Brachytherapy: The urologist opinion

Abstract

Prostate cancer remains a prevalent concern worldwide, necessitating continual advancements in treatment modalities. This abstract explores the role of brachytherapy as a viable and effective option in the management of prostate cancer. Brachytherapy involves the implantation of radioactive sources directly into the prostate, providing a localized dose of radiation. n recent studies and clinical trials, brachytherapy has demonstrated promising outcomes, particularly in terms of disease control and patient outcomes. The treatment’s ability to deliver a concentrated intraprostatic dose, often in combination with external beam radiotherapy, has shown favorable results. Furthermore, brachytherapy’s impact on disease-free survival and its potential in reducing urinary and bowel toxicity have been subjects of investigation. This abstract delves into the technical aspects, patient outcomes, and emerging trends in brachytherapy for prostate cancer. By examining the current literature and research findings, we aim to shed light on the evolving role of brachytherapy in the comprehensive management of prostate cancer, emphasizing its potential as a valuable therapeutic option.

Between 17% and 31% of individuals newly diagnosed with prostate cancer patients have disease classified as either high-risk localized or locally advanced. ¹ In contrast to low-risk prostate cancer, high-risk cases are more prone to exhibit biochemical recurrence (BCR), metastasis, and more likely to result in mortality. Surgery as radical prostatectomy (RP) and radiation therapy (RT) stand as the principal choices for achieving ideal local management when treatment is pursued with curative intent. ² As some clinical trials have shown, within the treatment with radiotherapy one option is also the use of external beam radiotherapy in conjunction with brachytherapy boost for high risk prostate cancer.^3,4 Brachytherapy is a treatment whereby high-dose radiotherapy is given while trying to spare the adjacent organs. Prostate choices integrate permanent seed low-dose-rate (LDR-BT) and high-dose-rate brachytherapy (HDR-BT). Currently, there is no widespread agreement on the favored approach for treating advanced-stage prostate cancer. Furthermore, as with any emerging treatment approach integrated into medical practice, focal treatment prompts numerous inquiries, including the identification of the ideal candidate, establishment of the optimal monitoring protocol, determination of the survival rate free from disease progression following the application of focal treatment and the side effects of the new treatment. Low-dose brachytherapy entails the enduring placement of radioactive seeds within the prostate. For individuals who decline or are inappropriate for active surveillance (AS), LDR monotherapy may be recommended, particularly for those with low-risk or NCCN favorable intermediate-risk and optimal urinary function (peak flow rate >15 mL/min on voiding flow test and with International Prostatic Symptom Score <12)^5,6 but patients should be advised that information about results is accessible solely from a restricted number of cases in highly proficient centers. The SPIRIT trial comparing RP and low-dose rate BT as monotherapy had to be discontinued due to inadequate participant enrollment. ⁷ The RTOG 0232 study, involved the randomization of patients with predominantly favorable intermediate-risk prostate cancer into two groups: one receiving LDR brachytherapy alone and the other receiving LDR brachytherapy with supplemental external beam radiotherapy (EBRT). The results indicated that the incorporation of EBRT did not enhance disease management over the long-term but did lead to an elevated incidence of treatment-related toxicity. ⁸ Concerns about the effectiveness of LDR monotherapy are heightened by a notable factor: individuals diagnosed with intermediate-risk prostate cancer are more likely to experience tumor extension beyond the prostate. ⁹ For this reason, some clinicians have included supplemental external beam radiotherapy (EBRT) in their treatment approach (before or after brachytherapy) to ensure sufficient coverage for areas that may not receive sufficient treatment through permanent prostate brachytherapy alone. Moreover, it facilitates the delivery of dosage to the seminal vesicles and pelvic lymph nodes, which may harbor micro metastases and are otherwise inaccessible with brachytherapy alone. Another option would be the addition of androgen-deprivation therapy (ADT) to brachytherapy, whose role in cancer control is, however, very uncertain. In a recent extensive database analysis involving more than 2000 patients diagnosed with intermediate-risk prostate cancer and received LDR brachytherapy, the incorporation of ADT led to a modest improvement in biochemical control (89% vs 86%) during the 10-year follow-up but at the same time a decline in overall survival was observed in patients treated with LDR-BT plus ADT. ¹⁰ This has been correlated with an increased risk of impaired cardiac function following the use of ADT. Acute and late genitourinary toxicities emerges as the prevailing adverse effects frequently documented following LDR brachytherapy. Risk factors linked to acute retention include an increased volume of the prostate, pre-existing urological issues, and a higher needle count used during the implantation procedure.^11,12 A further, albeit uncommon, adverse event is gastrointestinal toxicity because anterior rectal wall is situated in close proximity to the prostate. ¹³

Unlike LDR brachytherapy, which uses a permanent needle implant, temporary introduction of a radioactive source into the prostate characterizes the approach of high-dose brachytherapy. Administration of high-dose rate brachytherapy can occur in a solitary setting or multiple divisions, and it is frequently linked with EBRT.

Limited data are currently available regarding the application of HDR brachytherapy as a standalone treatment for individuals diagnosed with low-to-intermediate risk prostate cancer. In this patient population, the likelihood of substantial extraprostatic spread is infrequent, and brachytherapy alone is deemed sufficient to cover the entire misure of the disease. The primary benefit of HDR in this context lies in the swifter alleviation of sudden urological problems, a contrast to the more prolonged persistence of such symptoms for 6 months or more following an LDR implant due to the gradual delivery of the dose. One of the issues associated with using HDR brachytherapy as monotherapy is clarity regarding dose and fractionation. A further fact to be established and of which there is little clarity concerns the effectiveness of long-term therapy. In fact, as can be seen from the experience of Prada et al., after HDR brachytherapy, the initial data showed a cancer-free survival rate of over 90% with a median observation period of 19 months. However, with a more extended median surveillance duration of 6 years, the biochemical relapse-free survival exhibited a significant decline, reaching only 66%. ¹⁴ A notable concern is that 92% of these patients had a Gleason score of 6, and an additional one-third of them underwent androgen deprivation therapy (ADT).

When employed as an augmentation, brachytherapy administers a focused intraprostatic dose, complemented by the external beam component. This approach not only strengthens the concentration within the prostate but also targets possible spread beyond the prostate. In the ASCENDE-RT clinical trial, 398 men with 31% categorized as having intermediate-risk and 69% as having high risk condition, were assigned to receive either external beam radiotherapy (EBRT) with a dose of 78 Gy in 39 fractions or a combination of 46 Gy EBRT accompanied by a low-dose rate (LDR) boost using iodine-125 to achieve a total of 115 Gy. ¹⁵ The incorporation of a brachytherapy boost resulted in a reduction of recurrence risk by more than 50%, as evidenced by a 9-year recurrence rate of 38% in the EBRT arm compared to 17% in the brachytherapy boost arm.

The acute toxicity related to HDR brachytherapy lacks comprehensive documentation in a randomized controlled trial (RCT). Nevertheless, retrospective analyses consistently suggest decreased rates of gastrointestinal (GI) morbidity compared to EBRT alone. Grade 3 genitourinary was observed in 10% or fewer individuals, with an increased of urinary retention. ¹⁶ Similar observations are noted with hypofractioned radiotherapy (HFX). In a combined examination of 864 individuals undergoing extreme HFX and stereotactic radiotherapy, temporary decreases in urinary and gastrointestinal functions were observed at the 3-month mark. However, these symptoms either returned to baseline or showed improvement by the 6-month mark.

A valid use of brachytherapy instead seems to be its use in local recurrence after definitive RT.

Salvage options are prostatectomy (improvement of recurrence-free survival but with a notable risk of complications such as incontinence, anastomotic stricture, and rectal injury), high-intensity focused ultrasound (HIFU) or cryotherapy, as well as brachytherapy.

Several researchers have reported on salvage whole-gland LDR outcomes, showcasing efficacy comparable to that seen after radical prostatectomy. However, up to 30% of cases have reported grade 3 urinary toxicity, and rectal danger has been documented in 20%. In the RTOG 0526 clinical trial, the reported incidence of grade 3 late urinary toxicity after salvage whole-gland LDR was 14%. ¹⁷ One notable advantage of HDR brachytherapy lies in its capacity to administer targeted prostate-focused therapies. 95% of recurrences localized in the prostate are observed at the location of the original dominant condition,^18,19 current investigation is actively exploring localized salvage strategies led by multiparametric magnetic resonance imaging (mpMRI) or functional imaging.

Currently, brachytherapy (LDR and HDR) as monotherapy for prostate cancer treatment operates within a clinical context where indications are not entirely defined. The lack of clarity stems from the necessity for further in-depth studies involving larger patients cohorts. These additional investigations are crucial for a comprehensive assessment of the efficacy of brachytherapy in comparison to other available therapeutic approaches. Only through a more robust and representative evidence base can more reliable conclusions be drawn regarding its relative effectiveness and potential advantages over alternative treatments in prostate cancer management.