Whether or not the elective irradiation of pelvic nodes provides any benefit compared with treating the prostate only has been a longstanding therapeutic dilemma. The results of many retrospective studies were conflicting. Then, in 2003, the first results of Radiation Therapy Oncology Group (RTOG) 94-13 were published. This fourarm randomized trial for prostate cancer patients at high risk of occult nodal involvement compared whole pelvic (WP) versus prostate only (PO) fields with either neoadjuvant and concurrent hormone therapy (NHT) or adjuvant hormone therapy (AHT). It showed that when administered with NHT, there was improved progression-free survival (PFS) with WP compared with PO radiation fields (PFS: 60% v 44% at 4 years, respectively; P .008) and improved prostate-specific antigen (PSA) relapse-free survival (biochemically no evidence of disease [bNED]: 70% v 57% at 4 years, respectively; P .048). However, no overall survival (OS) differences were observed. What at first seemed to be a fairly clear-cut positive trial became complicated when, in 2007, a published update with 1.6 years longer follow-up demonstrated diminished differences in PFS (P .065), which were now interpreted as a trend in favor of WP with NHT. The bNED differences had now vanished (P .43) between these two treatment arms. In an unexpected twist, differences in OS were now emerging but were significant only when comparing WP with NHT versus WP with AHT (82% v 74%, respectively; P .019). However, the trial was not originally powered to test differences between these two treatment arms. These collective findings were interpreted as the result of an unexpected and unrecognized biologic interaction between the timing of hormone therapy and pelvic nodal radiotherapy, and the conclusion was still to recommend WP with NHT for high-risk prostate cancer. To complicate matters further, in 2007, the results of another randomized trial, Groupe d’Etude des Tumeurs Uro-Genitales (GETUG) -01, comparing WP versus PO fields with NHT for highrisk prostate cancer patients showed no difference in 5-year PFS (66% v 65%, respectively; P .34) or OS (86.5% v 88%, respectively; P .62). Although the results of RTOG 94-13 are provocative, they are puzzling and difficult to accept as evidence in support of WP radiotherapy given our lack of biologic understanding of why it is that these results would seem to change with longer follow-up. This leaves the issue of whether or not to electively irradiate pelvic nodes for high-risk patients with prostate cancer still without consensus. We propose a hypothesis for this unrecognized biologic interaction between the timing of hormone therapy and WP radiotherapy that could explain the curious results of RTOG 94-13. Our reasoning is as follows: there is a larger scatter dose to the testes with WP fields compared with PO fields; the negative effect on testosterone production is proportional to the dose to the testes (or more precisely the Leydig cells), and therefore, the time to testosterone recovery is proportional to testicular dose; and the increase in time to testosterone recovery leads to a delay in biochemical failure and therefore gives an apparent but temporary advantage for WP radiotherapy. With partial Leydig cell depletion from NHT, a synergistic effect leading to longer time to testosterone recovery from testicular dose would also be predicted for WP radiotherapy with NHT compared with WP radiotherapy with AHT. First, we will discuss higher testicular scattered dose with larger field size. We first look at the data that pertains to the scatter dose to the testes from megavoltage external-beam radiotherapy using threedimensional conformal four-field techniques for the treatment of prostate or rectal cancers, summarized in Table 1. None of the patients in these studies received hormone therapy. For a prostate-only field delivering 68 to 72 Gy, the mean scattered testicular dose is 2.1 Gy. For a course delivering 50 Gy to the pelvis, the mean scattered testicular dose is 3.6 to 8.4 Gy. From this data, the cumulative scatter dose from a course of radiotherapy with WP (45 to 50 Gy) and prostate boost (25 Gy) is calculated to be within the range of 4.3 to 9.1 Gy. Thus two to four times more scattered testicular dose is administered with WP fields compared with PO fields. Our second point concerns dose-response relationship on testicular function. The impact of testicular dose on hormonal function (including testosterone, luteinizing hormone, and follicle-stimulating hormone levels) is also summarized in Table 1. Significantly lower testosterone levels compared with baseline levels have been demonstrated after pelvic radiotherapy, with a mean decrease of 20% to 30% measurable within weeks of radiotherapy and persisting for months afterwards. In the largest and most detailed study of more than 600 patients receiving PO radiotherapy without hormones, the testosterone levels decreased by a mean of 17%. In 40% of patients, the testosterone recovery was never to their baseline levels. In addition, on multivariate analysis, the decrease in testosterone levels was greater among patients treated with larger field sizes and patients with lower JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 27 NUMBER 36 DECEMBER 2
[1]
H. Sandler,et al.
Does timing of androgen deprivation influence radiation-induced toxicity? A secondary analysis of radiation therapy oncology group protocol 9413.
,
2008,
Urology.
[2]
J. Svartberg,et al.
Radiotherapy for rectal cancer is associated with reduced serum testosterone and increased FSH and LH.
,
2008,
International journal of radiation oncology, biology, physics.
[3]
Sylvie Chabaud,et al.
Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01.
,
2007,
Journal of clinical oncology : official journal of the American Society of Clinical Oncology.
[4]
Charles R. Thomas,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.
,
2007,
International journal of radiation oncology, biology, physics.
[5]
Nicholas Bruchovsky,et al.
Locally advanced prostate cancer--biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen recurrence after radiotherapy.
,
2007
.
[6]
Charles R. Thomas,et al.
Whole-pelvis, "mini-pelvis," or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial.
,
2006,
International journal of radiation oncology, biology, physics.
[7]
H. Christiansen,et al.
Testicular dose and hormonal changes after radiotherapy of rectal cancer.
,
2005,
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.
[8]
V. Budach,et al.
Testicular Dose in Prostate Cancer Radiotherapy
,
2005,
Strahlentherapie und Onkologie.
[9]
D. Olsen,et al.
Radiation therapy induced changes in male sex hormone levels in rectal cancer patients.
,
2003,
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.
[10]
R K Valicenti,et al.
Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413.
,
2003,
Journal of clinical oncology : official journal of the American Society of Clinical Oncology.
[11]
T. Pickles,et al.
What happens to testosterone after prostate radiation monotherapy and does it matter?
,
2002,
The Journal of urology.
[12]
T. Pickles,et al.
What happens to testosterone after prostate radiation monotherapy, and does it matter
,
2001
.
[13]
D. Dearnaley,et al.
Recovery of serum testosterone, LH and FSH levels following neoadjuvant hormone cytoreduction and radical radiotherapy in localized prostate cancer.
,
2001,
Clinical oncology (Royal College of Radiologists (Great Britain)).
[14]
P. Stratte,et al.
Hypogonadism following prostate‐bed radiation therapy for prostate carcinoma
,
2001,
Cancer.
[15]
A. Pollack,et al.
Serum testosterone levels after external beam radiation for clinically localized prostate cancer.
,
1997,
International journal of radiation oncology, biology, physics.
[16]
R. Fisher,et al.
Testicular doses in definitive radiation therapy for localized prostate cancer.
,
1995,
International journal of radiation oncology, biology, physics.
[17]
Nicholas Bruchovsky,et al.
Locally advanced prostate cancer—biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate‐specific antigen recurrence after radiotherapy
,
2007,
Cancer.
[18]
Charles R. Thomas,et al.
Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen
,
2003
.