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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2413-2414 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.6124
Is Chemotherapy the Standard for Asymptomatic Androgen-Independent Prostate Cancer?Oncology Specialists SC, Lutheran General Hospital, Park Ridge, IL To the Editor: Androgen independence in prostate cancer is an inevitable process for all men with relapsed metastatic disease.1 The standard of care in men with androgen-independent prostate cancer (AIPC) has evolved over the years, but two randomized studies published in 2004 established that docetaxel-based chemotherapy is the acceptable standard as it has shown an improvement in overall survival (OS) compared with mitoxantrone.2,3 Long-term follow-up data of these studies are crucial, as they would validate earlier published results. To that extent, the recent updated survival analysis reported by Berthold and colleagues4 in the Journal is valuable, informative, and a report they should be congratulated on. Berthold et al updated the TAX327 study, which compared docetaxel given weekly or every 3 weeks with mitoxantrone, each administered with daily prednisone. The survival benefit noted earlier with docetaxel given every 3 weeks was sustained with this extended follow-up confirming that docetaxel should remain the standard of care in these patients. As robust as the data are, I have some concerns about the applicability of this information in AIPC patients who are asymptomatic or minimally symptomatic. Although subset analyses conducted by Berthold and colleagues suggested that the benefit of docetaxel therapy is evident across the board, the study was not designed to establish such benefit in all subsets. The TAX327 subgroup analyses showed that there is a benefit in patients who are younger or older (using 68 as the age cutoff), with or without pain, with or without visceral disease, and with high or low prostate-specific antigen (PSA; using 115 ng/dL as a cutoff). Although the authors state in their discussion that their analysis does not address whether docetaxel should be used in patients with minimal symptoms, I feel that this point needs to be emphasized further and confirmed with evidence. Based on current evidence, I would suggest that patients who are asymptomatic or at low-risk for developing rapid disease progression should not be offered docetaxel, rather they should be considered for clinical trials exploring novel therapies especially targeted agents and biologic approaches. PSA doubling time (PSA-DT) has been established as an important prognostic factor in men who have undergone radical prostatectomy, definitive radiation therapy, metastatic prostate cancer, and recently AIPC.5-7 Semeniuk et al8 reported that AIPC patients with a PSA-DT of 70 days or fewer have shorter OS compared with those with a PSA-DT of more than 70 days. The TAX327 investigators recently reported on a prognostic nomogram that would predict aggressive behavior, rapid progression, and shorter OS, although prospective validation of this nomogram is still lacking.9 Patients with a PSA higher than 114 ng/dL and a PSA-DT less than 55 days fared worse in terms of OS. Other variables that were significant in this nomogram included liver metastatses, poor performance status (PS), pain at baseline, and high-grade tumors. The American Society of Clinical Oncology recently endorsed the Cancer Care of Ontario guidelines for nonhormonal treatment of AIPC.10 Within these guidelines, the timing of docetaxel therapy was still questionable in men who have measurable disease but lack symptoms. Finally, the pathophysiology of how prostate cancer becomes androgen independent is fascinating. At the molecular level, deregulation of the apoptotic genes plays an important role in making the disease hormone refractory.11 In prostate cancer cells, the loss of phosphatase and tensin homolgue tumor suppressor gene activity increases protein Akt activation blocking apoptosis.12 This process could increase Bcl-2 expression allowing for enhanced cell survival. Furthermore, angiogenesis is an established mechanism by which tumors in general, and prostate cancer in particular, grows and become resistant to current therapies.13,14 These mechanisms are paramount in understanding the evolution of this disease and designing newer therapies that target one or more of these pathways. However, if these therapies are applied later in the natural course of the disease, activity might be minimal (if any) and patients who are heavily pretreated might not be able to tolerate therapy. Hence, it becomes important to establish when these novel therapies are to be studied. I would argue that AIPC patients who are asymptomatic or at low-risk for rapid progression and developing symptoms based on predefined parameters are the ideal candidates to study these newer targeted therapies to establish a signal of activity for continued investigation. As of 2005, we initiated a prostate cancer clinical trial program where patients are offered participation in clinical studies at any disease stage. Asymptomatic AIPC patients are encouraged to participate in nonchemotherapy-based clinical studies with compounds that are rationally targeted and designed. Patients who have minimal symptoms (pain score 3 of 10 or lower and a PSA-DT > 3 months) regardless of their visceral involvement are usually treated for 2 to 3 months on a nonchemotherapy-based clinical trial before deciding as to whether such treatment is effective. We believe that these studies are important to conduct early in the course of the disease, while reserving chemotherapy with docetaxel to symptomatic patients or rapidly progressing ones. The challenge is how to define minimally symptomatic patients. Our group and others have reported on studies conducted in this patient population confirming that within the context of clinical trials, withholding chemotherapy is not a deviation from the standard of care.15-18 I believe that Berthold and colleagues share these ideas, but if one reads their report and their subset analyses suggestion, it might be perceived that all patients regardless of their risk category should be offered chemotherapy, a strategy that has not been validated or supported by current evidence. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer. N Engl J Med 349:366-381, 2003 2. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004 3. 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 351:1513-1520, 2004 4. Berthold DR, Pond GR, Soban F, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 26:242-245, 2008 5. D'Amico AV, Moul JW, Carroll PR, et al: Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376-1383, 2003 6. Loberg RD, Fielhauer JR, Pienta BA, et al: Prostate-specific antigen doubling time and survival in patients with advanced metastatic prostate cancer. Urology 62:128-133, 2003 (suppl 1)[CrossRef][Medline] 7. Schmid HP, Morant R, Bernhard J, et al: Prostate specific antigen doubling time as auxiliary end point in hormone refractory prostatic carcinoma. Eur Urol 43:28-30, 2003[CrossRef][Medline] 8. Semeniuk RC, Venner PM, North S: Prostate-specific antigen doubling time is associated with survival in men with hormone-refractory prostate cancer. Urology 68:565-569, 2006[CrossRef][Medline] 9. Armstrong AJ, Garrett-Mayer ES, Yang YC, et al: A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A TAX327 study analysis. Clin Cancer Res 13:6396-6403, 2007 10. Basch EM, Somerfield MR, Beer TM, et al: American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration-resistant) prostate cancer. J Clin Oncol 25:5313-5318, 2007 11. Debes JD, Tindall DJ: Mechanisms of androgen-refractory prostate cancer. N Engl J Med 351:1488-1490, 2004 12. Chen CD, Welsbie DS, Tran C, et al: Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33-39, 2004[CrossRef][Medline] 13. Catena R, Muniz-Medina V, Moralejo B, et al: Increased expression of VEGF121/VEGF165-189 ratio results in a significant enhancement of human prostate tumor angiogenesis. Int J Cancer 120:2096-2109, 2007[CrossRef][Medline] 14. Kaygusuz G, Tulunay O, Baltaci S, et al: Microvessel density and regulators of angiogenesis in malignant and nonmalignant prostate tissue. Int Urol Nephrol 39:841-850, 2007[CrossRef][Medline] 15. Small EJ, Reese DM, Um B, et al: Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor. Clin Cancer Res 5:1738-1744, 1999 16. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006 17. Dreicer R, Klein EA, Elson P, et al: Phase II trial of GM-CSF + thalidomide in patients with androgen-independent metastatic prostate cancer. Urol Oncol 23:82-86, 2005[Medline] 18. Nabhan C, Tolzien K, Newman S, et al: Erlotinib has activity in androgen-independent prostate cancer (AIPC) patients who are chemotherapy-naive: A phase II trial. J Clin Oncol 25, 2007 Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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