Patterns of failure with 18F-DCFPyL PSMA-PET/CT in the post-prostatectomy setting: A regional cohort analysis.

INTRODUCTION: This study aimed to assess the detection rate of prostate cancer recurrence by prostate-specific member antigen positron emission tomography/computed tomography (PSMA PET/CT) with 18F-DCFPyL in patients with residual disease or biochemical recurrence (BCR), and its association with surgical pathology and prostate-specific antigen (PSA) kinetics. METHODS: Men from South Central Ontario enrolled in the PSMA Registry for Recurrent Prostate cancer (PREP) between April 2019 and December 2021 after radical prostatectomy (RP) and who had 1) pathologic stage N1 or persistent elevated PSA; or 2) BCR (PSA >0.10 ng/mL) where initial postoperative PSA was undetectable were included. RESULTS: A total of 169 men (median age 68 years; interquartile range [IQR] 62-71) with complete data met the above criteria. The median PSA was 0.27 ng/mL (IQR 0.16-0.85) prior to PSMA-PET. Overall positivity rate 59%; when PSA was <0.40 ng/mL, overall positivity rate 42% vs. 85% with PSA ≥0.40 ng/mL (p<0.001). Higher pathologic tumor stage increased detection of regional lymph nodes (LN) (pT2-3a: 32% vs. pT3b: 69%, p<0.001) but not distant metastases (pT2-3a: 12% vs. pT3b: 24%, p=0.15). PSMA-PET detected 18% with prostate bed, 42% with regional LN disease, and 44% with pelvic-only disease. The three most involved LN chains were the internal (21%) and external (20%) iliac, and obturator chains (16%). CONCLUSIONS: This prospective study of patients with residual disease or BCR after RP illustrates patterns of failure that could impact diagnosis and postoperative management. Such patients have significant risk of regional LN positivity on PSMA-PET highlighting a need to include pelvic LN within salvage radiotherapy volumes.

A randomized phase III trial of stereotactic ablative radiotherapy for patients with up to 10 oligometastases and a synchronous primary tumor (SABR-SYNC): study protocol.

BACKGROUND: Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. METHODS: One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. DISCUSSION: SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. TRIAL REGISTRATION: Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Ablative Radiation Therapy to Restrain Everything Safely Treatable (ARREST): A Phase 1 Study of Stereotactic Ablative Radiation Therapy for Polymetastatic Disease.

PURPOSE: This phase 1 study aimed to assess the safety and feasibility of SABR therapy delivery to all sites of polymetastatic disease (>10 metastases). METHODS AND MATERIALS: A 3 + 3 study design was used with 5 dose levels from 6 Gy (6 Gy × 1) to 30 Gy (6 Gy weekly × 5). Dose-limiting toxicity (DLT) was defined as any grade 4 or 5 toxicity or more than 3 grade 3 toxicities within 6 weeks of treatment. The primary endpoint was the maximal tolerated dose, defined as the dose level where ≥2/6 of patients experienced DLT. Secondary endpoints included quality of life (Functional Assessment of Cancer Therapy - General and European Quality of Life 5 Dimension 5 Level) at 6 weeks posttreatment, progression-free survival, and overall survival. RESULTS: Thirteen patients were accrued: 12 Gy (n = 3), 18 Gy (n = 3), 24 Gy (n = 4), and 30 Gy (n = 3), and 207 lesions were treated. Nine patients (69%) had acute toxicity: grade 1 (n = 6, 46%), grade 2 (n = 2, 15%; n = 1 pneumonitis and n = 1 fatigue), and grade 3 (n = 1, 7.7% neutropenia). There were no grade 4 or 5 toxicities. Mean ± SD quality of life (Functional Assessment of Cancer Therapy - General and European Quality of Life 5 Dimension 5 Level health state) was 80.4 ± 21.9 and 77.4 ± 20.9 at baseline versus 76.4 ± 21.8 and 68.0 ± 24.2 at 6-week follow-up, respectively (p = .009 and p = .055, respectively). With a median follow-up of 8.7 months posttreatment (IQR, 2.4-24 months), 8 of 13 patients had disease progression (62%). The median and 12-month progression-free survival were 3.6 months and 11.3%, respectively. The median and 12-month overall survival were 13.8 months and 62%, respectively. CONCLUSIONS: In this phase 1 trial, SABR therapy for polymetastatic disease was technically feasible with acceptable acute toxicity at dose levels up to 30 Gy (6 Gy weekly × 5). DLT was not observed.

Case report: Pediatric low-grade gliomas: a fine balance between treatment options, timing of therapy, symptom management and quality of life.

Introduction: Pediatric low-grade gliomas (pLGG) are the most common brain tumor in children and encompass a wide range of histologies. Treatment may pose challenges, especially in those incompletely resected or those with multiple recurrence or progression. Case description: We report the clinical course of a girl diagnosed with pilocytic astrocytoma and profound hydrocephalus at age 12 years treated with subtotal resection, vinblastine chemotherapy, and focal proton radiotherapy. After radiotherapy the tumor increased in enhancement temporarily with subsequent resolution consistent with pseudoprogression. Despite improvement in imaging and radiographic local control, the patient continues to have challenges with headaches, visual and auditory concerns, stroke-like symptoms, and poor quality of life. Conclusion: pLGG have excellent long-term survival; thus, treatments should focus on maintaining disease control and limiting long-term toxicities. Various treatment options exist including surgery, chemotherapy, targeted agents, and radiation therapy. Given the morbidity associated with pLGG, individualized treatment approaches are necessary, with a multi-disciplinary approach to care focused on minimizing treatment side effects, and promoting optimal quality of life for patients.

A Prospective Study of Machine Learning-Assisted Radiation Therapy Planning for Patients Receiving 54 Gy to the Brain.

PURPOSE: The capacity for machine learning (ML) to facilitate radiation therapy (RT) planning for primary brain tumors has not been described. We evaluated ML-assisted RT planning with regard to clinical acceptability, dosimetric outcomes, and planning efficiency for adults and children with primary brain tumors. METHODS AND MATERIALS: In this prospective study, children and adults receiving 54 Gy fractionated RT for a primary brain tumor were enrolled. For each patient, one ML-assisted RT plan was created and compared with 1 or 2 plans created using standard ("manual") planning procedures. Plans were evaluated by the treating oncologist, who was blinded to the method of plan creation. The primary endpoint was the proportion of ML plans that were clinically acceptable for treatment. Secondary endpoints included the frequency with which ML plans were selected as preferable for treatment, and dosimetric differences between ML and manual plans. RESULTS: A total of 116 manual plans and 61 ML plans were evaluated across 61 patients. Ninety-four percent of ML plans and 93% of manual plans were judged to be clinically acceptable (P = 1.0). Overall, the quality of ML plans was similar to manual plans. ML plans comprised 34.5% of all plans evaluated and were selected for treatment in 36.1% of cases (P = .82). Similar tumor target coverage was achieved between both planning methods. Normal brain (brain minus planning target volume) received an average of 1 Gy less mean dose with ML plans (compared with manual plans, P < .001). ML plans required an average of 45.8 minutes less time to create, compared with manual plans (P < .001). CONCLUSIONS: ML-assisted automated planning creates high-quality plans for patients with brain tumors, including children. Plans created with ML assistance delivered slightly less dose to normal brain tissues and can be designed in less time.

177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

Using multiparametric Magnetic Resonance Imaging and Prostate Specific Membrane Antigen Positron Emission Tomography to detect and delineate the gross tumour volume of intraprostatic lesions - A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Radiation therapy is used frequently for patients with prostate cancer. Dose escalation to intraprostatic lesions (IPLs) has been shown to improve oncologic outcomes, without increasing toxicity. Both multiparametric MRI (mpMRI) and PSMA PET can be used to identify IPLs. MATERIALS AND METHODS: A systematic review was conducted to determine the ability of mpMRI, PSMA PET and their combination to detect IPLs prior to radical prostatectomy (RP) as correlated with the histology. Trials included patients that had mpMRI, PSMA PET, or both, prior to RP. The quality of the histopathological-radiological co-registration was assessed as high or low for each study. Recorded outcomes include sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). A meta-analysis was conducted using a bivariate model to determine the pooled sensitivity and specificity for each imaging modality. This systematic review was registered through PROSPERO (CRD42023389092). RESULTS: Altogether, 42 studies were included in the systematic review. Of these, 20 could be included in the meta-analysis. The pooled sensitivity (95 % CI), specificity (95 % CI) and AUROC for mpMRI (n = 13 studies) were 64.7 % (50.2 % - 76.9 %), 86.4 % (79.7 % - 91.1 %), and 0.852; the pooled outcomes for PSMA PET (n = 12) were 75.7 % (64.0 % - 84.5 %), 87.1 % (80.2 % - 91.9 %), and 0.889; for their combination (n = 5), the pooled outcomes were 70.3 % (64.1 % - 75.9 %), 81.9 % (71.9 % - 88.8 %), and 0.796. When reviewing studies with a high-quality histopathological-radiological co-registration, IPL delineation recommendations varied by study and the imaging modality used. CONCLUSION: All of mpMRI, PSMA PET or their combination were found to have very good diagnostic outcomes for detecting IPLs. Recommendations for delineating IPLs varied based on the imaging modalities used and between research groups. Consensus guidelines for IPL delineation would help with creating consistency for focal boost radiation treatments in future studies.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update From the FASTR/FASTR-2 Trials.

PURPOSE: There is limited data on the long-term outcomes of ultrahypofractionated radiation therapy in high-risk prostate cancer. The FASTR and FASTR-2 trials were designed to assess the tolerability of stereotactic ablative radiation therapy (SABR) in this context. Herein, the long-term results are reported. METHODS AND MATERIALS: Eligible patients had localized high-risk prostate cancer and were either ≥70 years old, had a score of ≥3 on the Vulnerable Elderly Scale, or declined standard therapy. Nineteen patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 weekly fractions, with 12 months of androgen deprivation therapy (ADT). Thirty patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 weekly fractions, with 18 months of ADT. Updated toxicity and outcomes were assessed retrospectively. Kaplan-Meier estimates were calculated for biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival. RESULTS: Forty-four patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Thirty-four patients (77%) were >70 years old. High-risk features included Gleason score ≥8 (n = 20, 46%), T3-T4 disease (n = 12, 27%), and baseline prostate-specific antigen > 20 (n = 22, 50%). Median follow-up was 6.4 years. The 5-year cumulative incidence of late grade ≥3 genitourinary/gastrointestinal toxicity was 32% in FASTR and 11% in FASTR-2. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival were 72%, 90%, 92%, and 83%, respectively. CONCLUSIONS: SABR can be safely delivered in high-risk prostate cancer by optimizing technical delivery, particularly with adherence to strict dose constraints for organs at risk. The clinical outcomes in FASTR and FASTR-2 were largely comparable to more standard fractionation schemes plus ADT, but further modifications may improve disease control. Larger randomized trials are necessary to better understand the efficacy and tolerability of this approach.

Is Ultrahypofractionated Whole Pelvis Radiation Therapy (WPRT) as Well Tolerated as Conventionally Fractionated WPRT in Patients With Prostate Cancer? Early Results From the HOPE Trial.

OBJECTIVE: The aim of this work was to evaluate the acute toxicity and quality-of-life (QOL) impact of ultrahypofractionated whole pelvis radiation therapy (WPRT) compared with conventional WPRT fractionation after high-dose-rate prostate brachytherapy (HDR-BT). METHODS AND MATERIALS: The HOPE trial is a phase 2, multi-institutional randomized controlled trial of men with prostate-confined disease and National Comprehensive Cancer Network unfavorable intermediate-, high-, or very-high-risk prostate cancer. Patients were randomly assigned to receive conventionally fractionated WPRT (standard arm) or ultrahypofractionated WPRT (experimental arm) in a 1:1 ratio. All patients underwent radiation therapy with 15 Gy HDR-BT boost in a single fraction followed by WPRT delivered with conventional fractionation (45 Gy in 25 daily fractions or 46 Gy in 23 fractions) or ultrahypofractionation (25 Gy in 5 fractions delivered on alternate days). Acute toxicities measured during radiation therapy and at 6 weeks posttreatment were assessed using the clinician-reported Common Terminology Criteria for Adverse Events version 5.0, and QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC-50) and International Prostate Symptom Score (IPSS). RESULTS: A total of 80 patients were enrolled and treated across 3 Canadian institutions, of whom 39 and 41 patients received external radiation therapy with conventionally fractionated and ultrahypofractionated WPRT, respectively. All patients received androgen deprivation therapy except for 2 patients treated in the ultrahypofractionated arm. The baseline clinical characteristics of the 2 arms were similar, with 51 (63.8%) patients having high or very-high-risk prostate cancer disease. Treatment was well tolerated with no significant differences in the rate of acute adverse events between arms. No grade 4 adverse events or treatment-related deaths were reported. Ultrahypofractionated WPRT had a less detrimental impact on the EPIC-50 bowel total, function, and bother domain scores compared with conventional WPRT in the acute setting. By contrast, more patients treated with ultrahypofractionated WPRT reached the minimum clinical important difference on the EPIC-50 urinary domains. No significant QOL differences between arms were noted in the sexual and hormonal domains. CONCLUSIONS: Ultrahypofractionated WPRT after HDR-BT is a well-tolerated treatment strategy in the acute setting that has less detrimental impact on bowel QOL domains compared with conventional WPRT.

18F-DCFPyL PSMA-PET affects management of salvage radiotherapy for post-prostatectomy patients with biochemical failure: A matched cohort study.

INTRODUCTION: Our objective was to assess the effect of 18F-DCFPyL prostate-specific membrane antigen (PSMA) positron emission tomography (PET) on the management and outcomes of patients receiving salvage radiotherapy following biochemical failure (BF) post-radical prostatectomy (RP) using a matched cohort analysis. METHODS: A PSMA-PET cohort of patients with BF post-RP was identified through a prospective registry. Patients from this registry were included if they did not have disease outside of the pelvis and underwent salvage radiotherapy to the prostate and/or pelvis. Case-control matching was performed with a contemporary cohort of patients with BF post-RP without PSMA-PET information. RESULTS: Forty-four patients were included in the PSMA-PET cohort and 80 were analyzed in the non-PSMA-PET cohort. The PSMA-PET cohort had a significantly higher pre-radiotherapy median prostate-specific antigen (PSA) of 0.48 ng/mL compared to 0.20 ng/mL in the non-PSMA-PET cohort (p<0.001), but these levels were similar after matching. The PSMA-PET cohort had a higher proportion of patients receiving radiotherapy to pelvic lymph nodes (n=27 [61.4%] vs. n=16 [20.0%], p<0.001). Median followup was 26 months (interquartile range 18.8-33) for both cohorts. BF-free survival and event-free survival were not significantly different between the two cohorts for all (p=0.662 and >0.99) and matched patients (p=0.808 and 0.808), respectively. Metastasis-free survival was significantly higher in the matched PSMA-PET cohort compared to the matched non-PSMA-PET cohort (p=0.046), although a higher proportion of patients in the non-PSMA-PET cohort underwent PSMA-PET restaging after BF (52% vs. 20%, p=0.08726). CONCLUSIONS: Our study showed that patients undergoing PSMA-PET scans after BF post-RP had a higher likelihood of pelvic nodal treatment at the time of salvage RT. Despite higher PSA levels at salvage, we identified no recurrence or survival differences.

Influence of molecular imaging on patient selection for treatment intensification prior to salvage radiation therapy for prostate cancer: a post hoc analysis of the PROPS trial.

BACKGROUND: The impact of molecular imaging (MI) on patient management after biochemical recurrence (BCR) following radical prostatectomy has been described in many studies. However, it is not known if MI-induced management changes are appropriate. This study aimed to determine if androgen deprivation therapy (ADT) management plan is improved by MI in patients who are candidates for salvage radiation therapy. METHODS: Data were analyzed from the multicenter prospective PROPS trial evaluating PSMA/Choline PET in patients being considered for salvage radiotherapy (sRT) with BCR after prostatectomy. We compared the pre- and post-MI ADT management plans for each patient and cancer outcomes as predicted by the MSKCC nomogram. A higher percentage of predicted BCR associated with ADT treatment intensification after MI was considered as an improvement in a patient's management. RESULTS: Seventy-three patients with a median PSA of 0.38 ng/mL were included. In bivariate analysis, a positive finding on MI (local or metastatic) was associated with decision to use ADT with an odds ratio of 3.67 (95% CI, 1.25 to 10.71; p = 0.02). No factor included in the nomogram was associated with decision to use ADT. Also, MI improved selection of patients to receive ADT based on predicted BCR after sRT : the predicted nomogram 5-year biochemical-free survivals were 52.5% and 43.3%, (mean difference, 9.2%; 95% CI 0.8 to 17.6; p = 0.03) for sRT alone and ADT±sRT subgroups, while there was no statistically significant difference between subgroups before MI. CONCLUSIONS: PSMA and/or Choline PET/CT before sRT can potentially improve patient ADT management by directing clinicians towards more appropriate intensification.

What's to come in PSMA therapies and diagnostics: A summary of clinical trials involving PSMA radioligand-based therapeutic and/or diagnostic approaches with active recruitment.

INTRODUCTION: Prostate-Specific Membrane Antigen (PSMA)-based diagnostics and therapeutics are proving highly valuable in identifying disease sites and providing targeted radioligand therapy (RLT) for disseminated disease in prostate cancer (PC). With successful integration of these tools in limited PC presentations, there is a real need and excitement for trials testing PSMA-based approaches more broadly. AREAS COVERED: We review the ongoing trials registered on ClinicalTrials.gov which aim to evaluate PSMA-PET or PSMA-RLT applications. We outline clinical contexts which have significant ongoing study and therefore may see imminent change, as well as contexts which are lacking in study in the hopes of guiding future research. EXPERT OPINION: Trials examining intensification strategies through targeted radiotherapy, combination systemic therapies, and RLTs have the potential to demonstrate improved clinical outcomes using PSMA-PET CT for guidance. We expect that PSMA-PET will become fundamental in the work-up of patients before targeted radiotherapy or surgery. The results of ongoing trials will likely clarify the benefits of PSMA-RLT in metastatic PC including in oligometastatic and hormone-sensitive disease; however, there is a sparsity of trials evaluating PSMA-RLT outside of metastatic PC. Clinical trials with PSMA PET/CT as an endpoint for disease control are emerging and standardized reporting and metrics for PSMA staging and response will facilitate the inclusion of PSMA PET endpoints into therapeutic trials.

Planning for the Effect of the SC.24 Trial on Spine Stereotactic Body Radiation Therapy Utilization at a Tertiary Cancer Center.

Purpose: The goal of this study was to assess the potential real-world effect of the recently reported SC.24 trial on spine stereotactic body radiation therapy (SBRT) utilization. We estimated the proportion of patients treated with conventional radiation therapy (CRT) who would have been eligible for spine SBRT per trial inclusion criteria and analyzed the potential estimated increased costs to our institution. Methods and Materials: This was a retrospective review of patients who received spine CRT at our institution between August and October 2020. Data abstracted included demographics, SC.24 eligibility criteria, provider-reported pain response, and survival. A cost analysis and time survey was performed using institutional and provincial data. Results: Of 73 patients reviewed, 24 patients (33%) were eligible. The most common exclusion factors included irradiation of ≥3 consecutive spinal segments (n = 32, 44%), Eastern Cooperative Oncology Group performance status >2 (n = 17, 23%), and symptomatic spinal cord compression (n = 13, 18%). Of eligible patients, the mean age was 68.92 years, median spinal instability in neoplasia score was 8 (interquartile range, 7-9), and median Eastern Cooperative Oncology Group performance status was 2 (interquartile range, 1-2). The most common primary cancer types among eligible patients were lung (n = 10) and breast (n = 4). The median survival of eligible patients was 10 months (95% confidence interval, 4 months to not reached) with 58% surviving longer than 3 months. Of patients who had subjective pain documented after CRT, 54% had at least some response. The cost of spine SBRT was estimated at CA$4764.80 compared with $3589.10 for CRT, and tasks for spine SBRT took roughly 3 times as long as those for CRT. Conclusions: One-third of patients who received palliative spine CRT met eligibility criteria for SC.24. This possible expanded indication for spine SBRT can have a substantial effect on resource utilization. These data may be useful in guiding resource planning at institutions looking to commence a spine SBRT program.

Proton Radiotherapy for Management of Medulloblastoma: A Systematic Review of Clinical Outcomes.

Purpose: The aim of this study was to comprehensively review all studies examining clinical outcomes of craniospinal irradiation with proton radiotherapy for medulloblastoma (MB) to determine whether theoretical dosimetric advantages have translated into superior clinical outcomes (including survival and toxicities) compared with traditional photon-based techniques. Methods and Materials: We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles reporting on clinical outcomes of pediatric and/or adult patients with MB treated with proton radiotherapy were included. Evidence quality was assessed using a modified Newcastle Ottawa scale and GRADE score. Results: Thirty-five studies were included, with a total of 2059 patients reported (representing an estimated 630-654 unique patients). None of the studies were randomized, 12 were comparative, 9 were prospective, 3 were mixed, and 22 were retrospective. Average mean/median follow-up was 5.0 years (range, 4 weeks to 12.6 years). The majority of studies (n = 19) reported on treatment with passive scatter proton beams exclusively. Average study quality was 6.0 out of 9 (median, 6; standard deviation, 1.6). Nine studies scored ≥8 out of 9 on the modified Newcastle Ottawa Scale; an overall "moderate" GRADE score was assigned. Well-designed comparative cohort studies with adequate follow-up demonstrate superior neurocognitive outcomes, lower incidence of hypothyroidism (23% vs 69%), sex hormone deficiency (3% vs 19%), greater heights, and reduced acute toxicities in patients treated with protons compared to photons. Overall survival (up to 10 years), progression-free survival (up to 10 years), brain stem injury, and other endocrine outcomes were similar to those reported for photon radiation. There was insufficient evidence to make conclusions on endpoints of quality of life, ototoxicity, secondary malignancy, alopecia, scoliosis, cavernomas, and cerebral vasculopathy. Conclusions: Moderate-grade evidence supports proton radiotherapy as a preferred treatment for craniospinal irradiation of MB based on equivalent disease control and comparable-to-improved toxicity versus photon beam radiation therapy.

The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BACKGROUND: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. METHODS: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. DISCUSSION: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. TRIAL REGISTRATION: NCT05230251 (ClinicalTrials.gov).

Validation of a surface-based deformable MRI-3D ultrasound image registration algorithm toward clinical implementation for interstitial prostate brachytherapy.

PURPOSE: The purpose of this study was to evaluate and clinically implement a deformable surface-based magnetic resonance imaging (MRI) to three-dimensional ultrasound (US) image registration algorithm for prostate brachytherapy (BT) with the aim to reduce operator dependence and facilitate dose escalation to an MRI-defined target. METHODS AND MATERIALS: Our surface-based deformable image registration (DIR) algorithm first translates and scales to align the US- and MR-defined prostate surfaces, followed by deformation of the MR-defined prostate surface to match the US-defined prostate surface. The algorithm performance was assessed in a phantom using three deformation levels, followed by validation in three retrospective high-dose-rate BT clinical cases. For comparison, manual rigid registration and cognitive fusion by physician were also employed. Registration accuracy was assessed using the Dice similarity coefficient (DSC) and target registration error (TRE) for embedded spherical landmarks. The algorithm was then implemented intraoperatively in a prospective clinical case. RESULTS: In the phantom, our DIR algorithm demonstrated a mean DSC and TRE of 0.74 ± 0.08 and 0.94 ± 0.49 mm, respectively, significantly improving the performance compared to manual rigid registration with 0.64 ± 0.16 and 1.88 ± 1.24 mm, respectively. Clinical results demonstrated reduced variability compared to the current standard of cognitive fusion by physicians. CONCLUSIONS: We successfully validated a DIR algorithm allowing for translation of MR-defined target and organ-at-risk contours into the intraoperative environment. Prospective clinical implementation demonstrated the intraoperative feasibility of our algorithm, facilitating targeted biopsies and dose escalation to the MR-defined lesion. This method provides the potential to standardize the registration procedure between physicians, reducing operator dependence.

Does brachytherapy boost improve survival outcomes in Gleason Grade Group 5 patients treated with external beam radiotherapy and androgen deprivation therapy? A systematic review and meta-analysis.

Background: Localized Gleason Grade Group 5 (GG5) prostate cancer has a poor prognosis and is associated with a higher risk of treatment failure, metastases, and death. Treatment intensification with the addition of a brachytherapy (BT) boost to external beam radiation (EBRT) maximizes local control, which may translate into improved survival outcomes. Methods: A systematic review and meta-analysis was performed to compare survival outcomes for Gleason GG5 patients treated with androgen deprivation therapy (ADT) and either EBRT or EBRT + BT. The MEDLINE (PubMed), EMBASE and Cochrane databases were searched to identify relevant studies. Survival probabilities for distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were extracted and pooled to create a summary survival curve for each treatment modality, which were then compared at fixed points in time. An additional analysis was performed among studies directly comparing EBRT and EBRT + BT using a random-effects model. Results: Eight retrospective studies were selected for inclusion, representing a total of 1393 EBRT patients and 877 EBRT + BT patients. EBRT + BT was associated with higher DMFS starting at 6 years (86.8 % vs 78.8 %; p = 0.018) and extending out to 10 years (81.8 % vs 66.1 %; p < 0.001), with an overall hazard ratio of 0.53 (p = 0.02). There was no difference in PCSS or OS between treatment modalities. Differences in toxicity were not assessed. There was a wide range of heterogeneity between studies. Conclusion: The addition of BT boost is associated with improved long-term DMFS in Gleason GG5 prostate cancer, but its impact on PCSS and OS remains unclear. These results may be confounded by the heterogeneity across study populations with concern for a risk of bias. Therefore, prospective studies are necessary to further elucidate the survival advantage associated with BT boost, which must ultimately be weighed against the toxicity-related implications of this treatment strategy.

The impact of PSMA PET on the treatment and outcomes of men with biochemical recurrence of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Prostate-specific membrane antigen (PSMA) PET is highly sensitive in identifying disease recurrence in men with biochemical recurrence of prostate cancer (BCR) after primary therapy and is rapidly being adopted in clinical practice. The purpose of this systematic review and meta-analysis was to assess the documented impact of PSMA-PET on patient management and outcomes, including prostate-specific antigen (PSA) response, and intermediate and long-term outcome measures. MATERIALS AND METHODS: MBASE, PubMed, Web of Science, Cochrane and OVID databases were searched for studies reporting on the impact of PSMA-PET on the management and outcomes of patients with BCR after definitive primary therapy. Outcome measures assessed included biochemical response to therapy after PET and BCR-free survival (BRFS). The proportions of patients in whom management changed, and the proportion of patients in whom each outcome measure was obtained were tabulated and pooled into meta-analysis using DerSimonian-Laird method. RESULTS: A total of 34 studies with 3680 men reported change in management after PSMA-PET and 27 studies with 2639 men reported on at least one outcome measure and had follow-up data. PSMA-PET was positive in 2508/3680 (68.2%). The pooled proportion of change in management after PSMA-PET was 56.4% (95% CI, 48.0-63.9%). A decrease in serum PSA was documented in 72.4% of men (95% CI, 63.4-81.5%), and complete biochemical response in 23.3% (95% CI, 14.6-32.0%) at a median follow-up of 8.1 and 11 months, respectively. The pooled BRFS rate was 60.2% (95% CI, 49.1-71.4%) at a median follow-up of 20 months. CONCLUSION: In conclusion, PSMA PET is positive in more than 2/3 of men with BCR and impacts patient management in more than half of the men. BRFS after PET-directed management is 60% at a median of 20 months after salvage therapy, and complete biochemical response may be achieved in up to a quarter of men.