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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2255-2257 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.243
In Reply:Department of Radiation Oncology, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA It is each physician's right to use his or her best judgment in managing patients. We designed and carried out a large prospective randomized trial, and Dr Ennis is "hesitant to accept these results and apply them in practice."1 However, all his criticisms of Radiation Therapy Oncology Group (RTOG) 9413 could be made of every major positive randomized trial completed to date involving radiotherapy. 2–5 Of note, the first three of these trials used hormonal therapy and whole pelvic radiotherapy (WPRT). For example, he postulates that there may have been an imbalance with more 4 + 3s than 3 + 4s. As with the other trials, when patients are randomly assigned, the likelihood of a major imbalance is low. If there was an imbalance, it is equally likely that the imbalance occurred in favor of prostate-only radiotherapy. Of note, however, a subset analysis of patients treated on RTOG 8531 and 8610 failed to demonstrate a difference in outcome in patients with 4 + 3 compared with 3 + 4 when treated with neoadjuvant hormonal therapy and WPRT.6 Several other studies also fail to show a difference in outcomes between patients with biopsy Gleason scores of 3 + 4 compared with patients with 4 + 3.7,8 Thus, our colleague is selectively discounting the results of a large randomized trial for a hypothetical event that is unlikely to be present and the importance of which retrospective data from the RTOG fail to support. The primary end point was progression-free survival, which included biochemical failure as an event.9 Thus, to argue for prostate-only radiotherapy because there is not yet a survival advantage to WPRT is inappropriate. Should radiation oncologists omit the use of three-dimensional conformal radiotherapy and decline to use doses > 70 Gy because no survival advantage has yet been shown? Although there was a slightly higher rate of grade 2 toxicity (Table 1) in the WPRT arms, the differences were relatively small (10% to 15% for acute and 3% to 5% for late toxicity). Of note, however, three-dimensional conformal radiotherapy was not used routinely in RTOG 9413; had it been used, it would probably have resulted in a substantial reduction in complications on both arms.
As described in our report, the reason that "there is no benefit to this treatment among patients treated with neoadjuvant hormones followed by prostate-only radiotherapy" is that the biologic interaction between hormonal therapy and radiotherapy occurs in the pelvic lymph nodes. One explanation is that the interaction is seen in the lymph nodes, because at 50 Gy, one is still on the steep part of the dose-response curve, whereas at 70 Gy, one is approaching a plateau.10 Alternatively, the metastatic phenotype or the nodal environment may be different in the primary cancer from in the lymph nodes. For example, there may be local growth factors within the prostate that protect it against synergism between radiation and hormonal therapy that may not be present within nodal tissues. Clearly, more work is needed in this area. I would also argue that the relative benefit is larger than suggested in Dr Ennis' letter. Remember, the date to failure is measured from the date of randomization. Prostate-specific antigen levels are unlikely to start to rise until hormonal therapy is discontinued. Patients treated on arms 3 and 4 were on hormonal therapy for 2 months later than those on arms 1 and 2, creating a bias against these neoadjuvant hormone therapy arms. This is made more obvious by comparing arms 2 and 4, as shown in Figure 1. These curves are essentially parallel, separated by 2 months, demonstrating that when only the prostate is irradiated, there is no evidence of a sequence-dependent interaction. In contrast, when one compares arms 1 and 2 (omitting this timing bias), the benefits are much clearer, as shown in Figure 2. A hazard ratio of 1.5 is clearly a large effect, even if there is a slightly higher risk of grade 2 toxicity.
I congratulate our colleague for having the courage to voice his concerns in a public forum. (I am sure others had similar concerns.) Should he choose to continue to only irradiate the prostate in patients at risk for lymph node involvement, I would encourage him to inform his patients that this is being recommended despite the findings of RTOG 9413. I am certain that he has his patients' best interest at heart, and I hope that this letter clarifies issues in question, encouraging him and others to seriously reconsider "accepting the findings of this study" into their practice. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES
1. Roach M 3rd, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol21:1904–1911, 2003 2. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet360:103–106, 2002[CrossRef][Medline]
3. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserlin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Oncology Group Protocol 85–31. J Clin Oncol15:1013–1021, 1997
4. Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group protocol 92–02. J Clin Oncol21:3972–3978, 2003 5. Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M.D. Anderson phase III:randomized trial. Int J Radiat Oncol Biol Phys53:1097–1105, 2002[CrossRef][Medline] 6. Anderson PR, Winter KA, Hanks GE, et al: Gleason score 4 + 3 prostate cancer patients have worse outcome compared to Gleason score 3 + 4 treated with radiation therapy alone: Subset analysis of RTOG 85–31 and 8610, in Cox (ed): Proceedings of the American Society for Therapeutic Radiology and Oncology 42nd Annual Meeting. Boston, MA, Elsevier, 2000,pp 205 7. Lau WK, Blute ML, Bostwick DG, et al: Prognostic factors for survival of patients with pathological Gleason score 7 prostate cancer: Differences in outcome between primary Gleason grades 3 and 4. J Urol166:1692–1697, 2001[CrossRef][Medline] 8. Merrick GS, Butler WM, Galbreath RW, et al: Biochemical outcome for hormone-naive patients with Gleason score 3+4 versus 4+3 prostate cancer undergoing permanent prostate brachytherapy. Urology60:98–103, 2002[CrossRef][Medline] 9. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys50:1243–1252, 2001[CrossRef][Medline] 10. Zietman A, Nakfoor B, Prince E, et al: The effects of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: An in vitro and in vivo study. Cancer J Sci Am3:31–36, 1997[Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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