Stereotactic Body Radiation Therapy to the Prostate Bed: Results of a Phase 1 Dose-Escalation Trial

doi:10.1016/j.ijrobp.2019.11.005

International Journal of Radiation OncologyBiologyPhysics

Volume 106, Issue 3, 1 March 2020, Pages 537-545

https://doi.org/10.1016/j.ijrobp.2019.11.005 Get rights and content

Purpose

The primary objectives of this study were to evaluate toxicity of escalating doses of prostate bed stereotactic body radiation therapy and to provide dose recommendations for a phase 2 study.

Methods and Materials

Patients with organ-confined, node-negative prostate cancer who had biochemical failure (prostate-specific antigen [PSA] less than 2.0) after prostatectomy were eligible for this phase 1 dose-escalation trial. Doses delivered were 35 Gy, 40 Gy, and 45 Gy in 5 fractions, given every other day. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events (version 4.0) grade 3 or higher gastrointestinal or genitourinary (GU) toxicity within 90 days of treatment. Maximum tolerated dose was the highest dose to be tested where fewer than 2 of the patients experienced DLT. Patients completed quality-of-life questionnaires at regular time intervals.

Results

Twenty-six patients completed treatment between October 2013 and December 2017. Three patients received 35 Gy, 8 patients received 40 Gy, and 15 patients received 45 Gy. The median follow-up was 60 months for 35 Gy, 48 months for 40 Gy, and 33 months for 45 Gy. No acute DLT events were observed. Late grade ≥2 and ≥3 gastrointestinal toxicity occurred in 11% and 0%, respectively, and late grade ≥2 and ≥3 GU toxicity occurred in 38% and 15%, respectively. No difference was observed in late GU toxicity between 40 Gy and 45 Gy. Sexual function scores were significantly lower in the patients receiving androgen deprivation therapy (P < .01). In all patients, the crude rate of PSA control (<0.2 ng/mL) was 11 out of 26 (42%).

Conclusions

Dose escalation to 45 Gy did not result in acute DLT events, had similar rates of late grade 3 toxicity, and did not demonstrate higher rates of PSA control, compared with 40 Gy. While allowing for higher plan heterogeneity, the recommended dose for phase 2 study will be 40 Gy in 5 fractions.

Introduction

Biochemical recurrence rates after radical prostatectomy in patients with prostate cancer with adverse pathologic features are approximately 50%.1, 2, 3 Salvage radiation therapy can yield a 5-year and 10-year biochemical progression-free survival rate of 63% and 50%, respectively.⁴ Radiobiological studies have suggested that prostate cancer cells may have higher sensitivity to higher doses per fraction (ie, larger than 2 Gy) and share similar response characteristics to normal “later-responding” tissues.⁵^,⁶ The parameter used to describe this phenomenon, known as the alpha/beta value, has been analyzed extensively using large volumes of clinical data. The consensus is that the alpha-beta value is approximately 1.5 to 2.0, supporting the development of hypofractionated dose protocols in the intact gland setting.5, 6, 7, 8

Stereotactic body radiation therapy (SBRT) employs even shorter treatment schedules over 1.5 weeks, with maturing outcome data demonstrating promising efficacy and toxicity in selected patients.9, 10, 11

Given the promising toxicity and outcome reports from SBRT as definitive therapy for intact disease, there is a motivation to explore a similar strategy to treat the prostate bed for patients experiencing biochemical recurrence after surgery. Therefore, we conducted a phase 1 dose escalation trial with 2 aims: (1) to identify the maximum tolerated dose of SBRT up to 45 Gy in 5 fractions and (2) to provide guidance for a recommended phase 2 dose.

Section snippets

Methods and Materials

This was a single-institution, prospective, phase 1 dose-escalation trial approved by the institutional review board and registered at clinicaltrials.gov with trial ID NCT01923506. Patients were required to provide written informed consent before enrollment. Patients having received radical prostatectomy for localized prostate cancer with pN0 status were eligible if they had either a rising prostate-specific antigen (PSA) after surgery up to a value of 2.0, pT3a-b disease, or positive margins.

Results

A total of 26 patients completed SBRT between October 2013 and December 2017. The median follow-up for all patients was 40 months, and by individual dose levels as follows: 60 months for L1, 48 months for L2, and 33 months for L3. A complete list of pretreatment characteristics is displayed in Table 1. Two patients (1 in L2, 1 in L3) had findings on staging MRI suspicious for local recurrence in the prostate bed. These were deemed too small for an ultrasound-guided biopsy.

Discussion

This phase 1 dose-escalation trial, to our knowledge the first of its kind in the postprostatectomy setting, was also the first to explore extreme hypofractionation to the prostate bed across all 3 dose levels. The acute side effect profile up to 45 Gy was very favorable using dose constraints similar to intact prostate SBRT. By having the longest-reported median follow-up, we describe several late grade 3 events and present early efficacy data using this technique.

Intact prostate SBRT is

Conclusions

To our knowledge, this is the first phase 1 dose-escalation trial using SBRT to the prostate bed and has the longest clinical follow-up. Although late GU toxicity was higher than anticipated, we will be incorporating additional dose constraints for the bladder, which will be expected to lower this rate. We will be using 40 Gy in 5 fractions in an upcoming single-arm phase 1/2 dose trial, which will also incorporate ADT and coverage of pelvic nodal basins. Both toxicity and efficacy data from

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Cited by (28)

Intra-fractional geometric and dose/volume metric variations of magnetic resonance imaging-guided stereotactic radiotherapy of prostate bed after radical prostatectomy
2024, Physics and Imaging in Radiation Oncology
Magnetic Resonance Imaging (MRI)-guided Stereotactic body radiotherapy (SBRT) treatment to prostate bed after radical prostatectomy has garnered growing interests. The aim of this study is to evaluate intra-fractional anatomic and dose/volume metric variations for patients receiving this treatment.
Nineteen patients who received 30–34 Gy in 5 fractions on a 0.35T MR-Linac were included. Pre- and post-treatment MRIs were acquired for each fraction (total of 75 fractions). The Clinical Target Volume (CTV), bladder, rectum, and rectal wall were contoured on all images. Volumetric changes, Hausdorff distance, Mean Distance to Agreement (MDA), and Dice similarity coefficient (DSC) for each structure were calculated. Median value and Interquartile range (IQR) were recorded. Changes in target coverage and Organ at Risk (OAR) constraints were compared and evaluated using Wilcoxon rank sum tests at a significant level of 0.05.
Bladder had the largest volumetric changes, with a median volume increase of 48.9 % (IQR 28.9–76.8 %) and a median MDA of 5.1 mm (IQR 3.4–7.1 mm). Intra-fractional CTV volume remained stable with a median volume change of 1.2 % (0.0–4.8 %). DSC was 0.97 (IQR 0.94–0.99). For the dose/volume metrics, there were no statistically significant changes observed except for an increase in bladder hotspot and a decrease of bladder V_32.5 Gy and mean dose. The CTV V_95% changed from 99.9 % (IQR 98.8–100 %) to 99.6 % (IQR 93.9–100 %).
Despite intra-fractional variations of OARs, CTV coverage remained stable during MRI-guided SBRT treatments for the prostate bed.
Toxicity profile and Patient-Reported outcomes following salvage Stereotactic Ablative Radiation Therapy to the prostate Bed: The POPART multicentric prospective study
2024, Clinical and Translational Radiation Oncology
While SBRT to the prostate has become a valuable option as a radical treatment, limited data support its use in the postoperative setting. Here, we report the updated results of the multicentric Post-Prostatectomy Ablative Radiation Therapy (POPART) trial, investigating possible predictors of toxicities and patient-reported outcomes.
Patients with PSA levels between 0.1–2.0 ng/mL after radical prostatectomy received Linac-based SBRT to the prostate bed in five fractions every other day for a total dose of 32.5 Gy (EQD2_1.5 = 74.3 Gy). Late toxicity was assessed using CTCAE v.5 scale, while EPIC-CP, ICIQ-SF, IIEF 5 questionnaires and PSA levels measured quality of life and biochemical control. Pre- and post-treatment scores were compared using a paired t-test, with MID established at > 0.5 pooled SD from the baseline. A logistic regression analysis was performed to evaluate potential associations between specific patient/tumor/treatment factors and outcome deterioration.
From April 2021 to April 2023 a total of 50 pts were enrolled and treated. Median follow-up was 12.2 (3–27) months. No late ≥ G2 GI or GU toxicity was registered. Late G1 urinary and rectal toxicities occurred in 46 % and 4 % of patients, respectively. Among 47 patients completing all EPIC-CP domains, four (9 %) showed worsened QoL, and eleven (26 %) developed erectile dysfunction correlating with PTV D2% (P = 0.032). At Multivariate analysis bladder wall D10cc independently correlated with late G1 GU toxicity (P = 0.034). Median post-treatment PSA nadir was 0.04 ng/mL (0.00 – 0.84). At the last follow-up, six patients presented with biochemical failure, including two nodal relapses.
Our findings show that post-prostatectomy SBRT did not result in increased toxicity nor a significant decline in QoL measures, thus showing that it can be safely extended to the postoperative setting. Long-term follow-up and randomized comparisons with different RT schedules are needed to validate this approach.
Managing postoperative biochemical relapse in prostate cancer, from the perspective of the Francophone group of Urological radiotherapy (GFRU)
2023, Cancer Treatment Reviews
Up to 50% of patients treated with radical surgery for localized prostate cancer may experience biochemical recurrence that requires appropriate management. Definitions of biochemical relapse may vary, but, in all cases, consist of an increase in a PSA without clinical or radiological signs of disease. Molecular imaging through to positron emission tomography has taken a preponderant place in relapse diagnosis, progressively replacing bone scan and CT-scan. Prostate bed radiotherapy is currently a key treatment, the action of which should be potentiated by androgen deprivation therapy. Nowadays perspectives consist in determining the best combination therapies, particularly thanks to next-generation hormone therapies, but not exclusively. Several trials are ongoing and should address these issues. We present here a literature review aiming to discuss the current management of biochemical relapse in prostate cancer after radical surgery, in lights of recent findings, as well as future perspectives.
Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review
2023, eClinicalMedicine
Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs).
DFOTs published from June 2016–December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions.
Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians’ assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally.
This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting.
EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College.
The role of adaptive planning in margin-reduced, MRI-guided stereotactic body radiotherapy to the prostate bed following radical prostatectomy: Post-hoc analysis of a phase II clinical trial
2023, Radiotherapy and Oncology
We examined the interfractional variations of clinical target volumes (CTVs), planning target volumes (PTVs), and organs-at-risk (OARs) in patients receiving MRI-guided stereotactic body radiotherapy (SBRT) to the prostate bed and evaluated the potential role of adaptive planning.
31 patients received 30–34 Gy in five fractions to the prostate bed on a phase II clinical trial. OARs, CTVs, and PTVs were retrospectively contoured on daily pretreatment MRIs (n = 155). Geometric comparisons were made between initial planning contours and daily pretreatment contours. Predicted treatment plans for each fraction were evaluated using the following constraints: CTV V95%>93%, PTV V95%>90%, bladder Dmax < 36.7 Gy, bladder V32.5 Gy < 35%, rectum Dmax < 36.7 Gy, rectum V27.5 Gy < 45%, rectum 32.5 Gy < 30%, and rectal wall V24Gy < 50%. Adaptive planning was simulated for all fractions that failed to meet these criteria. Plans were then re-evaluated.
Median change in volume was 0.48% for CTV, −24.5% for bladder, and 6.95% for rectum. Median DSC was 0.89 for CTV, 0.79 for bladder, and 0.76 for rectum. 145/155 fractions (93.5%) met CTV V95%>93%. 75/155 fractions (48.4%) failed at least one OAR dose constraint. Overall, 83/155 fractions (53.5%) met criteria for adapting planning. This affected 24/31 patients (77.4%). Following adaptive planning, all fractions met CTV V95%>93% and PTV V95%>90% and 120/155 fractions (77.4%) met all OAR constraints.
Due to significant interfractional variations in anatomy, a majority of fractions failed to meet both target volume and OAR constraints. However, adaptive planning was effective in overcoming these anatomic changes. Adaptive planning should be routinely considered in prostate bed SBRT.
Treatment outcomes of postoperative ultra-hypofractionated stereotactic body radiotherapy in prostate cancer
2023, Urologic Oncology: Seminars and Original Investigations
This study aimed to evaluate the safety and efficacy of ultra-hypofractionated stereotactic body radiation therapy (SBRT) to prostate bed.
Sixty-six prostate cancer patients treated with postoperative ultra-hypofractionated SBRT between 2018 and 2020 were retrospectively reviewed. All patients received a total dose of 35 Gy to prostate bed in 5 fractions. Biochemical complete response (BCR), biochemical failure (BF), acute and late toxicities were assessed.
After a median follow-up of 24.2 months (range, 6.4–37.2), seven patients (10.6%) developed BF, and the 2-year freedom from BF (FFBF) rate was 88.4%. BCR was observed in 57 patients (86.4%). The 2-year FFBF in patients with pre-SBRT PSA value of <0.2 ng/mL was higher than those with pre-SBRT PSA of ≥0.2 ng/mL (100% vs. 81.4%; P = 0.04). The 2-year FFBF in patients with BCR was significantly higher than in those without BCR (94.5% vs. 58.3%; P < 0.001). In multivariate analysis, pre-SBRT PSA and post-SBRT PSA values were prognostic factors for FFBF (P = 0.009 and P = 0.01, respectively). Nine patients (13.6 %) developed acute and late grade 2 genitourinary (GU) toxicities. There was no acute or late grade ≥3 GU toxicity. Acute and late grade ≥2 gastrointestinal (GI) toxicity was observed in 9 (13.6%) and 2 (3%) patients, respectively.
Postoperative ultra-fractionated SBRT showed no severe acute toxicity and late toxicity rates of about 15%, in addition to excellent biochemical control rates. Pre- and post-SBRT PSA levels may be a predictor of BCR in patients receiving post-operative ultra-fractionated SBRT.

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Clinical InvestigationStereotactic Body Radiation Therapy to the Prostate Bed: Results of a Phase 1 Dose-Escalation Trial

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conclusions

Lancet

J Urol

Eur Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Eur J Cancer

Clinical Investigation
Stereotactic Body Radiation Therapy to the Prostate Bed: Results of a Phase 1 Dose-Escalation Trial