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Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from phase III randomized controlled trial

  • Vedang Murthy,
  • Priyamvada Maitre,
  • Sadhana Kannan,
  • Gitanjali Panigrahi,
  • Rahul Krishnatry,
  • Ganesh Bakshi,
  • Gagan Prakash,
  • Mahendra Pal,
  • Santosh Menon,
  • Reena Phurailatpam,
  • Smruti Mokal,
  • Dipika Chaurasiya,
  • Palak Popat,
  • Nilesh Sable,
  • Archi Agarwal,
  • Venkatesh Rangarajan,
  • Amit Joshi,
  • Vanita Noronha,
  • Kumar Prabhash,
  • Umesh Mahantshetty

Publication: Journal of Clinical Oncology, January 2021

Purpose
We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer.

Methods
This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk ≥ 20%. Randomization was 1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and secondary end points were disease-free survival (DFS) and overall survival (OS).

Results
From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT = 114, WPRT = 110). At a median follow-up of 68 months, 36 biochemical failures (PORT = 25, WPRT = 7) and 24 deaths (PORT = 13, WPRT = 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to 0.52; P < .0001). WPRT also showed higher 5-year DFS (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P = .002), but 5-year OS did not appear to differ (92.5% v 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; P = .83). Distant metastasis-free survival was also higher with WPRT (95.9% v 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; P = .01). Benefit in BFFS and DFS was maintained across prognostic subgroups.

Conclusion
Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and DFS as compared with PORT, but OS did not appear to differ.

Commentary by Dr. Roderick van den Bergh

It is unknown whether treating regional lymph nodes is beneficial to prostate cancer patients, and, if so, which patients have most to gain. The POP-RT study randomised patients planned for ADT (two years) and image-guided intensity-modulated radiotherapy to the prostate (68 Gy) to receive or not to receive radiotherapy of pelvic lymph nodes (50 Gy). The 224 participants had a >20% risk of pathological lymph node involvement (Roach formula) and negative imaging (rN0) for lymph node involvement (modern imaging with a PSMA-PET/CT was used for 80%). Overall, the group carried a high to very high risk; median PSA was 28, 50% had ISUP GG 4-5, and almost half had pT3b-4 disease.

In total, the number of patients with biochemical failure was low (36 events). The biochemical failure-free survival was 90.0% in patients who had received radiation to both the prostate and pelvis, versus 81.2% in the prostate-only arm (p<0.0001). Events started to occur and diverge 2-3 years after initiation of treatment, corresponding to the wearing-off of the effect of hormonal therapy. Disease-free survival was also in favour of prostate plus pelvic radiation (89.5% vs 77.2%; p 0.002), as well as metastasis-free survival (95.9% vs 89.2%; p 0.01). Recurrences occurred in regional lymph nodes in 50% of the patients who had received prostate-only radiation, in comparison with only 1 out of 8 of the patients who had received prostate plus pelvic radiation. Statistically, the overall survival was not significantly different, though in favour of prostate and pelvis (92.5% vs 90.8%). Late genitourinary toxicity was more than twice as frequent in the prostate plus pelvis group (20.0 vs 8.9%; p 0.02).

We can conclude that the high-risk patients included in the POP-RT study who were planned for ADT and radiation after high-standard imaging benefit from including the pelvic nodes in the radiation of the prostate. Earlier studies did not show these results, possibly due to inclusion of different risk groups, other radiotherapy techniques and fields, or different use of ADT schemes. The current study findings relate to the question whether treatment of pathologically involved pelvic lymph nodes (although not visible during imaging) could have a therapeutical effect. POP-RT clearly suggests that there is a therapeutical impact on the microscopically involved nodes. Men who have the highest risk of microscopically involved nodes are those who harbour aggressive tumour parameters while distant metastasis (M+ disease) is excluded using the best available imaging. Future research will address the question how these modern imaging techniques (PSMA-PET/CT) may improve the indication for treatment (either by using radiation or surgical dissection) of the pelvic lymph nodes in a multivariable approach. Also, it remains unknown whether nodes not visualised during imaging at diagnosis can be treated later after being visualised.

The discussion on the benefit of treatment of lymph nodes in prostate cancer patients should not be settled by abandoning it but by improving patient selection and radiation and surgical techniques. POP-RT provides invaluable information in this urological puzzle.