AUA 2019: Radiation Therapy in 2019: Practice Changing Clinical Trials

Chicago, IL (UroToday.com) Radiation oncologist Dr. Dan Spratt provided an update of practice changing trials over the past year specific to patients with prostate cancer the International Prostate Forum at AUA 2019. 

The Scandinavian HYPO-RT-PC randomized controlled phase III trial was presented at ESTRO 2018 that randomized men with intermediate and high-risk prostate cancer to either conventional fractionating (n=602; 39 x 2.0 Gy) over eight weeks or ultrahypofractionated (n=598; 7 x 6.1 Gy) over 2.5 weeks. The primary endpoint was time to biochemical or clinical failure. Over a median follow-up time of 59.7 months there were 102 biochemical events in the conventional fractionation arms and 100 in the ultrahypofractionated arm. The number of patients biochemically free at 5 years was 83.8% in the conventional and 93.7% in the ultrahypofractionated arm; as such this technique was found to be non-inferior to conventional fractionation (HR 0.992, 95%CI 0.753-1.307). PACE-B is a phase III open-label multiple-cohort RCT randomizing men with localized prostate cancer to SBRT or conventionally fractionated or moderately hypofractionated external beam radiotherapy2. No patients received rectal spacers. By per protocol analysis 430 men received conventionally fractionated or moderately hypofractionated external beam radiotherapy and 414 men received SBRT. Toxicity results were presented at GU ASCO 2019, noting that RTOG G2+ toxicity was not significantly different for GI events nor GU events between the two groups. 

Several studies have also assessed optimizing ADT duration – prior standard ADT duration was 28-36 months when combined with radiotherapy for high-risk disease. The TROG RADAR trial assessed whether the addition of 12 months of adjuvant ADT, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of ADT and prostate radiotherapy3. In 2019, this trial reported 10-year outcomes from this trial. There were 1,071 patients randomized to radiotherapy plus 6 months of ADT or radiotherapy plus 18 months of ADT. This trial found that 18 months of ADT plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of ADT plus radiotherapy (sHR 0.70, 95%CI 0.50-0.98), but the addition of zoledronic acid to this treatment regimen is not beneficial. The PCS IV Trial randomized 630 patients with a median follow-up of 9.4 years to radiotherapy + 18 months of ADT or radiotherapy + 36 months of ADT5. The 5-yr OS rates were 91% for long term ADT arm (95%CI 88-95%) and 86% for short term ADT arm (95%CI 83-90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 months of ADT.

The benefit of adding chemotherapy in the treatment of very high-risk disease has also been evaluated over the past year. Rosenthal et al.5 published the multicenter randomized NRG Oncology RTOG 0521 study which enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned (n=563) to receive standard long-term ADT plus radiotherapy with or without adjuvant chemotherapy. Over a median follow-up of 5.7 years, the 4-year OS rate was 89% (95%CI, 84% to 92%) for ADT and radiotherapy, compared to 93% (95% CI, 90% to 96%) for ADT and radiotherapy plus chemotherapy (HR 0.69, 90%CI 0.49-0.97). Six-year rate of distant metastasis was 14% for ADT and radiotherapy and 9.1% for ADT and radiotherapy plus chemotherapy, (HR 0.60; 95%CI, 0.37-0.99). 

The much-anticipated NRG Oncology/RTOG 0534 SPPORT trial reported initial results at the 2019 ASTRO meeting6. This trial randomized 1,736 patients to either (i) salvage radiotherapy to the prostate bed, (ii) salvage radiotherapy to the prostate bed + ADT, or (iii) salvage radiotherapy to the prostate bed + ADT + radiotherapy to the pelvic lymph nodes. The 5-year freedom from progression rate was 71% for salvage radiotherapy to the prostate bed, 81% for salvage radiotherapy to the prostate bed + ADT, and 87% for salvage radiotherapy to the prostate bed + ADT + radiotherapy to the pelvic lymph nodes. Based on only 108 patients with metastasis, there was minimal differences between the three arms with regards to metastasis free survival. Dr. Spratt feels that with continued follow-up these results will likely favor salvage radiotherapy to the prostate bed + ADT + radiotherapy to the pelvic lymph nodes.

The SABR-COMET trial was published last month assessing SBRT to oligometastatic disease7. The objective of this study was to assess standard of care palliative treatments with or without SBRT in up to 5 metastatic lesions. The author’s hypothesis was that patients with oligometastatic disease will have improved outcomes with treatment of their metastatic sites. This study included any cancer (primarily breast, prostate, colorectal, and lung) who were then randomized 1:2 to standard of care vs standard of care + SBRT. Standard of care was at the discretion of the physician and the primary endpoint was OS. There were 99 patients at 10 centers and median follow-up was 25.5 months. Median OS was 28 months (95%CI 19-33) in the control group versus 41 months (26-not reached) in the SBRT group (HR 0.57, 95%CI 0.30-1.10; p =0.090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SBRT group (p=0.026), an absolute increase of 20% (95%CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after SBRT, compared with none in the control group. The authors concluded that SBRT was associated with a 13-month increase in OS and doubling of PFS.

The final trial Dr. Spratt discussed was STAMPEDE arm H, assessing efficacy of radiotherapy to the primary in M1 disease8. This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) vs standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95%CI 0.68-0.84) but not OS (0.92, 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95%CI 0.52-0.90). 

Dr. Spratt concluded with several thoughts, specifically to treatment of the primary in M1 disease as there are open ended questions:
  • Further benefit in the context of better systemic therapy (abiraterone)? – the PEACE I RCT is accruing and maturing
  • Is there benefit from treatment of oligometastatic sites? This is presumed from the STAMPEDE Arm M and subset of SWOG 1802
  • Is there benefit from surgery? This is currently being tested in SOWG 1802 and Trombone
  • Is there benefit of dose intensified radiotherapy? 
  • Is there a role of molecular imaging? 
Dr. Spratt heeds that we must enroll on clinical trials to answer these important questions. 

Presented by: Daniel Spratt, MD, University of Michigan, Ann Arbor, MI

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia @zklaassen_md at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois

References:
  1. Widmark A, Gunniagsson A, Beckman L, et al. OC-0599 Ultrahypofractionation of prostate cancer: Outcome from the Scandinavian phase 3 HYPO-RT-PC trial. ESTRO 2018. 
  2. Van As NJ, Brand D, Tree A, et al. PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa). J Clin Oncol 37, no.7_suppl (March 1, 2019). 
  3. Denham JW, Joseph D, Lamb DS, et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomized, phase 3, factorial trial. Lancet Oncol 2019 Feb;20(2):267-281.
  4. Nabid A, Carrier N, Martin AG, et al. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol 2018 Oct;74(4):432-441.
  5. Rosenthal SA, Hu C, Sartor O, et al. Effect of Chemotherapy with Docetaxel with Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial. J Clin Oncol 2019 Mar 12:JCO1802158.
  6. Pollack A, Karrison TG, Balogh Jr. AG, et al. LBA5 - Short term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial. ASTRO 2019.
  7. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomized, phase 2, open-label trial. Lancet 2019 Apr 10 [Epub ahead of print].
  8. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomized controlled phase 3 trial. Lancet 2018 Dec 1;392(10162):2353-2366.
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