Should We Delay Prostate Radiotherapy?
Authors: John P. Petersen, Paul F. Schellhammer, Michael J. Zelefsky, Steven A. Leibel
Journal: Journal of Clinical Oncology (1999)

Article Tools Correspondence Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.4.1326 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10561196 Should We Delay Prostate Radiotherapy? John P. PetersenxJohn P. PetersenSearch for articles by this author , Paul F. SchellhammerxPaul F. SchellhammerSearch for articles by this author Michael J. ZelefskyxMichael J. ZelefskySearch for articles by this author , Steven A. LeibelxSteven A. LeibelSearch for articles by this author Show More Indian River Regional Cancer Center, Vero Beach, FLEastern Virginia Medical School, Norfolk, VAMemorial Sloan-Kettering Cancer Center, New York, NY https://doi.org/10.1200/JCO.1999.17.4.1326 First Page Full Text PDF Figures and Tables © 1999 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical Oncology 041999In Reply: We appreciate the excellent comments and issues raised by Drs Petersen and Schellhammer. In our report,1 we found an improved 5-year biochemical outcome among patients who achieved PSA nadir levels ≤ 0.5 ng/mL after a 3-month course of NAAD. One hypothesis to explain this observation is that patients who achieve such nadir levels within this short period of time after initiation of androgen deprivation therapy may represent those with radiosensitive tumor cells. It would then follow, as Petersen and Schellhammer suggest, that further delaying radiotherapy until nadir levels are achieved would result in an unnecessary delay of the local therapy and may not necessarily improve the outcome. On the other hand, it may be equally true that the prognostic advantage of achieving a PSA nadir with induction androgen deprivation is not a time-dependent phenomenon but rather depends ultimately upon the absolute nadir level, regardless of how long it takes to achieve such levels. The posthormone PSA nadir would then be an indicator of a maximal androgen suppression effect and minimal disease activity. If this latter hypothesis is correct, it would be more appropriate to initiate therapy only after PSA nadir levels are achieved, as we have suggested. Clearly, further prospective studies are needed to clarify these issues.Petersen and Schellhammer propose that delaying radiation therapy in lieu of NAAD may result in a detrimental clinical outcome. This view is based upon data on the sequencing of radiotherapy and systemic chemotherapy in patients with breast cancer.2 However, in that report, delaying local irradiation did not significantly affect the local control outcome, and deferring systemic therapy culminated in an increased incidence of distant metastases. Others3 have also failed to provide convincing evidence that systemic therapy “up front” before local irradiation has a deleterious effect on the local outcome. In addition, there is no evidence to date that the same conclusions would apply to patients treated for prostate cancer. The findings of Radiation Therapy Oncology Group (RTOG) trial 86-104 did not demonstrate a compromise in tumor control for patients with locally advanced prostate cancer whose therapy was delayed for 2 months while they received NAAD. In fact, the local outcome in NAAD patients was superior to that of patients treated with radiotherapy alone. Therefore, it seems unlikely that continuing NAAD for an additional 2 to 4 months to achieve a PSA nadir before the beginning of radiotherapy would result in a significant decrease in local control for patients with prostate cancer. Zeitman et al5 have observed in an experimental animal model that greater tumor control was achieved when androgen ablation preceded radiotherapy compared with a concomitant approach, suggesting the radiosensitization effect with NAAD was sequence-specific. Further, Gleave et al6 have suggested that longer durations of androgen deprivation were associated with more profound tumor effects observed in radical prostatectomy specimens. Taken together, these data support the notion that waiting for a maximum androgen suppression effect with nadir PSA levels ≤ 0.5 ng/mL may be associated with improved rather than inferior local control rates. To address this issue more definitively, we are conducting a phase III trial to compare the outcome of 2 months versus 8 months of NAAD before radiation therapy (3D-CRT).Finally, some skepticism is expressed regarding the potential for systemic chemotherapy in combination with radiotherapy. Although randomized trials have shown a benefit with the combination of NAAD and radiotherapy, there is significant room for improvement with these regimens for patients with locally advanced prostate cancer. For example, even among patients with locally advanced prostate cancer treated with NAAD and radiotherapy on RTOG protocol 86-10, the PSA relapse rate was as high as 65%.4 Clearly, more effective regimens for these patients are needed. Petersen and Schellhammer refer to the experience at the Henry Ford hospital7> with estramustine and vinblastine and indicate that these data are “worse” than standard radiotherapy and NAAD. However, a careful review of the article suggests, as the authors contend in that report, that the chemotherapy regimen achieved at least comparable, if not more promising, results than those reported for NAAD and radiotherapy.There are many unanswered questions regarding the use of NAAD when combined with radiotherapy. What is the best regimen? Is total androgen blockade required? How long a course of NAAD is considered optimal? Which patients will benefit most from this regimen—locally advanced patients or even those with earlier stages of disease? Is the neoadjuvant administration of androgen deprivation as effective as an adjuvant mode of administration, or are both required? Will systemic chemotherapy be more effective than standard androgen deprivation therapy for patients with locally advanced disease? Studies are currently underway to address some of these issues. In the meantime, we must be ever cognizant that patients with locally advanced prostatic disease will require more effective systemic regimens in combination with local therapy. We are in the midst of a phase I study to assess the feasibility of neoadjuvant paclitaxel and carboplatin in combination with 3D-CRT for high-risk prostatic cancer. Regimens such as these, which address both androgen-dependent and androgen-independent tumor clonogens, may provide the greatest promise for the patient with locally advanced disease. 1. Zelefsky MJ, Lyass O, Fuks Z, et al: Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy. J Clin Oncol 16::3380,1998-3385, Link, Google Scholar2. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334::1356,1996-1361, Crossref, Medline, Google Scholar3. McCormick B, Norton L, Yao TJ, et al: The impact of the sequence of radiation and chemotherapy on local control after breast-conserving surgery. Cancer J Sci Am 2::39,1996-45, Medline, Google Scholar4. Pilepich MV, Sause WT, Shipley WU, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic cancer: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45::616,1995-622, Crossref, Medline, Google Scholar5. Zeitman AL, Nakfoor BM, Prince EA, et al: The effect of androgen deprivation and radiation therapy on an androgen sensitive murine tumor: An in vitro and in vivo study. Cancer J Sci Am 3::31,1997-36, Medline, Google Scholar6. Gleave ME, Goldenberg K, Jones EC, et al: Biochemical and pathological effects of 8 months of neoadjuvant androgen withdrawal therapy before radical prostatectomy in patients with clinically confined prostate cancer. J Urol 155::213,1996-219, Crossref, Medline, Google Scholar7. Khil MS, Kim JH, Bricker LJ, et al: Tumor control of locally advanced prostate cancer following combined estramustine, vinblastine, and radiotherapy. Cancer J Sci Am 3::289,1997-296, Medline, Google Scholar