Association Between Up-front Surgery and Risk of Stroke in US Veterans With Oropharyngeal Carcinoma.

Importance: Cardiovascular events are an important cause of morbidity in patients with oropharyngeal squamous cell carcinoma (OPSCC). Radiation and chemotherapy have been associated with increased risk of stroke; up-front surgery allows the opportunity for (chemo)radiotherapy de-escalation. Objective: To evaluate whether up-front surgery was associated with decreased stroke risk compared to nonsurgical treatment for OPSCC. Design, Setting, and Participants: This cohort study was conducted at the US Veterans Health Administration and examined US veterans diagnosed with nonmetastatic OPSCC from 2000 to 2020. Data cutoff was September 17, 2021, and data analysis was performed from October 2021 to February 2022. Exposures: Up-front surgical treatment or definitive (chemo)radiotherapy as captured in cancer registry. Main Outcomes and Measures: Cumulative incidence of stroke, accounting for death as a competing risk; and association between up-front surgery and stroke risk. After generating propensity scores for the probability of receiving surgical treatment and using inverse probability weighting (IPW) to construct balanced pseudo-populations, Cox regression was used to estimate a cause-specific hazard ratio (csHR) of stroke associated with surgical vs nonsurgical treatment. Results: Of 10 436 patients, median (IQR) age was 61 (56-67) years; 10 329 (99%) were male; 1319 (13%) were Black, and 7823 (75%) were White; 2717 received up-front surgery, and 7719 received nonsurgical therapy with definitive (chemo)radiotherapy. The 10-year cumulative incidence of stroke was 12.5% (95% CI, 11.8%-13.3%) and death was 57.3% (95% CI, 56.2%-58.4%). Surgical patients who also received (chemo)radiotherapy had shorter radiation and chemotherapy courses than nonsurgical patients. After propensity score and IPW, the csHR of stroke for surgical treatment was 0.77 (95% CI, 0.66-0.91). This association was consistent across subgroups defined by age and baseline cardiovascular risk factors. Conclusions and Relevance: In this cohort study, up-front surgical treatment was associated with a 23% reduced risk of stroke compared with definitive (chemo)radiotherapy. These findings present an important additional risk-benefit consideration to factor into treatment decisions and patient counseling and should motivate future studies to examine cardiovascular events in this high-risk population.

Postoperative Radiation Therapy Refusal in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct clinical entity with good prognosis, unique demographics, and a trend toward treatment deintensification. Patients with this disease may opt out of recommended postoperative radiation therapy (PORT) for a variety of reasons. The aim of this paper was to examine factors that predict patient refusal of recommended PORT in HPV-associated OPSCC, and the association of refusal with overall survival. STUDY DESIGN: Retrospective population-based cohort study of patients in the National Cancer Database. METHODS: We conducted a retrospective cohort study of patients in the National Cancer Database diagnosed with OPSCC between January 2010 and December 2015. We primarily assessed overall survival and the odds of refusing PORT based on demographic, socioeconomic, and clinical factors. Analysis was conducted using multivariable logistic regression and multivariable Cox proportional hazards model. RESULTS: A total of 4229 patients were included in the final analysis, with 156 (3.7%) patients opting out of recommended PORT. On multivariable analysis, patient refusal of PORT was independently associated with a variety of socioeconomic factors such as race, insurance status, comorbidity, treatment at a single facility, and margin status. Lastly, PORT refusal was associated with significantly lower overall survival compared to receipt of recommended PORT (hazard ratio 1.69, confidence interval 1.02-2.82). CONCLUSIONS: Patient refusal of recommended PORT in HPV-associated OPSCC is rare and associated with variety of disease and socioeconomic factors. PORT refusal may decrease overall survival in this population. Our findings may help clinicians when counseling patients and identifying those who may be more likely to opt out of recommended adjuvant therapy. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:339-348, 2022.

A Phase 2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human Papilloma Virus-Related Squamous Cell Carcinoma of the Oropharynx.

PURPOSE: This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS: This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension. RESULTS: Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence-free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up. CONCLUSIONS: Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study.

Finding Value for Protons: The Case of Prostate Cancer?

The standard radiotherapy treatment for prostate cancer is intensity-modulated radiotherapy (IMRT). An alternative option is proton beam therapy (PBT). PBT is a safe and effective treatment, but does it add value over IMRT? We explore this controversial question by examining the available dosimetric and clinical evidence.

Insurance coverage decisions for pediatric proton therapy.

Proton beam therapy (PBT) holds promise for pediatric patients, but level 1 evidence is not available. In this context, we examined insurance coverage decisions at our facility from 2010 to 2015. PBT was initially denied for 11% of pediatric cases. However, nearly all denials were overturned on appeal-a process that often delayed care by more than a week. Despite unfavorable language in coverage policies, real-world decisions were eventual approval in >99% of cases. Payers appear to have largely accepted the current level-of-evidence for pediatric PBT, but all parties spend significant time and resources on appeals. Streamlined approval processes could align incentives among stakeholders.

Initiative to reduce bone scans for low-risk prostate cancer patients: A quasi-experimental before-and-after study in a Veterans Affairs hospital.

PURPOSE: Bone scans (BS) are a low-value test for asymptomatic men with low-risk prostate cancer. We performed a quality improvement intervention aimed at reducing BS for these patients. METHODS AND MATERIALS: The intervention was a presentation that leveraged the behavioral science concepts of social comparison and normative appeals. Participants were multidisciplinary stakeholders from the Radiation Oncology and Urology services at a Veterans Affairs hospital. We determined the baseline rate of BS by retrospectively analyzing cases of asymptomatic men with newly diagnosed low-risk prostate cancer. For social comparison, we presented contemporary peer BS rates in the United States-including Veterans Affairs hospitals. For normative appeals, we reviewed guidelines from various professional groups. To analyze the effect of this intervention, we performed a quasi-experimental, uncontrolled, before-and-after study. RESULTS: During the 1-year period before the intervention, 32 of 37 patients with low-risk prostate cancer (86.5%) received a BS. The contemporary peer rate was approximately 30%. All reviewed guidelines recommended against BS. During the 1-year period after the intervention, the rate of BS was reduced to 65.5% (19 of 29 patients; P = .043 by one-sided Fisher's exact test). CONCLUSIONS: We observed a modest reduction in guideline-discordant BS after the quality improvement intervention. BS rates might be influenced by initiatives that combine social comparisons with appeals to professional norms.

Radiation Treatment Time and Overall Survival in Locally Advanced Non-small Cell Lung Cancer.

PURPOSE: Prolonged radiation treatment (RT) time (RTT) has been associated with worse survival in several malignancies. The present study investigated whether delays during RT are associated with overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The National Cancer Database was queried for patients with stage III NSCLC who had received definitive concurrent chemotherapy and fractionated RT to standard doses (59.4-70.0 Gy) and fractionation from 2004 to 2013. The RTT was classified as standard or prolonged for each treatment regimen according to the radiation dose and number of fractions. Cox proportional hazards models were used to evaluate the association between the following factors and OS: RTT, RT fractionation, demographic and pathologic factors, and chemotherapeutic agents. RESULTS: Of 14,154 patients, the RTT was prolonged in 6262 (44.2%). Factors associated with prolonged RTT included female sex (odds ratio [OR] 1.21, P<.0001), black race (OR 1.20, P=.001), nonprivate health insurance (OR 1.30, P<.0001), and lower income (<$63,000 annually, OR 1.20, P<.0001). The median OS was significantly worse for patients with prolonged RTT than that for those with standard RTT (18.6 vs 22.7 months, P<.0001). Furthermore, the OS worsened with each cumulative interval of delay (standard RTT vs prolonged 1-2 days, 20.5 months, P=.009; prolonged 3-5 days, 17.9 months, P<.0001; prolonged 6-9 days, 17.7 months, P<.0001; prolonged >9 days, 17.1 months, P<.0001). On multivariable analysis, prolonged RTT was independently associated with inferior OS (hazard ratio 1.21, P<.0001). Prolonged RTT as a continuous variable was also significantly associated with worse OS (hazard ratio 1.001, P=.0007). CONCLUSIONS: Delays during RT appear to negatively affect survival for patients with locally advanced NSCLC. We have detailed the demographic and socioeconomic barriers influencing prolonged RTT as a method to address the health disparities in this regard. Cumulative interruptions of RT should be minimized.

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710.

BACKGROUND: Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil-to-lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC). METHODS: This study is an unplanned secondary analysis of SWOG 8710, a randomized phase 3 trial that assessed cystectomy with or without NAC in 317 patients with muscle-invasive BC. NLR was calculated from prospectively collected complete blood counts. For the prognostic analysis, 230 patients were identified; for the predictive analysis, 263 were identified. NLR was evaluated with proportional hazards models including prespecified factors (age, sex, T-stage, lymphovascular invasion, and treatment arm). RESULTS: With a median follow-up of 18.6 years, there were 172 and 205 deaths in the prognostic and predictive cohorts, respectively. In a multivariable analysis, NLR was not prognostic for OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.98-1.11; P = .24). Furthermore, NLR did not predict for the OS benefit from NAC (HR, 1.01; 95% CI, 0.90-1.14; P = .86). Factors associated with worse OS were older age (HR, 1.05; 95% CI, 1.04-1.07; P < .001) and surgery without NAC (HR, 1.39; 95% CI, 1.03-1.88; P = .03). CONCLUSIONS: This is the first analysis of NLR in BC to use prospectively collected clinical trial data. In contrast to previous studies, it suggests that NLR is neither a prognostic nor predictive biomarker for OS in muscle-invasive BC. Cancer 2017;123:794-801. © 2016 American Cancer Society.

Contemporary Trends in Radiation Oncology Resident Research.

PURPOSE: To test the hypothesis that recent resident research productivity might be different than a decade ago, and to provide contemporary information about resident scholarly activity. METHODS AND MATERIALS: We compiled a list of radiation oncology residents from the 2 most recent graduating classes (June 2014 and 2015) using the Association of Residents in Radiation Oncology annual directories. We queried the PubMed database for each resident's first-authored publications from postgraduate years (PGY) 2 through 5, plus a 3-month period after residency completion. We abstracted corresponding historical data for 2002 to 2007 from the benchmark publication by Morgan and colleagues (Int J Radiat Oncol Biol Phys 2009;74:1567-1572). We tested the null hypothesis that these 2 samples had the same distribution for number of publications using the Wilcoxon rank-sum test. We explored the association of demographic factors and publication number using multivariable zero-inflated Poisson regression. RESULTS: There were 334 residents publishing 659 eligible first-author publications during residency (range 0-17; interquartile range 0-3; mean 2.0; median 1). The contemporary and historical distributions were significantly different (P<.001); contemporary publication rates were higher. Publications accrued late in residency (27% in PGY-4, 59% in PGY-5), and most were original research (75%). In the historical cohort, half of all articles were published in 3 journals; in contrast, the top half of contemporary publications were spread over 10 journals-most commonly International Journal of Radiation Oncology • Biology • Physics (17%), Practical Radiation Oncology (7%), and Radiation Oncology (4%). Male gender, non-PhD status, and larger residency size were associated with higher number of publications in the multivariable analysis. CONCLUSION: We observed an increase in first-author publications during training compared with historical data from the mid-2000s. These contemporary figures may be useful to medical students considering radiation oncology, current residents, training programs, and prospective employers.

Impact of image guidance during whole-brain radiation therapy.

PURPOSE: Radiation oncologists are rapidly adopting image-guided radiation therapy (IGRT), warranting further evaluation of its role and value. We analyzed the impact of IGRT for one of the most common radiation treatments. METHODS AND MATERIALS: We retrospectively identified patients who received whole-brain radiation therapy (WBRT) with mask immobilization and who underwent routine IGRT with kilovoltage imaging. We calculated IGRT shifts by comparing couch positions before and after imaging. We determined the dosimetric impact of IGRT on lens maximum and dose received by 95% (D95%) of the brain and cribriform region. We calculated episode of care costs using the Medicare Physician Fee Schedule. RESULTS: A total of 206 patients received 2392 image-guided fractions. The median absolute shift was 1 mm, 1 mm, and 2 mm in the vertical, lateral, and longitudinal directions, respectively. Ninety-nine percent of shifts were ≤6 mm, 7 mm, and 9 mm in the vertical, lateral, and longitudinal directions, respectively. For the 22 patients with the largest average shift per fraction, treating without IGRT would have changed D95% brain by a median 3 cGy (interquartile range, 2-9) and D95% cribriform region by a median 39 cGy (interquartile range, 7-116). Without IGRT, lens doses would have increased for 11/22 patients and decreased for 11/22. Using a 700 cGy lens threshold, there was no net change in the proportion of patients above and below the threshold regardless of IGRT use. For a 10-fraction course, daily IGRT accounted for 10% of the total episode of care cost. CONCLUSIONS: IGRT results in small positional corrections during WBRT. Even among cases with the largest shifts, the dosimetric impact is minor for the brain and modest for the cribriform region and lenses. This study suggests mask immobilization alone is sufficient for routine cases, and it may help clinicians make evidence-based decisions about IGRT in this setting.

Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone. METHODS AND MATERIALS: We retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability. RESULTS: The median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1-2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively). CONCLUSIONS: We devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole-brain radiotherapy).

Intracranial control after Cyberknife radiosurgery to the resection bed for large brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is an alternative to post-operative whole brain radiation therapy (WBRT) following resection of brain metastases. At our institution, CyberKnife (CK) is considered for local treatment of large cavities ≥2 cm. In this study, we aimed to evaluate patterns of failure and characterize patients best suited to treatment with this approach. METHODS: We retrospectively reviewed 30 patients treated with CK to 33 resection cavities ≥2 cm between 2011 and 2014. Patterns of intracranial failure were analyzed in 26 patients with post-treatment imaging. Survival was estimated by the Kaplan-Meier method and prognostic factors examined with log-rank test and Cox proportional hazards model. RESULTS: The most frequent histologies were lung (43 %) and breast (20 %). Median treatment volume was 25.1 cm(3) (range 4.7-90.9 cm(3)) and median maximal postoperative cavity diameter was 3.8 cm (range 2.8-6.7). The most common treatment was 30 Gy in 5 fractions prescribed to the 75 % isodose line. Median follow up for the entire cohort was 9.5 months (range 1.0-34.3). Local failure developed in 7 treated cavities (24 %). Neither cavity volume nor CK treatment volume was associated with local failure. Distant brain failure occurred in 20 cases (62 %) at a median of 4.2 months. There were increased rates of distant failure in patients who initially presented with synchronous metastases (p = 0.02). Leptomeningeal carcinomatosis (LMC) developed in 9 cases, (34 %). Salvage WBRT was performed in 5 cases (17 %) at a median of 5.2 months from CK. Median overall survival was 10.1 months from treatment. CONCLUSIONS: This study suggests that adjuvant CK is a reasonable strategy to achieve local control in large resection cavities. Patients with synchronous metastases at the time of CK may be at higher risk for distant brain failure. The majority of cases were spared or delayed WBRT with the use of local CK therapy.

Authorship in Radiation Oncology: Proliferation Trends Over 30 Years.

PURPOSE: To investigate authorship trends in the radiation oncology literature. METHODS AND MATERIALS: We examined the authorship credits of "original research articles" within 2 popular radiation oncology journals-International Journal of Radiation Oncology, Biology, Physics and Radiotherapy and Oncology-in 1984, 1994, 2004, and 2014. We compared the number of authors per publication during these 4 time periods using simple linear regression as a test for trend. We investigated additional author characteristics in a subset of articles. RESULTS: A total of 2005 articles were eligible. The mean number of authors per publication rose from 4.3 in 1984 to 9.1 in 2014 (P<.001). On subset analysis of 400 articles, there was an increase in the percentage of multidisciplinary bylines (from 52% to 72%), multi-institutional bylines (from 20% to 53%), and publications with a trainee first author (from 16% to 56%) during the study period. CONCLUSIONS: The mean number of authors per publication has more than doubled over the last 30 years in the radiation oncology literature. Possible explanations include increasingly complex and collaborative research as well as honorary authorship. Explicit documentation of author contributions could help ensure that scientific work is credited according to accepted standards.

Adjuvant Radiation Therapy Treatment Time Impacts Overall Survival in Gastric Cancer.

PURPOSE: Prolonged radiation therapy treatment time (RTT) is associated with worse survival in several tumor types. This study investigated whether delays during adjuvant radiation therapy impact overall survival (OS) in gastric cancer. METHODS AND MATERIALS: The National Cancer Data Base was queried for patients with resected gastric cancer who received adjuvant radiation therapy with National Comprehensive Cancer Network--recommended doses (45 or 50.4 Gy) between 1998 and 2006. RTT was classified as standard (45 Gy: 33-36 days, 50.4 Gy: 38-41 days) or prolonged (45 Gy: >36 days, 50.4 Gy: >41 days). Cox proportional hazards models evaluated the association between the following factors and OS: RTT, interval from surgery to radiation therapy initiation, interval from surgery to radiation therapy completion, radiation therapy dose, demographic/pathologic and operative factors, and other elements of adjuvant multimodality therapy. RESULTS: Of 1591 patients, RTT was delayed in 732 (46%). Factors associated with prolonged RTT were non-private health insurance (OR 1.3, P=.005) and treatment at non-academic facilities (OR 1.2, P=.045). Median OS and 5-year actuarial survival were significantly worse in patients with prolonged RTT compared with standard RTT (36 vs 51 months, P=.001; 39 vs 47%, P=.005); OS worsened with each cumulative week of delay (P<.0004). On multivariable analysis, prolonged RTT was associated with inferior OS (hazard ratio 1.2, P=.002); the intervals from surgery to radiation therapy initiation or completion were not. Prolonged RTT was particularly detrimental in patients with node positivity, inadequate nodal staging (<15 nodes examined), and those undergoing a cycle of chemotherapy before chemoradiation therapy. CONCLUSIONS: Delays during adjuvant radiation therapy appear to negatively impact survival in gastric cancer. Efforts to minimize cumulative interruptions to <7 days should be considered.