Faculty Bibliography

PURPOSE:High-dose SABR for prostate cancer offers the radiobiologic potency of the most intensified radiation therapy regimens but was associated with >90% rates of ulceration of the anterior rectal wall on endoscopic assessment; this infrequently progressed to severe rectal toxicity in prior prospective series. A multi-institutional phase 2 prospective trial was conducted to assess whether placement of a perirectal hydrogel spacer would reduce acute periprostatic rectal ulcer events after high-dose (>40 Gy) SABR. METHODS AND MATERIALS:. Patients underwent perirectal hydrogel spacer placement, followed by SABR of 45 Gy in 5 fractions every other day to the prostate only. Androgen deprivation was not allowed except for cytoreduction. The rectal wall was directly assessed by serial anoscopy during follow-up to determine whether the spacer would reduce acute periprostatic rectal ulcer events from >90% to <70% within 9 months of treatment. RESULTS:Forty-four men were enrolled and 43 were eligible for protocol analysis. The median follow-up for surviving patients was 48 months. Acute periprostatic ulcers were observed in 6 of 42 patients (14.3%; 95% confidence interval, 6.0%-27%; P < .001) at a median of 2.9 months posttreatment (range, 1.7-5.6 months). All ulcers (grade 1, 5 ulcers; grade 2, 1 ulcer) resolved on repeat anoscopy within 8 months of incidence. There were no grade ≥3 late gastrointestinal toxicities; the incidence of late grade-2 gastrointestinal toxicities was 14.3%, with a prevalence at 3 years of 0%. No toxicities greater than grade 3 occurred in any domain. Four-year freedom from biochemical failure was 93.8% (95% CI, 85.2%-100.0%). CONCLUSIONS:Temporary hydrogel spacer placement before high-dose SABR treatment for localized prostate cancer and use of strict dose constraints are associated with a significant reduction in the incidence of rectal ulcer events compared with prior phase 1/2 trial results.

BACKGROUND:Sildenafil citrate has been shown to be protective of sexual function when given concurrently and following prostate radiation therapy (RT), but some evidence suggests an increased biochemical recurrence (BCR) risk in patients taking sildenafil after radical prostatectomy. AIM/OBJECTIVE:To evaluate whether sildenafil use is associated with increased risk of BCR in patients receiving prostate RT, we performed a secondary analysis of a randomized placebo-controlled trial (RPCT) that compared sildenafil citrate to placebo during and after prostate RT. METHODS:The study population consisted of prostate cancer patients who initiated radiation treatment at our institution and participated in our multi-institutional RPCT that compared 6 months of sildenafil 50 mg once a day to placebo with a 24-month follow-up. Androgen deprivation therapy (ADT) was allowed. Prostate cancer prognostic risk grouping was not an exclusion criterion, but most study participants had low- or intermediate-risk prostate cancer. Statistical analysis was performed using Kaplan-Meier plots and log-rank testing. OUTCOMES/RESULTS:The primary outcomes of this report were biochemical recurrence and overall survival rates, where BCR was defined according to the Phoenix definition. RESULTS:Data of 162 men were analyzed. Nine men had inadequate PSA follow-up and the remaining 153 men were included in the final report. Median age was 61 years. At a median follow-up of 8.3 years (range: 3.0-12.2), 5/94 (5.3%) and 2/59 (3.4%) patients developed BCR in the sildenafil and placebo groups, respectively. The 6-year BCR-free survival was 98.8% for all patients, 98.1% for the sildenafil cohort, and 100% for the placebo cohort. The 10-year BCR-free survival was 94.4% for all patients, 95.6% for the sildenafil cohort, and 92.9% for the placebo cohort. There was no difference in BCR-free survival between the sildenafil and placebo groups by log-rank comparison (p = 0.36). CLINICAL IMPLICATIONS/CONCLUSIONS:This analysis informs clinical decision making about the safety of using sildenafil during and after prostate RT. STRENGTHS AND LIMITATIONS/UNASSIGNED:This study included patients who were treated in the setting of a prospective, randomized placebo-controlled trial, and who attained high medication compliance. However, the study was limited by the post-hoc nature of the analysis, use of ADT in some patients, inadequate study power to detect a difference in BCR between sildenafil and placebo groups. CONCLUSION/CONCLUSIONS:Prophylactic sildenafil citrate was not associated with biochemical recurrence risk in prostate cancer patients treated with radiation. However, the study was inadequately powered to definitively conclude a negative finding.

BACKGROUND:Sildenafil citrate has been shown to be protective of sexual function when given concurrently and following prostate radiation therapy (RT), but some evidence suggests an increased biochemical recurrence (BCR) risk in patients taking sildenafil after radical prostatectomy. AIM:To evaluate whether sildenafil use is associated with increased risk of BCR in patients receiving prostate RT, we performed a secondary analysis of a randomized placebo-controlled trial (RPCT) that compared sildenafil citrate to placebo during and after prostate RT. METHODS:The study population consisted of prostate cancer patients who initiated radiation treatment at our institution and participated in our multi-institutional RPCT that compared 6 months of sildenafil 50 mg once a day to placebo with a 24-month follow-up. Androgen deprivation therapy (ADT) was allowed. Prostate cancer prognostic risk grouping was not an exclusion criterion, but most study participants had low- or intermediate-risk prostate cancer. Statistical analysis was performed using Kaplan-Meier plots and log-rank testing. OUTCOMES:The primary outcomes of this report were biochemical recurrence and overall survival rates, where BCR was defined according to the Phoenix definition. RESULTS:Data of 162 men were analyzed. Nine men had inadequate PSA follow-up and the remaining 153 men were included in the final report. Median age was 61 years. At a median follow-up of 8.3 years (range: 3.0-12.2), 5/94 (5.3%) and 2/59 (3.4%) patients developed BCR in the sildenafil and placebo groups, respectively. The 6-year BCR-free survival was 98.8% for all patients, 98.1% for the sildenafil cohort, and 100% for the placebo cohort. The 10-year BCR-free survival was 94.4% for all patients, 95.6% for the sildenafil cohort, and 92.9% for the placebo cohort. There was no difference in BCR-free survival between the sildenafil and placebo groups by log-rank comparison (p = 0.36). CLINICAL IMPLICATIONS:This analysis informs clinical decision making about the safety of using sildenafil during and after prostate RT. STRENGTHS AND LIMITATIONS:This study included patients who were treated in the setting of a prospective, randomized placebo-controlled trial, and who attained high medication compliance. However, the study was limited by the post-hoc nature of the analysis, use of ADT in some patients, inadequate study power to detect a difference in BCR between sildenafil and placebo groups. CONCLUSION:Prophylactic sildenafil citrate was not associated with biochemical recurrence risk in prostate cancer patients treated with radiation. However, the study was inadequately powered to definitively conclude a negative finding. Haseltine JM, Hopkins M, Schofield E, et al. Sildenafil Citrate and Risk of Biochemical Recurrence in Prostate Cancer Patients Treated With Radiation Therapy: Post-Hoc Analysis of a Randomized Controlled Trial. J Sex Med 2021;18:1467-1472.

BACKGROUND:Salvage partial gland ablation (sPGA) has been proposed to treat some localized radiorecurrent prostate cancer. The role of prostate biopsy and magnetic resonance imaging (MRI) characteristics to identify patients eligible for sPGA is unknown. OBJECTIVE:To evaluate the ability of MRI and prostate biopsy characteristics to identify an index lesion suitable for sPGA and validate this selection using detailed tumor maps created from whole-mount slides from salvage radical prostatectomy (sRP) specimens. DESIGN, SETTING, AND PARTICIPANTS:Men who underwent sRP for recurrent prostate cancer following primary radiotherapy with external beam radiotherapy (EBRT) and/or brachytherapy between 2000 and 2014 at a single high-volume cancer center were eligible. Those with tumor maps, MRI and biopsy data were included in analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Primary outcome was the ability of clinicopathologic and imaging criteria to identify patients who may be eligible for sPGA based on detailed tumor map from whole-mount sRP slides. RESULTS AND LIMITATIONS:Of 216 men who underwent sRP following whole gland radiotherapy, tumor maps, MRI, and biopsy data were available for 77. Of these, 15 (19%) were determined to be eligible for sPGA based on biopsy-proven unilateral disease in contiguous sextant segments, a dominant lesion on MRI concordant with biopsy location or no focal region of interest, and no imaging evidence of extraprostatic disease. Review of tumor maps identified 6 additional men who would have met criteria for sPGA, resulting in sensitivity of 71% (95% C.I. 48%-89%) and specificity of 100% (lower bound of 95% C.I. 94%). None of the 15 men who met the criteria for sPGA on clinical data were identified incorrectly on tumor maps to require full gland surgery (upper bound of 95% C.I. 22%). Median tumor volume of the index lesion was 0.4 cc and recurrent cancer was noted in the apex, mid-gland, and base in 81%, 100%, and 29% of men. CONCLUSIONS:In men with recurrent prostate cancer after radiotherapy, biopsy findings and MRI can be used to select index lesions potentially amenable for sPGA and can guide patient evaluation for inclusion in clinical trials of sPGA following radiation failure. Larger, prospective studies are required to evaluate both the role of MRI and clinical criteria in guiding focal salvage therapy and the effectiveness of this modality for radiorecurrent prostate cancer.

PURPOSE:This prospective phase 3 randomized trial was designed to test whether ultra high single-dose radiation therapy (24 Gy SDRT) improves local control of oligometastatic lesions compared to a standard hypofractionated stereotactic body radiation therapy regimen (3 × 9 Gy SBRT). The secondary endpoint was to assess the associated toxicity and the impact of ablation on clinical patterns of metastatic progression. METHODS AND MATERIALS:Between November 2010 and September 2015, 117 patients with 154 oligometastatic lesions (≤5/patient) were randomized in a 1:1 ratio to receive 24 Gy SDRT or 3 × 9 Gy SBRT. Local control within the irradiated field and the state of metastatic spread were assessed by periodic whole-body positron emission tomography/computed tomography and/or magnetic resonance imaging. Median follow-up was 52 months. RESULTS:A total of 59 patients with 77 lesions were randomized to 24 Gy SDRT and 58 patients with 77 lesions to 3 × 9 Gy SBRT. The cumulative incidence of local recurrence for SDRT-treated lesions was 2.7% (95% confidence interval [CI], 0%-6.5%) and 5.8% (95% CI, 0.2%-11.5%) at years 2 and 3, respectively, compared with 9.1% (95% CI, 2.6%-15.6%) and 22% (95% CI, 11.9%-32.1%) for SBRT-treated lesions (P = .0048). The 2- and 3-year cumulative incidences of distant metastatic progression in the SDRT patients were 5.3% (95% CI, 0%-11.1%), compared with 10.7% (95% CI, 2.5%-18.8%) and 22.5% (95% CI, 11.1%-33.9%), respectively, for the SBRT patients (P = .010). No differences in toxicity were observed. CONCLUSIONS:The study confirms SDRT as a superior ablative treatment, indicating that effective ablation of oligometastatic lesions is associated with significant mitigation of distant metastatic progression.

BACKGROUND AND PURPOSE:Artificial intelligence advances have stimulated a new generation of autosegmentation, however clinical evaluations of these algorithms are lacking. This study assesses the clinical utility of deep learning-based autosegmentation for MR-based prostate radiotherapy planning. MATERIALS AND METHODS:Data was collected prospectively for patients undergoing prostate-only radiation at our institution from June to December 2019. Geometric indices (volumetric Dice-Sørensen Coefficient, VDSC; surface Dice-Sørensen Coefficient, SDSC; added path length, APL) compared automated to final contours. Physicians reported contouring time and rated autocontours on 3-point protocol deviation scales. Descriptive statistics and univariable analyses evaluated relationships between the aforementioned metrics. RESULTS:Among 173 patients, 85% received SBRT. The CTV was available for 167 (97%) with median VDSC, SDSC, and APL for CTV (prostate and SV) 0.89 (IQR 0.83-0.95), 0.91 (IQR 0.75-0.96), and 1801 mm (IQR 1140-2703), respectively. Physicians completed surveys for 43/55 patients (RR 78%). 33% of autocontours (14/43) required major "clinically significant" edits. Physicians spent a median of 28 min contouring (IQR 20-30), representing a 12-minute (30%) time savings compared to historic controls (median 40, IQR 25-68, n = 21, p < 0.01). Geometric indices correlated weakly with contouring time, and had no relationship with quality scores. CONCLUSION:Deep learning-based autosegmentation was implemented successfully and improved efficiency. Major "clinically significant" edits are uncommon and do not correlate with geometric indices. APL was supported as a clinically meaningful quantitative metric. Efforts are needed to educate and generate consensus among physicians, and develop mechanisms to flag cases for quality assurance.

PURPOSE:To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. MATERIALS AND METHODS:257 patients treated with prostate SBRT to dose levels of 32.5 Gy to >40 Gy in 5-6 fractions underwent a post-treatment biopsy performed approximately two years after treatment to evaluate local control status. 73 had% intermediate-risk disease (n = 187) and the remaining 17% (n = 43) and 10% (n = 27) had low-risk and high-risk disease, respectively. RESULTS:The incidence of positive, negative, and treatment-effect post-treatment biopsies were 15.6%, 57.6%, and 26.8%, respectively. The incidence of a positive biopsy according to dose was 37.5% (n = 9/24), 21.4% (n = 6/28), 19.4% (n = 6/31), and 10.9% (n = 19/174) for 32.5 Gy, 35 Gy, 37.5 Gy, and >40 Gy, respectively. In a multivariable model, patients treated with SBRT doses of <40 Gy and those with unfavorable-intermediate-risk or high-risk disease had higher likelihood of a positive post-treatment biopsy. A positive post-SBRT biopsy was associated with a significantly higher likelihood of subsequent PSA relapse at five years (Positive biopsy: 57%, 95% CI: 29-77% compared to negative biopsy: 7%, 95% CI: 3-14%; p < 0.001). CONCLUSION:Based on two-year post-SBRT biopsies, excellent tumor control was achieved when dose levels of 40 Gy or higher were used. Standard SBRT dose levels of 35-37.5 Gy were associated with a higher likelihood of a positive post-treatment biopsy. Two-year positive post-treatment biopsies pre-dated the development of PSA failure in the majority of patients.

PURPOSE:We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival. MATERIALS AND METHODS:For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively. RESULTS:The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all). CONCLUSION:Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.

BACKGROUND:Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. METHODS:We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. RESULTS:Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. CONCLUSIONS:We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.