Many patients diagnosed with localized prostate cancer will undergo primary therapy with radical prostatectomy. An estimated 25% to 40% of such patients will eventually experience biochemical recurrence (BCR) by 10 years after primary therapy.1,2 Postprostatectomy patients with BCR may be offered salvage radiation therapy if they have a rising detectable prostate-specific antigen (PSA) level and no radiographic evidence of nodal or metastatic disease. At the American Society for Radiation Oncology (ASTRO) 2022 meeting, several authors presented abstracts on the topic of postprostatectomy radiation that are worth reviewing.
The NRG Oncology Group presented a timely abstract article entitled “The Influence of Pelvic Node Dissection Volumes on Clinical Outcomes in NRG/RTOG 0534.” RTOG 0534 was a phase 3 randomized, multicenter, clinical trial investigating the role of short-term androgen-deprivation therapy (ADT) or lymph node radiation therapy in treatment of patients receiving salvage prostate bed radiation therapy for BCR.3
RTOG 0534 Enrollment
Between March 2008 and March 2015, the authors of the study enrolled 1792 patients into 3 arms: prostate bed radiation alone (arm 1; control), prostate bed radiation plus short-term ADT (arm 2), and prostate bed radiation plus short-term ADT and lymph node radiation (arm 3). At the interim analysis, results reported in The Lancet demonstrated that addition of short-term radiation and pelvic lymph node radiation to prostate bed radiation improved 5-year freedom from progression compared with prostate bed radiation alone (P<0.0001). At ASTRO 2022, William A. Hall, MD, addressed another observation of this trial—the high variation in pelvic lymph node dissection volumes at the time of radical prostatectomy.
According to Dr. Hall, it has often been hypothesized that the volume of lymph nodes removed at the time of prostatectomy may affect the benefit the patient would receive from pelvic lymph node radiation. The rationale is that patients who have more lymph nodes removed would be more accurately staged and have less lymph node volume to benefit from radiation. However, this has not been corroborated by data. In each of the 3 arms of the RTOG 0534 trial, patients had a mean range of 4.4 to 4.8 lymph nodes at the time of prostatectomy, indicating relative similarity between the cohorts.
However, Dr. Hall also noted that a sizable portion of patients had no nodes removed (37%). In the abstract presented at ASTRO, the NRG group sought to evaluate the influence of pelvic lymph node dissection volumes on clinical outcomes.4 The primary outcomes of interest were freedom from progression, evaluation of toxicity, and development of distant metastatic disease. Using data from RTOG 0534, the authors constructed multivariable Cox proportional hazard models to evaluate these outcomes with dissection of 0 to 1 lymph nodes versus dissection of ≥2 nodes.
High Gleason Scores and Effect on Lymph Nodes
Descriptive analytics of the study population revealed some interesting trends. Dr. Hall remarked that patients with higher Gleason grade scores tended to have greater numbers of lymph nodes resected (Gleason grade 7; 66% of patients ≥2 lymph nodes). Additionally, patients with higher stage disease (cT3) and seminal vesicle involvement had higher rates of more aggressive lymph node dissection. Interestingly, patients who received pelvic lymph node dissection at academic centers had higher rates of more aggressive lymph node dissection (≥2 lymph nodes; 84.4%) compared with those treated at community hospitals (15.6%).
The hazard models produced by the authors demonstrated that when comparing arm 1 and arm 3 for patients with ≥2 lymph nodes resected, there was 140% benefit (hazard ratio [HR], 2.4 in arm 1 vs 1.8-3.19 in arm 3), demonstrating that the volume of original lymph node dissection does not appear to affect the therapeutic potential of lymph node radiation. Conducting the same analysis for development of distant metastases, the authors demonstrated that patients with 0 to 1 lymph nodes resected received the greatest oncologic benefit from addition of short-term ADT and lymph node radiation, and the benefit decreased linearly as the number of nodes dissected increased.
In concluding remarks, Dr. Hall summarized that for freedom from disease progression, no difference was seen between arm 2 and arm 3, but the results also suggested that patients with larger quantities of lymph nodes resected at prostatectomy may benefit more from lymph node radiation. Regarding development of distant metastasis, the multivariate analysis suggested that patients with ≥2 lymph nodes removed did not benefit from pelvic lymph node radiation.
A second interesting phase 2 trial on the topic of postprostatectomy radiation therapy investigated the role of enzalutamide in salvage radiation therapy after radical prostatectomy. Phuoc Tran, MD, PhD, presented results from the SALV-ENZA trial, a phase 2 randomized trial of salvage radiation therapy plus either enzalutamide or placebo in high-risk patients with PSA recurrence after radical prostatectomy for prostate cancer.5 Enzalutamide is a third-generation nonsteroidal androgen receptor antagonist approved for use in patients with metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer. There has been widespread interest in employing enzalutamide in other clinical scenarios such as BCR, which the SALV-ENZA trial intends to investigate.
Dr. Tran remarked that several trials have demonstrated the benefit of adding ADT to salvage radiation therapy for patients with BCR; however, ADT is not benign. He explained that patients receiving ADT often experience several adverse events, including metabolic syndrome, erectile dysfunction, lower quality of life, and decreases in bone mineral density. In comparison, Dr. Tran explained that patients receiving enzalutamide in this setting have stable rates of bone mineral density, improved quality of life, and stable metabolic profiles. Therefore, the authors of the trial made the case that enzalutamide, when compared with traditional ADT, may be better for patients undergoing salvage radiation therapy for BCR after prostatectomy.
Comparing Enzalutamide and ADT
The authors enrolled 86 patients (162 screened) who had received prostatectomy for high-risk prostate cancer and had experienced evidence of recurrence. Specifically, patients enrolled had either Gleason grade 7 disease with an advanced clinical stage (cT3 or positive margins) or Gleason grade 8 to 10 disease. Patients were randomized into 2 arms of salvage radiation plus placebo or salvage radiation plus enzalutamide. The primary endpoint sought by the trial was freedom from PSA progression.
Dr. Tran depicted the results of the trial on a Kaplan-Meier curve showing the probability of freedom from PSA progression. Overall, patients in the experimental (enzalutamide) arm demonstrated significant (58%) benefit regarding freedom from PSA progression compared with those who received placebo (HR, 0.42; P=0.027). Furthermore, Dr. Tran remarked that at 24 months, there was an 18% difference in freedom from PSA progression between the 2 arms.
The subcohort analysis also demonstrated interesting results. Dr. Tran remarked that patients with positive margins and T3 disease likely received the most benefit. The subcohort analysis also showed that nearly all patients benefited to some extent, with most HRs between 0.25 to 0.90. In terms of the toxicity profile with addition of enzalutamide, Dr Tran remarked that, overall, the therapy was well tolerated with few grade 3 complications (3 total). Most toxicity was grade 1 to 2, with 18.7% of patients experiencing nausea and 25.6% experiencing breast pain and tenderness.
In concluding, Dr. Tran noted that one of the limitations of the SALV-ENZA trial was the use of freedom from PSA progression instead of overall survival (OS) as an endpoint, and stated that future studies must address OS. He also remarked that the data provided in this phase 2 trial give credence to the utility of enzalutamide monotherapy with salvage radiation therapy for BCR in patients after radical prostatectomy. He emphasized that the phase 2 data are promising, and the benefit should be further explored in a phase 3 trial.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
References
- Roehl KA, Han M, Ramos CG, Antenor JAV, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004;172(3):910-914. doi: 10.1097/01. ju.0000134888.22332.bb
- Lee EK, Thrasher JB. Management strategies for biochemical recurrence of prostate cancer. In: Partin AW, Dmochowski RR, Kavoussi LR, Peters CA, Wein A, eds. Campbell-Walsh-Wein Urology, 12th ed. Philadelphia: Elsevier; 2020:chapter 160, pp 3659-3670.e4.
- Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/ RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial. Lancet. 2022;399(10338):1886-1901. doi: 10.1016/S0140-6736(21)01790-6
- Hall WA, Pugh S, Pollack A, et al. The Influence of Pelvic Lymph Node Dissection Volumes on Clinical Outcomes in NRG/RTOG 0534. Int J Radiat Oncol Biol Phys. 2022;114(3 suppl):S36. Abstract 158. doi: 10.1016/j.ijrobp.2022.07.396
- Tran PT, Lowe K, Wang H, et al. Phase II Randomized Study of Salvage Radiation Therapy (SRT) plus Enzalutamide or Blinded Placebo for High-Risk PSA-Recurrent Prostate Cancer after Radical Prostatectomy: The SALV-ENZA Trial. Int J Radiat Oncol Biol Phys. 2022;114(3 suppl):S37. Abstract 159. doi: 10.1016/j.ijrobp.2022.07.397
