There are many treatment options for localized prostate cancer, and all of them provide excellent overall survival [2]. It is therefore of the outmost importance that the delivered treatment leads to as little toxicity as possible. Hoffman et al. showed a slight advantage of radiotherapy compared with surgery in terms of GU toxicity [16], looking at EBRT and LDR-BT.

As for tumor control, we were able to reproduce the expected results, showing no significant differences between treatment types, and when looking at LR and IR separately. However, there was a tendency for improved BC in the HF group, possibly due to the slight dose escalation that was performed in this group. This is in line with the ASCENDE trials, which demonstrated benefits of dose escalation in patients with IR and high-risk prostate cancer [17].

For late toxicity, we were able to observe a very low rate of both GU and especially GI toxicity in the HDR group. There are several studies looking at the effects of HDR-mono-BT as a stand-alone [18] compared with stereotactic EBRT [19, 20] or to LDR and EBRT with and without an HDR boost [21]. In all of them, HDR toxicity rates were very low. Morton et al. [22] compared 19 Gy single fraction HDR-BT with 2 × 13.5 Gy and were able to display an advantage regarding BC in the 2‑fraction group, but did not find an advantage regarding toxicity. Corkum et al. did the same [23], and were also unable to find differences regarding toxicity. Assuming an α/β of 1.5 Gy, 1 × 19 Gy and 2 × 13.5 Gy are 111 and 115 Gy EQD2. Yamazaki et al. [24] compared different schedules and fractionations between 7 and 9 fractions and found the least toxicity, with reported grade 2 or higher comparable to what we observed, when using 7 × 6.5 Gy, which equals an EQD2 of 104 Gy and is close to the 108 Gy EQD2 used in our study, while the others, with higher doses, led to more toxicity. However, the shorter follow-up might also, at least partly, contribute to the observed lower rates of toxicity in patients treated with HDR.

This is especially important, as the NCCN guidelines recommend HDR-mono-brachytherapy with 2 × 13.5 Gy or 2 × 9.5 Gy twice a day [5], while the GEC-ESTRO ACROP prostate brachytherapy guidelines [25] and the German S3 guideline [26] do not recommend the routine use of HDR-mono-BT at all, therefore limiting access to a treatment with comparable tumor control and low toxicity. With these results and discussed points in mind, we strongly suggest a randomized study be conducted to further investigate HDR-BT compared with EBRT; it should also look at different fractionation schemes, as 3 × 10.5 Gy does seem to provide an excellent safety profile, to provide the required evidence.

Regarding the higher maximal GU toxicity in patients treated with LDR-BT, this is mostly due to the continued use of tamsulosin after 3 months, which was routinely prescribed for every patient treated with LDR-BT. As shown in Fig. 2a, toxicity reported by patients treated with LDR-BT declines over time. For patients treated with moderate HF, we observed high rates of toxicity after 7 years for both GI and GU toxicity. This is most likely due to the fact that there are only two patients left in this group, with one of them reporting toxicity. Besides, we were unable to observe major differences regarding toxicity in patients treated with EBRT, although the CF group was mostly treated with 3D-conformal radiotherapy and the HF group exclusively with IMRT or VMAT. With the CHHiP trial showing no relevant differences between CF and HF in patients treated with IMRT [27], it is unlikely that the fractionation scheme is the cause of negating the expected lower toxicity in patients treated with HF due to IMRT. With the FLAME trial showing no major differences after dose escalation in patients treated with IMRT or VMAT either [28], we suspect that we are unable to observe a major difference in GU toxicity due to the proximity of the prostate to bladder and urethra, whereas for GI toxicity the use of the rectal balloon might lead to similar toxicities, as it creates a close proximity of the anterior wall of the rectum to the prostate and increases the distance for the other parts, possibly evening out the advantages of IMRT.

However, although the observed toxicities were low across the board, it is important to note that Hamdy et al. [2] showed the oncological feasibility of active surveillance in localized prostate cancer compared to surgery and radiotherapy. Therefore, one has to keep in mind, that no treatment at all leads to the least toxicities.

Regarding strengths of our study, we are able to report the results of a large bicenter cohort comparison of four available radiooncological treatment modalities in low- and intermediate-risk prostate cancer, which, to our knowledge, is the first such study. Assessment of toxicities was performed according to the RTOG/EORTC criteria in both centers. Interobserver variability in terms of toxicity is an old problem in radiotherapy [29]. Besides, missing values after 3 months for patients treated with HDR-BT might, at least in part, explain the excellent HDR-BT results regarding GI and GU toxicities in this group. However, looking at the DVH data in Supplement 2, we observed very low rectal D1 cm3, D0.1 cm3, and V75%. Therefore, with all the aforementioned bias, we still consider the low GI rates plausible.

A major weakness of our study is the uneven distribution of treatment types by center, as only one center provided patient data for patients treated with EBRT. This might contribute to the differences in reported side effects by treatment type. However, all the senior physicians were trained in the same institution, potentially reducing the extent of this problem. Another point is the fact that patients were able to decide which treatment they wanted, assuming an anatomy allowing for BT and meeting requirements for anesthesia for BT, leading to a selection bias with healthier patients in the BT groups. Besides, the included patients were treated over a period of more than 20 years, leading to other potential biases, such as stage migration, for example changes regarding the classification of patients with a T2c-staged prostate cancer, or changing treatment practices.