Dosimetric Features of Ultra-Hypofractionated Intensity Modulated Proton Therapy for Prostate Cancer.

Purpose: To report clinical and dosimetric characteristics of 5-fraction stereotactic ablative radiotherapy (SABR) using intensity modulated proton therapy (IMPT) for localized prostate cancer. Materials and Methods: All patients receiving IMPT SABR from 2017 to 2021 for localized prostate cancer at our institution were included. Five fractions were delivered every other day to the prostate +/- seminal vesicles [clinical target volume (CTV)] with 3 mm/3% robustness. A 4-field arrangement with 2 anterior oblique and 2 opposed lateral beams was used in most patients (97%), and most (99%) had a retroprostatic hydrogel spacer. Results: A total of 534 patients with low (14%), favorable intermediate (45%), unfavorable intermediate (36%), high (4.0%), or very high-risk (0.6%) disease are evaluated. Prescription dose was 36.25 Gy (31%), 38 Gy (38%), or 40 Gy (31%) was prescribed. Median volume percentage of CTV receiving at least 100% of prescription dose [V100% (%)] was 100% [interquartile range: 99.99-100]. Rectum V50% (%), V80% (%), and V90% (%) were significantly lower in patients who had spacer, with a mean difference of -9.70%, -6.59%, and -4.42%, respectively, compared to those who did not have spacer. Femoral head dose was lower with a 4-field arrangement. Mean differences in left and right femoral head V40% (%) were -6.99% and -10.74%, respectively. Conclusion: We provide a large, novel report of patients treated with IMPT SABR for localized prostate cancer. Four-field IMPT with hydrogel spacer provides significant sparing of rectum and femoral heads without compromising target coverage.

Preliminary Analysis of a Phase II Trial of Stereotactic Body Radiation Therapy for Prostate Cancer With High-Risk Features After Radical Prostatectomy.

Purpose: There are limited data regarding using stereotactic body radiation therapy (SBRT) in the postprostatectomy setting. Here, we present a preliminary analysis of a prospective phase II trial that aimed to evaluate the safety and efficacy of postprostatectomy SBRT for adjuvant or early salvage therapy. Materials and Methods: Between May 2018 and May 2020, 41 patients fulfilled inclusion criteria and were stratified into 3 groups: group I (adjuvant), prostate-specific antigen (PSA) < 0.2 ng/mL with high-risk features including positive surgical margins, seminal vesicle invasion, or extracapsular extension; group II (salvage), with PSA ≥ 0.2 ng/mL but < 2 ng/mL; or group III (oligometastatic), with PSA ≥ 0.2 ng/mL but < 2 ng/mL and up to 3 sites of nodal or bone metastases. Androgen deprivation therapy was not offered to group I. Androgen deprivation therapy was offered for 6 months for group II and 18 months for group III patients. SBRT dose to the prostate bed was 30 to 32 Gy in 5 fractions. Baseline-adjusted physician reported toxicities (Common Terminology Criteria for Adverse Events), patient reported quality-of-life (Expanded Prostate Index Composite, Patient-Reported Outcome Measurement Information System), and American Urologic Association scores were evaluated for all patients. Results: The median follow-up was 23 months (range, 10-37). SBRT was adjuvant in 8 (20%) patients, salvage in 28 (68%), and salvage with the presence of oligometastases in 5 (12%) patients. Urinary, bowel, and sexual quality of life domains remained high after SBRT. Patients tolerated SBRT with no grade 3 or higher (3+) gastrointestinal or genitourinary toxicities. The baseline adjusted acute and late toxicity grade 2 genitourinary (urinary incontinence) rate was 2.4% (1/41) and 12.2% (5/41). At 2 years, clinical disease control was 95%, and biochemical control was 73%. Among the 2 clinical failures, 1 was a regional node and the other a bone metastasis. Oligometastatic sites were salvaged successfully with SBRT. There were no in-target failures. Conclusions: Postprostatectomy SBRT was very well tolerated in this prospective cohort, with no significant effect on quality of life metrics postirradiation, while providing excellent clinical disease control.

Late Toxicity of Moderately Hypofractionated Intensity-Modulated Proton Therapy Treating the Prostate and Pelvic Lymph Nodes for High-Risk Prostate Cancer.

PURPOSE: To evaluate late gastrointestinal (GI) and genitourinary (GU) toxicity of moderately hypofractionated intensity modulated proton therapy (IMPT) targeting the prostate and pelvic lymph nodes. METHODS AND MATERIALS: A target accrual of 56 patients with high-risk or unfavorable intermediate risk prostate cancer were enrolled into a prospective study (ClinicalTrials.gov: NCT02874014) of moderately hypofractionated IMPT. IMPT with pencil beam scanning was used to deliver 6750 and 4500 cGy relative biological effectiveness in 25 daily fractions simultaneously to the prostate and pelvic lymph nodes, respectively. All received androgen deprivation therapy. Late GI and GU toxicity was prospectively assessed using Common Terminology Criteria for Adverse Events version 4.0, at baseline, weekly during radiation therapy, 3-month postradiation therapy, and then every 6 months. Actuarial rates of late GI and GU toxicity were estimated using Kaplan-Meier method. RESULTS: Median age was 75.5 years. Fifty-four patients were available for late toxicity evaluation. Median follow-up was 43.9 months (range, 16-66). The actuarial rate of late grade ≥2 GI toxicity at both 2 and 3 years was 7.4% (95% confidence interval [CI], 0.2%-14.2%). The actuarial rate of late grade 3 GI toxicity at both 2 and 3 years was 1.9% (95% CI, 0%-5.4%). One patient experienced grade 3 GI toxicity with proctitis. The actuarial rate of late grade ≥2 GU toxicity was 20.5% (95% CI, 8.9%-30.6%) at 2 years, and 29.2 % (95% CI, 15.5%-40.7%) at 3 years. None had grade 3 GU toxicity. The presence of baseline GU symptoms was associated with a higher likelihood of experiencing late grade 2 GU toxicity. CONCLUSIONS: A moderately hypofractionated IMPT targeting the prostate and regional pelvic lymph nodes was generally well tolerated. Patients with pre-existing GU symptoms had a higher rate of late grade 2 GU toxicity. A phase 3 study is needed to assess any therapeutic gain of IMPT, in comparison with photon-based radiation therapy.

A Phase II prospective study of hypofractionated proton therapy of prostate and pelvic lymph nodes: Acute effects on patient-reported quality of life.

BACKGROUND: The objective of this study was to report acute changes in patient-reported quality of life (PRQOL) using the 26-item Expanded Prostate Index Composite (EPIC-26) questionnaire in a prospective study using hypofractionated intensity-modulated proton beam therapy (H-IMPT) targeting the prostate and the pelvic lymph nodes for high-risk or unfavorable intermediate-risk prostate cancer. METHODS: Fifty-five patients were enrolled. H-IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC-26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation. RESULTS: The mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (-13.5 and -2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (-13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful. CONCLUSIONS: UO, UI, and BF scores of PRQOL declined at the end of H-IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.

The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

Approaching automated applicator digitization from a new angle: Using sagittal images to improve deep learning accuracy and robustness in high-dose-rate prostate brachytherapy.

PURPOSE: To automate the segmentation of treatment applicators on computed tomography (CT) images for high-dose-rate (HDR) brachytherapy prostate patients implanted with titanium needles with the goals of improving plan quality and reducing the patient's time under anesthesia. METHODS: The investigation was performed using 57 retrospective, interstitial prostate treatments randomly assigned to training (n = 27), validation (n = 10), and testing (n = 20). Unique to this work, the CT image set was reformatted into 2D sagittal slices instead of the default axial orientation. A deep learning-based segmentation was performed using a 2D U-Net architecture followed by a density-based linkage clustering algorithm to classify individual catheters in 3D. Potential confounders, such as gold seeds and conjoined applicators with intersecting needle geometries, were corrected using a customized polynomial fitting algorithm. The geometric agreement of the automated digitization was evaluated against the clinically treated manual digitization to measure tip and shaft errors in the reconstruction. RESULTS: The proposed algorithm achieved tip and shaft agreements of -0.1 ± 0.6 mm (range -1.8 mm to 1.4 mm) and 0.13 ± 0.09 mm (maximum 0.96 mm), respectively on a data set with 20 patients and 353 total needles. Our method was able to separate all intersecting applicators reliably. The time to generate the automated applicator digitization averaged approximately 1 min. CONCLUSIONS: Using sagittal instead of axial images for 2D segmentation of interstitial brachytherapy applicators produced submillimeter agreement with manual segmentation. The automated digitization of interstitial applicators in prostate brachytherapy has the potential to improve quality and consistency while reducing the patient's time under anesthesia.

Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.

Proton Therapy of Prostate and Pelvic Lymph Nodes for High Risk Prostate Cancer: Acute Toxicity.

PURPOSE: To assess acute gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and pelvic lymph nodes for prostate cancer. MATERIALS AND METHODS: A prospective study (ClinicalTrials.gov: NCT02874014), evaluating moderately hypofractionated IMPT for high-risk or unfavorable intermediate-risk prostate cancer, accrued a target sample size of 56 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 6750 and 4500 centigray radiobiologic equivalent (cGyRBE), respectively, in 25 daily fractions. All received androgen-deprivation therapy. Acute GI and GU toxicities were prospectively assessed from 7 GI and 9 GU categories of the Common Terminology Criteria for Adverse Events (version 4), at baseline, weekly during radiotherapy, and 3-month after radiotherapy. Fisher exact tests were used for comparisons of categorical data. RESULTS: Median age was 75 years. Median follow-up was 25 months. Fifty-five patients were available for acute toxicity assessment. Sixty-two percent and 2%, respectively, experienced acute grade 1 and 2 GI toxicity. Grade 2 GI toxicity was proctitis. Sixty-five percent and 35%, respectively, had acute grade 1 and 2 GU toxicity. The 3 most frequent grade 2 GU toxicities were urinary frequency, urgency, and obstructive symptoms. None had acute grade ≥ 3 GI or GU toxicity. The presence of baseline GI and GU symptoms was associated with a greater likelihood of experiencing acute GI and GU toxicity, respectively. Of 45 patients with baseline GU symptoms, 44% experienced acute grade 2 GU toxicity, compared with only 10% among 10 with no baseline GU symptoms (P = 0.07). Although acute grade 1 and 2 GI and GU toxicities were common during radiotherapy, most resolved at 3 months after radiotherapy. CONCLUSION: A moderately hypofractionated IMPT targeting the prostate/seminal vesicles and regional pelvic lymph nodes was well tolerated with no acute grade ≥ 3 GI or GU toxicity. Patients with baseline GU symptoms had a higher rate of acute grade 2 GU toxicity.

Assessing concordance between patient-reported and investigator-reported CTCAE after proton beam therapy for prostate cancer.

PURPOSE: We report acute patient-reported outcomes using CTCAE (PRO-CTCAE) of proton beam radiotherapy for high-risk or unfavorable intermediate-risk prostate cancer in a prospective clinical trial. PRO-CTCAE were correlated with investigator reported-CTCAE (IR-CTCAE) to assess the degree of concordance. METHODS AND MATERIALS: 11 PRO-CTCAE questions assessed gastrointestinal (GI), genitourinary (GU), or erectile function side effects. The correlation scheme between PRO-CTCAE and IR-CTCAE was independently developed by two physicians. Analyses of PRO-CTCAE and IR-CTCAE were conducted using both descriptive terms and the converted grade scores. The Kappa statistic described the degree of concordance. RESULTS: 55 patients were included. IR-CTCAE underestimated diarrhea compared to PRO-CTCAE at the end of treatment (EOT), with a 28% rate of underestimation (11% by ≥ 2 toxicity grades). Similarly, urinary tract pain was underestimated in 45% of cases (17% by ≥ 2 grades) at EOT. Differences were less pronounced at baseline or 3 months after radiotherapy. The incidence of urinary urgency and frequency tended to be overestimated prior to treatment (36% and 24%, respectively) but underestimated at EOT (35% and 31%, respectively). The degree of interference with daily activities was consistently overestimated by investigators (45%-85%). Finally, erectile dysfunction showed a 36-56% rate of discordance by ≥ 2 toxicity grades. CONCLUSIONS: Our study shows a low agreement between IR-CTCAE and PRO-CTCAE in the setting of proton therapy for prostate cancer. Compared to patient-reported outcomes, physicians underestimated the frequency and severity of urinary symptoms and diarrhea at the end of treatment. Continued use of PROs should be strongly encouraged.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Elective pelvic nodal irradiation with a simultaneous hypofractionated integrated prostate boost for localized high risk prostate cancer: Long term results from a prospective clinical trial.

BACKGROUND: To report on long-term results of elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost for high-risk prostate cancer. MATERIALS AND METHODS: This was a prospective single-arm study. Patients with high-risk disease (cT3, PSA >20 ng/mL, or Gleason score 8-10) were eligible. Patients received 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous intensity-modulated radiotherapy boost of 22.5 Gy to the prostate (total dose 67.5 Gy in 25 fractions), with androgen deprivation therapy (ADT) for 2-3 years. The primary endpoint was biochemical failure. Secondary endpoints included distant metastases and overall survival. Multivariable analysis was performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0. RESULTS: 230 patients enrolled. Median follow-up was 11.2 years (IQR 8.1-12.9). At 10 years, cumulative incidence of biochemical failure was 33.4%, distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir ≥0.05 ng/mL was associated with biochemical failure (HR 6.8, 95% CI 4-11.8, p < 0.001) and distant metastases (HR 7.5, 95% CI 3.9-14.5, p < 0.0001). PSA nadir ≥0.1 ng/mL (HR 5.2, 95% 2.2-12, p = 0.0001) and ADT use ≤12 months (versus >24 months) (HR 2.3, 95% CI 1.3-3.9, p = 0.004) were associated with worse survival. The 5-year cumulative incidence of any late grade ≥3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively. CONCLUSION: EPNI and a simultaneous hypofractionated prostate boost combined with long-term ADT for high-risk prostate cancer resulted in acceptable 10-year biochemical control and survival with low grade ≥3 toxicity.

Predictors of Locoregional Recurrence and Delineation of Adjuvant Radiation Therapy Fields for Patients With Upper Tract Urothelial Carcinoma Receiving Nephroureterectomy.

PURPOSE: To identify factors predictive of locoregional recurrence (LRR) in upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy and to propose adjuvant radiation therapy (ART) fields. METHODS AND MATERIALS: Clinical and pathologic variables for patients receiving nephroureterectomy for UTUC between 1995 and 2009 were analyzed for associations with outcomes. Sites of LRR from all patients with available imaging (39) were contoured on computed tomography image sets of patients with representative anatomy, and ART fields were proposed based on these distributions. RESULTS: A total of 279 patients with a median follow-up of 13.0 years were analyzed. The 5-year cumulative incidence of LRR was 16.7% (95% CI, 12.2-21). Pathologic risk factors (PRFs) associated with increased risk of LRR included tumor in both the renal pelvis and ureter, T stage ≥2, lymph node involvement, grade 3 histology, and positive surgical margins (P < .05). Patients with an increased number of PRFs had a significantly greater risk of LRR. The 5-year cumulative incidence estimates of LRR were 5.3% (95% CI, 1.8%-16.0%), 15.6% (95% CI, 9.5%-25.7%), and 43.9% (95% CI, 31.1%-62.1%) for those with 1, 2, and ≥3 PRFs, respectively. ART fields covering the renal fossa and retroperitoneal lymph nodes from the superior border of L1 through the aortic bifurcation would encompass all sites of LRR for 33 of 46 patients (72%). Non-LRR bladder and distant failure occurred in 101 (36.2%) and 73 (26.2%) of the patients, respectively. The 5-year cumulative incidence estimate of distant failure was 22.5% (95% CI, 17.4%-27.3%). CONCLUSIONS: In patients receiving nephroureterectomy for UTUC, LRR is significantly increased in patients with 2 or more PRFs. These data provide clinically valuable insight into the selection of candidates for ART and the design of ART fields.

Comparing bowel and urinary domains of patient-reported quality of life at the end of and 3 months post radiotherapy between intensity-modulated radiotherapy and proton beam therapy for clinically localized prostate cancer.

PURPOSE: To prospectively assess acute differences in patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer. METHODS AND MATERIALS: Bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26 were collected in patients with T1-T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015-2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post-radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation. RESULTS: A total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (-13.0 vs -6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post-radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (-9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (-1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post-radiotherapy. CONCLUSIONS: PBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

Outcomes and Profiles of Older Patients Receiving Definitive Radiation Therapy for Muscle-Invasive Bladder Cancer at a Tertiary Medical Center.

PURPOSE: Our purpose was to evaluate the outcomes and profiles of older patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiation therapy (RT) with or without chemotherapy (CHT) at a tertiary medical center. METHODS AND MATERIALS: A retrospective study was conducted for older patients with MIBC who were ≥70 years old and underwent RT with or without CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model. RESULTS: A total of 84 patients underwent definitive RT with or without CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy, and the remainder were medically unfit or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal transurethral resection of bladder tumor before RT. Seventy-three percent received CHT with RT, and 27% had RT alone. Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo radical cystectomy, receipt of CHT, lower T stage, and maximal transurethral resection of bladder tumor were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 genitourinary and gastrointestinal toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity. CONCLUSIONS: Older patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT with or without CHT was well tolerated and yielded encouraging treatment outcomes.

Is there any benefit in adding postoperative adjuvant concurrent radiotherapy and chemotherapy for penile cancer with regional lymph node metastasis?

BACKGROUND: The aim of this study was to evaluate whether there is any benefit in adding postoperative adjuvant concurrent radiotherapy and chemotherapy (RT-CHT) for penile cancer with regional lymph node metastasis (RLNM). METHODS: A single institution, retrospective study was conducted for a total of 23 patients with RLNM from penile squamous cell carcinoma. All underwent a definitive surgical intervention for both primary tumor and RLNM. Of these, 11 patients received adjuvant concurrent RT and CHT within 3 months after surgery (RT-CHT group), while 12 patients received no additional treatment (Surveillance Group). Overall survival was calculated with the Kaplan-Meier method. The difference in survival between the two groups was tested using the log-rank test. A potential prognostic factor for survival was evaluated using a univariate Cox-proportional hazards model. RESULTS: Median follow-up for the entire group was 15.8 months (17.1 months for the RT-CHT group and 10.7 months for the Surveillance Group). Overall survival at 1 and 2 years were 54.5% and 27.2%, respectively, for the RT-CHT Group, compared to 57.1% and 28.4% for the Surveillance Group (log-rank=0.68). On a univariate analysis, the number of involved lymph nodes and the presence of pN3 disease were associated with poor prognosis (P>0.001 and P=0.049, respectively). The RT-CHT Group had more extensive RLNM with a higher median number of positive nodes (5 vs. 3) and more pN3 disease (72.7% vs. 16.7%) than the Surveillance Group. The rate of complications requiring hospitalization was higher in the RT-CHT Group (63.6% vs. 16.6%; P=0.02), as was the rate of systemic complications (34.7% vs. 0%; P<0.01). CONCLUSIONS: Penile cancer with extensive RLNM carries a poor prognosis. Despite having more extensive RLNM, the RT-CHT group had a similar overall survival as the Surveillance Group. This suggests a potential benefit of postoperative adjuvant concurrent RT-CHT for patients with extensive RLNM, although it carries an increased risk of complications. Further study is warranted to assess the benefit-to-risk ratio of this combined adjuvant therapy.

IMPT versus VMAT for Pelvic Nodal Irradiation in Prostate Cancer: A Dosimetric Comparison.

PURPOSE: To compare dosimetric data of the organs at risk (OARs) and clinical target volumes (CTVs) between intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT) for patients undergoing prostate and elective, pelvic lymph node radiotherapy in the setting of unfavorable, intermediate and high-risk prostate carcinoma. METHODS AND MATERIALS: A study of moderately hypofractionated proton therapy (6750 centigray [cGy] in 25 fractions) is in progress for unfavorable, intermediate and high-risk prostate cancer where treatment includes an elective pelvic nodal CTV (4500 cGy in 25 fractions). Ten consecutively accrued patients were the subjects for dose-volume histogram comparison between IMPT and VMAT. Two treatment plans (IMPT and VMAT) were prepared for each patient with predefined planning objectives for target volumes and OARs. The IMPT plans were prepared with 2 lateral beams and VMAT plans with 2 arcs. RESULTS: The CTV coverage was adequate for both plans with 99% of CTVs receiving ≥ 100% of the prescription doses. Mean doses to the bladder, rectum, large bowel, and small bowel were lower with IMPT versus VMAT. Mean femoral head dose was greater with IMPT. The percentage of volumes of rectum receiving ≤ 47.5 Gy, large bowel receiving ≤ 27.5 Gy, small bowel receiving ≤ 30 Gy, and bladder receiving ≤ 37.5 Gy was less with IMPT versus VMAT, largely because of reduction in the low-dose "bath" associated with VMAT. CONCLUSIONS: In the setting of prostate and elective, pelvic nodal radiotherapy for prostate cancer, IMPT can significantly reduce the dose to OARs, in comparison to VMAT, and provide adequate target coverage.

Single-fraction Stereotactic Body Radiation Therapy versus Conventionally Fractionated Radiation Therapy for the Treatment of Prostate Cancer Bone Metastases.

PURPOSE: This study aimed to compare outcomes of patients with prostate cancer with bone metastases treated with stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT). METHODS AND MATERIALS: An institutional, retrospective review was conducted of patients with prostate cancer receiving radiation therapy to bone metastases. In-field failure (IFF) was the primary outcome of the study, and distant failure (DF) and biochemical failure (BF) were secondary outcomes. RESULTS: A total of 249 metastases (191 SBRT; 58 CFRT) in 201 patients with a median follow-up of 2.2 years were analyzed. The SBRT prescription dose was predominantly 18 Gy (45.5%) or 20 Gy (46.6%) in a single fraction. CFRT was given either as 8 Gy in 1 fraction (56.9%) or 20 Gy in 5 fractions (41.4%). Imaging follow up was performed most frequently with 11C-choline positron emission tomography/computed tomography (79%) or bone scan (10%). The median time to IFF was 1.6 years for CFRT-treated lesions and not met (>4.4 years) for SBRT. The 1- and 3-year IFF estimates were 34.4% (95% confidence interval [CI], 19.9-46.2) and 53.3% (95% CI, 34.3-66.8) for lesions treated with CFRT compared with 4.5% (95% CI, 1.4-7.5) and 12.9% (95% CI, 6.6-18-8) for those treated with SBRT (P < .01). On multivariate regression, the hazard ratio (HR) for IFF with CFRT compared with SBRT was 6.8 (95% CI, 3.7-12.5; P < .01). There were nonsignificant reduced rates of BF (HR, 1.4; 95% CI, 1.0-2.1; P = .05) and DF (HR, 1.3; 95% CI, 1.0-1.8; P = .08) in patients who received SBRT. The 3-year BF and DF estimates in these patients were 88.6% (95% CI, 82.0-92.8) and 82.2% (95% CI, 74.5-87.6), respectively. CONCLUSIONS: SBRT for the management of prostate cancer bone metastases significantly reduces radiographic IFF. However, the high rate of subsequent DF and BF highlights the challenges in selecting patients who may benefit from aggressive radiation therapy.

Low dose rate prostate brachytherapy.

Low dose rate (LDR) prostate brachytherapy is an evidence based radiation technique with excellent oncologic outcomes. By utilizing direct image guidance for radioactive source placement, LDR brachytherapy provides superior radiation dose escalation and conformality compared to external beam radiation therapy (EBRT). With this level of precision, late grade 3 or 4 genitourinary or gastrointestinal toxicity rates are typically between 1% and 4%. Furthermore, when performed as a same day surgical procedure, this technique provides a cost effective and convenient strategy. A large body of literature with robust follow-up has led multiple expert consensus groups to endorse the use of LDR brachytherapy as an appropriate management option for all risk groups of non-metastatic prostate cancer. LDR brachytherapy is often effective when delivered as a monotherapy, although for some patients with intermediate or high-risk disease, optimal outcome are achieved in combination with supplemental EBRT and/or androgen deprivation therapy (ADT). In addition to reviewing technical aspects and reported clinical outcomes of LDR prostate brachytherapy, this article will focus on the considerations related to appropriate patient selection and other aspects of its use in the treatment of prostate cancer.

Increased utilization of external beam radiotherapy relative to cystectomy for localized, muscle-invasive bladder cancer: a SEER analysis.

OBJECTIVE: To assess recent utilization patterns of radiotherapy (RT) relative to cystectomy for muscle-invasive bladder cancer (MIBC) and evaluate survival trends over time in patients receiving RT. MATERIALS AND METHODS: The surveillance, epidemiology, and end results program (SEER) was used to identify patients diagnosed between 1992 and 2013 with localized MIBC. Patients with a prior history of non-bladder malignancy, who received no treatment, or did not have available treatment information, were excluded. Treatment utilization patterns were assessed using Cochran-Armitage tests for trend, and patient characteristics were compared using chi-square tests. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. All-cause (ACM) and cause-specific mortality (CSM) were evaluated with multivariable Cox proportional hazards regression. RESULTS: Of 16175 patients analyzed, 11917 (74%) underwent cystectomy, and 4258 (26%) were treated with RT. Patients who received RT were older (median age 79 vs. 68, P < 0.01). Over time, the proportion of patients receiving RT relative to cystectomy increased (24% 1992-2002 vs. 28% 2003-2013, P < 0.01), despite median patient age throughout the study period remaining unchanged (71 for each 1992-2002 and 2003-2013, P = 0.41). For RT, compared with patients diagnosed earlier, those diagnosed from 2010-2013 showed improved OS (64% vs. 60% at 1 year, P < 0.01; 38% vs. 29% at 3 years, P < 0.01) and CSS (71% vs. 67% at 1 year, P = 0.01; 51% vs. 40% at 3 years, P < 0.01). On multivariable analysis, diagnosis from 2010-2013 was associated with a lower estimated risk of ACM (hazard ratio 0.77; 95% confidence interval 0.66-0.89, P < 0.001) and CSM (hazard ratio 0.81; 95% confidence interval 0.67-0.97, P = 0.02). CONCLUSION: Utilization of RT for localized MIBC increased relative to cystectomy from 1992 to 2013, despite the median age of treated patients remaining unchanged. More recent survival outcomes for patients receiving RT were improved, supporting continued use of bladder preservation strategies utilizing RT.

Proton Therapy for Stage IIA-B Seminoma: A New Standard of Care for Treating Retroperitoneal Nodes.

Currently there has been no published report describing the use of proton beam therapy for stage II testicular seminoma. A 31-year-old man presenting with a right testicular mass and a 2.7-cm aortocaval lymph node received a diagnosis of stage IIB testicular seminoma. He was treated with scanning proton beam therapy, as a means of improving the therapeutic ratio of radiation therapy over conventionally used x-ray radiation therapy. The patient achieved a complete response and remained free of relapse at 15 months post proton beam therapy. The advantageous dose deposition characteristics of proton beam, allowing much lower radiation doses to normal tissues, should be exploited when radiation therapy is applied for stage II testicular seminoma or for an isolated retroperitoneal lymph node relapse of stage I disease initially managed with surveillance.