Current controversies in prostate brachytherapy for prostate cancer

Prostate LDR-BT dates back approximately 100 years, when radium was used to deliver radiation for enlarged prostates and prostate cancer. ^2,3 Given the poor efficacy and significant toxicity associated with radium, this isotope was abandoned in favor of radioactive gold isotopes (¹⁹⁸Au). ⁴ Iodine-125 (¹²⁵I) and other isotopes largely replaced ¹⁹⁸Au due to radiobiological and physical advantages. ⁵ Modern techniques with template and transrectal ultrasound (TRUS) guidance have been used for 30 years with excellent treatment tolerance and long-term control. ^5-7 The two most widely used radioactive sources in prostate LDR-BT are ¹²⁵I and palladium-103 (¹⁰³Pd) ( Table 1 ). Peschel et al studied 272 patients treated with ¹²⁵I or ¹⁰³Pd and found no difference in biochemical disease-free survival. ⁸ However, complication rates appeared to be higher for ¹²⁵I, which is consistent with its radiobiological characteristics. ⁸ Given their excellent disease control rates, ¹²⁵I, ¹⁰³Pd and, more recently, radioactive cesium (cesium-131) are now preferred options for LDR-BT in patients who meet modern eligibility and indications criteria. ^9-11

Indications for prostate LDR-BT have been continuously evolving over the past decade. The 1999 American Brachytherapy Society (ABS) recommendations by Nag et al initially suggested prostate brachytherapy as a monotherapy only for patients with low-risk disease defined per the D’Amico criteria ¹² as T1-T2a, Gleason sum < 6, and PSA < 10 ng/ml, ¹³ respectively. The ABS guidelines were subsequently updated to include prostate LDR monotherapy as an option for both low-risk and selected patients with intermediate-risk prostate cancer. ¹⁴ Currently, the National Comprehensive Cancer Network (NCCN) recommends brachytherapy monotherapy for very low, low, and low-volume-intermediate-risk prostate cancer patients. ¹⁵ Contraindications for brachytherapy have also been changing; previous ABS guidelines used a prostate volume of > 60 cc as a cutoff to recommend against brachytherapy, ^13,14 while more recent NCCN guidelines consider only “very large” gland size as a relative contraindication for brachytherapy without specifying a cutoff value. ¹⁵ A summary of the current guidelines is provided in Table 2 . Use of brachytherapy monotherapy or in combination with androgen deprivation therapy (ADT) for high-volume-intermediate-risk or high-risk prostate cancer patients remains an area of debate. Despite the absence of level-I evidence or randomized trials in this patient population, unfavorable intermediate-risk and high-risk men are generally not offered brachytherapy as monotherapy.

The initial report of the Nuclear Research and Consultancy Group (NRG) Oncology/Radiation Therapy Oncology Group (RTOG) 0232 comparing LDR-BT monotherapy to combined EBRT followed by an LDR-BT boost for intermediate-risk prostate cancer patients showed no difference in progression-free survival and overall survival with a median follow-up of 6.7 years. Moreover, there was no overall acute grade 3+ toxicity difference in both groups, but rather an overall grade 3+ late and grade 3+ GU toxicity profile favoring LDR monotherapy alone. ¹⁶ Another recent randomized trial, Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT), evaluated the role of LDR-BT in the management of intermediate- and high-risk prostate cancer and revealed a biochemical progression-free survival (bPFS) advantage favoring the addition of LDR-BT to EBRT for intermediate- and high-risk groups. ¹⁷ This trial did indicate a higher grade 3 GU toxicity at 5 years in the LDR-BT group, with half of those attributed to urethral strictures, while no other statistically significant differences in toxicity were found ( Table 3 ). ¹⁸ These two trials, in addition to two previous prospective trials comparing EBRT alone to EBRT in combination with HDR-BT, ^19,20 formed the basis for updated American Society of Clinical Oncology (ASCO) guidelines in 2017. ¹¹ These guidelines support LDR-BT monotherapy as an option for low-intermediate-risk patients, and recommend a brachytherapy boost for intermediate- and high-risk patients treated with EBRT, conceding that there may be increased GU toxicity compared to EBRT alone. ¹¹

It is important to note that the recent ASCO guidelines did not address the impact of the interim analysis of the NRG oncology/RTOG 0232 study, which was originally designed to test for a 10% increase in the 5-year PFS for EBRT with LDR-BT boost. ¹⁶ The RTOG 0232 findings suggest LDR-BT monotherapy is at least as effective for patients with favorable intermediate-risk prostate cancer when compared to combined modality treatment. ¹⁶ Moreover, absent from the guidelines is an acknowledgement of the important finding that LDR-BT monotherapy had a better toxicity profile compared to combined modality therapy. ^11,16 Similarly for high-risk prostate cancer patients, in the absence of randomized data comparing brachytherapy monotherapy (with or without ADT) against other treatment modalities, it seems worthwhile for the guidelines to incorporate two recent large retrospective series from the Cleveland Clinic and from the National Cancer Database. ^21,22 These studies demonstrated a biochemical relapse-free survival (bRFS) and prostate-cancer-specific mortality (PCSM) advantage to LDR-BT monotherapy over radical prostatectomy and EBRT, respectively, in patients with high-risk prostate cancer. ^21,22 Importantly, the toxicity profile in these retrospective studies again favored LDR-BT over EBRT or surgery when comparing an ¹²⁵I LDR-BT dose of 144 Gray (Gy) to an EBRT dose of at least 78 Gy or 70 Gy in 2 or 2.5 Gy per fraction, respectively, both with or without ADT, and radical prostatectomy followed by adjuvant or salvage EBRT to a median dose of 70 Gy in 2 Gy per fraction. ²¹ Finally, we believe that LDR-BT monotherapy is a sufficient treatment option for patients with localized intermediate-risk or high-risk prostate cancer. If combined modality radiation therapy was offered for these patients, we favor brachytherapy after EBRT. One reason is the uncertainty of calculating cumulative dose with external beam after the implant was placed and the potential for increased toxicity of delivering EBRT on top of an active implant. That said, we believe either could be reasonable depending on physician and institutional experience.

While available guidelines provide indications, outcome, toxicity, and, more recently, cost-effectiveness for prostate brachytherapy, ^11-13 these guidelines seldom address the radiobiological and dosimetric advantage of brachytherapy. With EBRT it is necessary to account for setup error, patient (external) movement and organ (internal) movement, which are used to generate a planning target volume (PTV). The PTV typically ranges from 0.5 - 1 cm around the clinical target volume (CTV) depending on the method of immobilization and use of image-guided radiation therapy (IGRT). ²³ Kneebone et al showed a reduction in the average deviations to 2.9 mm, 2.1 mm and 3.9 mm in the anteroposterior, right-left, and superoinferior directions, respectively, with the incorporation of rigid external immobilization. ²⁴ Internal immobilization with endorectal balloon or spacers are used to further maximize treatment reproducibility, but may result in tissue deformation, increased anterior rectal wall contact to target, diminished patient compliance, increased costs, and possibly increased treatment failure. ^25-28 Another challenge sometimes faced during EBRT treatment planning involves imaging artifacts associated with a hip prosthesis that can obscure pelvic anatomy and impair the ability of the treatment-planning system to accurately determine densities for dose modeling. ²⁹ Finally, obese patients tend to be at a higher risk of interfraction setup errors resulting in a higher risk of relapse post EBRT. ^30,31 Despite that, adequate EBRT coverage mandates that 3D-CRT or IMRT doses be normalized so that 98% of the PTV receive the prescription dose as per the current ongoing RTOG 0924 trial protocol. ³² For stereotactic body radiation therapy (SBRT) or hypofractionated radiation therapy cases, the dose is prescribed to cover at least 95% of the PTV ³³ ( Figure 1A-C ).

On the other hand, for LDR-BT, optimal placement of sources is the key to achieving adequate dose to the prostate while minimizing toxicity to normal tissues ( Figure 1D ). ³⁴ The photon decay characteristics of modern prostate brachytherapy sources result in highly local energy deposition, and generally yield a more conformal dose distribution. ³⁵ Georg et al studied the dosimetric differences among modern radiation therapy techniques including volumetric-modulated arc therapy (VMAT), intensity-modulated proton therapy (IMPT), intensity-modulated carbon-ion therapy (IMIT), LDR-BT, and HDR-BT. All doses were clinically appropriate and were normalized to biologically equivalent fractionations. Brachytherapy was found to be superior in sparing normal tissues ( Figure 2 ). ³⁶ Moreover, despite modern EBRT and IGRT techniques, given brachytherapy’s significant inverse-square dose falloff advantage, intraprostate doses remain significantly higher with brachytherapy compared to EBRT. ³⁷ This allows for dose escalation and increased biological effective dose, hence possibly explaining the improvement in PFS and PCSM, even in men with high-risk prostate cancer. ^17,21,22

In summary, prostate LDR-BT is a well-established treatment modality with excellent long-term outcomes for patients with localized prostate cancer, with similar outcomes between different radionuclides. ^10,7 Appropriate patient selection remains a moving target in the modern era, and eligibility guidelines continue to evolve accordingly. ^11-13 While brachytherapy as monotherapy is accepted as a standard for low-risk and low-volume-intermediate-risk prostate cancer patients, no randomized data show inferiority to combined treatment modalities in high-volume-intermediate-risk or high-risk prostate cancer patients. Recent multicenter randomized studies (RTOG 0232) have shown similar outcomes and favorable toxicity profiles for LDR-BT monotherapy compared to combined therapy with EBRT for patients with favorable intermediate-risk prostate cancer. ¹⁶ Retrospective data from the Cleveland Clinic and National Cancer Database have shown similar efficacy and toxicity results in high-risk patients. ^21,22 These outcomes data are underpinned by the dosimetric advantage of brachytherapy over EBRT. ³⁶ Prospective trials to evaluate the role of brachytherapy monotherapy in well-selected high-risk patients are needed to address gaps and shape future guidelines.