alone, findings for the risk of death with the most commonly used regimens were:

• Mortality risk decreased with the addition of irinotecan plus bevacizumab (hazard ratio [HR] 0.60, 95% credibility intervals (CrI) 0.44-0.84);
• Considerable benefits were noted with the addition of irinotecan plus oxaliplatin (HR 0.72 [CrI 0.54-0.97]);
• With oxaliplatin plus bevacizumab (HR 0.72 [CrI 0.57-0.90]);
• With bevacizumab alone (HR 0.78 [CRI 0.60-1.03]);
• With oxaliplatin alone (HR 0.87 [CrI 0.78-0.98]).

The disease progression benefits were even more prominent for the addition of:

• irinotecan plus bevacizumab (HR 0.41 [0.28-0.60]);
• irinotecan plus oxaliplatin (HR 0.53 [0.38-0.73]);
• oxaliplatin plus bevacizumab (HR 0.46 [0.34-0.61]);
• bevacizumab alone (HR 0.56 [0.41-0.76]);
• irinotecan plus cetuximab (HR 0.62 [0.42-0.92]);
• oxaliplatin alone (HR 0.64 [0.56-0.73]);
• irinotecan alone (HR 0.73 [0.65-0.82]).

Reviewing absolute survival benefits, the researchers said that compared with a patient with an anticipated one-year survival when treated with fluorouracil and leucovorin, the absolute survival benefit was estimated at eight months' prolongation with the addition of irinotecan plus bevacizumab.

The survival benefit amounted to a 4.7 months' prolongation with the addition of oxaliplatin plus bevacizumab or irinotecan plus oxaliplatin.

For the addition of oxaliplatin alone, added survival was 1.8 months and for irinotecan alone, one month.

However, the researchers pointed out that they were not able to make direct comparisons of effectiveness between the different regimens, so that uncertainty remains for the ranking of specific regimens.

Generally, treatment effects seemed larger for disease progression than for survival, the researchers said, but added that many patients switch regimens when they progress and, therefore, survival differences are diluted. So, they said, some caution should be advised when progression-free survival is used as a surrogate marker of survival.

Furthermore, effectiveness should be balanced against tolerability. Multidrug combinations including irinotecan, oxaliplatin, or bevacizumab can cause serious toxic effects, mainly severe hematological toxicity, diarrhea, thrombotic events, and neurosensory disorders.

The fluorouracil, leucovorin, irinotecan, plus bevacizumab regimen, which was likely to be the best in improving survival, might be complicated with up to a 84.9% chance of grade 3 or grade 4 adverse events, including a 1.5% chance of gastrointestinal perforation, the researchers said.

The risk of hemorrhage can be explained by the mechanism of action of bevacizumab, and has been reported in trials in other cancers. Additional and longer follow-up data on toxicity in different settings and on the newest regimens should be collected, the researchers advised.

New drugs are currently being tested for patients with advanced colorectal cancer, the researchers wrote. Although the meta-analysis included considerable data on bevacizumab, fewer data on cetuximab were available. However, additional evidence will probably become available in the next few years, including data on the ideal duration of use.

Although molecular-targeted treatments have a continuously increasing range of applications for different cancers, trials with less impressive results might still be ongoing and the complete picture might be less favorable. Future trials designed to fill in important gaps in information would be useful, the researchers wrote.

Their analysis, they added, was based on published group data, rather than individual patient information, a study limitation. Nonetheless, the power to detect survival prolongation even with information on individual patients might still be limited in such a complex network of multiple treatments. Therefore strong inferences about the value of certain regimens should be avoided.

"Our meta-analysis concludes that progress has definitely been made in this area of research, but the existing uncertainties suggest that more data are needed especially for the newest regimens," Dr. Ioannidis said.