Treatment failure after primary and salvage therapy for prostate cancer

Does salvage therapy in prostate cancer have a benefit? If so, then which therapies are beneficial and in whom? In this issue of Cancer, Agarwal et al.1 report that they observed no survival benefit for a particular combination of primary and salvage therapy in their study of 5277 men. However, it would be folly to conclude from their report that salvage therapy is futile.

One disquieting finding of their report is how uncommonly potentially curative salvage therapy is being employed in patients who initially receive radiation therapy. Of the 430 patients in their series who experienced disease relapse after radiation therapy, 402 men (93.5%) received salvage hormone therapy, an approach that is known as noncurative. Only 17 men received potentially curative therapy, including 4 patients who underwent salvage radical prostatectomy and 13 patients who underwent salvage cryotherapy. The Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database reflects what is being used to treat these patients in the community and reflects national trends. Why is such a nihilistic approach being used in the majority of patients with recurrence after radiation therapy? There are a number of single-institution reports demonstrating excellent oncologic outcomes for salvage radical prostatectomy. For example, the recent study by Ward et al.2 demonstrated biochemical progression-free survival rates of 58% and 40% at 5 years and 10 years, respectively, after salvage radical prostatectomy, and the respective prostate cancer-specific survival rates were 79% and 65%. Furthermore, the complication rates for this surgery have been reduced greatly in the last 10 to 15 years because of improvements in surgical technique.2 One of the greatest limitations to the widespread implementation of salvage radical prostatectomy as a treatment is the limited number of surgeons who have experience operating in previously radiated fields. Just 4 major academic centers—the University of Texas M. D. Anderson Cancer Center, the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and the University of Southern California—account for the majority of salvage radical prostatectomies. Several other major academic centers have more limited experience with salvage radical prostatectomy, and this surgery almost never is performed in a community setting. Salvage cryotherapy is easier to perform and is much less demanding technically. Complication rates of salvage cryotherapy have been reduced dramatically through the implementation of third-generation cryotherapy probes, the judicious use of thermocouples, and effective urethral warming.3–5 In addition to favorable single-institution reports, a recent pooled analysis of 277 patients who underwent salvage cryotherapy demonstrated that 55% of patients were biochemically free of disease 5 years later.6 Because cryotherapy is less demanding technically, it is available in more locations, including both academic and community practices.

Patients who have rising prostate-specific antigen (PSA) levels after initial radiation therapy should consider referral to a center at which either salvage cryotherapy or salvage radical prostatectomy (or preferably both) are being offered. Based on a comparative study of salvage prostatectomy versus cryotherapy, salvage radical prostatectomy appears to produce better long-term biochemical disease-free survival compared with salvage cryotherapy and may be suited better for younger patients with postradiation recurrence.7 Salvage cryotherapy is far less invasive and may be more appropriate for older patients with postradiation recurrence.

Is radiation beneficial for those patients who have a disease relapse after initial radical prostatectomy? A randomized trial of adjuvant external-beam radiation versus watchful waiting by Bolla et al. convincingly demonstrated improved progression-free survival for patients who had positive margins or pathologic T3 tumors. Even a low dose of radiation (60 centigrays) was beneficial in reducing the risk of subsequent biochemical disease relapse.8 Although there are hazards in extrapolating Bolla et al.'s positive, randomized, adjuvant trial to a salvage setting, a recent pooled analysis of 501 patients suggested a benefit for salvage radiation therapy, particularly if it is administered when the PSA level is low (<1.0 ng/mL).9 The report by Stephenson et al. also suggested a potential benefit for select patients with high-grade tumors and rapid PSA doubling times. Agarwal et al.'s report suggests that salvage radiation therapy is being used in approximately 40% of patients who develop a disease relapse after radical prostatectomy.

Local control of prostate cancer is a rarely reported endpoint that deserves special attention separate from the consideration of prostate cancer mortality. Local progression of prostate cancer can result in the development of debilitating local symptoms caused by invasion of surrounding organs and obstruction. Invasion of the bladder can cause hematuria, urethral obstruction, and pelvic pain, necessitating chronic tube drainage, multiple surgical procedures, and numerous emergency room visits. Invasion of the cancer into the rectum can cause debilitating pain and tenesmus. We observed that approximately 8% of the patients who developed a biochemical relapse after initial radiation therapy went on to develop severely symptomatic local disease progression.10 Symptomatic local progression also may occur in patients who undergo an initial radical prostatectomy. Prostate cancer is a chronic disease, and patients with debilitating symptomatic local recurrences can live for many years. Salvage cystoprostatectomy and total pelvic exenteration can be highly effective in the palliation of patients with symptomatic local progression.11–13 The report by Agarwal et al.1 focuses on prostate-cancer mortality, and there were only 75 prostate cancer deaths in this 5277-patient study. Their report (like many others) does not examine local control as an endpoint. It is highly probable that salvage local therapy (prostatectomy or cryotherapy for patients who initially receive radiation and radiation for patients who initially undergo radical prostatectomy) may reduce the risk of symptomatic local progression. Thus, another salient benefit of salvage therapy may be improved local control, separate from any impact on overall survival.

In conclusion, the article by Agarwal et al. is valuable as a descriptive look at the frequency of salvage therapies in a large community population. Sadly, the overwhelming majority of patients who develop a disease relapse after initial radiation therapy are being offered noncurative therapies despite the finding that both salvage prostatectomy and salvage cryotherapy are safe and effective. What can be done to improve this situation? I believe that we need to redouble our efforts to educate both patients and community physicians on the safety and potential benefits of salvage local therapies.