Currently, three major prospective randomized trials have investigated the role of BTB compared with EBRT alone, mostly in patients with IR and HR PC [2,3,4]. Each trial showed an advantage for BTB regarding BC, but none showed significant improvement for overall survival after BTB [2, 15, 16]. In two of these studies, EBRT groups received insufficient radiation doses by current guidelines [2, 3], and IR and HR PC were included without distinction. Moreover, ADT was not used at all in one study [3], and in another, it was used for an insufficient duration for HR PC [4]. Only one study included pelvic irradiation [4], a factor that also was associated with improvement in BC for HR PC in the POP-RT trial [17], and in IR PC [18]. In the current study, we investigated total dose and the eventual influence of BTB on BC based on real-world data and with up-to-date treatment standards, stratifying for IR and HR PC.

In the univariable and multivariable analyses, dose strongly influenced BC in both IR and HR PC. Even with current standards in EBRT, such as sufficient ADT combined with pelvic irradiation in HR and an increased EBRT dose, the benefit of further dose escalation using BTB with a dose of at least 113 Gy EQD2 persisted.

We found a significant influence of ADT duration on BC in both the IR and HR groups. This finding is important because of a tendency in patterns of care to reduce ADT when dose escalation is employed [19, 20], despite studies showing the importance of ADT in combination with BTB in IR [21] and HR [22] PC. In their retrospective study, Kishan et al. also found improvements in disease-specific survival when comparing BTB with ADT and EBRT with ADT, but many patients with EBRT and ADT received insufficient EBRT doses [23]. A propensity score–matched analysis by Tamiharda et al. showed no significant difference between EBRT and BTB, although many patients did not receive ADT or pelvic irradiation in that study, and the BTB dose was only 100 Gy EQD2Gy [24].

In considering toxicity, most [7, 25] but not all [2] studies showed increased toxicity with BTB. This consideration is relevant because the FLAME trial, by providing dose escalation as a simultaneously integrated boost, showed improved BC without increasing toxicity or impacting quality of life [8]. The results offer a potential alternative to BTB if further dose escalation is desired, but the trial did not show a benefit regarding overall survival with a median follow-up of 72 months. In a propensity score–matched analysis, we also found a survival benefit of dose escalation with BTB after a median follow-up of 117.8 months [26], leaving open the possibility that this outcome could still change in the FLAME trial.

The use of ultrasound-based dose planning for BTB is accepted state of the art. Using a 0-mm margin for the PTV is important. Comparing dose values with series applying a margin of 3–5 mm might result in uncertainties, as margins even compensated with more interstitial needles for conformal plans still result in higher CTV D90 doses if the planning aim is extended to the D90 for a larger PTV. The reported results for prescribed doses < 113 Gy EQD2 might be compared to series applying a D90 to a PTV with margins of much lower doses than this threshold.

The calculation of the EQD2 is limited to the cases involving use of BTB. For this reason, the spatial dose distribution of BTB cases cannot be directly compared with external beam dose applying the EQD2 concept. Total BTB dose distributions reported using a D90 include large parts of the prostate treated at substantially higher doses, especially within the peripheral zone, where interstitial needles usually are placed. The entire EQD2 comparison also depends on the contribution of EBRT versus BTB doses, which changes the entire total spatial dose distribution between the homogeneous EBRT and heterogeneous brachytherapy portion. The heterogeneity was caused by needle spacing and placement around the urethra, as well as the sharp decline in dose around the inserted catheters. Most cases included in this comparison involved 50–54 Gy EBRT, and the total EQD2 difference was dominated by 10 Gy versus 15 Gy applied in one or two fractions. Uncertainties included in the simple EQD2 summation are therefore limited.

This study has some further limitations, however, most prominently its retrospective nature. This feature could have led to a bias through informative censoring due to center effects in follow-up and might explain the BC differences in the HR group, as shown in Fig. 1. In the HR group in particular, some characteristics (e.g., age, IR, ADT use and duration and median follow-up) differed between treatment arms, which would not have been the case in a randomized controlled trial and is especially problematic for ADT use and duration as well as the short follow-up, especially in the EBRT group. We tried to mitigate this limitation by applying multivariable analyses, which confirmed our results showing that dose escalation led to improved BC. Another limitation is the uneven distribution of treatment arms between countries, as shown in supplement 1, as well as the long time frame of 20 years. For example, a recent study by Michalski et al. showed no benefit regarding tumor control of EBRT with BTB compared to brachytherapy alone [27].

Nevertheless, we report an analysis of data from a large group of patients treated according to current EBRT standards compared with high dose–rate BTB and provide evidence supporting the dose recommendation of 113–121 Gy EQD2Gy, in keeping with the GEC-ESTRO ACROP prostate brachytherapy guidelines [14]. The findings show a clear dose-response curve for both IR and HR PC.