RADICALS-RT compared efficacy and safety of ADJUVANT RT VERSUS AN OBSERVATION policy with salvage RT for prostate-specific antigen (PSA) failure.

RADICALS-RT compared efficacy and safety of ADJUVANT RT VERSUS AN OBSERVATION policy with salvage RT for prostate-specific antigen (PSA) failure.

1. Adverse Features? Salvage RT ? PSA Failure? Adjuvant RT?

2. The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been UNCERTAIN . RADICALS-RT compared ef fi cacy and safety of ADJUVANT RT VERSUS AN OBSERVATION policy with salvage RT for prostate-speci fi c antigen (PSA) failure.

3. Radical prostatectomy is a standard treatment for localized prostate cancer and may be followed by post-operative radiotherapy (RT) to the prostate bed. There has been uncertainty about the optimal timing of RT after radical prostatectomy. It is possible that Adjuvant RT might be more effective than a policy of salvage RT for recurrence. However, the salvage RT avoids unnecessary treatment of those cured by surgery alone and so may lead to less treatment-related morbidity. Adjuvant RT may be given early to those with no evidence of residual disease after surgery to reduce the risk of subsequent recurrence S alvage RT may be given later in the event of recurrent disease. SCHOOL OF THOUGHTS

4. Eligibility Criteria Patients with non-metastatic adenocarcinoma of the prostate, had undergone R adical Prostatectomy H ad post-operative PSA ~ 0.2 ng/ml and at least one Risk factor from the following: P athological T-stage 3 or 4 Gleason score 7-10 P ositive margins or Preoperative PSA ~ >10 ng/ml.

5. Radical Prostatectomy Within 22 weeks Adjuvant RT Close Observation Salvage RT PSA Failure ( i ) two consecutive rising PSA levels with a PSA of > 0.1 ng/ml, or (ii) three consecutive rising PSA levels Commenced within 2 months of randomization and within 26 weeks of radical prostatectomy Commenced within 2 months after PSA failure

6. Radical Prostatectomy (n = 1396) Within 22 weeks Adjuvant RT ( n = 697) Close Observation (n = 699) Salvage RT PSA Failure ( i ) two consecutive rising PSA levels with a PSA of > 0.1 ng/ml, or (ii) three consecutive rising PSA levels Commenced within 2 months of randomization and within 26 weeks of radical prostatectomy Commenced within 2 months after PSA failure Patients could also receive up to 2 years of hormone therapy (either a luteinizing hormone-releasing hormone (LHRH) analogue or bicalutamide 150 mg daily, starting before and continuing during and after their postoperative RT.

7. Assessment for ef fi cacy and adverse events Patients were seen by a site investigator every 4 months from randomization for 2 years then, 6-monthly until 5 years and Then, annually until 15 years. Clinician-reported data were collected at each follow-up visit on diarrhea , proctitis, cystitis, hematuria and urethral stricture

8. Outcome measures Primary Outcome: The primary outcome measure was freedom-from-distant-metastasis (FFDM) Distant metastasis could be bone, liver, lung, distant node or other metastasis, but did not include pelvic nodes Secondary Outcome B iochemical progression-free survival, initiation of non- protocol hormone therapy, treatment toxicity and patient reported outcomes. B iochemical progression-free survival was de fi ned as freedom from PSA ~ 0.4 ng/ml following postoperative RT, or PSA > 2.0 ng/ml at any time, or clinical progression, initiation of non-protocol hormone therapy or death from any cause.

9. Most participants allocated to the Adjuvant-RT Group began treatment, as planned, shortly after randomization. Ninety-three percent (648/697) in the Adjuvant-RT Group reported starting RT within 6 months at a median of 4.9 months after prostatectomy. At the time of analysis, 39% (270/699) of the Salvage-RT Policy Group had now reported starting salvage RT following PSA failure. In these 270 participants, the median time from randomization to starting salvage RT was 1.5years and their median PSA level at the time of starting salvage RT was 0.2 ng/ml.

10. Result 6% (80/1396) Distant Mets/ death Adjuvant RT (32 patients) Salvage RT (48 patients ) Salvage RT complete (37 patients) PSA Failure but Salvage RT not received (7 patients) occurred in the absence of reported PSA failure (4 patients)

11. Result 6% (80/1396) Distant Mets/ death Adjuvant RT (28 patients) Salvage RT (35 patients ) 63 patients had Distant Metastasis but Alive Remaining 17, 4 in the Adjuvant-RT Group and 13 in the Salvage-RT Policy Group reported metastasis followed by death due to prostate cancer

12. The difference between randomized groups was not statistically significant [HR ~ 0.681] for the Adjuvant-RT Group

13. Secondary outcome measures When Trial was stopped, 109/1396 patients had died Adjuvant RT 52 patients Salvage RT 57 patients The difference between groups was not statistically signi fi cant, HR ~ 0.980 for adjuvant treatment Only 17 deaths were directly attributed to prostate cancer d 4 in the Adjuvant-RT Group and 13 in the Salvage-RT Policy Group

14. The difference between groups was not statistically significant, HR ~ 0.980 for adjuvant treatment

15. N o difference in bPFS between randomized groups after a median 7.8 years of follow-up. HR ~ 0.972 for Adjuvant-RT

16. Non-protocol hormone therapy was initiated by 134 participants during follow-up, 59 in the Adjuvant-RT Group and 75 in the Salvage-RT Policy Group. The difference between groups was not statistically significant, HR ~ 0.832 for Adjuvant-RT

17. Toxicities Toxicity was more commonly-reported in the Adjuvant-RT Group, mainly a result of more grade 1 or 2 events, with late toxicity remaining signi fi cantly higher

18. From patient-reported outcome measures, the Adjuvant-RT Group reported signi fi cantly worse incontinence 1 year after randomization ( P = 0.001), but the evidence of difference lessened at later points. Faecal incontinence was was statistically signi fi cantly worse after 1 year in the Adjuvant-RT Group ( P < 0.001), and was also statistically signi fi cantly different in participants with an assessment at 10 years after randomization ( P = 0.017)

19. Conclusion

20. Thank you

21. Radiation Therapy Oncology Group (RTOG) toxicity score