A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

BACKGROUND: We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). METHODS: This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. RESULTS: 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). CONCLUSIONS: This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

A dosimetric analysis of rectal hydrogel spacer use in patients with recurrent prostate cancer undergoing salvage high-dose-rate brachytherapy.

PURPOSE: We hypothesize rectal hydrogel spacer (RHS) improves rectal dosimetry in patients undergoing salvage high-dose-rate brachytherapy (HDR-BT) for intact, recurrent prostate cancer (PC). METHODS AND MATERIALS: A prospectively collected institutional database was queried for recurrent PC patients treated with salvage HDR-BT from September 2015 to November 2021. Patients were offered RHS beginning June 2019. Dosimetric variables were compared between RHS and no-RHS groups for the average of two fractions using Wilcoxon rank-sum tests. Primary outcomes were rectal volume receiving 75% of prescription dose (V75%) and prostate volume receiving 100% of prescription dose (V100%). Generalized estimating equation (GEE) model was used to evaluate the association between other planning variables and rectal V75%. RESULTS: Forty-one PC patients received salvage HDR-BT, of whom 20 had RHS. All patients received 2400cGy in 2 fractions. Median RHS volume was 6.2cm3 (Standard deviation [SD]: ± 3.5cm3). Median follow-up was 4 months and 17 months in the RHS and no-RHS groups, respectively. Median rectal V75% with and without RHS were 0.0cm3 (IQR: 0.0-0.0cm3) and 0.06cm3 (IQR: 0.0-0.14cm3), respectively (p<0.001). Median prostate V100% with and without RHS were 98.55% (IQR: 97.86-99.22%) and 97.78% (IQR: 97.50-98.18%), respectively (p = 0.007). RHS, rectum, and prostate volumes did not significantly affect rectal V75% per GEE modeling. There was 10% G1-2 and 5% G3 rectal toxicity in RHS group. There was 9.5% G1-2 and no G3+ rectal toxicities in the no-RHS group. CONCLUSIONS: Absolute improvement in rectal V75% and prostate V100% was significant with RHS in PC patients undergoing salvage HDR-BT, but clinical benefit is marginal.

A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites. INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer.

PURPOSE: The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. METHODS AND MATERIALS: A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. RESULTS: Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P = .53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P = .86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P = .54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P = .77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. CONCLUSIONS: ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Early Prostate-Specific Antigen Kinetics for Low- and Intermediate-Risk Prostate Cancer Treated With Definitive Radiation Therapy.

PURPOSE: This study used a patient-specific model to characterize and compare ideal prostate-specific antigen (PSA) kinetics for low- and intermediate-risk prostate cancer after definitive radiation treatment with conventionally fractionated, hypofractionated, stereotactic body radiation therapy, or brachytherapy, both high-dose and low-dose rate. METHODS AND MATERIALS: This retrospective analysis includes low- and intermediate-risk patients with prostate cancer treated between 1998 and 2018 at an National Cancer Institute-designated comprehensive cancer center. Demographics and treatment characteristics were prospectively collected. Patients had at least 2 PSA measurements within 24 months of treatment and were free from biochemical recurrence. The incidence of, time to, and risk factors for PSA nadir (nPSA) and bounce (bPSA) were analyzed at 24 months after radiation therapy. Ideal PSA kinetics were characterized for each modality and compared. RESULTS: Of 1042 patients, 45% had low-risk cancer, 37% favorable intermediate risk, and 19% unfavorable intermediate risk. nPSAs were higher for ablative modalities, both as absolute nPSA and relative to initial PSA. Median time to nPSA ranged from 14.8 to 17.1 months. Over 50% treated with nonablative therapy (conventionally fractionated, hypofractionated, and low-dose rate) reached an nPSA threshold of ≤0.5 ng/mL compared with 23% of stereotactic body radiation therapy and 33% of high-dose rate cohorts. The incidence of bPSA was 13.3% and not affected by treatment modality, Gleason score, or prostate volume. PSA decay rate was faster for ablative therapies in the 6- to 24-month period. CONCLUSIONS: Analysis of PSA within 24 months after radiation therapy revealed ablative therapies are associated with a latent PSA response and higher nPSA. Multivariable logistics modeling revealed younger age, initial PSA above the median, presence of bPSA, and ablative therapy as predictors for not achieving nPSA ≤0.5 ng/mL. PSA decay rate appears to be faster in ablative therapies after a latent period. Understanding the different PSA kinetic profiles is necessary to assess treatment response and survey for disease recurrence.

Identification of oncological characteristics associated with improved overall survival in patients with adrenocortical carcinoma treated with adjuvant radiation therapy: Insights from the National Cancer Database.

OBJECTIVES: To test for an association between oncological risk factors and overall survival in patients with non-metastatic adrenocortical carcinoma treated with adjuvant radiation therapy at high-risk for recurrence per NCCN guidelines. MATERIALS AND METHODS: We analyzed data from patients undergoing surgical resection with or without aRT in the NCDB from 2004 to 2017. A multivariable Cox proportional hazards model was fit to assess for an association of aRT and OS. To determine whether aRT was associated with improved OS in patients with specific NCCN risk factors, we fit three multivariable Cox proportional hazard models with an interaction term between NCCN risk factors and the use of aRT. RESULTS: We identified 1,433 patients treated surgically for adrenocortical carcinoma with at least one risk factor. 259 patients received adjuvant radiation therapy (18%) while 1,174 (82%) patients did not. After adjustment, we noted a significant association between adjuvant radiation therapy and overall survival in the entire cohort in the multivariable Cox proportional hazards model (HR 0.68, 95% CI 0.55-0.85, P = 0.001). Adjuvant radiation therapy was associated with increased overall survival in patients with positive surgical margins (HR 0.47, 95% CI 0.35-0.65, P < 0.001), large tumor size ≥6 cm (HR 0.69, 95% CI 0.55-0.87, P = 0.002), and high-grade disease (HR 0.61, 95% CI 0.37-0.99, P = 0.046). CONCLUSIONS: Patients with ACC at high-risk for recurrence were associated with improved overall survival when treated with adjuvant radiation therapy. These data may help identify which patients should consider aRT after resection of clinically localized ACC.

Patient-reported Quality of Life After SBRT, LDR, and HDR Brachytherapy for Prostate Cancer: A Comparison of Outcomes.

PURPOSE: We sought to compare changes in patient-reported quality of life (PRQOL) following stereotactic body radiation therapy (SBRT), high dose rate (HDR), and low dose rate (LDR) brachytherapy for prostate cancer. MATERIALS AND METHODS: International Prostate Symptom Score (IPSS), Sexual Health Inventory For Men (SHIM), and Expanded Prostate cancer Index Composite Short Form (EPIC-26) were prospectively collected for men with low/intermediate-risk cancer treated at a single institution. We used Generalized Estimating Equations to identify associations between variables and early (3 to 6 mo) or late (1 to 2 y) PRQOL scores. Minimally important differences (MID) were compared with assess clinical relevance. RESULTS: A total of 342 LDR, 159 HDR, and 112 SBRT patients treated from 2001 to 2018 were eligible. Gleason score, PSA, and age were lower among LDR patients compared with HDR/SBRT. Unadjusted baseline IPSS score was similar among all groups. Adjusted IPSS worsened at all time points compared with baseline after LDR/HDR. At early/late time points, rates of IPSS MID after LDR were higher compared to HDR/SBRT. There were no IPSS differences between SBRT and HDR. All modalities showed early and late SHIM worsening. There were no temporal differences in SHIM between SBRT and brachytherapy. There were no differences in EPIC subdomains between HDR and SBRT. Bowel symptoms worsened early after SBRT, whereas urinary irritative/obstructive symptoms worsened late after HDR. Among all domains, MID after SBRT and HDR were similar. CONCLUSIONS: In a cohort of patients treated with modern radiotherapy techniques, HDR and SBRT resulted in clinically meaningful improved urinary PRQOL compared with LDR.

Pelvic Reirradiation Utilizing Pulsed Low-dose Rate Radiation Therapy.

Pulsed low-dose rate radiation therapy has been shown to reduce normal tissue damage while decreasing DNA damage repair in tumor cells. In a cohort of patients treated with palliative or definitive pelvic reirradiation using pulsed low-dose rate radiation therapy, we observed substantial local control and low rates of toxicity.

Increasing the speed of frequency-domain, homodyne thermoreflectance imaging.

Charge coupled device (CCD)-based thermoreflectance imaging using a "4-bucket" lock-in imaging algorithm is a well-established, powerful method for obtaining high spatial and thermal resolution two-dimensional thermal maps of optoelectronic, electronic, and micro-electro-mechanical systems devices. However, the technique is relatively slow, limiting broad commercial adoption. In this work, we examine the underlying limit on the image acquisition speed using the conventional "4-bucket" algorithm and show that the straightforward extension to an n-bucket technique by faster sampling does not address the underlying statistical bias in the data analysis and hence does not reduce the image acquisition time. Instead, we develop a modified "enhanced n-bucket" algorithm that halves the image acquisition time for every doubling of the number of buckets. We derive detailed statistical models of the algorithms and confirm both the models and the resulting speed enhancement experimentally, resulting in a practical means of significantly enhancing the speed and utility of CCD-based frequency domain, homodyne thermoreflectance imaging.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS: Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS: Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION: H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

Predictors of Distant Recurrence Following Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

OBJECTIVE: The objective of this study was to characterize patients at an increased risk of distant metastasis (DM) following stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We identified patients undergoing SBRT for stage I NSCLC between 2005 and 2016. Patients with a prior lung cancer diagnosis, receiving a biological effective dose <100 Gy, or receiving chemotherapy were excluded. Patients underwent pretreatment staging and were classified according to the American Joint Committee for Cancer (AJCC) 8th edition staging. The primary endpoint was DM. The Kaplan-Meier method and the Cox proportional hazards model were used for survival analysis and to identify predictors of DM. RESULTS: A total of 174 patients were included, with a median age 75 years (range, 49 to 96 y) and a median follow-up of 24 months (range, 3 to 123 mo). The 2- and 4-year cumulative incidences of DM were 14.2% and 19.1%, respectively. Patients who developed DM had worse overall survival versus patients developing a locoregional recurrence (P=0.023). On multivariable analysis, having stage IB disease (hazard ratio: 2.95; 95% confidence interval: 1.06-8.23; P=0.039) or a lower/middle lobe tumor (hazard ratio: 2.67; 95% confidence interval: 1.07-6.69; P=0.036) was associated with increased risk of DM. The 2-year cumulative incidences of DM were 10.9% and 35.7% (P=0.002) for patients with stage IA versus IB tumors, respectively, and 11.3% and 19.7% (P=0.049) for patients with upper lobe versus lower/middle lobe tumors, respectively. CONCLUSIONS: Patients with stage IB disease or lower/middle lobe tumors may have an increased risk of DM following SBRT. Randomized controlled trials are needed to further identify patients who may benefit from adjuvant systemic therapy after SBRT for stage I NSCLC.

Local Control and Toxicity of External Beam Reirradiation With a Pulsed Low-dose-rate Technique.

PURPOSE: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique. METHODS AND MATERIALS: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the χ2 and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression. RESULTS: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade ≥2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade ≥4 acute or subacute toxicity. The only grade ≥2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief. CONCLUSION: Reirradiation with PLDR is effective and well-tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort.

Effects of interruptions of external beam radiation therapy on outcomes in patients with prostate cancer.

INTRODUCTION: To evaluate if interruptions of external beam radiation therapy impact outcomes in men with localized prostate cancer (PCa). METHODS: We included men with localized PCa treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) of escalated dose (≥74 Gy in 1.8 or 2 Gy fractions) between 1992 and 2013 at an NCI-designated cancer centre. Men receiving androgen deprivation therapy were excluded. The non-treatment day ratio (NTDR) was defined as the number of non-treatment days divided by the total elapsed days of therapy. NTDR was analysed for each National Comprehensive Cancer Network (NCCN) risk group. RESULTS: There were 1728 men included (839 low-risk, 776 intermediate-risk and 113 high-risk), with a median follow up of 53.5 months (range 12-185.8). The median NTDR was 31% (range 23-71%), translating to approximately 2 breaks (each break represents a missed treatment that will be made up) for 8 weeks of RT with 5 treatments per week. The 75 percentile of NTDR was 33%, translating to approximately 4 breaks, which was used as the cutoff for analysis. There were no significant differences in freedom from biochemical failure, freedom from distant metastasis, cancer specific survival, or overall survival for men with NTDR ≥33% compared to NTDR<33% for each risk group. Multivariable analyses including NTDR, age, race, Gleason score, T stage, and PSA were performed using the proportional hazards regression procedure. NTDR≥33% was not significantly associated with increased hazard ratio for outcomes in each risk group compared to NTDR<33%. CONCLUSION: Unintentional treatment breaks during dose escalated external beam radiation therapy for PCa did not cause a significant difference in outcomes, although duration of follow up limits the strength of this conclusion.

Tissue TGF-ß expression following conventional radiotherapy and pulsed low-dose-rate radiation.

The release of inflammatory cytokines has been implicated in the toxicity of conventional radiotherapy (CRT). Transforming growth factor ß (TGF-ß) has been suggested to be a risk marker for pulmonary toxicity following radiotherapy. Pulsed low-dose rate radiotherapy (PLDR) is a technique that involves spreading out a conventional radiotherapy dose into short pulses of dose with breaks in between to reduce toxicities. We hypothesized that the more tolerable toxicity profile of PLDR compared with CRT may be related to differential expression of inflammatory cytokines such as TGF-ß in normal tissues. To address this, we analyzed tissues from mice that had been subjected to lethal doses of CRT and PLDR by histology and immunohistochemistry (IHC). Equivalent physical doses of CRT triggered more cellular atrophy in the bone marrow, intestine, and pancreas when compared with PLDR as indicated by hematoxylin and eosin staining. IHC data indicates that TGF-ß expression is increased in the bone marrow, intestine, and lungs of mice subjected to CRT as compared with tissues from mice subjected to PLDR. Our in vivo data suggest that differential expression of inflammatory cytokines such as TGF-ß may play a role in the more favorable normal tissue late response following treatment with PLDR.

The need for androgen deprivation therapy in patients with intermediate-risk prostate cancer treated with dose-escalated external beam radiation therapy.

INTRODUCTION: To evaluate if androgen deprivation therapy (ADT) improves outcomes for patients with localized, intermediate-risk prostate cancer treated with definitive external beam radiation therapy (EBRT) in the dose-escalated era. MATERIALS AND METHODS: This is a retrospective study using a single institutional database. We included patients with localized, intermediate-risk prostate cancer treated with dose-escalated radiation therapy (RT) with 3D conformal radiotherapy or intensity-modulated radiotherapy (74-80 Gy in daily fraction of 1.8 Gy-2.0 Gy, or 70.2 Gy in daily fraction of 2.7 Gy) from 1992 to 2013. To further risk stratify the patients, PSA 10 ng/mL-20 ng/mL, Gleason 3+4, and T2b-T2c were assigned risk score (RS) of 1, while Gleason 4+3 was assigned RS of 2. Patients with prior treatment for prostate cancer, those on long term ADT (>= 23 months), or those with follow up < 1 year were excluded. We defined initial ADT as initiation within 9 months prior to the start of RT, during RT, or within 2 months after the completion of RT. Outcomes for patients who received initial ADT were compared to men treated with RT alone. Covariates included number of intermediate risk factors, age, and baseline comorbidities. Kaplan Meier estimates were compared using log rank tests. Competing risk regression and Cox proportional hazards regression were used to estimate hazard ratios adjusted for covariates. RESULTS: Of 1,134 patients included in this study, 155 received initial ADT with median duration of 4.0 months (m) (range 0.5 m-22.0 m). The median follow up was 56.4 m (range 12.3 m-200.7 m). Patients on ADT had higher RS compared to those with radiation alone (RS 1: 48% versus 58%; RS 2: 35% versus 32%; RS 3: 14% versus 9%; RS 4: 3% versus 1%; p=0.01). When patients with ADT were compared to those treated with radiation alone, there were no significant differences in freedom from biochemical failure (FFBF) (84.0% versus 87.3%, p = 0.83), freedom from distant metastasis (FFDM) (94.4% versus 96.9%, p = 0.41), or overall survival (OS) (92.3% versus 90.7%, (p = 0.48) at 5 years. Among patients with RS >= 2, there were still no significant differences in FFBF, FFDM, or OS when patients treated with ADT were compared to those treated with radiation alone. In multivariable analyses adjusting for RS and age, the adjusted hazard ratio for ADT use was sHR = 0.89 (95% CI = 0.64-1.66, p = 0.64) for BCF; sHR = 1.13 (95% CI = 0.48-2.65, p = 0.77) for DM. For overall mortality, adjusted HR = 1.23 (95% CI = 0.76-2.01, p = 0.40) where comorbidities (including diabetes, cardiac disease, and hypertension) were also included as covariates. CONCLUSION: Our study suggested that treatment of intermediate-risk prostate cancer with definitive dose-escalated EBRT alone resulted in acceptable outcomes, and it failed to show improved outcomes in patients who received short term ADT.

Therapeutic management options for stage III non-small cell lung cancer.

Lung cancer is the leading cause of cancer death worldwide. Majority of newly diagnosed lung cancers are non-small cell lung cancer (NSCLC), of which up to half are considered locally advanced at the time of diagnosis. Patients with locally advanced stage III NSCLC consists of a heterogeneous population, making management for these patients complex. Surgery has long been the preferred local treatment for patients with resectable disease. For select patients, multi-modality therapy involving systemic and radiation therapies in addition to surgery improves treatment outcomes compared to surgery alone. For patients with unresectable disease, concurrent chemoradiation is the preferred treatment. More recently, research into different chemotherapy agents, targeted therapies, radiation fractionation schedules, intensity-modulated radiotherapy, and proton therapy have shown promise to improve treatment outcomes and quality of life. The array of treatment approaches for locally advanced NSCLC is large and constantly evolving. An updated review of past and current literature for the roles of surgery, chemotherapeutic agents, radiation therapy, and targeted therapy for stage III NSCLC patients are presented.

Long-Term Patient-Reported Outcomes From a Phase 3 Randomized Prospective Trial of Conventional Versus Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: To assess the long-term quality of life (QoL) outcomes from a phase 3 trial comparing 2 modes of intensity modulated radiation therapy (IMRT): conventional IMRT (CIMRT) versus hypofractionated IMRT (HIMRT) in patients with localized prostate cancer. METHODS AND MATERIALS: Between 2002 and 2006, 303 men with low-risk to high-risk prostate cancer were randomized to 76 Gy in 38 fractions (CIMRT) versus 70.2 Gy in 26 fractions (HIMRT). QoL was compared by use of the Expanded Prostate Cancer Index Composite (EPIC), the International Prostate Symptom Score (IPSS), and EuroQoL (EQ5D) questionnaires. The primary outcome of the QoL analysis was a minimum clinically important difference defined as a 0.5 standard deviation change from baseline for each respective QoL parameter. Treatment effects were evaluated with the use of logistic mixed effects regression models. RESULTS: A total of 286, 299, and 218 patients had baseline EPIC, IPSS, or EQ5D data available and were included in the analysis. Overall, there was no statistically significant difference between the 2 treatment arms in terms of EPIC, IPSS, or EQ5D scores over time, although there was a trend toward lower EPIC urinary incontinence scores in the HIMRT arm. More patients in the HIMRT arm had a lower EPIC urinary incontinence score relative to baseline versus patients in the CIMRT arm with long-term follow-up. On multivariable analysis, there was no association between radiation fractionation scheme and any QoL parameter. When other clinical factors were examined, lymph node radiation was associated with worse EPIC hormonal scores versus patients receiving no lymph node radiation. In general, QoL outcomes were generally stable over time, with the exception of EPIC hormonal and EQ5D scores. CONCLUSIONS: In this randomized prospective study, there were stable QoL changes in patients receiving HIMRT or CIMRT. Our results add to the growing body of literature suggesting that HIMRT may be an acceptable treatment modality in clinically localized prostate cancer.

Prostate Cancer Patients With Unmanaged Diabetes or Receiving Insulin Experience Inferior Outcomes and Toxicities After Treatment With Radiation Therapy.

BACKGROUND: The purpose of the study was to determine the effect of type 2 diabetes mellitus (T2DM) on outcomes and toxicities among men with localized prostate cancer receiving definitive radiation therapy. PATIENTS AND METHODS: We performed a retrospective review of 3217 patients, from 1998 to 2013, subdivided into 5 subgroups: (I) no T2DM; (II) T2DM receiving oral antihyperglycemic agent that contains metformin, no insulin; (III) T2DM receiving nonmetformin oral agent alone, no insulin; (IV) T2DM receiving any insulin; and (V) T2DM not receiving medication. Outcome measures were overall survival, freedom from biochemical failure (BF), freedom from distant metastasis, cancer-specific survival, and toxicities. Kaplan-Meier analysis, log rank tests, Fine and Gray competing risk regression (to adjust for patient and lifestyle factors), Cox models, and subdistribution hazard ratios (sHRs) were used. RESULTS: Of the 3217 patients, 1295 (40%) were low-risk, 1192 (37%) were intermediate-risk, and 652 (20%) were high risk. The group I to V distribution was 81%, 8%, 5%, 3%, and 4%. The median dose was 78 Gy, and the median follow-up time was 50 (range, 1-190) months. Group V had increased mortality (sHR, 2.1; 95% confidence interval [CI], 0.66-1.54), BF (sHR, 2.14; 0.88-1.83), and cause-specific mortality (sHR, 3.87; 95% CI, 1.31-11). Acute toxicities were higher in group IV versus group I (genitourinary: 38% vs. 26%; P = .01; gastrointestinal: 21% vs. 5%; P = 001). Late toxicities were higher in groups IV and V versus group I (12%-14% vs. 2%-6%; P < .01). CONCLUSION: Men with T2DM not receiving medication and men with T2DM receiving insulin had worse outcomes and toxicities compared to other patients.

Patient reported outcomes among treatment modalities for prostate cancer.

INTRODUCTION: To characterize patient reported outcomes for urinary and sexual function using International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) comparing intensity modulated radiation therapy (IMRT), low dose rate brachytherapy (LDR), post-prostatectomy IMRT (PPRT), and radical prostatectomy (RP). MATERIALS AND METHODS: Patients treated for prostate cancer from 2001-2012 completed self-reported SHIM and IPSS surveys. Subgroups were created by baseline score. Mean change from baseline was determined at each time point for the cohort and subgroups. Statistical analysis was performed with generalized estimating equation method. Incontinence was not captured in the questionnaires. RESULTS: A total of 14,523 IPSS surveys from 3,515 men were evaluated. Patients treated with IMRT experienced a minimal decrease in IPSS score from baseline. PPRT scores did not differ from IMRT at any time point (range: +/- 3 points from baseline in IPSS score over 50 months). LDR had an initial IPSS rise (between 5-10 points on the IPSS over 1-9 months) versus IMRT but returned to comparable levels at 34 months. RP was associated with a lower IPSS versus IMRT. LDR had the largest rise from baseline, with return toward baseline. A total of 2,624 SHIM surveys from 857 men were evaluated. LDR and PPRT did not differ from IMRT at any time point (range: +/- 5 points from baseline in SHIM score for 36 months). RP experienced the largest decline from baseline (up to -7 points on SHIM score), at 3 to 7 months; RP had a larger early decrease in SHIM score versus IMRT between 3 and 22 months, after which there was no difference. CONCLUSIONS: IPSS and SHIM score patterns differed among treatment modalities. These data can be used to predict changes in urinary and sexual function over time based on modality and baseline score.

Patient-reported quality of life after stereotactic body radiation therapy versus moderate hypofractionation for clinically localized prostate cancer.

BACKGROUND AND PURPOSE: Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer. MATERIALS AND METHODS: In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression. RESULTS: 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]). CONCLUSIONS: Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.