(UroToday.com) The 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting included a Prostate Cancer Oligometastases session and a presentation by Dr. Ryan Phillips discussing where to focus the beam for treating newly diagnosed oligometastatic prostate cancer.
Dr. Phillips started his presentation with a case of a 69-year-old man with a medical history of insulin-dependent diabetes, hypertension, hypercholesterolemia, with no prior abdominal surgery who presented to his PCP for his annual visit. On review of systems, he had a mildly weak urinary stream, mild urinary urgency, erectile dysfunction, and chronic constipation. His digital rectal examination showed no palpable irregularity, and his most recent PSA was 2.1 ng/mL in 2016. At his PCP visit, his PSA was rechecked and noted to be 350 ng/mL, and subsequent TRUS-guided biopsy showed 4+5 disease in 20% of 1/12 cores, 4+4 in 20% of 1/12 cores, and 4+3 in 75% of 1/12 cores. A CT of the abdomen and pelvis showed a 2.2 x 1.9 cm right obturator node and a 1.4 x 1.3 cm left external iliac node, while his bone scan was highly suspicious for metastatic disease in the sacrum and right pubis:
Based on work from Guckenberger et al1 the European Society for Radiotherapy and Oncology (ESRO) and European Organization for Research and Treatment of Cancer (EORTC) consensus recommendation for the characterization and classification of oligometastatic disease is as follows:
Beyond ADT, the first option available was docetaxel based on the CHAARTED study.2 This trial randomized 790 men with metastatic hormone sensitive prostate cancer to receive either ADT + docetaxel (75 mg/m2 every 3 weeks for six cycles) or ADT alone, with OS as an endpoint. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT + docetaxel than with ADT alone (57.6 months vs. 44.0 months; HR 0.61; 95%CI 0.47-0.80). Furthermore, the median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the ADT + docetaxel group, as compared with 11.7 months in the ADT-alone group (HR 0.61, 95%CI 0.51-0.72). This trial ushered into clinical practice ADT + docetaxel E as standard of care for men with metastatic hormone sensitive prostate cancer.
Currently, the metastatic hormone sensitive prostate cancer disease space, with regards to systemic therapy, looks as follows:
For local treatment of the primary tumor, Dr. Phillips notes that the STAMPEDE arm H clinical trial assessed the efficacy of radiotherapy to the primary in M1 disease.3 This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus 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 (HR 0.92, 95% CI 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):
With regards to radiation to the metastatic lesions, the SABR-COMET provides evidence of utility and survival advantage. This randomized, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia that randomized 99 patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus stereotactic body radiotherapy to all metastatic lesions (SABR group).4 Over a median follow-up was 25 months (IQR 19-54) in the control group versus 26 months (23-37) in the SABR group, median overall survival was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the SABR group (HR 0.57, 95% CI 0.30-1.10; p=0.090). Recently published long-term outcomes of this trial showed durable findings.5 Over a median follow-up of 51 months, the 5-year OS rate was 17.7% in the control group (95% CI 6% to 34%) versus 42.3% in SABR group (95% CI 28% to 56%; stratified log-rank p = 0.006), and the 5-year PFS rate was not reached in the control group (3.2%; 95% CI 0% to 14% at 4 years with last patient censored) and 17.3% in the SABR group (95% CI 8% to 30%; p = 0.001):
Taking a “total eradication therapy” approach, Reyes et al.6 prospectively followed 12 men with newly diagnosed prostate cancer with <= 5 metastases. These patients were sequentially treated with neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiotherapy to the prostate bed/pelvis, SABR to the metastases, and adjuvant ADT. At 1 year, the undetectable PSA rate was 100%, at 2 years was 83%, and at 3 years was 67%. Furthermore, all patients experienced a return to normal testosterone level, and no patients developed castrate resistance.
Among 37 patients at the University of Rome with newly diagnosed prostate cancer and <5 metastases, these patients received 25 fractions simultaneous integrated boost approach including 6875 cGy to the prostate, 5500-6875 cGy to the seminal vesicles, 4500 cGy to the pelvis, 5500-6000 cGy to involved nodes, and 4500-5500 cGy to bone metastases (extrapelvic lesions treated with SBRT).7 The 2-year OS rate was 96.9% and the 5-year OS rate was 65.4%. At San Raffaele in Milan, Deantoni et al.  retrospectively analyzed 39 patients with bone-only synchronous oligometastatic prostate cancer (<=2 metastases), treating them with 28 fraction simultaneous integrated boost of 7420 cGy to the prostate, 5180 cGy to the pelvis/para-aortic nodes, and 4000-5000 cGy EGD2 to osseous lesions. The median duration of ADT was 44.8 months, and the outcomes at four years included a biochemical recurrence free survival rate of 53.3%, clinical recurrence free survival rate of 65.7%, a freedom from distant metastases rate of 73.4%, and overall survival rate of 82.4%.
Back to the clinical case presented at the beginning of the presentation, Dr. Phillips notes that this patient was initiated on Day 0 with leuprolide and bicalutamide followed by a consultation at the Mayo Clinic on Day 30, transitioning bicalutamide to enzalutamide on Day 34, and starting radiotherapy on Day 50. With regards to common dosing regimens, Dr. Phillips highlighted the following:
- Primary tumor only (ie. STAMPEDE Arm H): 5500 cGy in 20 once daily fractions or 3600 cGy in 6 once weekly fractions
- Simultaneous integrated boost approach (in 25-28 fractions): 6875-7420 cGy to the prostate, 4500-5180 cGy to elective nodes, and 4500-5850 cGy to involved nodes and bone lesions
- SABR to isolated metastases: 2000-2400 cGy in one fraction or 3000 cGy in 3 fractions
Dr. Phillips emphasized that there are several unanswered questions in this disease space:
- Will prostate radiation continue to show benefit for low volume metastatic disease in conjunction with advanced systemic therapies?
- Does metastasis-directed therapy truly add value to prostate-only radiation?
- Is involved node radiation sufficient?
- Do SABR and moderate hypofractionation produce different effects?
- Can biomarkers or molecular imaging better define oligometastasis?
Dr. Phillips concluded his presentation of treating newly diagnosed oligometastatic prostate cancer with the following take-home messages:
- Systemic therapy remains standard for metastatic prostate cancer and low-volume patients may benefit from advanced systemic therapy
- Treatment of the prostate in addition to ADT is safe and may improve overall survival in prostate cancer patients with low metastatic burden
- Metastasis-directed therapy may add value in the setting of a controlled primary tumor
- Evidence for the best treatment of synchronous metastatic prostate cancer is limited and many questions remain
Presented by: Ryan Phillips, MD, PhD, Department of Radiation Oncology, Mayo Clinic, Rochester, MN
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.
- Guckenberger M, Lievens Y, Bouma AB, et al. Characterization and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organization for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21:e18-e28.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
- 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 May 18;393(10185):2051-2058.
- Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020 Sep 1;38(25):2830-2838.
- Reyes DK, Rowe SP, Schaeffer EM, et al. Multidisciplinary total eradication therapy (TET) in men with newly diagnosed oligometastatic prostate cancer. Med Oncol. 2020 Jun 10;37(7):60.
- Reverberi C, Massaro M, Osti MF, et al. Local and metastatic curative radiotherapy in patients with de novo oligometastatic prostate cancer. Sci Rep. 2020 Oct 15;10(1):17471.
- Deantoni CL, Fodor A, Cozzarini C, et al. Prostate cancer with low burden skeletal disease at diagnosis: Outcome of concomitant radiotherapy on primary tumor and metastases. Br J Radiol. 2020 Apr;93(1108):20190353.