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© 1999 American Society for Clinical Oncology
Should We Delay Prostate Radiotherapy?
Indian River Regional Cancer Center, Vero Beach, FL In the October 1998 issue of the Journal of Clinical Oncology, Zelefsky et al1 reported a novel predictive marker for neoadjuvant androgen ablation therapy (NAAD) and three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. This prognostic indicator is the preradiotherapy prostate-specific antigen (PSA) nadir after 3 months of NAAD. Patients who have a PSA nadir greater than 0.5 ng/mL have a poor 5-year PSA relapse-free survival rate. The hypothesis can be generated that this predictor may prove to be of enormous benefit in the management of patients with prostate cancer. Early in the course of therapy, it may become possible to identify patients who will require more or less intensive regimens. A prospective randomized clinical trial would be needed to test the hypothesis. However, there is a surprising conclusion in the article that is not substantiated by the data presented or by the data from other series. The authors state, "Based on these findings, it is our current practice to delay initiation of radiotherapy for patients pretreated with NAAD until the PSA level has plateaued to nadir levels." The evidence presented in the article only shows that patients who have a PSA nadir greater than 0.5 ng/mL do worse. No evidence of any benefit from delaying the radiotherapy is provided. The rapid fall to nadir may be a marker of radiosensitivity and identify a selected population who will do well. Prolonging hormonal therapy and delaying radiotherapy in patients slow to nadir may be detrimental by withholding the effective component of therapy. There is ample evidence in the treatment of other cancers that delaying radiotherapy while the patient is receiving systemic therapy leads to an increased local failure rate.2 The two commonly accepted rationales for delaying radiotherapy are to decrease toxicity and to achieve a smaller target volume. The authors report that the predominant clinical motivation for NAAD is to achieve target volume reduction, but it seems to be the PSA level that actually will determine the length of the delay of the radiotherapy. Other studies have shown a benefit from increasing the duration of androgen deprivation in conjunction with radiotherapy, but the additional months or years of androgen deprivation therapy are given after the radiotherapy has been completed rather than before it is administered.3 Also stated in the article is the important concept that patients with advanced prostate cancer have a high systemic failure rate and that the focus of future endeavors should include this aspect of the disease. Systemic hormonal therapy of long duration combined with radiotherapy has produced both increased survival and decreased rates of metastatic disease for certain patients. The authors show that the addition of even a relatively short course of NAAD resulted in a higher clearance of prostate cancer from prostate biopsy specimens compared with patients who received higher doses of radiation without NAAD. However, the investigators are now moving to more cytotoxic compounds, using a combination of estramustine, vinblastine, and 3D-CRT. A previous study using radiotherapy and this medication regimen produced results worse than those obtained with extended NAAD and radiotherapy.4 The mechanisms by which NAAD works are incompletely understood. There is evidence of a direct effect on the cancer by luteinizing hormone–releasing hormone (LHRH) agonists and estrogens independent of testosterone.5,6 The addition of an estrogen with cytotoxic characteristics to neoadjuvant therapy may prove beneficial. However, there is no proof that just because there are roughly equivalent results with antiandrogens, LHRH agonists, and estrogen compounds in metastatic disease, the mechanisms are the same. Since conventional extended NAAD therapy has been shown to be beneficial, perhaps research efforts should be directed toward finding what additional therapy can be added to NAAD other than substituting agents without a proven neoadjuvant role. REFERENCES 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 16:3380-3385, 1998[Abstract]
2.
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 334:1356-1361, 1996
3.
Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295-300, 1997 4. 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 3:289-296, 1997[Medline]
5.
Dondi D, Limonta P, Moretti RM, et al: Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: Evidence for an autocrine-inhibitory LHRH loop. Cancer Res 54:4091-4095, 1994 6. Schneider MR, Humm A, Graf AH: The tumor-inhibiting effect of diethylstilbestrol and its diphosphate on the Nb-H and Nb-R prostatic carcinomas of the rat. J Cancer Res Clin Oncol 116:159-167, 1990[Medline]
Memorial Sloan-Kettering Cancer Center, New York, NY
In 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
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 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. REFERENCES 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 16:3380-3385, 1998 2. 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 334:1356-1361, 1996 3. 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 2:39-45, 1996[Medline] 4. 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 45:616-622, 1995[Medline] 5. 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 3:31-36, 1997[Medline] 6. 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 155:213-219, 1996[Medline] 7. 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 3:289-296, 1997
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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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. 
