The Role of Chemotherapy in Advanced Prostate Cancer: An Expert Interview With Daniel P. Petrylak, MD
Posted 06/23/2004
A Discussion of Chemotherapy for Advanced Prostate Cancer
There has been little change over the past few years in the management of patients with hormone-refractory prostate cancer. Despite various clinical studies that tested a range of cytotoxic regimens, men were left with no viable chemotherapeutic option that offered a survival benefit. But now, 2 separate teams have found that combining docetaxel with other chemotherapy agents leads to a modest but significant improvement in overall survival.
In one randomized trial presented at the 40th Annual Meeting of the American Society of Clinical Oncology, researchers led by Daniel P. Petrylak, MD, of the Columbia-Presbyterian Medical Center in New York, tested the combination of docetaxel and estramustine against mitoxantrone and prednisone;[1] in the second, researchers led by Mario A. Eisenberger, MD, PhD, of the Johns Hopkins Medical Center in Baltimore, Maryland, evaluated docetaxel and prednisone vs mitoxantrone and prednisone.[2] Both phase 3 studies found that a docetaxel-based chemotherapeutic regimen could extend life by roughly 2 months compared with the standard regimen of mitoxantrone and prednisone. The results suggest a new option for a type of cancer that has long been considered intractable.
Based on results from these 2 trials, the US Food and Drug Administration recently approved docetaxel for use in hormone-refractory prostate cancer, in addition to its other indications for breast and lung cancer. Still unknown, however, is which combination of agents works best in this patient population, and whether an even greater benefit can be seen with other docetaxel-based regimens. On behalf of Medscape, Eric Sabo interviewed Dr. Petrylak in an attempt to explore the role that chemotherapy can play in hormone-refractory advanced prostate cancer.
Medscape: The idea that outcomes in patients with hormone-refractory prostate cancer could be improved by chemotherapy had been largely written off by the oncology community. What caused you to rethink this as a treatment option?
Dr. Petrylak: When we tested it in the lab, we had seen some activity with docetaxel in prostate cancer cell lines and thought that the evidence presented a good opportunity to see what it does in patients. A phase 1 study, published in 1999, found a 23% increase in survival in patients treated with the agent.[3] This was a group of patients with fairly advanced disease, and it surprised us to see such a big advantage. A phase 2 trial found similar results,[4] so it made sense at that point to go ahead with a phase 3 study. Our trial was designed to confirm whether this was a real observation or whether lead-time bias, patient selection, or some other factor had something to do with the outcome.
Medscape: Your study used docetaxel in combination with estramustine, while Dr. Eisenberger's used docetaxel in combination with prednisone. Is there any way of knowing which regimen works best?
Dr. Petrylak: Unfortunately, we can't really tell from these trials. A study published in 1993 found that single-agent paclitaxel given once every 3 weeks had virtually no activity,[5] and early studies of weekly paclitaxel plus estramustine improved outcomes but increased toxicity.[6] So we had all of these data floating around on the use of taxanes and estramustine -- all of which influenced how we designed our trial.
Given the data from Dr. Eisenberger's study, on the surface, it may seem like we don't need estramustine. But the problem is that it's very difficult to tell. Our 2 groups started these trials at the same time and the entry criteria and patient characteristics are very similar. However, Dr. Eisenberger's study has a much lower crossover rate. His is at 20%, ours is around 55%. That may be the reason we didn't see as high a survival as we thought we would originally.
Medscape: Are we then really just opening the door for testing docetaxel with other regimens?
Dr. Petrylak: Both trials established docetaxel as the cornerstone of therapy in this setting. There may be better drugs to combine it with, but yes, what we have now is a start.
Medscape: The survival advantage of 2 months is relatively small. Given what men with late-stage disease may have already been through, are they going want further treatment?
Dr. Petrylak: You have to keep in mind that there's a spread -- some men survived for 3 years on this drug. The 2 months is an average number. And again, the crossover is a big issue; there's no way you can design that out of a trial. Nearly 35% of patients received docetaxel without mitoxantrone or prednisone, which clearly has to have an effect, although the question of how to quantitate it remains very difficult. A small survival difference, given those qualifications, is very important.
Medscape: Is this likely to become the new standard of care, or will this become another hard choice that prostate cancer patients have to face? In other words, how would you counsel your hormone-refractory patients about using docetaxel-based chemotherapy?
Dr. Petrylak: Because we've shown a survival benefit, I think this should now be the front-line therapeutic choice for patients with hormone-refractory prostate cancer. Clearly, any time you show a survival benefit, that therapy should be first choice. You have to discuss the side-effect profile with each patient, but in my experience, seeing how patients tend to react to these situations, they'll want the treatment. In fact, we had some problems in the study where the patients' prostate-specific antigen did not decline as rapidly as they would like, and they said, "If I come off study, will you treat me with docetaxel?"
Ultimately, it's only one option, but I think it should be the first option.
Medscape: What's the next step in refining the optimal treatment regimen for patients with hormone-refractory prostate cancer?
Dr. Petrylak: The next step is to evaluate a combination of docetaxel and another agent that will further increase survival without significantly increasing toxicity. It could be any of the new signal transduction agents, or possibly high-dose vitamin D. We actually have a lot of new agents that we can test. But clearly docetaxel will be the cornerstone. Patients can now be entered on a trial using an agent that we know can help them live longer, with the potential of augmenting that even further. |
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