Salvage Whole-Pelvic Radiation and Long-Term Androgen-Deprivation Therapy in the Management of High-Risk Prostate Cancer: Long-Term Update of the McGill 0913 Study.

PURPOSE: To report the long-term outcomes of the McGill 0913 study and the potential benefits of combining prostate-bed radiotherapy (PBRT), pelvic-lymph-node radiotherapy (PLNRT), and long term ADT (LT-ADT). MATERIALS AND METHODS: From 2010 to 2016, 46 high-risk prostate cancer patients who experienced biochemical recurrence (BCR) after radical prostatectomy (RP) were enrolled in this single-arm phase II clinical trial. The patients were eligible if they had a Gleason score > 8, locally advanced disease (≥pT3), a preoperative PSA of >20 ng/mL, or positive lymph nodes (LN). The patients were treated with a combination of 24 months of ADT, PBRT, and PLNRT. The primary outcome was biochemical progression-free survival (bPFS) and the predefined secondary endpoints included distant-metastasis-free survival (DMFS), overall survival (OS), and toxicity. In this update, we also report the median follow-up of 8.8 years and 10 years OS. RESULTS: At a median follow-up of 8.8 years, 43 patients were eligible for analysis. The median pre-salvage PSA was 0.30 µg/L. Half (51%) of the patients (n = 22) had positive margins, 40% (n = 17) had Gleason scores > 8, 63% (n = 27) had extracapsular extension, 42% (n = 18) had seminal vesicle invasion, and 19% (n = 8) had LN involvement. The 10-year bPFS was 68.3 %. The 10-year DMFS was 72.9%. The 10-year OS was 97%. There were two non-cancer-related deaths. The first patient died of congestive heart failure while the other died of an unknown cause. No new toxicity was observed after the initial report. CONCLUSIONS: Our study demonstrates that treatment escalation with PBRT, PLNRT, and LT-ADT improves long term outcomes. In view of the recently published SPPORT study, we conclude that this novel approach of treatment intensification in high-risk post-prostatectomy patients is safe and effective, and that it should be offered as the standard of care.

Neoadjuvant versus Concurrent Androgen Deprivation Therapy in Localized Prostate Cancer Treated with Radiotherapy: A Systematic Review of the Literature.

BACKGROUND: There is an ongoing debate on the optimal sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) in patients with localized prostate cancer (PCa). Recent data favors concurrent ADT and RT over the neoadjuvant approach. METHODS: We conducted a systematic review in PubMed, EMBASE, and Cochrane Databases assessing the combination and optimal sequencing of ADT and RT for Intermediate-Risk (IR) and High-Risk (HR) PCa. FINDINGS: Twenty randomized control trials, one abstract, one individual patient data meta-analysis, and two retrospective studies were selected. HR PCa patients had improved survival outcomes with RT and ADT, particularly when a long-course Neoadjuvant-Concurrent-Adjuvant ADT was used. This benefit was seen in IR PCa when adding short-course ADT, although less consistently. The best available evidence indicates that concurrent over neoadjuvant sequencing is associated with better metastases-free survival at 15 years. Although most patients had IR PCa, HR participants may have been undertreated with short-course ADT and the absence of pelvic RT. Conversely, retrospective data suggests a survival benefit when using the neoadjuvant approach in HR PCa patients. INTERPRETATION: The available literature supports concurrent ADT and RT initiation for IR PCa. Neoadjuvant-concurrent-adjuvant sequencing should remain the standard approach for HR PCa and is an option for IR PCa.

Prophylactic A-Blockers for Radiotherapy-Induced Lower Urinary Tract Symptoms in Men with Prostate Cancer: A Phase III Randomized Trial.

PURPOSE: The present phase III randomized trial assessed the efficacy of prophylactic versus therapeutic α-blockers at improving RI-LUTSs in prostate cancer patients receiving external beam radiotherapy (EBRT). METHODS: A total of 148 prostate cancer patients were randomized 1:1 to receive either prophylactic silodosin on day one of EBRT or the occurrence of RI-LUTSs. LUTSs were quantified using the international prostate symptom score (IPSS) at regular intervals during the study. The primary endpoint was the change in the IPSS from baseline to the last day of radiotherapy (RT). Secondary endpoints included changes in IPSS from baseline to 4 weeks and 12 weeks after the start of RT. RESULTS: Patient demographics, baseline IPSS, and prescribed radiation doses were balanced between arms. On the last day of RT, the mean IPSS was 14.8 (SD 7.6) in the experimental arm and 15.7 (SD 8.5) in the control arm (p = 0.40). There were no significant differences in IPSSs between the study arms in the intention-to-treat (ITT) analysis at baseline, the last day of RT, and 4 and 12 weeks post-RT. CONCLUSION: Prophylactic α-blockers were not effective at significantly reducing RI-LUTSs in prostate cancer patients treated with EBRT. Treating patients with α-blockers at the onset of RI-LUTSs will avoid unnecessary drug exposure and toxicity.

Advances in PARP Inhibitors for Prostate Cancer.

Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction in the last decade with good outcomes in different cancers. Several trials have sought to test its effectiveness in metastatic castration resistant prostate cancer (mCRPC). We conducted a comprehensive literature review to evaluate the current role of PARPi in this setting. To this effect, we conducted queries in the PubMed, Embase and Cochrane databases. We reviewed and compared all major contemporary publications on the topic. In particular, recent phase II and III studies have also demonstrated the benefits of olaparib, rucaparib, niraparib, talazoparib in CRPC. Drug effectiveness has been assessed through radiological progression or overall response. Given the notion of synthetic lethality and potential synergy with other oncological therapies, several trials are looking to integrate PARPi in combined therapies. There remains ongoing controversy on the need for genetic screening prior to treatment initiation as well as the optimal patient population, which would benefit most from PARPi. PARPi is an important asset in the oncological arsenal for mCRPC. New combinations with PARPi may improve outcomes in earlier phases of prostate cancer.

Port-Site Metastasis Identified on Prostate-Specific Membrane Antigen-Targeted 18 F-DCFPyL PET/CT After Robot-Assisted Laparoscopic Radical Prostatectomy.

ABSTRACT: Port-site metastasis is an extremely rare complication following minimally invasive oncologic surgery for prostate cancer. We present the case of a 74-year-old man who underwent robot-assisted laparoscopic radical prostatectomy followed by salvage radiotherapy. Despite treatment, he developed biochemical recurrence. However, there was no evidence of disease on CT and bone scan at a prostate-specific antigen of 4.6 ng/mL. Subsequently, 18 F-DCFPyL PET/CT revealed a solitary focus of intense uptake in the right rectus abdominis muscle that was felt to represent a port-site metastasis. Histopathologic evaluation with immunostaining following ultrasound-guided needle biopsy confirmed the presence of metastatic adenocarcinoma of the prostate.

Comparison between postoperative TRUS-CT fusion with MRI-CT fusion for postimplant quality assurance in prostate LDR permanent seed brachytherapy.

PURPOSE/OBJECTIVE Permanent seed Low-Dose-Rate brachytherapy is planned and delivered using transrectal ultrasound (TRUS). Post-implant evaluation for quality assurance is usually performed using Computed Tomography (CT). Registration of the CT images with MRI reduces subjectivity in contouring by improving prostate edge detection. We hypothesized that a set of TRUS images post procedure may provide the same benefit. MATERIAL/METHODS Consecutive patients undergoing Low-Dose-Rate prostate brachytherapy were recruited. TRUS images were recorded under anesthesia at completion of their implant. In addition, all patients underwent standard post-implant quality assurance including prostate CT and MRI at day 30. These were co-registered, contoured and seeds were identified. Three independent observers contoured and registered the post implant TRUS images to the Day 30 CT using seed matching. Prostate volumes and dosimetric parameters were compared through Intraclass Correlation Coefficient (ICC) to evaluate the concordance between MRI and ultrasound (US). RESULTS 26 patients were recruited from 10/17 to 01/18. Mean prostate volume was 34.5 (SD 10.8) cm3 at baseline on planning TRUS images, 37.4 (SD 11.3) cm3 on Day 0 post implant TRUS and 36.7 (SD 11.7) cm3 on Day 30 MRI. D90 was 112.6% (SD 9.3) on CT-MRI and 112.9% (SD 11.1) on CT-US. V100 was 94.6% (SD 3.8) for CT-MRI, 95.1% (SD 4.3) for CT-US. Student t-tests were used to compare groups. No significant differences were noted. CONCLUSION Post implant TRUS may be useful for quality assurance for post-implant dosimetry particularly if access to an MRI is limited.

Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create "space" in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called "sanctuary" sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

A surrogate urethra for real-time planning of high-dose-rate prostate brachytherapy.

PURPOSE: This study characterizes prostatic urethra cross-section to develop a surrogate urethra for accurate prediction of urethral dose during real-time high-dose-rate prostate brachytherapy. MATERIALS AND METHODS: Archived preoperative transrectal ultrasound images from 100 patients receiving low-dose-rate prostate brachytherapy were used to characterize the prostatic urethra, contoured on ultrasound using aerated gel. Consensus contours, defined using majority vote, described commonalities in cross-sectional shape across patients. Potential simplified surrogates were defined and evaluated against the true urethra. The best performing surrogate, a circle of varying size (CS) was retrospectively contoured on 85 high-dose-rate prostate brachytherapy treatment plans. Dose to this recommended surrogate was compared with urethral doses estimated by the standard 6 mm circle surrogate. RESULTS: Clear variation in urethral cross-sectional shape was observed along its length and between patients. The standard circle surrogate had low predictive sensitivity (61.1%) compared with true urethra because of underrepresentation of the verumontanum midgland. The CS best represented the true urethra across all validation metrics (dice: 0.73, precision: 67.0%, sensitivity: 83.2%, conformity: 0.78). Retrospective evaluation of planned doses using the CS surrogate resulted in significant differences in all reported urethral dose parameters compared with the standard circle, with the exception of D100%. The urethral dose limit (115%) was exceeded in 40% of patients for the CS surrogate. CONCLUSIONS: The proposed CS surrogate, consisting of circles of varying diameter, is simple yet better represents the true urethra compared with the standard 6 mm circle. Higher urethral doses were predicted using CS, and the improved accuracy of CS may offer increased predictive power for urethral toxicity, a subject of future work.

The role of salvage brachytherapy for local relapse after external beam radiotherapy for prostate cancer.

Prostate cancer is the most prevalent cancer amongst men. For localized disease, there currently exist several reliable treatment modalities including surgery, radiotherapy and brachytherapy. Our growing understanding of this disease indicates that local control plays a very important role in prevention of subsequent dissemination. Many improvements to external beam radiotherapy over recent years have decreased toxicity and improved outcomes, but nonetheless, local relapse remains common. Many salvage options exist for locally recurrent prostate cancer, but are rarely offered, partly because of the fear of toxicity. Many men with isolated local recurrence therefore do not receive potentially curative second line treatment and are instead treated with palliative androgen suppression. Selection plays an important role in determining which individuals are likely to benefit from salvage. Those at high risk of pre-existing micro-metastatic disease despite negative staging scans are unlikely to benefit. Prostate brachytherapy has evolved over the more than 3 decades of experience. Modern techniques allow more precise tumor localization and dose delivery. Better understanding of dosimetric parameters can distinguish optimal from suboptimal implants. Salvage brachytherapy can be an effective treatment for locally recurrent prostate cancer after prior external beam radiotherapy. We review the literature pertaining to both low dose rate (LDR) and high dose rate (HDR) salvage brachytherapy and discuss patient selection, optimal dose, treatment volume and toxicity avoidance.