High‐dose‐rate brachytherapy for prostate cancer: Rationale, current applications, and clinical outcome

Abstract Background High‐dose‐rate brachytherapy (HDR BRT) has been enjoying rapid acceptance as a treatment modality offered to selected prostate cancer patients devoid of risk group, employed either in monotherapy setting or combined with external beam radiation therapy (EBRT) and is currently one of the most active clinical research areas. Recent findings This review encompasses all the current evidence to support the use of HDR BRT in various clinical scenario and shines light to the HDR BRT rationale, as an ultimately conformal dose delivery method enabling safe dose escalation to the prostate. Conclusion Valid long‐term data, both in regard to the oncologic outcomes and toxicity profile, support the current clinical indication spectrum of HDR BRT. At the same time, this serves as solid, rigid ground for emerging therapeutic applications, allowing the technique to remain in the spotlight alongside stereotactic radiosurgery.


| INTRODUCTION
Validated therapeutic modalities considered for patients diagnosed with organ-confined prostate cancer are radical prostatectomy, 1,2 external beam radiation therapy (EBRT), 3-5 permanent low-dose rate (LDR) brachytherapy (BRT), [6][7][8] and temporary high-dose-rate (HDR) BRT. [9][10][11][12][13][14][15][16][17][18][19] However, owing to the unavailability of randomized clinical trials, the optimal management remains trivial, with proposed treatment assignment being mainly determined by physician's biased guidance and patient's preference. In this regard, choice of treatment and consecutively its impact on quality of life have gained increasing importance, with BRT being favored due to its high effectiveness and, at the same time, its relatively low morbidity. Currently, validated long-term data endorse the efficacy of BRT in the management of locally confined prostate cancer with technological advancements fueling active research in the field of HDR BRT owed mainly to refinement of the technique, 20 employment of modern biomolecular imaging, [21][22][23] and investigation of focal and focused approaches, 24 all of which ensure high standards of implant quality and precision. The dosimetric superiority of HDR BRT translates into excellent clinical results, [25][26][27] thus backing up the notion that HDR BRT is a novel alternative to permanent LDR BRT. 28 This review presents a comprehensive analysis of the rationale, current clinical indications, and oncologic outcomes, including a representative data report.

| Rationale for HDR brachytherapy
Dose escalation data suggest that the utilization of comparatively higher dose for definitive radiation therapy (RT) in organ-confined prostate adenocarcinoma improves biochemical control (BC) 4,5,29 but, at the same time, results in improved metastasis-free survival (MFS). 5,[30][31][32][33][34] Adding to that, the rational assumption can be made that further therapeutic impact improvement could be attained through dose escalation, while simultaneously enhancing dose conformity, especially in patients devoid of regionally advanced and/or metastatic tumor load. HDR BRT fully exploits its radiobiological advantage to perfectly meet this objective, through the utilization of extreme hypofractionation [35][36][37] and, at the same time, its incomparably superior three-dimensional (3D) dosimetry. 38 HDR treatment planning enables dose optimization through multiparametric modulation, for example, catheter geometry, precalculated dwell positions, and times. 39,40 This allows for optimal dose modulation, with higher dose delivery to target volume and/or selectively dose reduction to organs at risk (OARs). 25 In relation, HDR BRT employs "high-density" dosimetry, owed to the roughly twofold dwell positions number when compared to seeds in a typical LDR implant. Again in comparison to LDR, anatomic and, thus, dosimetric changes are kept to a minimum, since issues associated with LDR BRT such as migration of seed/source and deformation of tissue do not occur. [41][42][43] On the other hand, intrafractional anatomic alteration caused by organ motion during EBRT delivery, [44][45][46] as well as setup inaccuracies, is overcomed with HDR due to rectification of theses error during the implantation procedure with interactive online dosimetry or modified prior to dose delivery with real-time anatomy-based treatment planning. 25 This minimization of errors allows for a decrease in the therapeutic margins required beyond the intended target, thus exposing less healthy tissue in unnecessary radiation, transforming HDR BRT to the optimal intraprostatic dose-escalation technique, where needed, especially when combined with EBRT. This proved especially important in patients whose treatment volume includes the regional lymphatic drainage, being treated to a moderate dose, yet offering an escalated intraprostatic escalated dose.

| Radiobiological considerations
Radiobiological data suggest that there is variability between normal and malignant tissue and the probability of acute and late radiation sequelae development, variation which is also being noted in-between different fractionation schedules. Adhering to the linear-quadratic model, 47 the sensitivity of a particular tissue to altered fraction size is expressed by the α/β ratio, allowing comparison between various treatment schedules and, at the same time, estimates the impact of each given fractionation schedule on tumor control and toxicity.
Recent radiobiological reports suggest an α/β ratio for prostate cancer ranging between 1.2 and 3.0 Gy, which is relatively lower than the α/β ratio of acutely and late-reacting normal tissues. 36,48,49 Having this in mind, hypofractionated dose schemes are favored and seem to result in superior tumor control with remarkable reduction in late side effects. In this background, HDR BRT represents the ideal method for conformal dose escalation. 50

| Patient selection for HDR brachytherapy
Based on the hypothesis that failure of local control in organ-confined prostate cancer may lead to regional and distant metastasis development, histologically confirmed localized disease is the fundamental indication for HDR BRT in patients, who are considered suitable candidates for definite treatment. 51,52 In line with the National Comprehensive Cancer Network (NCCN) guidelines, 53 [55][56][57][58] Again, HDR BRT may find implementation in the regional lymphadenopathy setting, with or without the presence of distant metastatic spread, as a combination with EBRT as part of an individualized treatment concept, aiming at minimizing toxicity, with the goal of maximizing local disease control.
In the local recurrence setting after definitive RT, as proposed by international guidelines, 51,52,59 any patient presenting histological and/or radiological (also biomolecular imaging) proved prostateconfined disease is a potential candidate for local radical treatment, therefore prostate salvage HDR BRT (sHDR BRT) should be considered.
Prior to HDR BRT, complete clinical staging should be attempted following the European Association of Urology, 60 European Society for Radiotherapy and Oncology (ESTRO), 52  When comparing HDR to LDR or EBRT, the exacerbation of lower urinary tract symptoms appears to be less prolonged, based on the fact that even patients with high International Prostate Symptom Score (IPSS; ≥20) tend to have a rather rapid recovery to pretreatment baseline urinary function. 65 Selection criteria for HDR BRT as monotherapy, combined with EBRT and in the salvage setting, are presented in Table 1.
In contrary to permanent LDR implants, HDR BRT after loading catheters can be implanted accordingly, in order to cover areas of extracapsular or the seminal vesicles' infiltration or even the bladder pouch, extending its indication to coverage of even T4 tumors, as part of individualized curative treatment concepts. 14,66,67 Previous pelvic EBRT, prior pelvic surgery, and inflammatory bowel disease are not considered absolute contraindications for HDR prostate BRT but always a very thorough evaluation of the potential risks and benefits should take place, based on anatomy-based dosimetry including carefully defined OARs dose constraints. 25

| Implantation techniques
Anaesthesia, spinal or general, is required for interstitial catheter implantation. It should be stated that catheter implantation can be carried out using TRUS-guided technique, 13,68,69 where extensive experience exists or by MRI-assistance. 52,53 Table 2 describes key features of the technique. higher-grade GU as well as GI toxicity not reaching statistical significance. In an earlier study, 56

| HDR monotherapy
As already mentioned, HDR BRT was originally used in combination with EBRT, as a boost modality mainly due to concerns regarding normal tissue toxicity with the application of hypofractionated treatment regimes. The safety and efficacy range for HDR in the context of com-  indicating that temporary HDR is being associated with significantly less grade 1-2 GU toxicity, in the form of chronic dysuria (LDR 22% vs. HDR 15%) and urinary frequency/urgency (LDR 54% vs. HDR 43%). The incidence of urethral stricture was equal for both therapeutic modalities (LDR 2.5% vs. HDR 3%), while late Grade 3 GU sequelae was insignificant in both groups. At last, the 5-year potency preservation rate was 80% for temporary HDR versus 70% for permanent seeds BRT.
Overall, the reproducible clinical data in favor of HDR monotherapy clearly reflect the current radiobiological notion for optimal tumor control through hypofractionation. Table 5 describes T A B L E 5 Late toxicity data of HDR monotherapy for localised prostate cancer  concerning the clinical impact will be resolved. Adding to that, given the relatively restricted "surgical margin" associated with SBRT, it is clearly not recommended for more advanced disease presenting with extracapsular extension or seminal vesicle involvement. 136,141 In conclusion, HDR BRT as monotherapy proves to be an excellent modality for the management of low-, intermediate-, as well as carefully selected cases of high-risk prostate cancer with long-term follow-up data justifying its safety and low side-effect rate.

| HDR monotherapy as salvage treatment
The optimal management of patients treated previously with defini- Salvage HDR BRT (sHDR BRT) with or without ADT for clinically, histologically, and metabolically proven local recurrence after previous radical RT appears to be a safe, effective, and well-tolerated therapeutic option which can be favorably compared with other nonradiotherapeutic local treatment modalities, in regard to disease control and toxicity rates. [152][153][154] Considering that reports about local salvage modalities are in general scarce, only a few studies report the long-term oncological outcomes following sHDR BRT. Even though all data arise from retrospective reports and are unfortunately relatively restricted in regard to patient sample size, with reported BC of the order of up to 77%, some of them have reached a 5-year follow-up.  123 Similarly, late grade 3 GU and GI toxicity rates in the sLDR BRT literature range from 0% to 47% and 0%-20%, respectively. 164,165 Once again, the heterogeneity of clinically implemented protocols makes uniform recommendations concerning the optimal dosefractionation scheme for whole gland sHDR BRT trivial. However, the oncological results arising from single-or multiple-implant regimes are considered consistent and reproducible, irrespective of the exploiting extreme hypofractionated or moderately hypofractionated treatment.
At the same time, sHDR BRT has been applied in the focal setting for the reirradiation of radiologically detectable recurrent disease. 166,167 Although it is clear that a significant dose reduction to OARs can be achieved by the implication of focal HDR BRT, 168 further investigation is guaranteed to calculate the possible clinical impact both on morbidity and tumor control.
Currently, no consensus involving patient's eligibility for repeating a local therapy of organ-confined recurrent prostate cancer exists, and the most suitable candidates have yet to be defined. Table 1 describes the selection criteria and contraindications. Nevertheless, the main rationale for HDR salvage treatment remains unchanged and is based solely on the presence of local disease in nonmetastatic patients, who are considered suitable candidates for radical therapy.
The safe utilization of sHDR BRT either solely or as part of individualized treatment approach also for high-risk patients is supported by an ever growing literature body. 148,156,157,160 4 | CONCLUSION HDR BRT is an excellent radio-oncological modality for the management of prostate cancer granting an extraordinary low side-effect rate. Valid mature follow-up data support its safe and effective implementation in the treatment of prostate-confined cancer regardless of risk group. However, further prospective and randomized studies are warranted to fully establish its role in clinically challenging prostate cancer cases.

CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsi-

ETHICAL STATEMENT
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DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analysed in this study.