|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.11.934 on February 28 2005 © 2005 American Society of Clinical Oncology.
What Is More Exciting? The Activity of Docetaxel in Early Prostate Cancer or the Successful Collaboration Between Urologists and Medical Oncologists to Complete a Study in Early Prostate Cancer?Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD In this issue, Goodin et al1 report on the activity of docetaxel in androgen-dependent prostate cancer. This relatively small, single-institution phase II study found that docetaxel lowered prostate-specific antigen (PSA) by greater than half in 43% of patients with prostate cancer recurrence manifested by a rise in PSA after definitive local therapy. Patients maintained noncastrate levels of testosterone throughout the study, suggesting that docetaxel, a cytotoxic agent, has clinical activity against androgen-dependent prostate cancer.1 The authors suggest that this is the first published report of docetaxel activity in this specific patient population. During the last few years, a number of publications have reported similar phase I and II studies consistently demonstrating safety and activity of docetaxel throughout the continuum of prostate cancer, from the neoadjuvant setting to the metastatic hormone-refractory state, supporting a number of phase III studies.2-5 Recent reports of the TAX 327 and Southwest Oncology Group (SWOG) 9916 phase III trials in men with progressive metastatic hormone-refractory prostate cancer (HRPC) demonstrated a 2 to 2.5 month improvement in median survival of a docetaxel regimen over mitoxantrone and prednisone, and defined a role for chemotherapy in advanced disease.6,7 The report by Goodin et al, in conjunction with these advanced disease studies, clearly supports the need to conduct larger clinical trials to define the role of chemotherapy in earlier stages of prostate cancer. Reporting the docetaxel data across the spectrum of disease states may then influence treatment for those patients who would be eligible for, but who are not currently receiving, appropriate chemotherapy. Additionally, more patients should then be referred for clinical trials of chemotherapy or biologic agents in advanced and early-stage disease. Numerous clinical trial opportunities exist for patients with HRPC, both metastatic and nonmetastatic, and androgen-dependent prostate cancer, including the neoadjuvant, adjuvant and PSA recurrence-only disease settings through the cooperative groups. Accrual to North America cooperative group trials requiring multidisciplinary management of prostate cancer patients in early stages of disease is often slow, despite successful pilot studies from single institutions. These studies in earlier stages of prostate cancer will require greater communication between medical and urologic oncologists. As principal investigator of one of the large phase III randomized, cooperative group studies in earlier-stage prostate cancer that recently closed secondary to poor accrual (Eastern Cooperative Oncology Group [ECOG] study 1899), I have spent substantial time developing educational programs for medical oncologists, urologists, and radiation oncologists on the merits and problems of such studies. These studies include Cancer and Leukemia Group B (CALGB) trial 90203 (neoadjuvant setting), SWOG 9921 (adjuvant setting), SWOG 9482 (new D2 disease), Radiation Therapy Oncology Group (RTOG) 0014 (rising PSA after local therapy without metastasis), and ECOG 1899 (rising PSA on hormonal therapy without metastasis8-10; Table 1). These studies are addressing innovative neoadjuvant and adjuvant chemotherapy approaches, rising PSA levels after local therapy without metastasis (either before initiation of androgen ablation or while on androgen ablation), as well as metastatic disease at diagnosis. All are open through the Cancer Trials Support Unit (CTSU) and are endorsed by multiple cooperative groups. (The CTSU Web site is www.ctsu.org.) These national trials are in need of increased accrual. Taken together, as of October 14, 2004, these studies have only accrued 25% of their target population, with some having been open to accrual for as long as 6 years. For the seven CTSU prostate cancer studies, the average time that the studies have been open to accrual is 32 months (range, 9 to 79 months). Each of these studies may experience a boost in accrual as a result of the data presented at the 2004 Annual Meeting of the American Society of Clinical Oncology (ASCO), which demonstrated survival benefit of docetaxel in metastatic hormone-refractory prostate cancer, as well as studies like the article by Goodin et al, presented in this issue.1 If we are unable to complete such important studies, then prostate cancer patients and their health care providers will remain uncertain as to optimal therapy along the continuum of high-risk or recurrent prostate cancer.
This concern over accrual to large-scale studies in prostate cancer may be unique to the cooperative groups. Investigator-initiated studies are being completed; these typically require small patient numbers and are often pilot studies. The mechanics of such studies are likely to have been worked out between the involved investigators within an institution. Funding for such studies is either from different grant mechanisms or pharmaceutical support. The Goodin et al study is an example of this. These data are encouraging and provide support for larger studies in this same patient population, in which chemotherapy is tested early in the course of prostate cancer progression defined by biochemical progression without metastasis, such as the recently closed studies RTOG 0014 and ECOG 1899. Large-scale, industry-supported studies have been completed in the same clinical settings that many cooperative group studies are addressing. For example, the patient population for E1899 is similar to that of the Abbott Laboratories M00-244 study, in which patients with nonmetastatic hormone-refractory prostate cancer are randomly assigned to atrasentan or placebo. E1899 compared second-line hormonal therapy (ketoconazole and hydrocortisone) to chemotherapy (docetaxel and prednisone) in delaying time to progression (first metastases) in nonmetastatic HRPC. M00-244 accrued 941 patients in a 20-month period, whereas E1899 has accrued 17 since activation in May 2003. Why the difference in accrual? One reason may be that atrasentan is an oral agent and can be administered by urologists, who make up more than half of the investigators. The other reason for more rapid accrual is the level of pharmaceutical financial support, as well as the multinational accrual for that study, compared with cooperative group support and collaboration. Improved financial support of patients enrolled on cooperative group studies is becoming critical to the prostate cancer clinical trials community. Another example of accrual rates that differ by study sponsorship is in the adjuvant chemotherapy setting. SWOG 9921 randomly assigns patients with high risk for recurrence after radical prostatectomy to androgen ablation or androgen ablation and chemotherapy. This trial has enrolled less than half of the 1,360 patients needed to reach primary end points. This important adjuvant trial struggles for a number of reasons. First, there are issues concerning collaboration between urologists, who must identify the high-risk patient, and medical oncologists who administer the assigned therapy. The choice of chemotherapy has also come under scrutiny, given the recent data for docetaxel in advanced disease. Although this is a potential criticism, SWOG 9921 can be seen as addressing the more generalizable question of whether chemotherapy added to androgen ablation improves survival, rather than whether mitoxantrone/prednisone added to androgen ablation improves survival. I believe that mitoxantrone is well tolerated and remains an appropriate choice in this study. However, studies incorporating docetaxel in the adjuvant setting have gained momentum. One such study was presented in abstract form at the ASCO 2004 Annual Meeting. In this study, 77 patients were enrolled at seven sites during an 18-month period; 6 months of adjuvant docetaxel was given to patients defined as high risk for PSA recurrence after prostatectomy.11 This pilot study demonstrates both the feasibility of identifying patients at high risk for recurrence and the safety of administering docetaxel in the adjuvant setting. A definitive phase III trial is planned. The speed at which this study can be conducted, given pharmaceutical support, will be of interest and will potentially provide further contrast to the speed at which cooperative group studies are completed. These examples highlight the need for us all to focus on accrual to cooperative group studies, since the cooperative group trials are asking critical questions, relevant to both treating physicians and to patients, that would not necessarily be addressed in pharmaceutical studies. If these studies take too long to accrue or close for lack of accrual, we lose important opportunities to ask the right questions, now and in the future. As always, there is a tendency to extrapolate the docetaxel data in advanced disease (primarily by medical oncologists) to support the use of docetaxel earlier in the course of disease, simply because one can. In addition, patients are concerned about dying from their disease and often demand more aggressive therapies earlier in the disease, without compelling data to demonstrate benefit. Studies such as those by Goodin et al demonstrate feasibility and declines in PSA but do not provide sufficient evidence of clinical benefit to recommend the routine use of docetaxel in this patient population. Large phase III studies in early prostate cancer may be ahead of their time for the mechanics and logistics required to make them happen. More work needs to be done by all of us to open these studies at our institutions and to provide a venue for communication between medical, urologic, and radiation oncologists. If the community-based medical oncologist can see the magnitude of the prostate cancer patient population, then more medical oncologists would participate in clinical trials. If medical oncologists’ practices spanned from prostate cancer patients at high risk for relapse to those with a rising PSA and to those with metastatic disease, then more would expertly manage the nuances and subtleties of prostate cancer. Prostate cancer patients often require the expertise of all disciplines to provide optimal care. To improve accrual to high priority national studies in prostate cancer, the medical oncology community must have access to these trials and get the word out to urologists and radiation oncologists that progress is being made in the use of chemotherapy and other targeted agents for advanced prostate cancer. Additionally, urologists should be more involved in the planning and design of clinical trials for early states of disease so that the success of the trial is shared among all specialties involved in the care and management of these patients. Author’s Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Michael A. Carducci, Abbott Laboratories, Bristol-Myers Squibb, Cougar Biotechnology, CuraGen. Honoraria: Michael A. Carducci, Abbott Laboratories, Aventis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
REFERENCES
1. 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 23:3352-3357, 2005 2. Berger AP, Niescher M, Fischer-Colbrie R, et al: Single-agent chemotherapy with docetaxel significantly reduces PSA levels in patients with high-grade localized prostate cancers. Urol Int 73:110-112, 2004[CrossRef][Medline] 3. Dreicer R, Magi-Galluzzi C, Zhou M, et al: Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer. Urology 63:1138-1142, 2004[CrossRef][Medline]
4. Kumar P, Perrotti M, Weiss R, et al: Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate. J Clin Oncol 22:1909-1915, 2004
5. Beer TM, Garzotto M, Lowe BA, et al: Phase I study of weekly mitoxantrone and docetaxel before prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res 10:1306-1311, 2004
6. Tannock IF, deWit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004
7. Petrylak DP, Tangen C, Hussain M, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004 8. Eastham JA, Kelly WK, Grossfeld GD, et al: Cancer and Leukemia Group B (CALGB) 90203: A randomized phase 3 study of radical prostatectomy alone versus estramustine and docetaxel before radical prostatectomy for patients with high-risk localized disease. Urology 62:55-62, 2003 (suppl 1) 9. Pienta KJ: Radiation Therapy Oncology Group P-0014: A phase 3 randomized study of patients with high-risk hormone-naive prostate cancer—Androgen blockade with 4 cycles of immediate chemotherapy versus androgen blockade with delayed chemotherapy. Urology 62:95-101, 2003 (suppl 1) 10. Walczak JR, Carducci MA: Phase III randomized trial evaluating second-line hormonal therapy versus docetaxel-estramustine combination chemotherapy on progression-free survival in asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for prostate cancer: An Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support Unit study. Urology 62:141-146, 2003 (suppl 1) 11. Rosenbaum E, Kibel A, Roth BJ, et al: Adjuvnat weekly docetaxel for high risk prostate cancer patients after radiatcal prostatectomy: Preliminary data of a multicenter pilot trial. Proc Am Soc Clin Oncol 23:417, 2004 (abstr 4649) Related Article
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
