Deciding Which Patients to Treat With Salvage Radiotherapy After Prostatectomy

In their article, Raldow et al provide an excellent summary of the issues surrounding the use of salvage radiotherapy for a post-prostatectomy recurrence.

For practicing clinicians, the pressing issue is how to appropriately select patients for treatment with salvage radiotherapy. Conventional wisdom would suggest that salvage radiotherapy should be offered to patients with the highest likelihood of harboring local-only disease (eg, PSA doubling time > 12 months, positive surgical margins, interval to PSA failure > 3 years, Gleason 7 or lower), while patients with a high likelihood of distant micrometastatic disease (eg, PSA doubling time < 6 months, Gleason 8-10, interval to PSA failure < 3 years, PSA at failure > 2.0 ng/mL) are unlikely to benefit from salvage local treatment.[1-3] As seen in the multi-institutional data from Stephenson et al, patients with the favorable features tended to have good 4-year PSA control (i.e. > 50%) after salvage radiotherapy, while PSA control was poor (ie, < 30%) for patients with the unfavorable features.[4]

However, this does not necessarily mean that unfavorable patients should not be offered salvage radiotherapy. In fact, surprisingly, the Trock et al retrospective data from Johns Hopkins published in JAMA in 2008 found that while salvage radiotherapy was associated with an improvement in prostate cancer–specific survival and overall survival, the benefit was limited only to men with a short doubling-time (ie, < 6 months), who are precisely the group traditionally thought to harbor micrometastatic disease.[5] Conversely, no benefit in prostate cancer–specific survival could be detected from salvage radiotherapy in men with PSA doubling time > 6 months. Despite these results, in practice, we continue to fully support salvage radiotherapy for men with a PSA doubling time > 6 months, as the Trock study (with only 6 years of follow-up) may not have followed patients long enough to detect a benefit from salvage radiotherapy among those with slowly progressing disease. However, because of the Trock data, we are also offering salvage radiotherapy to more patients with short doubling times and other unfavorable features, as the data suggest that there may be a group of patients with aggressive and rapidly progressing disease that remains localized to the prostate bed and that can be effectively salvaged by radiotherapy.

Two other important questions remain unanswered for the delivery of salvage radiotherapy. First, should the pelvic lymph nodes be treated, or only the prostate bed? Second, should concurrent androgen deprivation be used? The use of pelvic nodal radiation for intermediate- and high-risk disease in the intact setting remains controversial despite the publication of two randomized trials addressing the issue.[6-10] In the salvage setting, no randomized trials have been published, although the RTOG 05-34 (opened Feb 2008, requires 1764 patients), seeks to answer this question by randomizing patients to pelvic radiation, plus 4-6 months of ADT vs. prostate-bed only radiation, plus 4-6 months of ADT. Currently at our institution, we are not routinely irradiating pelvic lymph nodes in the intact prostate or post-operative settings unless there is evidence of nodal involvement, but we will use it in certain select cases with features such as seminal vesicle involvement and Gleason 9 or 10 disease.

A third arm in the RTOG 05-34 study is prostate-bed-only radiation without ADT, which will allow this study to answer the question of whether ADT improves outcomes when added to salvage radiation. Two other ongoing randomized trials are also hoping to answer this question: the UK-NCIC RADICALS Trial (opened Jan 2007, requires 1,600 patients), and the EORTC 22043 (opened 2009, requires 600 patients). In addition, we are awaiting publication of the RTOG 96-01, which has been completed and which tested whether bicalutamide 150 mg QD (a dose that is no longer FDA approved in the US) improves survival when added to salvage radiotherapy. The available retrospective data from Trock did not find that ADT plus salvage radiotherapy improved prostate cancer–specific survival over salvage radiation alone, but in any retrospective study it is hard to remove the selection bias, ie, that men with more aggressive disease will be chosen to receive ADT and so this makes it harder to show a benefit due to ADT. As we await the results of randomized trials, we are extrapolating from the randomized trials in the intact setting and adding ADT to salvage radiotherapy for patients who would have been offered ADT in the intact setting, such as those with Gleason 8-10 disease or seminal vesicle invasion.[11-13] Adding ADT may also be reasonable for patients with a short PSA doubling time (ie, less than 6 months), but we will need to await the results of randomized trials before reaching definitive conclusions.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Nguyen, PL, D’Amico, AV, Lee AK, et al: Patient selection, cancer control, and complications after salvage local therapy for postradiation prostate-specific antigen failure: A systematic review of the literature. Cancer 110:1417, 2007.

2. Freedland SJ, Humphreys EB, Mangold LA, et al: Risk of prostate cancer- specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433, 2005.

3. Stephenson AJ, Shariat SF, Zelefsky MJ, et al: Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 291:1325, 2004.

4. Stephenson AJ, Scardino PT, Kattan MW, et al: Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 25:2035, 2007.

5. Trock BJ, Han M, Freedland SJ, et al: Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 299:2760, 2008.

6. Roach , 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 Oncol 21:1904, 2003.

7. Lawton CA, DeSilvio M, Roach M, 3rd , 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, 2007.

8. 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, 2007.

9. Nguyen PL, D’Amico AV: Targeting pelvic lymph nodes in men with intermediate- and high-risk prostate cancer despite two negative randomized trials. J Clin Oncol, 26:2055, 2008.

10. Roach M, 3rd: Targeting pelvic lymph nodes in men with intermediate- and high risk prostate cancer, and confusion about the results of the randomized trials. J Clin Oncol 26:3816, 2008.

11. 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, 1997.

12. D’Amico AV, Chen MH, Renshaw AA, et al: Androgen suppression and radiation vs radiation alone for prostate cancer: A randomized trial. JAMA 299:289, 2008.

13. Horwitz EM, Bae K, Hanks GE, et al: Ten-year follow-up of radiation therapy oncology group protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 26:2497, 2008.