Comparison of acute toxicities between contemporary forward-planned 3D conformal radiotherapy and inverse-planned intensity-modulated radiotherapy for whole breast radiation.

The use of inverse-planned intensity-modulated radiation therapy for whole breast radiation treatment has become more prevalent, but this may impose an increased cost on the health system. We hypothesized that when applied with the same treatment planning goals, tangential forward-planned field-in-field 3D conformal radiotherapy and tangential inverse-planned intensity-modulated radiotherapy would be associated with comparable toxicities. Women who underwent tangential whole breast irradiation at our institution from 2011 to 2015 planned using either forward-planned field-in-field 3D conformal radiotherapy or intensity-modulated radiotherapy were retrospectively analyzed. Grade 2+ Radiation dermatitis was the primary endpoint. A total of 201 and 212 women had undergone field-in-field 3D conformal radiotherapy and intensity-modulated radiotherapy, respectively. No differences were observed between the two modalities regarding acute radiation dermatitis, breast pain, or fatigue. In a multivariable logistic regression that incorporated the use of boost, hypofractionation, use of chemotherapy, patient positioning, use of a supraclavicular field, and breast planning target volume, intensity-modulated radiotherapy was not correlated with different rates of Grade 2+ radiation dermatitis. This study supports the routine first-line use of field-in-field 3D conformal radiotherapy for whole breast radiation instead of tangential intensity-modulated radiotherapy from the standpoint of equivalence in acute toxicity. Further investigation is needed to assess whether there are subgroups of women who may still benefit from intensity-modulated radiotherapy.

Patterns of Failure for Pediatric Glioblastoma Multiforme Following Radiation Therapy.

Despite aggressive multimodal therapy for pediatric glioblastoma multiforme (GBM), patient survival remains poor. This retrospective review of patients with GBM aims to evaluate the patterns of failure after radiation therapy (RT). The study included 14 pediatric patients treated with RT at the Children's Hospital of Philadelphia from 2007 to 2015. With a median follow-up of 16.9 months, 13 (92.9%) developed recurrent disease. Of recurrences, nine (69.2%) were in-field, three (23.1%) were marginal, and one (7.7%) was distant. The majority of patients treated with adjuvant radiation failed in the region of high-dose RT, indicating the need for improvements in local therapy.

The Impact of Adjuvant Therapy on Survival and Recurrence Patterns in Women With Early-Stage Uterine Carcinosarcoma: A Multi-institutional Study.

OBJECTIVE: The aim of the study was to characterize the impact of adjuvant therapy on survival in women with stage I/II uterine carcinosarcoma after primary surgery. METHODS: We reviewed records of 118 consecutively treated women with 2009 International Federation of Gynecology and Obstetrics stage I/II uterine carcinosarcoma who underwent hysterectomy between 1990 and 2014 at 4 academic institutions. Patients were categorized by adjuvant treatment group into observation, chemotherapy only, radiation only, and combined chemotherapy and radiation. Survival analyses were conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: Median follow-up was 28 months (range, 1-244 months). Lymphadenectomy was performed in 94 patients (80%). Postoperative management included observation (n = 37 [31%]), chemotherapy alone (n = 19 [16%]), radiation therapy (RT) alone (n = 24 [20%]), and combined RT and chemotherapy (n = 38 [32%]). Radiation therapy modality included vaginal brachytherapy in 22 patients, pelvic external beam RT in 21 patients, and combination in 19 patients. In 58% of women, chemotherapy consisted of carboplatin/paclitaxel. Median overall survival for all women was 97 months. On univariate analysis, adjuvant treatment group was associated with improved overall survival (hazard ratio [HR], 0.74; confidence interval [CI], 0.58-0.96; p = 0.02), freedom from vaginal recurrence (HR, 0.55; CI, 0.37-0.82]; p = 0.004), and freedom from any recurrence (HR, 0.70; CI, 0.54-0.92; p = 0.01). Pairwise comparisons demonstrated a significant benefit to chemoradiation over other adjuvant treatments. Adjuvant treatment group remained a significant covariate for all 3 end points on multivariate analysis as well. In addition, lymphadenectomy improved overall survival on multivariate analysis (HR, 0.24; CI, 0.09-0.61; p = 0.003). Of patients under observation only who had a recurrence, 8 (44%) of 18 had a recurrence in the vagina as the sole site of recurrence. By contrast, of women who received vaginal brachytherapy, significantly fewer had a recurrence in the vagina (1/42 [2.3%]; p < 0.003, log-rank test). CONCLUSIONS: In women with early-stage uterine carcinosarcoma, our data suggest superior survival end points with combined RT and chemotherapy. The frequency of vaginal recurrence suggests a role for incorporating vaginal brachytherapy in the adjuvant management of this disease.

Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial.

PURPOSE: External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE). METHODS: In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS). RESULTS: A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01). CONCLUSION: Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

BACKGROUND AND PURPOSE: A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. METHODS: We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. RESULTS: Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. CONCLUSION: In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Implementation Strategies to Promote Short-Course Radiation for Bone Metastases.

Importance: For patients with nonspine bone metastases, short-course radiotherapy (RT) can reduce patient burden without sacrificing clinical benefit. However, there is great variation in uptake of short-course RT across practice settings. Objective: To evaluate whether a set of 3 implementation strategies facilitates increased adoption of a consensus recommendation to treat nonspine bone metastases with short-course RT (ie, ≤5 fractions). Design, Setting, and Participants: This prospective, stepped-wedge, cluster randomized quality improvement study was conducted at 3 community-based cancer centers within an existing academic-community partnership. Rollout was initiated in 3-month increments between October 2021 and May 2022. Participants included treating physicians and patients receiving RT for nonspine bone metastases. Data analysis was performed from October 2022 to May 2023. Exposures: Three implementation strategies-(1) dissemination of published consensus guidelines, (2) personalized audit-and-feedback reports, and (3) an email-based electronic consultation platform (eConsult)-were rolled out to physicians. Main Outcomes and Measures: The primary outcome was adherence to the consensus recommendation of short-course RT for nonspine bone metastases. Mixed-effects logistic regression at the bone metastasis level was used to model associations between the exposure of physicians to the set of strategies (preimplementation vs postimplementation) and short-course RT, while accounting for patient and physician characteristics and calendar time, with a random effect for physician. Physician surveys were administered before implementation and after implementation to assess feasibility, acceptability, and appropriateness of each strategy. Results: Forty-five physicians treated 714 patients (median [IQR] age at treatment start, 67 [59-75] years; 343 women [48%]) with 838 unique nonspine bone metastases during the study period. Implementing the set of strategies was not associated with use of short-course RT (odds ratio, 0.78; 95% CI, 0.45-1.34; P = .40), with unadjusted adherence rates of 53% (444 lesions) preimplementation vs 56% (469 lesions) postimplementation; however, the adjusted odds of adherence increased with calendar time (odds ratio, 1.68; 95% CI, 1.20-2.36; P = .003). All 3 implementation strategies were perceived as being feasible, acceptable, and appropriate; only the perception of audit-and-feedback appropriateness changed before vs after implementation (19 of 29 physicians [66%] vs 27 of 30 physicians [90%]; P = .03, Fisher exact test), with 20 physicians (67%) preferring reports quarterly. Conclusions and Relevance: In this quality improvement study, a multicomponent set of implementation strategies was not associated with increased use of short-course RT within an academic-community partnership. However, practice improved with time, perhaps owing to secular trends or physician awareness of the study. Audit-and-feedback was more appropriate than anticipated. Findings support the need to investigate optimal approaches for promoting evidence-based radiation practice across settings.

Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response.

The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in redox homeostasis and amino acid metabolism and transport. Because both inhibition and overactivation of the ISR can induce tumor cell death, modulators of ATF4 expression could prove to be clinically useful. In this study, chemical libraries were screened for modulators of ATF4 expression. We identified one compound, E235 (N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide), that activated the ISR and dose-dependently increased levels of ATF4 in transformed cells. A dose-dependent decrease in viability was observed in several mouse and human tumor cell lines, and knockdown of ATF4 significantly increased the antiproliferative effects of E235. Interestingly, low µM doses of E235 induced senescence in many cell types, including HT1080 human fibrosarcoma and B16F10 mouse melanoma cells. E235-mediated induction of senescence was not dependent on p21 or p53; however, p21 conferred protection against the growth inhibitory effects of E235. Treatment with E235 resulted in an increase in cells arrested at the G2/M phase with a concurrent decrease in S-phase cells. E235 also activated DNA damage response signaling, resulting in increased levels of Ser15-phosphorylated p53, γ-H2AX, and phosphorylated checkpoint kinase 2 (Chk2), although E235 does not appear to cause physical DNA damage. Induction of γ-H2AX was abrogated in ATF4 knockdown cells. Together, these results suggest that modulation of the ISR pathway with the small molecule E235 could be a promising antitumor strategy.

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma.

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Personalized Treatment Selection Leads to Low Rates of Local Salvage Therapy for Bone Metastases.

PURPOSE: Local therapy for patients with nonspine bone metastases is evolving, with data supporting the use of single-fraction treatments, and more recently, showing possible benefit from stereotactic body radiation therapy (SBRT). However, the rate of local salvage therapy (LST) after each technique has not been characterized in real-world clinic settings where patients are selected at physician discretion. We examined rates of LST in patients with nonspine bone metastases. METHODS AND MATERIALS: We reviewed records of RT for nonspine bone metastases at our institution from January 1, 2016, to December 31, 2018. We defined LST as the first occurrence of RT or surgery for oncologic progression to a bone metastasis after initial RT. Cumulative incidence functions for retreatment were generated. We conducted multivariate analysis to identify variables associated with LST. RESULTS: A total of 1754 patients were analyzed, with median follow-up of 16.2 months (range, 0-36.8 months). Of all episodes of RT, 51.5% were multifraction external beam radiation therapy (EBRT), 7.0% were single-fraction EBRT, and 41.4% were SBRT. Altogether, 88 patients (5.0%) required LST, with an incidence at 6 months of 2.5%. Incidence of LST at 6 months was 2.1% for SBRT, 5.3% for single-fraction conventional regimens, and 2.4% for multifraction conventional regimens (P = .26). Patients of younger age, who had a higher Karnofsky performance status, and/or who had lesions in the pelvis had a higher risk of retreatment. CONCLUSIONS: In this large institutional cohort, the rate of LST was low, with no difference between RT techniques. The findings indicated that SBRT for patients at high risk for treatment failure may reduce the rate of retreatment overall. When treatment modality was selected based on patient characteristics, rates of LST were lower than when treatment was randomly selected.

Prospective Clinical Evaluation of Integrating a Radiation Anatomist for Contouring in Routine Radiation Treatment Planning.

Purpose: A radiation anatomist was trained and integrated into clinical practice at a multi-site academic center. The primary objective of this quality improvement study was to determine whether a radiation anatomist improves the quality of organ-at-risk (OAR) contours, and secondarily to determine the impact on efficiency in the treatment planning process. Methods and Materials: From March to August 2020, all patients undergoing computed tomography-based radiation planning at 2 clinics at Memorial Sloan Kettering Cancer Center were assigned using an "every other" process to either (1) OAR contouring by a radiation anatomist (intervention) or (2) contouring by the treating physician (standard of care). Blinded dosimetrists reported OAR contour quality using a 3-point scoring system based on a common clinical trial protocol deviation scale (1, acceptable; 2, minor deviation; and 3, major deviation). Physicians reported time spent contouring for all cases. Analyses included the Fisher exact test and multivariable ordinal logistic regression. Results: There were 249 cases with data available for the primary endpoint (66% response rate). The mean OAR quality rating was 1.1 ± 0.4 for the intervention group and 1.4 ± 0.7 for the standard of care group (P < .001), with subset analysis showing a significant difference for gastrointestinal cases (n = 49; P <.001). Time from simulation to contour approval was reduced from 3 days (interquartile range [IQR], 1-6 days) in the control group to 2 days (IQR, 1-5 days) in the intervention group (P = .007). Both physicians and dosimetrists self-reported decreased time spent contouring in the intervention group compared with the control group, with a decreases of 8 minutes (17%; P < .001) and 5 minutes (50%; P = .002), respectively. Qualitative comments most often indicated edits required to bowel contours (n = 14). Conclusions: These findings support improvements in both OAR contour quality and workflow efficiency with implementation of a radiation anatomist in routine practice. Findings could also inform development of autosegmentation by identifying disease sites and specific OARs contributing to low clinical efficiency. Future research is needed to determine the potential effect of reduced physician time spent contouring OARs on burnout.

Multidisciplinary Treatment of Non-Spine Bone Metastases: Results of a Modified Delphi Consensus Process.

Purpose: Local treatment for bone metastases is becoming increasingly complex. National guidelines traditionally focus only on radiation therapy (RT), leaving a gap in clinical decision support resources available to clinicians. The objective of this study was to reach expert consensus regarding multidisciplinary management of non-spine bone metastases, which would facilitate standardizing treatment within an academic-community partnership. Methods and Materials: A multidisciplinary panel of physicians treating metastatic disease across the Memorial Sloan Kettering (MSK) Cancer Alliance, including community-based partner sites, was convened. Clinical questions rated of high importance in the management of non-spine bone metastases were identified via survey. A literature review was conducted, and panel physicians drafted initial recommendation statements. Consensus was gathered on recommendation statements through a modified Delphi process from a full panel of 17 physicians from radiation oncology, orthopaedic surgery, medical oncology, interventional radiology, and anesthesia pain. Consensus was defined a priori as 75% of respondents indicating "agree" or "strongly agree" with the consensus statement. Strength of Recommendation Taxonomy was employed to assign evidence strength for each statement. Results: Seventeen clinical questions were identified, of which 11 (65%) were selected for the consensus process. Consensus was reached for 16 of 17 answer statements (94%), of which 12 were approved after Round 1 and additional 4 approved after Round 2 of the modified Delphi voting process. Topics included indications for referral to surgery or interventional radiology, radiation fractionation and appropriate use of stereotactic approaches, and the handling of systemic therapies during radiation. Evidence strength was most commonly C (n = 7), followed by B (n = 5) and A (n = 3). Conclusions: Consensus among a multidisciplinary panel of community and academic physicians treating non-spine bone metastases was feasible. Recommendations will assist clinicians and potentially provide measures to reduce variation across diverse practice settings. Findings highlight areas for further research such as pathologic fracture risk estimation, pre-operative radiation, and percutaneous ablation.

Malfunctioning and infected tunneled infusion catheters: over-the-wire catheter exchange versus catheter removal and replacement.

PURPOSE: To compare the safety and effectiveness of over-the-wire catheter exchange (catheter-exchange) with catheter removal and replacement (removal-replacement) at a new site for infected or malfunctioning tunneled infusion catheters. MATERIALS AND METHODS: Using a quality assurance database, 61 patients with tunneled infusion catheters placed during the period July 2001 to June 2009 were included in this study. Patients receiving hemodialysis catheters were excluded. Catheter-exchange was performed in 25 patients, and same-day removal-replacement was performed in 36 patients. Data collected included demographic information, indication for initial catheter placement and replacement, dwell time for the new catheter, and ultimate fate of the new device. Statistical comparisons between the two cohorts were analyzed using the Kaplan-Meier technique and Fisher exact test. RESULTS: Catheters exchanged over the wire remained functional without infection for a median of 102 days (range, 2-570 days), whereas catheters removed and replaced were functional for a median 238 days (range, 1-292 days, P = .12). After catheter replacement, there were 11 instances of subsequent infection in the catheter-exchange group and 7 instances in the removal-replacement cohort, accounting for infection rates of 4.4 and 2.3 per 1,000 catheter days (P = .049). Patients in the catheter-exchange group had 3.2 greater odds of infection compared with patients in the removal-replacement group. Five malfunction events occurred in each group, accounting for 2.0 and 1.7 malfunctions per 1,000 catheter days in the catheter-exchange and removal-replacement groups (P = .73). CONCLUSIONS: Catheter-exchange of tunneled infusion catheters results in a higher infection rate compared with removal-replacement at a new site. The rate of catheter malfunction is not significantly different between the two groups. Catheter-exchange is an alternative for patients with tunneled infusion catheters who have limited venous access, but this technique should not be expanded for use in all patients. Because of the size of this initial study, further investigation is needed to verify the results in a larger sample size.

Neoadjuvant chemoradiation is associated with improved overall survival in older patients with esophageal cancer.

OBJECTIVES: The aim of this study was to characterize outcomes associated with neoadjuvant chemoradiation prior to esophagectomy, compared to esophagectomy alone, in older patients with esophageal cancer. MATERIALS AND METHODS: We conducted an observational cohort study in patients ≥70years with locally-advanced esophageal cancer undergoing esophagectomy ± neoadjuvant chemoradiation between 2006 and 2012 using the National Cancer Database. A Cox proportional hazards model with inverse probability of treatment weighting (IPTW) using the propensity score was developed to assess the association between trimodality therapy and overall survival. Perioperative complications and pathologic outcomes associated with trimodality therapy were identified with multivariable logistic regression. RESULTS: 1364 patients were included; the mean age was 75 (range 70-90). 904 (66%) were treated with trimodality therapy and 460 (34%) were treated with esophagectomy alone. On IPTW Cox analysis, neoadjuvant chemoradiation was associated with improved overall survival (HR=0.76, 95%CI [0.70-0.82], p≤0.001). Further, trimodality therapy was associated with lower rates of margin-positive resection (5% vs. 18%; OR=0.26, 95%CI [0.18-0.37], p<0.001) and in 18% of trimodality patients, there was no detectable tumor at surgery. 90-day mortality rates were not statistically different (14% vs. 12%; OR=0.99, 95%CI [0.73-1.36], p=0.22). Neoadjuvant chemoradiation was associated with lower 30-day readmission rates (5% vs. 8%; OR=0.48, 95%CI [0.31-0.73], p=0.004) and shorter surgical hospital stay (median 10 vs. 12days, p<0.001) compared to esophagectomy alone. CONCLUSION: In older patients with esophageal cancer, trimodality therapy, compared to esophagectomy alone, is associated with improved overall survival and favorable pathologic and perioperative outcomes. Further studies are needed to identify which older patients are most suitable for trimodality therapy.

Trends and Patterns of Utilization of Hypofractionated Postmastectomy Radiotherapy: A National Cancer Database Analysis.

BACKGROUND: The acceptance of hypofractionated radiotherapy in treating breast cancer in the breast conservation therapy setting has stimulated interest in hypofractionated postmastectomy radiotherapy (PMRT). We assessed national trends and patterns of utilization of hypofractionated PMRT. PATIENTS AND METHODS: Women 18 years of age or older with breast cancer treated with mastectomy and PMRT to the chest wall with or without regional lymph nodes from 2004 to 2014 were identified from the National Cancer Database. A standard fractionation cohort was defined as patients receiving 180 to 200 cGy per fraction to a total dose of 4500 to 7000 cGy over 5 to 7 weeks, and a hypofractionation cohort was defined as those receiving 250 to 400 cGy per fraction to a total dose of 3000 to 6000 cGy over 2 to 5 weeks. Multivariable logistic regression was used to determine factors associated with hypofractionated PMRT use. RESULTS: We identified 113,981 patients who met study criteria. Overall, hypofractionated PMRT use was low (1.1%) although utilization increased over time (P ≤ .001). Older age, greater comorbidity, further distance from treatment facility, treatment at academic facilities, less extensive disease, and recent treatment year were statistically significant predictors of hypofractionation use compared with standard fractionation. Conversely, breast reconstruction and receipt of chemotherapy were negative predictors. CONCLUSION: Because of the absence of high-level evidence to support its use, hypofractionated PMRT was uncommonly utilized in the United States from 2004 to 2014, although a small increase in use was noted over time. Findings from this study might be useful in designing future studies, and might serve as a baseline for evaluation of future changes in practice patterns.

Definitive local therapy is associated with improved overall survival in metastatic cervical cancer.

PURPOSE: Definitive local therapy is often used in metastatic cervical cancer to reduce morbidity associated with local tumor progression. However, the potential benefit of this therapeutic approach has not been rigorously investigated. We hypothesized that definitive local therapy is associated with improved overall survival (OS) in metastatic cervical cancer. METHODS AND MATERIALS: Patients aged ≥18 years with newly diagnosed metastatic cervical cancer who were treated with chemotherapy were identified from the National Cancer Database. Patients were dichotomized into the following cohorts: definitive local therapy (defined as either concurrent chemoradiation therapy or definitive surgery) or conservative therapy (defined as systemic therapy with or without palliative radiation therapy). The association between definitive local therapy and OS was assessed using propensity score-weighted Cox proportional hazards models. Potential unmeasured confounding was assessed through sensitivity analyses. Factors associated with the receipt of definitive local therapy were identified with multivariable logistic regression. RESULTS: A total of 2838 patients were identified, of whom 1194 (42%) and 1644 (58%) were treated with definitive local and conservative therapy, respectively. Receipt of definitive local therapy was statistically significant, associated with less comorbidity, lower clinical T stage, and node negative disease. Compared with conservative therapy, definitive local therapy was associated with improved OS (hazard ratio: 0.57; 95% confidence interval, 0.52-0.62; P ≤ .001). The median OS rate was 19.2 months in the definitive local therapy cohort and 10.1 months in the conservative therapy cohort. These findings were robust to potential unmeasured confounding in sensitivity analyses and on landmark analyses of patients who survived at least 12 months (hazard ratio: 0.71; 95% confidence interval, 0.62-0.82; P ≤ .001). CONCLUSIONS: Definitive local therapy is associated with improved OS in patients with metastatic cervical cancer. These findings suggest a novel setting for the use of definitive local therapy in the metastatic setting.

Use and Effectiveness of Adjuvant Endocrine Therapy for Hormone Receptor-Positive Breast Cancer in Men.

Importance: Although adjuvant endocrine therapy confers a survival benefit among females with hormone receptor (HR)-positive breast cancer, the effectiveness of this treatment among males with HR-positive breast cancer has not been rigorously investigated. Objective: To investigate trends, patterns of use, and effectiveness of adjuvant endocrine therapy among men with HR-positive breast cancer. Design, Setting, and Participants: This retrospective cohort study identified patients in the National Cancer Database with breast cancer who had received treatment from 2004 through 2014. Inclusion criteria for the primary study cohort were males at least 18 years old with nonmetastatic HR-positive invasive breast cancer who underwent surgery with or without adjuvant endocrine therapy. A cohort of female patients was also identified using the same inclusion criteria for comparative analyses by sex. Data analysis was conducted from October 1, 2017, to December 15, 2017. Exposures: Receipt of adjuvant endocrine therapy. Main Outcomes and Measures: Patterns of adjuvant endocrine therapy use were assessed using multivariable logistic regression analyses. Association between adjuvant endocrine therapy use and overall survival was assessed using propensity score-weighted multivariable Cox regression models. Results: The primary study cohort comprised 10 173 men with HR-positive breast cancer (mean [interquartile range] age, 66 [57-75] years). The comparative cohort comprised 961 676 women with HR-positive breast cancer (mean [interquartile range] age, 62 [52-72] years). The median follow-up for the male cohort was 49.6 months (range, 0.1-142.5 months). Men presented more frequently than women with HR-positive disease (94.0% vs 84.3%, P < .001). However, eligible men were less likely than women to receive adjuvant endocrine therapy (67.3% vs 79.0%; OR, 0.61; 95% CI, 0.58-0.63; P < .001). Treatment at academic facilities (odds ratio, 1.13; 95% CI, 1.02-1.25; P = .02) and receipt of adjuvant radiotherapy (odds ratio, 2.83; 95% CI, 2.55-3.15; P < .001) or chemotherapy (odds ratio, 1.20; 95% CI, 1.07-1.34; P < .001) were statistically significantly associated with adjuvant endocrine therapy use in men. A propensity score-weighted analysis indicated that relative to no use, adjuvant endocrine therapy use in men was associated with improved overall survival (hazard ratio, 0.70; 95% CI, 0.63-0.77; P < .001). Conclusions and Relevance: There is a sex disparate underuse of adjuvant endocrine therapy among men with HR-positive breast cancer despite the use of this treatment being associated with improved overall survival. Further research and interventions may be warranted to bridge gaps in care in this population.

Association Between Treatment at High-Volume Facilities and Improved Overall Survival in Soft Tissue Sarcomas.

PURPOSE: Soft tissue sarcomas (STS) are rare malignancies that require complex multidisciplinary management. Therefore, facilities with high sarcoma case volume may demonstrate superior outcomes. We hypothesized that STS treatment at high-volume (HV) facilities would be associated with improved overall survival (OS). METHODS AND MATERIALS: Patients aged ≥18 years with nonmetastatic STS treated with surgery and radiation therapy at a single facility from 2004 through 2013 were identified from the National Cancer Database. Facilities were dichotomized into HV and low-volume (LV) cohorts based on total case volume over the study period. OS was assessed using multivariable Cox regression with propensity score-matching. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 9025 total patients, 1578 (17%) and 7447 (83%) were treated at HV and LV facilities, respectively. On multivariable analysis, high educational attainment, larger tumor size, higher grade, and negative surgical margins were statistically significantly associated with treatment at HV facilities; conversely, black race and non-metropolitan residence were negative predictors of treatment at HV facilities. On propensity score-matched multivariable analysis, treatment at HV facilities versus LV facilities was associated with improved OS (hazard ratio, 0.87, 95% confidence interval, 0.80-0.95; P = .001). Older age, lack of insurance, greater comorbidity, larger tumor size, higher tumor grade, and positive surgical margins were associated with statistically significantly worse OS. CONCLUSIONS: In this observational cohort study using the National Cancer Database, receipt of surgery and radiation therapy at HV facilities was associated with improved OS in patients with STS. Potential sociodemographic disparities limit access to care at HV facilities for certain populations. Our findings highlight the importance of receipt of care at HV facilities for patients with STS and warrant further study into improving access to care at HV facilities.

National disparities in treatment package time for resected locally advanced head and neck cancer and impact on overall survival.

BACKGROUND: The purpose of this study was to determine national disparities in head and neck cancer treatment package time (the time interval from surgery through the completion of radiation) and the associated impact on survival. METHODS: We conducted an observational cohort study using the National Cancer Database of 15 234 patients with resected head and neck cancer who underwent adjuvant radiotherapy from 2004-2012. Predictors of prolonged package time were identified by multivariable linear regression. Survival outcomes were assessed using a multivariable Cox model. RESULTS: Mean package time was 100 days (SD 23). Package time was 7.52 days (95% confidence interval [CI] 6.23-8.81; P < .001) longer with Medicaid versus commercial insurance. Low income and African American race also predicted for longer package times. All-cause mortality increased an average of 4% with each 1 week increase in treatment package time (hazard ratio [HR] 1.04; 95% CI 1.03-1.05; P < .001). CONCLUSION: Significant national socioeconomic disparities exist in treatment package time. Treatment delays in this setting may contribute to worse survival outcomes.

Improved Overall Survival with Aggressive Primary Tumor Radiotherapy for Patients with Metastatic Esophageal Cancer.

OBJECTIVES: The aim of this study was to characterize utilization and survival outcomes associated with primary tumor-directed radiotherapy (PTDRT) in patients with newly diagnosed metastatic esophageal cancer. METHODS: We conducted an observational cohort study using the National Cancer Data Base to evaluate patients with newly diagnosed metastatic esophageal cancer between 2004 and 2012. Overall survival outcomes after treatment with chemotherapy plus conventional palliative dose radiotherapy (<5040 cGy), chemotherapy plus definitive dose radiotherapy (≥5040 cGy), or chemotherapy alone were compared by using Cox proportional hazards models with inverse probability of treatment weighting using the propensity score. Potential unmeasured confounding was assessed through sensitivity analyses. RESULTS: The final cohort consisted of 12,683 patients: 57% were treated with chemotherapy alone, 24% were treated with chemotherapy plus palliative dose radiotherapy, and 19% were treated with chemotherapy plus definitive dose radiotherapy. Compared with chemotherapy alone, chemotherapy plus definitive dose radiotherapy was associated with improved survival (median overall survival of 8.3 versus 11.3 months [hazard ratio = 0.72, 95% confidence interval: 0.70-0.74, p ≤ 0.001]), whereas chemotherapy plus palliative dose radiotherapy was associated with slightly inferior outcomes (median overall survival of 8.3 months versus 7.5 months (hazard ratio = 1.10, 95% confidence interval 1.07-1.13, p ≤ 0.001). These findings were robust to potential unmeasured confounding in sensitivity analyses. Additionally, landmark analyses confirmed these findings in patients surviving 12 months or longer. CONCLUSIONS: Definitive dose, but not conventional palliative dose, PTDRT is associated with improved overall survival in metastatic esophageal cancer, suggesting that local control may be important to prognosis. These findings support integrating PTDRT into future clinical trials aimed at refining personalized treatment for patients with metastatic esophageal cancer.

Predictors of Wound Complications following Radiation and Surgical Resection of Soft Tissue Sarcomas.

Wound complications represent a major source of morbidity in patients undergoing radiation therapy (RT) and surgical resection of soft tissue sarcomas (STS). We investigated whether factors related to RT, surgery, patient comorbidities, and tumor histopathology predict the development of wound complications. An observational study of patients who underwent STS resection and RT was performed. The primary outcome was the occurrence of any wound complication up to four months postoperatively. Significant predictors of wound complications were identified using multivariable logistic regression. Sixty-five patients representing 67 cases of STS were identified. Median age was 59 years (range 22-90) and 34 (52%) patients were female. The rates of major wound complications and any wound complications were 21% and 33%, respectively. After adjusting for radiation timing, diabetes (OR 9.6; 95% CI 1.4-64.8; P = 0.02), grade ≥2 radiation dermatitis (OR 4.8; 95% CI 1.2-19.2; P = 0.03), and the use of 3D conformal RT (OR 4.6; 95% CI 1.1-20.0; P = 0.04) were associated with an increased risk of any wound complication on multivariable analysis. These data suggest that radiation dermatitis and radiation modality are predictors of wound complications in patients with STS.