Dendreon Corp fka DNDNQ

[nivasvs]

See the last line... about Scher's relationship with Sanofi-Aventis


http://italia.medscape.com/viewarticle/524950

From Medscape Hematology-Oncology

Expert Interview
Chemotherapy for Advanced Prostate Cancer: An Expert Interview With Dr. Howard I. Scher
Posted 04/05/2006


Editor's Note:
It has been 2 years since the publication of phase 3 results showing that systemic therapy with docetaxel provides a significant survival advantage for patients with metastatic prostate cancer who are no longer responding to hormonal therapy. Since then, many studies have been undertaken to extend those results. Medscape spoke with Howard I. Scher, MD, Chief, Genitourinary Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York, after the Prostate Cancer Symposium held recently in San Francisco, about current developments in systemic chemotherapy for patients with advanced prostate cancer.

Medscape: In her presentation on Sunday morning, Dr. Cora Sternberg made a point about the TAX 327 and SWOG 9916 trials[1,2] that I'm hoping you can clarify. She said that one could get the wrong idea about the clinical benefit of docetaxel by looking only at the relatively modest difference in median survival. Patients in the docetaxel groups lived about 2 months longer than those in the mitoxantrone groups. Dr. Sternberg said it was much more important to think in terms of reduction in mortality, which was about 24% in these trials. Can you comment on this distinction?

Dr. Scher: When evaluating the results of clinical trials, some only look at the absolute difference in the median survival. And with the TAX 327 and SWOG 9916 trials, they would say that the difference is modest. Presented in a different way, as was done by Dr. Sternberg, this difference translates into a 24% reduction in mortality, which reflects how trials in breast cancer are presented and discussed. One must also recognize that within this population will be some patients who respond well (who would presumably benefit more) and others who do not respond (and do not benefit). We do not know upfront which group a patient will fall into; hence, we can only discuss an overall reduction in mortality.

Medscape: Can you briefly discuss what, if anything, we've learned since the results of TAX 327 and SWOG 9916 were published in 2004 about the use of docetaxel in patients with androgen-independent metastatic disease?

Dr. Scher: Those trials clearly established for the first time that the lives of patients with advanced prostate cancer who have progressed on hormone therapy can be prolonged with systemic chemotherapy. In the TAX 327 analysis, there was also a clear demonstration of improvement in quality of life. Right now, there are 2 new phase 3 trials that have opened; one on the effect of docetaxel with or without bevacizumab (CALGB-90401) and the other -- the ASCENT-2 trial -- studying the effect of calcitriol [a biologically active form of vitamin D] in combination with docetaxel. If you look at the phase 2 data for these studies, and rely strictly on prostate-specific antigen (PSA) changes as the indicator of efficacy, you would not have moved to phase 3 trials. It was really the final survival data that provided the impetus or justification, if you will, to move forward.

Medscape: What about other patient populations? A couple of studies[3,4] have shown that docetaxel lowers PSA in androgen-sensitive disease, but is there any evidence of a clinical benefit in this population?

Dr. Scher: No, there is not. Lowering PSA in this patient group is not direct evidence of clinical benefit, although clinical trials that are designed to specifically address whether docetaxel provides clinical benefit in earlier stages of disease are being undertaken. There is going to be a careful examination of what PSA does and does not tell us in this disease, because changes up or down are often not the whole story.

Medscape: And in androgen-independent nonmetastatic disease? I understand that a trial [Eastern Cooperative Oncology Group 1899] in this population had to be halted because of a low rate of accrual.

Dr. Scher: The trial you mention compared ketoconazole/hydrocortisone with docetaxel/prednisone -- so the difference in treatments was significant. Because many physicians probably felt they "knew" the answer, and had specific biases about how to approach such patients, the accrual did not proceed as originally planned. Nevertheless, the trial would have addressed an important question regarding earlier vs later chemotherapy and its effect on overall survival.

Medscape: What about regimens?

Dr. Scher: There is a myriad of regimens under study. There are trials exploring nonchemotherapy approaches before a patient has had docetaxel, and there are combination trials that are looking to enhance the effects of docetaxel as first-line therapy. For example, there are 2 trials that are open and accruing at the moment, one involving the combination of docetaxel with bevacizumab and the second with calcitriol. In addition, the SWOG S0421 will study an atrasentan combination. All of these are phase 3 studies. Many phase 2 trials are looking at new approaches for this group of patients: combinations with signaling inhibitors, etc. The question will be how do we determine in the phase 2 setting which regimen or approach merits a phase 3 trial?

There are also trials in patients who have failed first-line chemotherapy, the most mature of which is with satraplatin (accrued and completed). Epothilones and other therapies are also being tested.

Medscape: All treatment options for prostate cancer seem to present doctors and patients with the need to perform very complex analyses to determine whether the risks and side effects of a given therapy are worth the clinical benefit. Can you comment briefly on the toxicity of chemotherapy for prostate cancer in relation to its benefit?

Dr. Scher: If chemotherapy is needed, I would say it is clearly worth it. I am treating octogenarians with chemotherapy in the appropriate context. I make the determination solely on the basis of a patient's current status, which includes whether or not there are symptoms present, and if not, when the patient is likely to run into trouble either from symptoms or when he might die from his disease.

Medscape: What do you see going forward? Do you anticipate any resistance on the part of urologists to the growing role of chemotherapy in the treatment of prostate cancer?

Dr. Scher: The trials are definitive. The question for any individual patient is what he feels is the best approach based on the potential benefits and risks. The latter depends on the disease and its tempo, as well as comorbidities. Although some data suggest that earlier hormone therapy improves survival, not all physicians recommend it. Obviously, this is not a straightforward question, but a young person might accept a lower success and greater toxicity because the stakes are higher... you really can't be categorical about this. There shouldn't be territorial issues in this, but I understand there are some who feel that urologists should give chemotherapy. Let's just say, I don't do surgery.

References
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. Abstract
Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. Abstract
Goodin S, Medina P, Capanna T, et al. Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol. 2005;23:3352-3357. Abstract
Kassabian VS, Sherlag A, Allen JG, et al. Docetaxel in hormone-sensitive prostate cancer patients failing primary therapy. Program and abstracts of the 2005 Multidisciplinary Prostate Cancer Symposium; February 17-19, 2005; Orlando, Florida. Abstract 151.


Related Links
Resource Centers
Prostate Diseases


Funding Information

Supported by an independent educational grant from Sanofi-Aventis.




Howard I. Scher, MD, Professor of Medicine, Weill Medical College, Cornell University, New York, NY; Chief, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY


Disclosure: David McNeel has disclosed no relevant financial relationships.

Disclosure: Howard I. Scher, MD, has disclosed that he has received grants for clinical research from Sanofi-Aventis.