Optimal Therapy in Localized Prostate Cancer: An Unfolding Story

The optimal treatment for clinically localized prostate cancer is an ongoing subject of controversy.[1] As pointed out by Drs. Mirhadi and Sandler, no randomized trial has compared radical prostatectomy (RP) to radiation therapy (RT), and no study has definitively “proven” the superiority of one technique over the other. Therefore, we disagree with the author’s conclusion that RT “is the ‘only way to go’ when managing early-stage prostate cancer.”

To support their conclusion, the authors cite several investigations that have suggested similar short- to intermediate-term biochemical progression-free survival rates with RP and RT. However, biochemical failure is a ­heterogeneous phenomenon and a poor surrogate for clinical endpoints.[2]

Moreover, Klein et al recently reported a significantly more favorable clinical progression-free survival rate for intermediate-risk prostate cancer with RP than RT.[3] Overall, due to the lengthy natural history of prostate cancer, a comparison of more long-term outcomes is essential.

Other Confounders
Furthermore, retrospective attempts to compare oncologic outcomes between RP and RT have been complicated by numerous factors. For example, both the dose and technique of RT have changed considerably over time, in contrast to the relative stability of the anatomic RP technique since its description in the early 1980s.[4] Correspondingly, long-term data are not yet available for the modern RT techniques described by the authors. Additionally, even the definition for biochemical failure after RT has changed over time,[5] and the use of these different definitions can affect comparisons of relative treatment efficacy.[6] The current Phoenix definition (nadir + 2) is more specific for clinical endpoints, but is less sensitive. This in turn makes comparisons with RP (using a much lower prostate-specific antigen threshold of 0.2 or 0.4 ng/ mL) more difficult, particularly during the first 5 years after treatment.[7]

Another confounder discussed by the authors is the differing patient profiles in RP and RT series. Generally, older patients with more comorbidities receive RT, and these competing risks also complicate attempts to compare cancer-specific survival (ie, death from other causes reduces time at risk for prostate cancer mortality).

Finally, an issue not raised by the authors is the disparity in options for salvage therapy after failure of local therapy. Following RP, both locoregional and systemic options are available; whereas options for local salvage therapy after RT are more limited and fraught with complications.[8] Accordingly, systemic therapy with sustained hormonal therapy traditionally remains the cornerstone of management for RT failure.

Side-Effect Profiles
With regard to quality of life, both RP and RT have potential side effects, although the nature of these associated morbidities differs substantially.[9] However, as with oncologic comparisons, disparities between the patient populations undergoing RP and RT also cloud the ability to compare their functional outcomes.

Although the authors suggest that RT in itself may offer a more favorable side-effect profile in selected patients, the concurrent use of hormonal therapy in many cases could alter this drastically. Side effects of hormonal therapy include osteopenia, decreased libido, erectile dysfunction, cognitive decline, metabolic syndrome, and cardiovascular effects.[10,11] Notably, both the indications (intermediate- and high-risk disease[12]) and recommended duration of hormonal therapy with RT have increased over time. Indeed, a recent randomized controlled trial reported an overall survival advantage using 3 years (vs 6 months) of hormonal therapy with RT, making this issue all the more apropos.[13] In that study, global quality of life declined significantly after RT with 6 months of hormonal therapy. Extending the duration of hormonal therapy for an additional 2.5 years was associated with significantly higher rates of sexual dysfunction, hot flushes, breast enlargement, leg swelling, and insomnia. A further consideration is the added cost associated with an extended duration of hormonal therapy. Overall, the emerging trend toward a combined-modality approach for many intermediate- and high-risk patients undergoing RT must be taken into consideration when evaluating complications.

Conclusions
Ongoing follow-up is necessary to further examine long-term survival and quality of life following modern RT with or without hormonal therapy. Because randomized trials are not available to compare oncologic and functional outcomes between RT and RP, there is no conclusive evidence that either is the “way to go” for all men with localized prostate cancer. In the future, well-conducted studies may help to better define the optimal form of local therapy for specific patient subgroups. In the meantime, the story will continue to unfold, as both radiation oncologists and urologists strive to improve both primary forms of treatment for localized prostate cancer.

References:

1. Walsh PC, DeWeese TL, Eisenberger MA: Clinical practice. Localized prostate cancer. N Engl J Med 357:2696-2705, 2007.
2. Swindle PW, Kattan MW, Scardino PT: Markers and meaning of primary treatment failure. Urol Clin North Am 30:377-401, 2003.
3. Klein EA, Ciezki J, Kupelian PA, et al: Outcomes for intermediate risk prostate cancer: Are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol 27:67-71, 2009.
4. Walsh PC, Lepor H, Eggleston JC: Radical prostatectomy with preservation of sexual function: Anatomical and pathological considerations. Prostate 4:473-485, 1983.
5. Roach M, 3rd, Hanks G, Thames H Jr, et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 65:965-974, 2006.
6. Kupelian PA, Mahadevan A, Reddy CA, et al: Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer. Urology 68:593-598, 2006.
7. Nielsen ME, Makarov DV, Humphreys E, et al: Is it possible to compare PSA recurrence-free survival after surgery and radiotherapy using revised ASTRO criterion-”Nadir + 2”? Urology 72:389-395 (incl discussion), 2008.
8. 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 110:1417-1428, 2007.
9. Sanda MG, Dunn RL, Michalski J, et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250-1261, 2008.
10. Kumar RJ, Barqawi A, Crawford ED: Preventing and treating the complications of hormone therapy. Curr Urol Rep 6:217-223, 2005.
11. D’Amico AV, Denham JW, Crook J, et al: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25:2420-2425, 2007.
12. D’Amico AV, Schultz D, Loffredo M, et al: Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 284:1280-1283, 2000.
13. Bolla M, de Reijke TM, Van Tienhoven G, et al: Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360:2516-2527, 2009.