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Androgen Deprivation Therapy in Men with Node-positive Prostate Cancer Treated with Post-operative Radiotherapy - Beyond the Abstract

Lymph node metastases are found in approximately 15% of patients treated by radical prostatectomy (RP). Although nodal involvement is clearly a poor prognostic sign, it is not an inevitable harbinger of recurrence: about one in three patients with positive lymph nodes remain recurrence free at long-term follow-up even in the absence of post-operative treatment.1 This suggests prognostic heterogeneity in men with positive lymph nodes that should be taken into consideration in order to avoid overtreatment.

Androgen deprivation therapy (ADT) is the gold standard treatment for metastatic prostate cancer.2,3 Historically, patients with nodal metastases after radical prostatectomy were managed with ADT on the grounds of improved survival over postoperative observation.4 Subsequent evidence proved that a combination of ADT and adjuvant radiotherapy is beneficial over ADT alone.5,6 However, evidence that ADT is beneficial for patients receiving postoperative radiotherapy is scarce. It is well known that ADT causes a large number of side-effects, including hot flashes, fatigue and impaired libido, as well as risks such as metabolic and cardiovascular complications.7 As such, the use of ADT in combination with postoperative radiotherapy for node-positive prostate cancer would only be justified if it resulted in a substantial decrease in cancer-specific death.

To test whether the addition of ADT to postoperative radiotherapy improves survival compared to radiotherapy alone, we examined data of 372 patients with node-positive prostate cancer treated with RP an extended pelvic lymph node dissection at San Raffaele Hospital between 1991 and 2017.8 Within six months from surgery, patients received radiotherapy alone or in combination with ADT. The decision to administer additional ADT was based on the clinical judgment of each treating physician according to individual patient and cancer characteristics.

In brief, there were 48 all-cause and 18 cancer-specific deaths. Median (interquartile range) follow-up for survivors was 77 (44, 113) months. After adjusting for age, PSA level at RP, stage, grade and number of positive nodes, there was no significant difference in overall survival between men treated by radiotherapy + ADT vs. radiotherapy alone (hazards ratio [HR]: 0.91; 95%CI: 0.45, 1.84; p=0.8). Similarly, the risk of cancer-specific death was not significantly different between men treated with radiotherapy + ADT vs. those who received radiotherapy alone (HR: 5.39; 95%CI 0.70, 41.39; p=0.11). This finding was confirmed in the competing risk analysis used to predict cancer-specific death with death from other causes as the competing event (HR: 5.60; 95%CI 0.68, 45.86; p=0.11). Moreover, we repeated the analysis in a subcohort of 286 patients after propensity score matching, with no significant difference between radiotherapy + ADT vs. radiotherapy alone for cancer-specific survival (HR: 3.27; 95%CI: 0.37; 28.46; p=0.3).

Although consideration of the 95% C.I. indicates that a clinically relevant effect of ADT cannot be excluded, these results are compatible with a limited oncologic benefit of androgen deprivation therapy when administered in combination with radiotherapy for node-positive prostate cancer. Note that we do not claim that ADT increases the risk of cancer death but, rather, that the confidence interval for cancer-specific survival does not seem to include a clinically relevant effect. Since a clear survival benefit is necessary to justify the increased risk of death from other causes associated with ADT,5,7 caution should be paid in administering ADT to men with pN+ prostate cancer treated with postoperative radiotherapy. Awaiting confirmatory studies, our results suggest that a combination strategy should not be given outside well-controlled clinical trials. Note also that we are not making a general claim about the value of ADT in prostate cancer patients undergoing radiotherapy. ADT is of proven benefit for patients undergoing initial treatment by radiotherapy9 or in the case of salvage radiotherapy for patients with node-negative disease.10,11

If replicated, our results argue against current guidelines that recommend a combination of ADT and radiotherapy as a treatment option for node-positive disease.2,3 Rather, our findings support the inclusion of radiotherapy alone among postoperative strategies. It is well known that patients with nodal metastases have better prognosis than that of those who have bone or visceral metastases,12,13 suggesting that these are biologically different phases of tumor spread. For this reason, it is plausible that ADT might not be as effective in nodal metastases as it is for systemic disease. Having said that, while radiotherapy is a well-established treatment for node-positive disease after radical prostatectomy, there is currently no evidence supporting the addition of ADT to radiation therapy. Our findings have thus also implications for empirical research. The benefits and harms of ADT in combination with postoperative radiotherapy should be properly assessed (i.e. using the adequate reference group). In this regard, we call for randomized controlled trials testing radiotherapy vs. radiotherapy + ADT in patients with node-positive prostate cancer after radical prostatectomy.

Written by: Carlo Andrea Bravi, MD, Division of Oncology, Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy; Department of Epidemiology, & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA


References:

  1. Touijer K, Mazzola CR, Sjoberg DD, Scardino PT, Eastham JA. Long-term Outcomes of Patients with Lymph Node Metastasis Treated with Radical Prostatectomy Without Adjuvant Androgen- deprivation Therapy. European Urology. 2014;65(1):20-25. doi:10.1016/j.eururo.2013.03.053.
  2. Mottet N., Bellmunt J., Briers E., Bolla M., Bourke L., Cornford P., De Santis M., Henry a., Joniau S., Lam T., Mason M.D., Van Den Poel H., Van Den Kwast T.H., Rouvière O., Wiegel T.; Members of the EAU – ESTRO – ESUR –SIOG Prostate Cancer Guidelines Panel. EAU – ESTRO – ESUR – SIOG Guidelines on Prostate Cancer. Retrieved From: Https://Uroweb.org/Guideline/Prostate-Cancer/ Access Date [Insert Date the Information Was Accessed].
  3. NCCN Clinical Practice Guidelines in Oncology, Version 2018 - Prostate Cancer. August 2018:1-151.
  4. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate Hormonal Therapy Compared with Observation after Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer. N Engl J Med. 1999;341(24):1781-1788. doi:10.1056/NEJM199912093412401.
  5. Touijer KA, Karnes RJ, Passoni N, et al. Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies. European Urology. 2018;73(6):890-896. doi:10.1016/j.eururo.2017.09.027.
  6. Abdollah F, Karnes RJ, Suardi N, et al. Impact of Adjuvant Radiotherapy on Survival of Patients With Node-Positive Prostate Cancer. JCO. 2014;32(35):3939-3947. doi:10.1200/JCO.2013.54.7893.
  7. Allan CA, Collins VR, Frydenberg M, McLachlan RI, Matthiesson KL. Androgen deprivation therapy complications. Endocrine-Related Cancer. 2014;21(4):T119-T129. doi:10.1530/ERC-13-0467.
  8. Bravi CA, Tin A, Vertosick E, et al. Androgen deprivation therapy in men with node-positive prostate cancer treated with postoperative radiotherapy. Urologic Oncology: Seminars and Original Investigations. October 2019:1-6. doi:10.1016/j.urolonc.2019.09.018.
  9. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncology. 2010;11(11):1066-1073. doi:10.1016/S1470-2045(10)70223-0.
  10. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017;376(5):417-428. doi:10.1056/NEJMoa1607529.
  11. Carrie C, Magne N, Burban-Provost P, et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncology. October 2019:1-10. doi:10.1016/S1470-2045(19)30486-3.
  12. Moschini M, Sharma V, Zattoni F, et al. Natural History of Clinical Recurrence Patterns of Lymph Node–Positive Prostate Cancer After Radical Prostatectomy. European Urology. 2016;69(1):135-142. doi:10.1016/j.eururo.2015.03.036.
  13. Gandaglia G, Karakiewicz PI, Briganti A, et al. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. European Urology. 2015;68(2):325-334. doi:10.1016/j.eururo.2014.07.020.
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