Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer

Strahlenther Onkol (2022) 198:735–743 https://doi.org/10.1007/s00066-022-01953-y ORIGINAL ARTICLE Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer Jörg Tamihardja1 Michael Flentje1 · Ingulf Lawrenz1 · Paul Lutyj1 · Stefan Weick1 · Matthias Guckenberger2 · Bülent Polat1 · Received: 27 January 2022 / Accepted: 20 April 2022 / Published online: 12 May 2022 © The Author(s) 2022 Abstract Purpose Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost. Methods From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (DMean). Combined treatment was delivered as 46 Gy (DMean) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D90%). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0). Results The estimated 10-year bRFS was 82.0% vs. 76.4% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9% vs. 87.0% (p = 0.195) and the 10-year OS was 65.7% vs. 68.9% (p = 0.303), respectively. Cumulative 5-year late GU ≥ grade 2 toxicities were seen in 23.6% vs. 19.2% (p = 0.086) and 5-year late GI ≥ grade 2 toxicities in 11.1% vs. 5.0% of the patients (p = 0.002); cumulative 5-year late grade 3 GU toxicity occurred in 4.2% vs. 3.6% (p = 0.401) and GI toxicity in 1.0% vs. 0.3% (p = 0.249), respectively. Conclusion Both treatment groups showed excellent long-term outcomes with low rates of severe toxicity. Keywords Long-term outcome · Dose escalation · High-dose-rate brachytherapy boost · Propensity score matching · Toxicity Data availability statement for this work The data that support the findings of this study are available from the corresponding author upon reasonable request. Matthias Guckenberger  Jörg Tamihardja Bülent Polat Michael Flentje Ingulf Lawrenz Paul Lutyj 1 Department of Radiation Oncology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany Stefan Weick 2 Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland K 736 Strahlenther Onkol (2022) 198:735–743 Introduction Treatment External beam radiation therapy (EBRT) and EBRT combined with high-dose-rate brachytherapy (HDR-BT) boost are well-established options for treating localized prostate cancer. Both radiation therapy modalities are widely practiced, but the question arises of which modality offers the best oncologic outcome while minimizing toxicity. Although HDR-BT offers excellent dose conformity, EBRT may be beneficial for ablating periprostatic disease extension in high-risk cancer [1]. Several randomized controlled trials showed an increase in biochemical control by dose escalation, which Hoskin et al. was able to demonstrate for the addition of HDR-BT boost to EBRT [2–7]. While doseescalated EBRT + HDR-BT boost has proven to be superior to EBRT with an EQD2 of 66–74 Gy, data on the comparison of dose-escalated treatment modalities above 80 Gy remain scarce [7]. As dose escalation above 80 Gy remains controversial and has yet to show an improvement of clinically important outcome parameters, the present study aims at improving the evidence base for dose escalation beyond 80 Gy [8, 9]. In the absence of randomized controlled trials for the comparison of dose-escalated EBRT above 80 Gy versus EBRT + HDR-BT boost, we performed a propensity score matching-based single-center analysis to address this question. Specifically, we compared the long-term biochemical relapse-free survival (bRFS), metastasis-free survival (MFS), overall survival (OS), and the long-term side effects of dose-escalated EBRT with an equivalent dose in 2 Gy fractions (EQD2) of 83 Gy (α/β 1.5 Gy) versus combined dose-escalated EBRT + HDR-BT boost with an EQD2 of 100 Gy for localized prostate cancer. The treatment procedures have been described in detail before and will be summarized briefly in the following [11, 12]. For the EBRT cohort, radiation therapy was delivered with intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) in 33 fractions with simultaneous integrated boost and two dose levels of 1.82 Gy and 2.31 Gy per fraction, resulting in a prescribed planning target volume (PTV) dose of 60.06 Gy (D95) and a PTVBoost mean dose of 76.23 Gy. Concerning contouring, a clinical target volume (CTV), CTVP–SV, was generated which consisted of the prostate and the proximal seminal vesicles, whereas the CTVP+SV included the prostate and the whole seminal vesicles. The PTVBoost was defined by placing a 5-mm margin around CTVP–SV with avoidance of the rectum. The PTV was created with a 10-mm margin around CTVP+SV in all but the dorsal direction, where a 7mm margin was applied. For the combined treatment cohort, EBRT was delivered with 3D-conformal radiation therapy, IMRT, or VMAT in 23 fractions with 2 Gy per fraction, resulting in a prescribed PTV dose of 46 Gy (DMean). A CTV was generated consisting of the prostate and the seminal vesicles. The PTV was created by a 10-mm margin around the CTV in all but the dorsal direction, where a 7 mm margin was used. Approximately 2 weeks after completion of EBRT, two HDRBT boost fractions were performed with a 14-day interval between the two applications. The HDR-BT boost PTV was defined as the entire prostate without the seminal vesicles and additional margin. The prescription dose for the PTV was 9 Gy (D90%) per fraction. Pinnacle3 (Philips Radiation Oncology Systems, Fitchburg, WI, USA) was used for EBRT treatment planning for both treatment cohorts. Materials and methods Outcomes Study design and participants Biochemical failure was defined according to the Phoenix definition as nadir plus a ≥ 2-ng/ml increase in prostatespecific antigen (PSA). Biochemical relapse-free survival, defined as the time between the conclusion of radiation therapy treatment and the date of biochemical failure, was the primary reported endpoint of this retrospective study. Secondary endpoints were metastasis-free survival, ov (...truncated)