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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2055-2056 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.9939
Targeting Pelvic Lymph Nodes in Men With Intermediate- and High-Risk Prostate Cancer Despite Two Negative Randomized TrialsHarvard Radiation Oncology Program, Boston, MA
Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA To the Editor: Two landmark trials1,2 evaluating the role of pelvic radiation in intermediate- and high-risk prostate cancer have recently been published that should change practice, but it is not clear if the needed changes will actually happen. The authors of the European Groupe d'Etude des Tumeurs Uro-Génitales (GETUG-01) trial did not have the updated results of the corresponding American Radiation Therapy Oncology Group (RTOG) 94-13 trial when they wrote their discussion, and we would like to try put these two studies into context. When the initial results of the RTOG 94-13 were published in the Journal of Clinical Oncology by Roach et al3 in 2003, suggesting that pelvic radiation improved the primary end point of progression-free survival compared with prostate-only radiation among patients with a greater than 15% chance of lymph node involvement, the use of a pelvic field became standard of care in the United States for this higher-risk population. However, 3 months ago, the RTOG published an update of this study showing that with longer follow-up, there was no difference in progression-free survival among the patients randomly assigned to whole pelvis radiation versus those randomly assigned to prostate-only radiation.2 The face value interpretation is that adding pelvis radiation therapy (RT) did not improve outcome in these men. However, the authors concluded that for men with high-risk prostate cancer, "whole pelvis RT with long term hormonal therapy remains the standard against which future trials should be developed."2 The rationale for their claim was two-fold. The first was that four randomized trials showing a benefit for hormonal therapy used pelvic fields.4-7 Therefore, to obtain the benefits of a treatment in a study, we must treat our patients the exact same way the study did. The other rationale was related to the 2 x 2 design of RTOG 94-13. Patients in this study were also simultaneously randomly assigned to neoadjuvant hormonal therapy or adjuvant hormonal therapy, and the authors believe that an unexpected interaction has obscured the underlying benefit of a pelvic field, although no formal test for interaction was reported. Although the pairwise comparison between the whole pelvis plus neoadjuvant arm showed a trend toward improved progression-free survival over the prostate-only plus neoadjuvant arm, the P value (.066) did not reach statistical significance, particularly when adjusted for multiple comparisons, and the study was unfortunately not powered for such pairwise comparisons. Moreover, the prostate-only and adjuvant RT arm surprisingly performed similarly to the whole pelvis and neoadjuvant RT arm, showing how a conclusion that does not seem to have a logical clinical basis can be reached when looking at four arms in a study powered and designed to look at two arms. So, what is the take-home message for practicing clinicians? Should we keep treating pelvic fields because we cannot be sure the RTOG 94-13 was really negative, and because four trials4-7 demonstrating a benefit to hormonal therapy used pelvic fields, or should we stop using it because there is no evidence from randomized clinical trials1,2 that pelvic fields are beneficial? We believe that the use of the pelvic field should be restricted to men on studies evaluating its use among those whose risk of nodal involvement is higher than the patients typically enrolled onto RTOG 94-13 and GETUG-01. With regard to the argument that we should continue to use the pelvic field because it is what was used in the prior randomized trials, we would respond by suggesting that the disease afflicting men in the trials of the 1980s and early 1990s is not the same as the disease we see today. Screening with prostate-specific antigen (PSA) and the resulting stage migration have shifted patients into earlier-stage disease and lower-risk groups with less chance of having nodal involvement.8,9 Even patients who have a greater than 15% risk of nodal involvement by the Roach formula10 ([2/3 x PSA] + [Gleason score – 6] x 10), which was required for entry into the RTOG 94-13, have a much lower actual risk of nodal involvement today than 15 years ago. When Dr Roach derived his widely used formula in 1994, 40% of the patients with a Roach formula score higher than 15% had actual lymph node involvement. As presented in Table 1, applying the same formula to patients from the Surveillance Epidemiology and End Results data set in 2004 with PSAs less than 100 ng/mL who had nodes examined pathologically shows that only 8% of patients with a Roach formula score greater than 15% had positive nodes, and that at every range of scores shown, the Roach formula overestimates the risk of nodal involvement for current-era patients. Therefore, today's patients are much less likely to have nodal involvement for a given PSA and Gleason score, which may partially explain the negative results of the RTOG 94-13.
Fortunately, the publication of the GETUG-01 in the December 1, 2007, issue of JCO provides validation of the results of RTOG 94-13. This two-arm trial randomly assigned 444 patients to pelvic radiation versus prostate-only radiation. Concomitant hormonal therapy was given at the physician's discretion to high-risk patients and was balanced between both randomized treatment arms. Like the updated RTOG 94-13, the GETUG-01 showed no difference in progression-free survival between the pelvis and prostate-only arms. Certainly, there are potential caveats to the trial, including the fact that a lower dose was used for many patients (66 Gy), the pelvic field was slightly smaller than the one used in RTOG 94-13 (superior border was only up to S1/S2), and the posthoc calculated risk of nodal positivity by the Roach formula was less than 15% for more than half the patients. Yet despite these potential limitations, negative results of two large prospective randomized trials make it difficult to justify the uniform use of pelvic field We admire and are grateful to the authors of both studies for designing and conducting these landmark trials to answer a very important clinical question. Since both randomized trials failed to demonstrate an advantage to treating the pelvic lymph nodes when compared with treatment of the prostate and seminal vesicles alone. Therefore, evidence to justify the use of the pelvic field is lacking for men with intermediate- and high-risk localized prostate cancer. An additional randomized study is needed in men with T3/T4 and Gleason 4+3 or higher prostate cancer, who represent those with highest risk locally advanced disease and are similar to the patients in RTOG 8610, 8531, and 9202, and EORTC 22863, to test the hypothesis that the use of the pelvic field contributed to the benefit observed in those studies. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Pommier P, Chabaud S, Lagrange JL, et al: Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 25:5366-5373, 2007 2. Lawton CA, DeSilvio M, Roach M III, et al: An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: Updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys 69:646-655, 2007[Medline] 3. Roach M III, 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 Oncol 21:1904-1911, 2003 4. 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 Phys 50:1243-1252, 2001[CrossRef][Medline] 5. Pilepich MV, Winter K, Lawton CA, et al: Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma–long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 61:1285-1290, 2005[CrossRef][Medline] 6. 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. Lancet 360:103-106, 2002[CrossRef][Medline] 7. 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 Oncol 21:3972-3978, 2003 8. Catalona WJ, Smith DS, Ratliff TL, et a: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 270:948-954, 1993 9. Cooperberg MR, Lubeck DP, Meng MV, et al: The changing face of low-risk prostate cancer: Trends in clinical presentation and primary management. J Clin Oncol 22:2141-2149, 2004 10. Roach M III, Marquez C, Yuo HS, et al: Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 28:33-37, 1994[Medline]
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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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