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are here: Home: CCU 3 | 2003: Norman Wolmark, MD
Edited comments by Dr Wolmark
Bevacizumab as first-line therapy for metastatic disease
The ASCO meeting was very exciting in terms of the research data in colorectal cancer. For the first time in my memory, the session for colorectal cancer had a larger audience than the breast cancer session. Certainly, the prolongation in overall survival for humanized monoclonal antibody to VEGF bevacizumab, was impressive, and I think it exceeded even the most enthusiastic expectations.
The Phase II data for bevacizumab weren’t nearly as exciting as that, and I think it brings up a good point, because it’s simply assumed that bevacizumab in breast cancer, for example, is not effective. It’s very important that we not confuse no effect for no contest. I don’t look upon bevacizumab as negative in breast cancer. That trial was asking a great deal of bevacizumab in advanced breast cancer, and it showed an increased response rate. Fortunately, there is an ongoing first-line trial in advanced disease that will further elucidate the role of this agent in breast cancer. We’re also very excited about the potential of bringing bevacizumab into the adjuvant breast setting.
Identifying a target for bevacizumab
There are other adjuvant colorectal trials being planned with bevacizumab. The Intergroup is currently discussing a bevacizumab monotherapy trial in patients with Dukes B colorectal cancer. We’d like to demonstrate a clear benefit in the adjuvant setting and determine the degree of benefit. We haven’t identified a target for bevacizumab — one that we could use to restrict its use to a subset of the population — but clearly that’s a goal.
It’s often pointed out that if we had conducted the trastuzumab trials on the entire population of patients with breast cancer, we would not have seen an effect. Fortunately, there was a target that could be measured. On the other hand, even without a target, the survival advantage of bevacizumab is clear, so if we find a target, the effects may be impressive.
Proposed NSABP-C-08 adjuvant colorectal trial
For many months, we’ve been discussing bevacizumab in the adjuvant setting for colorectal cancer and have proposed NSABP-C-08, a three-by-two factorial adjuvant study for Dukes B and C — Stages II and III — colon cancer. It will compare weekly bolus 5-FU/leucovorin/oxaliplatin (FLOX) plus or minus bevacizumab, to every-two-week infusions of 5-FU/leucovorin/oxaliplatin (FOLFOX) plus or minus bevacizumab, to capecitabine/oxaliplatin (CAPOX) plus or minus bevacizumab.
We included the capecitabine/oxaliplatin combination because we are committed to bringing oral regimens into the adjuvant setting. We conducted trial C-06, comparing leucovorin-modulated 5-FU to oral UFT. However, despite a unanimous ODAC recommendation, UFT was not approved in advanced disease. It’s unclear what the status of UFT will be if C-06 demonstrates
noninferiority. Some are skeptical about the possibility of the CAPOX arm demonstrating superiority in C-08, but we’ve been surprised before and no doubt will be again.
Bevacizumab is to be administered for one year in C-08, which is an empirical choice. We don’t really know the optimal duration — one year parallels the duration with which trastuzumab has been used, and until we have data proving otherwise, we have to start somewhere.
Oxaliplatin-associated neurotoxicity
Neurotoxicity is a major concern with oxaliplatin, but in the MOSAIC trial the Grade III neurotoxicity was reversible in the majority of cases. The data presented at ASCO regarding the use of magnesium and calcium to decrease the neurotoxicity is based on preclinical studies by Erick Gamelin. His hypothesis is that oxalate associated with oxaliplatin is responsible for the neurotoxicity, and that these agents can reduce neurotoxicity. It’s an interesting hypothesis, but the studies need to be done. A number of neuroprotective agents are being considered, and hopefully one can be found that can attenuate the neurotoxicity without diminishing efficacy.
Proposed NSABP adjuvant trial comparing capecitabine to observation in frail elderly patients
Margaret Kemeny presented a proposed adjuvant trial to assess the effectiveness of capecitabine in treating the elderly. It’s an interesting study, but the eligibility criteria present a dilemma. Rather than an age cutoff, I would prefer we target individuals who are not eligible for standard adjuvant chemotherapy regimens. An age cutoff does not reflect that and “frail” is not a readily measurable discriminate. You don’t want to eliminate a significant proportion of the population who might be eligible and who would tolerate and benefit from the regimen simply because one cannot clearly define the population.
NSABP-R-04: Preoperative radiation therapy with capecitabine
R-04 is a two-by-two trial designed to determine if oral capecitabine can replace prolonged venous infusion 5-FU during radiotherapy in preoperative therapy. Initially, we were going to compare UFT to venous infusion, but when it became apparent UFT would not be on the market and the data relative to capecitabine and radiotherapy became available, we embraced that regimen.
Erythropoietin was added because we found in our previous colorectal trial that over 20 percent of the patients required transfusions. As proposed, patients on the erythropoietin arms will receive it whether or not they are anemic, but we are still discussing that with the FDA, and it could change.
The regimen of radiation therapy plus capecitabine as outlined in R-04 has an acceptable toxicity. The data relative to response rates are not extensive, but small studies have shown significant pathologic complete responses more impressive than those we saw in NSABP-R-03. The data justify studying this combination in the preoperative setting in order to determine the efficacy once and for all.
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