NEW YORK CITY—Higher-dose chemotherapy schedules for breast cancer patients, with drugs administered more often than current guidelines recommend, may cut total treatment time and increase survival, according to data presented here at the Chemotherapy Foundation Symposium.
“The point is: We need a more rational system for determining the dosing schedule than the one currently in use, especially since we now have available oral agents that could be administered frequently,” said Larry -Norton, MD, Deputy Physician-in-Chief for Breast Cancer Programs and the Norna S. Sarofim Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center.
Dr. Norton presented highlights from a study subsequently presented at the San Antonio Breast Cancer Symposium that optimized the chemotherapy dose schedule based on a new mathematical model. The data show that a seven-day-on, seven-day-off schedule of capecitabine administration produced more tumor regression and more than a doubling of the life span of tumor-bearing mice compared with a 14-day-on, seven-day-off schedule, each at the maximum tolerated dose.
“According to the standard system currently in place,” he said in an interview, “we administer chemotherapy treatments for as long as possible until toxicity appears. At that point, we give the patient a break based on recovery from toxicity and then start over. But since we are focused on the toxicity of the agent rather than its efficacy, we often find that during the break the tumor cells have regrouped and started growing again.”
The best way to measure the efficacy of an agent is to have an endpoint—tumor size, for example—and measure the changes due to the treatment, Dr. Norton explained.
“Similarly, if you use vascular density as an endpoint and your drug is an antivascular agent, you can first measure the vascular density and then measure the changes that you can specifically attribute to the agent. At the same time, you can look at the changes compared with the way the cells—i.e., tumor volume—would grow if the tumor were not being treated.”
Using this approach it is possible to find the point at which the effect—the “perturbation”—of the therapy is at a maximum, Dr. Norton said.
“From a mathematical point of view, according to our theory, that's the point at which you stop, give a break, and come back to the patient as quickly as possible with another cycle of the same length. If you do this, our theory says, you would get more total perturbations of tumor size, for example, than with a conventional, more empirically derived, schedule that's zeroing in on toxicity.”
The dose-dense approach of giving drugs with a shorter inter-treatment interval reduces the opportunity for tumor regrowth. Thus, he said, “if the patient receives treatment more often, each time you treat, you start with a smaller amount of tumor.”
‘Focus on Efficacy, Not Toxicity’
The key is to focus on efficacy, not on toxicity, Dr. Norton reiterated, defining efficacy as the optimal perturbation compared with the way the cells would behave if they were not being treated. “We significantly found that when using the standard 14-day conventional regimen, only the first week revealed any worthwhile anticancer activity,” he said.
As a result, the researchers designed the seven-days-on, seven-days-off regimen that they are currently studying. “We're finding that by treating for only seven days, we can escalate the dose of capecitabine—a fixed dose, orally, twice daily—much more than we could have anticipated. This should translate into a very significant increase in anticancer efficacy,” he said.
-“The approach will minimize toxicity by using potentially shorter regimens and at the same time maximize efficacy by escalating the dose. This is clearly a promising mathematical model.”
Asked why the MSKCC research team selected capecitabine (an effective but toxic agent) for this study of dose scheduling, coauthor Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service, replied, “Capecitabine, which is approved for use in breast and other cancers, is an oral drug with effectiveness in patients with cancers that have progressed despite doxorubicin and taxanes. The development of capecitabine proved its effectiveness in this setting but did not fully explore the balance among dose, schedule, effectiveness, and toxicity.
“Additionally, many patients do not tolerate the recommended dose well. Thus, it was a drug that in particular offered the promise of both improved efficacy and less toxicity based on rational dosing and scheduling.”