(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) held in Lugano, Switzerland between April 25th and 27th was host to a high-risk and locally advanced prostate cancer session. Dr. Neha Vapiwala discussed contemporary radiotherapy schedules and target fields for patients with high-risk and locally advanced prostate cancer.
Dr. Vapiwala noted that standard fractionation refers to the delivery of 1.8–2 Gy of radiotherapy per fraction, whereas moderate and ultrahypofractionation refer to doses of 2.5–3.5 Gy/fraction and >5 Gy/fraction, respectively.
Current evidence suggests that dose escalation is associated with improved outcomes, namely biochemical progression-free and distant metastasis-free survivals, among prostate cancer patients receiving external beam radiotherapy. The recently presented GETUG-AFU 18 trial demonstrated that modern dose-escalated external beam radiotherapy improves progression-free, cancer-specific, and overall survivals in combination with long-term ADT. 
Why is there increased interest in delivering higher doses of radiation in less fractions (i.e., moderate and ultrahypofractionation)? Alpha/beta ratio indicates how resistant a cell is to radiation damage. Prostate cancer cells have low alpha/beta ratios and, as demonstrated in the linear quadratic model curve below, are more sensitive to higher doses per fraction.
The safety analyses of the Prostate Cancer Study-5, a non-inferiority phase III trial of standard fractionation versus hypofractionation in high-risk patients receiving dose-escalated external beam radiotherapy + long-term ADT, were recently published. The investigators demonstrated that moderately hypofractionated radiotherapy is well-tolerated and a viable alternative to standard hypofractionation for high-risk patients with prostate cancer treated with long-term ADT plus pelvic radiotherapy.1
What about ultrahypofractionation via stereotactic body radiotherapy, which allows for the safe delivery of a higher dose in fewer fractions and thus a shorter period? This approach should theoretically allow for an escalated target dose while sparing normal tissue via tight margins and steep gradients.
A SHARP (Stereotactic Body Radiotherapy [SBRT] for High-Risk Localized Carcinoma of the Prostate) Consortium analysis of 344 prospectively treated high-risk patients demonstrated that SBRT combined with ADT is associated with 4-year biochemical recurrence-free survival and distant metastases-free survival rates of 82% and 89%, respectively. The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%. As such, these data support a favorable toxicity and efficacy profile for SBRT for high-risk prostate cancer patients.2 Accordingly, the NCCN states that: "SBRT is acceptable for the treatment of primary prostate cancer across all risk groups & for locoregional &/or distant metastases in practices with appropriate technology and expertise”.
Another technique that allows for a boost/dose escalation is brachytherapy, which allows for the delivery of more radiotherapy in less time leading to direct and efficient dose escalation to the gland. The ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) trial randomized NCCN intermediate- and high-risk prostate cancer patients to low-dose-rate brachytherapy boost or dose-escalated external beam boost. All patients received 1 year of ADT and 46 Gy in 23 fractions of pelvic radiotherapy. Patients in the dose-escalated external beam radiotherapy arm received an additional 32 Gy in 16 fractions, and those in the brachytherapy arm received a 125I implant prescribed to a minimum peripheral dose of 115 Gy. At a median follow-up of 6.5 years, low-dose-rate brachytherapy improved biochemical control at the cost of worse late genitourinary toxicity. At the updated 10-year follow-up analysis, there were no observed differences in distant metastases-free and overall survivals.3
Dr. Vapiwala noted that high-dose-rate (HDR) brachytherapy is more commonly utilized in clinical practice. A randomized phase III trial compared external beam radiotherapy +/- HDR brachytherapy boost in patients with localized prostate cancer. The median time to relapse was 137 months in the HDR brachytherapy boost arm compared to 82 months for external beam radiotherapy alone (p = 0·01). A 27% risk of recurrence with external beam radiotherapy alone was observed (p = 0·001), resulting in a 21% improvement in recurrence-free survival at 12 years with external beam radiotherapy + HDR brachytherapy boost. To date, there are no significant differences in overall survival.4
An emerging tool in this space is ‘microboost’ using imaging-enabled dose escalation for the dominant intraprostatic lesion using mpMRI or PSMA PET/MRI guidance. The FLAME (Focal Lesion Ablative Microboost in Prostate Cancer) trial enrolled 571 patients with intermediate/high-risk disease planned for prostate radiotherapy without elective nodal radiotherapy (65% received neoadjuvant ADT). These patients received 77/2.2 Gy + /- focal simultaneous integrated boost to the dominant intraprostatic lesions with doses up to 95/2.7 Gy. This focal boost decreased both local and regional + distal failure rates.
Dr. Vapiwala highlighted numerous ongoing trials evaluating the use of SBRT to allow for an additional ‘micro’ boost, as summarized in the slide below:
What about the role of elective pelvic nodal radiotherapy? This has been a subject of significant debate over the past years with two notable trials attempting to address this question: NRG Oncology/RTOG 9413 and POP-RT.5,6
The NRG Oncology/RTOG 9413 trial was a 2 x 2 factorial study that evaluated the role of whole pelvic radiotherapy (versus prostate only) and timing of hormone therapy (neoadjuvant versus adjuvant). This phase III trial randomized 1,322 patients with prostate cancer who had an estimated risk of lymph node involvement of at least 15% in a 1:1:1:1 fashion to one of four treatment arms: whole pelvic radiotherapy plus neoadjuvant hormone suppression, prostate-only radiotherapy plus neoadjuvant hormone suppression, whole pelvic radiotherapy plus adjuvant hormone suppression, and prostate only radiotherapy plus adjuvant hormone suppression. Neoadjuvant ADT was initiated two months before radiotherapy and was continued until radiotherapy completion, whereas adjuvant androgen deprivation therapy was given at the completion of radiotherapy for 4 months. The pelvic radiation dose was 70 Gy. Updated 10-year results were published in Lancet Oncology in 2018 with a median follow-up of 8.8 years. Progression-free survival across all time points differed significantly across the four treatment groups (p = 0.002). The 10-year progression-free survival estimate was 28.4% in the whole pelvic irradiation + neoadjuvant hormone arm compared to 23.5% for the prostate-only radiotherapy + neoadjuvant arm, 19.4% in the whole pelvic irradiation + adjuvant arm, and 30.2% in the prostate-only radiotherapy + adjuvant arm:
There were no significant differences in grade 3 or worse late bladder toxicities between the four arms, however, late grade 3 or worse gastrointestinal adverse events occurred in 7% of patients in the whole pelvis + neoadjuvant arm compared to 2-3% in the other arms.5
POP-RT was a phase III trial that randomized 224 prostate cancer patients with clinically node-negative disease and an estimated nodal risk ≥ 20% to either prostate-only radiation therapy (68 Gy in 25 fractions) or whole pelvic radiotherapy (68 Gy in 25 fractions to the prostate plus 50 Gy to the pelvic nodes, including common iliac). All patients received image-guided, intensity-modulated radiotherapy and a minimum of two years of androgen deprivation therapy. The primary endpoint was 5-year biochemical failure-free survival. Over a median follow-up of 68 months, the 5-year biochemical failure-free survival was superior in the whole pelvis arm (95% versus 81.2%; HR: 0.23; p < 0.001), as were 5-year disease-free (89.5% versus 77.2%; HR: 0.40, p = 0.002) and distant metastasis-free survivals (95.9% versus 89.2%; HR: 0.35, p = 0.01). No significant differences in 5-year overall survival rates were noted (92.5% versus 90.8%, HR: 0.92, p = 0.93):6
There appears to be a benefit for radiotherapy in patients with clinical node-positive prostate cancer. Various US retrospective series have demonstrated an overall survival benefit to the addition of radiotherapy to ADT. In a STAMPEDE exploratory multivariate analysis of radiotherapy impact, James et al. demonstrated that addition of whole pelvic radiotherapy improved 5-year failure-free survival from 71% to 82% in 177 patients with cN+M0 disease.7
Finally, Dr. Vapiwala noted that the use of radiotherapy for PET-detected nodal oligorecurrences is an emerging field. PEACE V- STORM (Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases) is a phase II randomized superiority trial of metastasis-directed therapy (lymph node dissection or SBRT) with or without elective nodal pelvic radiotherapy. In the analysis of acute toxicity data published in 2023, there were no clinically meaningful differences observed in worst grade ≥2 acute gastrointestinal or genitourinary toxicity or in quality of life subdomains between metastasis-directed therapy and elective nodal pelvic radiotherapy.8 The OLIGOPELVIS-GETUG P07 single arm phase II trial of 6 months ADT + pelvic radiotherapy with simultaneous integrated boost to PET-positive nodes demonstrated 2- and 3-year progression-free survival rates of 81% and 58%, with a median progression-free survival of 45.3 months. The 2-year grade ≥2 genitourinary and gastrointestinal toxicities were 10% and 2%, respectively.9
Presented by: Neha Vapiwala, MD, FACR, FASTRO, FASCO, Professor, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
Written by: Rashid Sayyid, MD, MSc - Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference, Lugano, Switzerland, April 25th - April 27th, 2024
Related content: Hypofractionation in Prostate Cancer Radiotherapy: Balancing Efficacy and Safety - Neha Vapiwala
References:
- Niazi T, Nabid A, Malagon T, et al. Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial. Int J Radiat Oncol Biol Phys. 2024;118(1): 52-62.
- Van Dams R, Jiang NY, Fuller DB, et al. Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients. Int J Radiat Oncol Biol Phys. 2021;110(3): 731-7.
- Oh J, Tyldesley S, Pai H, et al. An Updated Analysis of the Survival Endpoints of ASCENDE-RT. Int J Radiat Oncol Biol Phys. 2023;115(5): 1061-70.
- Hoskin PJ, Rojas AM, Ostler PJ, Bryant L, Lowe GJ. Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results. Radiother Oncol. 2021:154: 214-9.
- Roach M, Moughan J, Lawton CA, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1504-1515.
- Murthy V, Maitre P, Kannan S, et al. 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. J Clin Oncol. 2021;39(11):1234-42.
- James ND, Spears MR, Clarke NW, et al. Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial. JAMA Oncol. 2016;2(3): 348-57.
- Ost P, Siva S, Brabrand S, et al. PEACE V—Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): Acute Toxicity of a Randomized Phase 2 Trial. Eur Urol Oncol. 2023; S2588-9311(23)00199-2.
- Supiot S, Vaugier L, Pasquier D, et al. OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer. Eur Urol. 2021;80(4): 405-14.