Editorial: Advancing external beam radiotherapy—and rediscovering what brachytherapy already provides?

We read with interest the article entitled “Reducing adverse effects in hypofractionated radiotherapy for prostate cancer: Clinical evidence and emerging mitigation strategies,” and commend the authors for their comprehensive synthesis of toxicity data in this evolving field. In this systematic review, evidence from 32 phase III clinical trials was analyzed and summarized. The principal conclusions are that both moderate and extreme hypofractionated radiotherapy regimens are generally safe, although they are associated with modest increases in acute and late genitourinary (GU) toxicity compared with conventionally fractionated radiotherapy. In contrast, the impact on gastrointestinal (GI) toxicity appears less consistent across studies [1].

The authors further discuss a range of technological strategies proposed to mitigate the side effects associated with delivering treatment in fewer fractions. Approaches such as margin reduction enabled by fiducial markers or by MR-guided radiotherapy, intrafraction motion management, and adaptive treatment based on daily anatomy may contribute to reducing dose to adjacent organs at risk (OARs) and thereby lowering toxicity. Notably, several of these concepts—although now considerably more sophisticated—were already described over 60 years ago by Bagshaw et al. (Fig. 1A–F) [2] including early forms of anatomical surrogacy, volumetric targeting, and image guidance.

Fig. 1: Prostate cancer treatment then and now.

A Kilovoltage lateral simulator image used to set isocentre and field borders (square) based on inferential information of the prostate based on surrounding anatomy (rectal and bladder contrast, foley balloon, bony pelvis) B rotational therapy that creates an in-plane conformal delivery but lack of dynamic beams eye view shaping limits the ability to conform the beam to the actual prostate shape; such rotational delivery allowed the treatment of deep seated tumors with lower energy (1–4MV) x-rays C) image guidance using “port film” acquired by exposing an x-ray film prior to treatment showing alignment of the treatment beam (dark square) in relation to bony anatomy. D Digitally reconstructed radiograph of anterior view of pelvis reconstructed from CT imaging with superimposed contours for prostate (blue) rectum (brown) bladder (yellow) and MLC aperture design at start of a dynamic, intensity modulated arc (note the aperture is only treating part of the prostate) E conformal dose distribution from the volumetric dynamic arc therapy also demonstrating a fiducial marker used for image guidance F on board imaging used for dynamic tracking of the implanted fiducial marker during treatment.

Another modality that has incorporated many of these principles for decades is prostate brachytherapy. Since 1917, transperineal implantation of radioactive sources has been used in the treatment of prostate cancer (PubMed: 17863718). As with external-beam techniques, prostate brachytherapy has undergone substantial refinement, including source miniaturization, the introduction of afterloading systems, and the routine use of intraoperative planning. Today, the procedure is typically performed under general anesthesia in a patient-friendly and controlled environment. By immobilizing the prostate through transperineal needle fixation and exploiting the highly favorable dose distribution inherent to brachytherapy, this modality offers precise dose delivery with minimal intraprocedural motion—features that align closely with many of the technological solutions highlighted in the review. In analogy to the described urethra-sparing EBRT strategies, brachytherapy has been for decades treating prostates with a horseshoe dose distribution shape that not only reduces dose to the urethra, but also heats-up dose the peripheral zone. Finally, the utilization of brachytherapy as a boost has been demonstrated to reduce biochemical disease progression and local relapse when compared to augmented radiotherapy schedules [3,4,5], a feature just recently achieved by external beam alone, through focal boosting to the dominant lesions as nicely demonstrated in the FLAME-trial [NCT01168479].

Toxicity associated with prostate brachytherapy has been raised as a concern, leading some to forgo this treatment strategy in favor of external beam radiotherapy (EBRT) alone. In the ASCENDE-RT trial, two grade 5 toxicities were reported among patients receiving low-dose-rate (LDR) brachytherapy as a boost. What is less well recognized, however, is that this trial enrolled patients between 2002 and 2011, and that the technical recommendations used at the time for the brachytherapy boost—such as inferior planning target volume (PTV) expansion—are no longer employed. Furthermore, other randomized trials have failed to demonstrate an excess in toxicity compared with EBRT alone [3, 4], or to report clinically meaningful levels of severe toxicity [6] comparable to those observed in ASCENDE-RT [5].

Certainly, not all patients are candidates for prostate brachytherapy or should undergo boost treatment with this modality. Continued improvements in external-beam radiotherapy techniques are therefore essential, and meaningful progress has been made in improving treatment efficiency (CHIPP, PROFITT, Hypo-RT PC, and PACE-B), albeit with a modest increase in toxicity, as nicely summarized in this review. What remains to be determined is whether hypofractionated radiotherapy regimens can improve oncological outcomes compared with conventional fractionation and match the results achieved with brachytherapy as a boost. In this context, we highlight the efforts of the PR24 trial for directly comparing brachytherapy boost versus SBRT in a large international phase III study [NCT06235697].