The Role of Radical Prostatectomy and Lymph Node Dissection in the Treatment of Young Men With High-Grade Node-Positive Prostate Cancer: There May Be No RCTs-but There Are Good Reasons to Include Surgery

In the current controversies about the optimal management of prostate cancer, it is essential for patients and providers to recognize that this prevalent malignancy remains the leading cause of cancer-related death in men and claims 30,000 lives each year in the United States.[1] Although lower stage and Gleason score migration have been attributed to the widespread adoption of prostate-specific antigen (PSA) screening, 15% to 28% of patients are currently diagnosed with high-risk disease features: Gleason score > 8 on prostate biopsy, clinical stage > T3a, or PSA > 20 ng/mL.[2,3] Moreover, 7% to 15% of patients have lymph node metastasis at the time of presentation.[4] Clinical practice guidelines vary in their recommendations, from systemic therapy with primary androgen deprivation therapy (ADT) alone, to local therapy with radiotherapy in conjunction with ADT.[5,6]

The key clinical questions with regard to patients who present with lymph node–positive prostate cancer primarily revolve around whether local treatment confers better oncologic outcomes compared with primary ADT alone; and if so, whether surgery or radiation therapy is the superior local treatment modality. At issue is whether local therapy for high-risk prostate cancer with nodal metastasis can either possibly be curative or provide a durable response, such that primary ADT can be minimized-a desirable goal given the well-recognized adverse side effects of long-term medical castration.[7,8] Although radical prostatectomies in patients with clinical lymphadenopathy were abandoned in the era before widespread adoption of PSA screening,[9] we suggest that radical prostatectomy with extended pelvic lymphadenectomy can help achieve durable cancer control in the contemporary era. Selecting the appropriate multimodal treatment for high-risk and lymph node–positive prostate cancer is largely based on the heterogeneity in cancer outcomes and tumor aggressiveness at presentation-in particular since the number of positive lymph nodes is a strong predictor of biochemical-free, cancer-specific, and overall survival.[4] For example, a historical single-institution study from the Mayo Clinic of 507 patients with lymph node–positive disease treated surgically with radical prostatectomy and lymph node dissection demonstrated that the 10-year cancer-specific survival and freedom from biochemical recurrence were 86% and 56%, respectively.[10] Moreover, patients with 1 positive lymph node had markedly better cancer-specific survival than those patients with > 2 positive lymph nodes at 10 years (90% vs 79%; P < .001). One limitation of this study, however, was that 90% of patients received ADT following surgery, and as a result, the clinical efficacy of surgery alone was unclear.

To address this important clinical question, Touijer et al investigated the durable response to surgery alone without any adjuvant ADT or external beam radiation therapy (XRT), using retrospective institutional data from Memorial Sloan-Kettering Cancer Center.[11] In the 389 patients with nodal metastasis at the time of radical prostatectomy, the 10-year overall and cancer-specific survival were 60% and 72%, respectively, while the 10-year probability of freedom from distant metastasis was 65%. Similar to the Mayo Clinic series, patients with > 3 positive lymph nodes had a higher risk of biochemical recurrence than those with < 3 positive lymph nodes on multivariable analysis (hazard ratio = 2.61; P < .001). A recent systematic review of radical prostatectomy with lymph node dissection for lymph node–positive prostate cancer also suggested that aggressive surgical intervention should be included as a possible treatment option on the basis of the existing, albeit poor-quality, evidence.[12] Furthermore, the authors concluded that treatment for patients undergoing radical prostatectomy ought to include an extended pelvic lymph node dissection, since the internal and common iliac nodes are commonly identified sites of metastasis.

It is essential to acknowledge that defining the ideal multimodal management strategy for patients with high-risk, lymph node–positive prostate cancer remains challenging and uncertain, given the clinical practice guidelines and current poor quality of evidence available to guide treatment decisions. In our contribution to this “pro/con” debate, we have aimed to demonstrate that radical prostatectomy with extended pelvic lymph node dissection can achieve durable cancer control in appropriately selected patients, such as younger patients who present with < 3 clinically positive lymph nodes at the time of surgery. We recognize the lack of clinical trials randomizing patients to different local therapies (surgery vs radiotherapy) and systemic therapies, as well as the bias and confounding that result from the use of retrospective studies. It is also unlikely that the needed randomized clinical trials will ever be conducted.

Moreover, a recent population-based study of Medicare beneficiaries with nodal metastasis demonstrated similar survival for radical prostatectomy compared with radiotherapy, as well as radical prostatectomy with and without adjuvant radiotherapy.[13] This study also showed improved survival with either surgery or radiotherapy compared with no local therapy for these high-risk patients. However, radical prostatectomy with extended pelvic lymph node dissection should be included in the disease management strategy either to provide durable freedom from secondary therapies such as ADT and adjuvant XRT, or to be possibly curative for high-risk and node-positive prostate cancer.

Furthermore, upfront surgery allows for greater freedom to use all secondary treatment options for local and distant control, including adjuvant radiotherapy and ADT, thereby hopefully obviating the significant adverse quality-of-life sequelae from salvage surgery and brachytherapy for local relapse.[14] The use of multimodal treatment, including surgery, adjuvant radiotherapy, and ADT, is particularly relevant for younger patients who are at high risk for local and distant relapse over the course of their lives and who may need all treatments to achieve optimal outcomes.

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

References:

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.

2. Meng MV, Elkin EP, Latini DM, et al. Treatment of patients with high risk localized prostate cancer: results from cancer of the prostate strategic urological research endeavor (CaPSURE). J Urol. 2005;173:1557-61.

3. Bastian PJ, Boorjian SA, Bossi A, et al. High-risk prostate cancer: from definition to contemporary management. Eur Urol. 2012;61:1096-106.

4. Swanson GP, Thompson IM, Basler J. Current status of lymph node-positive prostate cancer: incidence and predictors of outcome. Cancer. 2006;107:439-50.

5. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-79.

6. Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw. 2010;8:162-200.

7. Keating NL, O'Malley A, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2012;104:1518-23.

8. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-64.

9. Olsson CA. Staging lymphadenectomy should be an antecedent to treatment in localized prostatic carcinoma. Urology. 1985;25(2 suppl):4-6.

10. Boorjian SA, Thompson RH, Siddiqui S, et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol. 2007;178:864-70; discussion 870-1.

11. Touijer KA, Mazzola CR, Sjoberg DD, et al. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol. 2014;65:20-5.

12. Gakis G, Boorjian SA, Briganti A, et al. The role of radical prostatectomy and lymph node dissection in lymph node-positive prostate cancer: a systematic review of the literature. Eur Urol. 2013:S0302-2838. [Epub ahead of print]

13. Rusthoven CG, Carlson JA, Waxweiler TV, et al. The impact of definitive local therapy for lymph node-positive prostate cancer: a population-based study. Int J Radiat Oncol Biol Phys. 2014;88:1064-73.

14. Peters M, Moman MR, van der Poel HG, et al. Patterns of outcome and toxicity after salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review. World J Urol. 2013;31:403-9.