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Management of symptomatic brain metastases often includes surgical resection with postoperative radiotherapy. Postoperative whole-brain radiotherapy (WBRT) improves intracranial control but detrimentally impacts quality of life and neurocognition. We sought to characterize the use in the United States of postoperative stereotactic radiosurgery (SRS), an evolving standard-of-care associated with reduced cognitive effects.With the MarketScan Commercial Claims and Encounters Database from 2007 to 2015, we identified patients aged 18-65 years treated with resection of a brain metastasis followed by SRS or WBRT within 60 days of surgery. Logistic regression estimated associations between co-variables (treatment year, age, sex, geographic region, place of service, insurance type, disease histology, comorbidity score, and median area household income and educational attainment) and SRS receipt.Of 4007 patients included, 1506 (37.6%) received SRS and 2501 (62.4%) received WBRT. Postoperative SRS increased from 16.5% (2007-2008) to 56.8% (2014-2015). Patients residing in areas with a median household income or an educational attainment below 50th percentile were significantly less likely to receive SRS after controlling for treatment year and other demographic characteristics (P0.01). Factors associated with greater odds of receiving SRS included younger age, female sex, melanoma histology, Western region location, hospital-based facility, and high-deductible health plan enrollment (P0.05 for each).Postoperative SRS for brain metastases has increased from 2007 to 2015, with the majority of patients now receiving SRS over WBRT. Patients in areas of lower socioeconomic class were less likely to receive SRS, warranting further investigation of barriers to SRS adoption.

The past decade has seen considerable innovation in the delivery of care and payment in oncology. Key initiatives have included the development of oncology medical home care delivery standards, the Medicare Oncology Care Model, and multiple commercial payer initiatives. Looking forward, our next challenge is to reflect on lessons learned from these limited-scale demonstration projects and work toward models that are scalable and sustainable and reflect true collaboration between payers and providers sharing common objectives and methods to advance cancer care delivery. To this end, ASCO continues its work on care delivery standards, quality measurement, and alternative payment models. Over the past year, ASCO has received input from physicians, administrators, payers, and employers to update its Patient-Centered Oncology Payment (PCOP) model. PCOP incorporates current work on provider-payer collaboration, the oncology medical home, and the value of clinical pathways and recognizes the need for common quality measurement, performance methodology, and payment structure across multiple sources of payment. The following represents a summary of the entire model. The model includes chapters on PCOP communities, clinical practice transformation, payment methodology, consolidated payments for oncology care, performance methodology, and implementation considerations. In future work, ASCO will continue its support of the PCOP model, including further development of care delivery standards, quality measures, and technology solutions (eg, CancerLinQ).

To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66 mo [95% confidence interval (CI), 31-96], 34 mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31 mo, P=0.02 and 35 vs 16 mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.

Purpose A novel value-based approach to evaluate costly specialty drugs for formulary addition was developed. Summary In February 2016, Stanford Health Care launched the specialty drug subcommittee (SDSC), a subcommittee of the pharmacy and therapeutics committee, responsible for the formulary review of specialty pharmaceuticals. A process was developed for value-based review that includes not only consideration of clinical trial data and institutional acquisition costs but also internal patient outcomes and a cost-effectiveness model using internal financial data. A Markov model was developed to assess the value of trabectedin, which was approved for formulary addition in April 2016, relative to the addition of dacarbazine. The economic model and internal patient outcome analysis were presented to the prescribing oncologist and the SDSC for review. Internal data revealed that fewer patients than had been estimated received trabectedin, with outcomes significantly worse than those observed in the clinical trial leading to Food and Drug Administration approval. In the cost-effectiveness model, trabectedin had higher costs and poorer outcomes compared with dacarbazine. Based on the economic model, low utilization, and real-world outcomes, trabectedin was removed from formulary and a restrictive treatment pathway for nonformulary use, developed by the primary prescriber, was implemented. This process has since been applied to 11 more specialty drugs. Conclusion Internal cost-effectiveness models in combination with real-world patient outcomes data can be effective formulary management tools. Engagement and collaboration with the requesting provider are key to developing thoughtful treatment pathways.

PURPOSE/OBJECTIVE(S) Rapid and accurate estimation of tumor burden in biomedical images is essential for precisely monitoring cancer progression and assessing therapeutic response. The ability to detect and segment tumors using an automated approach is a key part of this task. Despite recent advances from deep learning, lung tumor delineation remains challenging, particularly when the tumor bounding box is not provided to the model. We hypothesized that clinical radiation oncology contours could supply a large enough dataset of 3D tumor segmentations to enable more accurate models. We developed and validated a deep learning-based model to identify and segment primary and metastatic lung tumors on computed tomography (CT) images. MATERIALS/METHODS We curated a dataset consisting of CT images and clinical segmentations of 1,916 lung tumors in 1,504 patients who received radiation treatment for one or more primary or metastatic lung tumors. Segmentation quality was independently verified by a radiation oncologist using a custom web application. This dataset was used to train two 3D U-Net convolutional neural networks with varying model properties: one using high-resolution and small input volumes, and one using low-resolution and large input volumes. Models were ensembled together during validation. Performance was evaluated using an external held-out test set of CT images and segmentations from 59 patients with a single primary or metastatic lung tumor, treated at a separate clinical site. This test set consisted of 50 primary lung cancers and 9 metastases. To benchmark model performance against physicians, the test set was also contoured by two additional radiation oncologists. RESULTS Median tumor volume in the external test set was 80.48 cubic centimeters (interquartile range [IQR]: 14.40 to 177.65). The segmentations generated by the ensembled model produced a mean Dice coefficient of 0.62 (IQR: 0.47 to 0.85) on the test set. The sensitivity for detecting a tumor, as defined by correctly predicting at least one voxel within a ground truth tumor, was 93.2%, and the Dice coefficient for the scans with correctly identified lesions was 0.67 (IQR: 0.53 to 0.85). In comparison, the mean interobserver Dice coefficient for the three physicians on the test set was 0.76 (IQR: 0.70 to 0.84). We observed strong correlation between physician-determined tumor size and model-predicted tumor size (Pearson correlation, r = 0.69, P < 0.0001). CONCLUSION An end-to-end deep learning-based model was able to identify and segment lung tumors in a completely automated fashion, with near-expert level performance. Such models could soon be useful for clinical contouring and automatic quantification of tumor burden.

PURPOSE/OBJECTIVE(S) The first clinical biology-guided radiation therapy (BgRT) system - RefleXion X1 - is installed and is being commissioned for clinical use at our institution. The system delivers 6MV-FFF beam via 50 firing positions at 850 cGy/min dose rate on 60 rpm rotating gantry with the couch advancing in 2.1 mm increments. Collimation is achieved through a binary multi-leaf collimator system composed of 64 (6.25 mm width at 850 cm SAD) leaves and 10mm or 20mm jaws. The purpose of this study was to compare the treatment plan quality and delivery efficiency for SBRT cases without PET-guidance. MATERIALS/METHODS Five lung cancer patients (50 Gy/4fx) with motion-inclusive PTV previously treated with VMAT SBRT were selected for this retrospective study. For each VMAT plan a corresponding plan was generated on the RefleXion treatment planning system (TPS) using our institutional planning constraints. VMAT SBRT plans used 1-2 partial arcs with 10MV-FFF energy and 2400 MU/min dose rate. RefleXion SBRT plans used all 50 firing positions and 1 cm jaw collimation. As plan normalization option does not yet exist in the RefleXion TPS, the plans were optimized to achieve PTV D95% coverage with 100% of prescription dose to the best of planner's ability. All clinically relevant metrics in this study, including plan PTV D95%, PTV D1%, 50% isodose volume (I50%), Conformity Index (CI), organs at risk constraints, and treatment time were analyzed and compared between VMAT and RefleXion plans using paired t-tests. RESULTS Clinically acceptable plans were obtained with both techniques. The average PTV volume was 14.1 ± 6.4cc. For VMAT and RefleXion plans, no statistically significant difference was observed in PTV D95%, PTV D1%, CI or I50%. Ipsilateral lung volume spared at 12.4 Gy (VS12.4) was slightly greater (31.6cc increase, P < 0.035) and skin Dmax was slightly lower (1.4 Gy decrease, P < 0.038) for RefleXion plans. Treatment beam-on time was significantly longer for RefleXion plans (23.4min increase, P < 0.0002). CONCLUSION RefleXion TPS provided comparable plan quality to lung SBRT VMAT plans. Treatment beam-on time is significantly longer for the RefleXion system.

BACKGROUND Adherence to endocrine therapy for breast cancer is often inadequate, in part because of out-of-pocket costs for medication. Numerous states have enacted parity laws to limit patient cost-sharing for oral anticancer drugs. The objective of this study was to estimate the impact of these laws on patient copayments for and adherence to oral endocrine therapy for breast cancer. METHODS Administrative health insurance claims data from 2007 to 2014 derived from a US health care database were used to identify female patients aged 18 to 64 years with invasive cancer or ductal carcinoma in situ of the breast who initiated endocrine therapy and were enrolled in fully insured health plans in states that either enacted parity legislation between 2008 and 2013 or had not yet enacted such legislation by 2015. Differences-in-differences analysis was used to compare copayments for and adherence to endocrine therapy during the 1-year period before and after each year of legislation enactment. RESULTS In total, 6900 individuals who received 7778 unique drug therapy courses were identified. Parity legislation was associated with significant decreases in the 25th percentile of copayments for anastrozole of $4.39 (95% confidence interval [CI], -$4.52 to -$4.26; P < .001) and for exemestane of $3.08 (95% CI, -$4.80 to -$1.35; P < .001). The median copayment for exemestane decreased by $10.25 (95% CI, -$12.61 to -$7.89; P < .001). A higher median monthly copayment was significantly associated with a greater risk of medication nonadherence (adjusted risk ratio, 1.006 per dollar increase; P < .001). CONCLUSIONS Parity laws had a modest effect on lowering the cost of anastrozole and exemestane, but more focused efforts to limit out-of-pocket costs for endocrine therapy may have a greater impact on medication adherence.

Background Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data. Objective To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors. Methods We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. Results Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed. Conclusion Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

Stereotactic radiosurgery is a standard of care for the definitive treatment of benign intracranial tumors such as meningiomas, schwannomas, neurofibromas, and hemangioblastomas. Stereotactic radiosurgery for benign spinal tumors was not practical with frame-based radiosurgery devices. With the advent of frameless radiosurgical treatment pioneered by the CyberKnife, intracranial radiosurgical principles are now applied in the spine. Treatment outcomes from early reports in the 2000s of radiosurgery for benign spinal tumors suggested short-term efficacy for controlling tumor growth. Recently, published series demonstrate long-term durable tumor control with limited toxicity similar to what is seen for radiosurgery to benign intracranial tumors. Treatment outcomes and planning guidelines are presented that support single fraction or hypofractionated stereotactic radiosurgery as a standard of care for benign spinal tumors.

Neoadjuvant chemotherapy (NAC) is used to allow more limited breast surgery without compromising local control. We sought to evaluate nationwide surgical trends in patients with operable breast cancer treated with NAC and factors associated with surgical type. We used the National Cancer Database to identify 235,339 women with unilateral T1-3 N0-3 M0 breast cancer diagnosed between 2010 and 2014 and treated with surgery and chemotherapy. Of these, 59,568 patients (25.3%) were treated with NAC. Rates of pathological complete response (pCR) to NAC increased from 33.3% at the start of the study period in 2010 to 46.3% at the end of the period in 2014 (p = 0.02). Rates of breast-conserving surgery (BSC) changed little, from 37.0 to 40.8% (p = 0.22). Although rates of unilateral mastectomy decreased from 43.3 to 34.7% (p = 0.02) and rates of bilateral mastectomy without immediate reconstruction remained similar (11.7-11.5%; p = 0.82), rates of bilateral mastectomy with immediate reconstruction rose from 8.0 to 13.1% (p = 0.02). Patients who were younger, with private/managed care insurance, and diagnosed in more recent years were more likely to achieve pCR; however, these same characteristics were associated with receipt of bilateral mastectomy (vs. BCS). In addition, non-Hispanic white ethnic and higher area education attainment were both associated with bilateral mastectomy. These findings did not differ by age or molecular subtype. Further study of nonclinical factors that influence selection of more extensive surgery despite excellent response to NAC is warranted.

Purpose The purpose of this study was to determine the impact of splenic and thoracic bone marrow irradiation on hematologic toxicity in the setting of chemoradiation therapy for esophageal cancer. Methods and materials We analyzed 60 patients with carcinoma of the distal esophagus or gastroesophageal junction who received concurrent chemoradiation in the preoperative or definitive setting. Dosimetric and volumetric parameters were calculated for the spleen, thoracic spine, and posterior ribs. The primary endpoint was grade ≥3 hematologic toxicity (HT3+). Associations were assessed using logistic and linear regression models. Results Twenty-one patients (35%) experienced HT3+, including 18 patients with leukopenia and 5 with thrombocytopenia. Higher spleen V5-V20 was correlated with a lower risk of HT3+ on multivariable analysis (odds ratio: 0.83 per 10 cm3 increase in V10; P = .013). A dose-dependent decrease in spleen volume was observed after radiation therapy, and a greater decrease was independently associated with a lower risk of HT3+ (odds ratio: 0.93 per 1% volume decrease; P = .014). Dosimetric parameters of the thoracic spine were not significantly associated with HT3+. Conclusions A greater decrease in spleen size after radiation therapy and a higher spleen V5-V20 were independently associated with a lower risk of severe hematologic toxicity. Splenic irradiation may mitigate leukopenia associated with chemoradiation therapy.

Purpose/objective(s) Soft tissue sarcomas (STSs) are diverse mesenchymal tumors that are primarily managed with surgery. Radiation therapy (RT) is frequently added pre- or post-operatively for localized disease but uncommonly used as definitive treatment because the majority of unresected tumors progress with RT alone. Advances in next-generation sequencing have led to the widespread use of clinical genomic profiling, but the genetic determinants of radiation response in STSs are unknown. We hypothesized that integrating patient outcome data and clinical tumor mutation profiling could identify genomic predictors of recurrence patterns after RT for localized STS. Materials/methods We retrospectively identified 31 patients treated at our institution with definitive RT with or without surgery for localized STS who underwent tumor genomic profiling using a sequencing platform. For genes altered in at least 10% of patients, the associations between genetic alterations and local failure or distant metastasis were analyzed with univariable and multivariable competing risk regression adjusted for the competing risk of death. Age, maximum tumor diameter, tumor grade, and extent of resection were included as co-variables, and P values were adjusted for multiple hypothesis testing. Results Median follow up was 24 months, and the median RT dose was 50.4 Gy in 28 fractions. The most common histologies were leiomyosarcoma (n = 4) and myxofibrosarcoma (n = 4). The majority of tumors were located in the trunk and extremities (68%) with the remaining tumors originating in the head and neck (16%) or abdomen and pelvis (16%). 48% of patients underwent margin-negative resection, 36% had microscopically positive margins, and 16% were unresected or had gross residual disease following surgery. Median age was 58, median tumor size was 7.5 cm, and 65% of tumors were high grade. On univariable analysis, younger age (P = 0.02) and extent of resection (P = 0.0002) were significantly associated with local recurrence, and there was a trend towards association between higher grade and distant metastasis (P = 0.09). On univariable analysis, amplification of FRS2 in isolation or in combination with MDM2 and CDK4 was associated with a significantly increased risk of local recurrence (n = 4, HR 4.3), and genetic alterations in FBXO11 were associated with a significantly increased risk of distant metastasis (n = 4, HR 3.9). On multivariable analysis, FBXO11 alterations continued to predict for distant metastasis (HR 5.7, P = 0.0002), but there were no significant predictors of local recurrence. Conclusion Our results suggest that somatic tumor mutations may contribute to the risk of local recurrence and distant metastasis in patients treated with RT for localized STS. Additional analysis and validation in larger multi-institutional cohorts will be critical to identify molecular predictors of prognosis and patterns of recurrence.

Purpose/Objective(s) Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR. Materials/Methods This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test. Results Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 – 12.4) and 10.1 (6.8 –13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 – 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P Conclusion INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

Purpose/Objective(s) Hemoptysis is a rare but potentially fatal toxicity associated with thoracic stereotactic ablative radiotherapy (SABR). Prior studies have suggested that vascular endothelial growth factor inhibitors (VEGFI) may potentiate the risk for pulmonary hemorrhage in patients treated with SABR for centrally located lung tumors. To what degree the risk of toxicity varies by timing of therapies or tumor location is uncertain. The purpose of this study is to evaluate the combined toxicity of VEGFIs and SABR for peripheral, central, or ultra-central tumors. Materials/Methods We evaluated patients with primary or metastatic lung tumors treated with SABR between 2008 and 2018 at a single institution. Baseline patient, tumor and treatment characteristics were evaluated. Pulmonary bleeding events were graded using CTCAE version 5.0. Rates of a grade three or higher (G3+) or any ipsilateral pulmonary hemorrhage at three years were estimated using the Kaplan-Meier method. We compared rates of bleeding by tumor location, treatment with a VEGFI, sequence of therapy and VEGFI within 90 days of SABR using the log-rank test. Results This retrospective cohort study included a total of 925 pulmonary tumors treated with SABR in 691 patients. There were 44 patients treated with a VEGFI (bevacizumab, sorafenib, pazopanib, sunitinib or ramucirumab), with the majority receiving bevacizumab (n = 38, 86.3%). Among those treated with a VEGFI, the median interval between VEGFI therapy and SABR was 16 weeks, ranging from zero days to 3.7 years, with 15 (34.0%) patients treated within 90 days of SABR. Patients were treated with SABR to peripheral (738, 79.8%), central (137, 14.8%) and ultra-central (50, 5.4%) locations with a median BED10 of 87.5 Gy. Median follow-up was 32.2 months for the overall cohort and 46.4 months for VEGFI patients. The rate of G3+ hemorrhage was significantly higher in patients treated with a VEGFI (7.3 vs 0.8%, P or ≤ 90 days (12.0 vs 0.0%, P = 0.17). Similarly, there was no significant difference between rates of G3+ hemorrhage when VEGFI was given before (12.9%), after (8.3%), or before and after SABR (0.0%). Conclusion VEGFI therapy was associated with an increased rate of high-grade hemorrhage in patients undergoing SABR to pulmonary tumors. Rates of high-grade hemorrhage were increased with VEGFI for both central/ultra-central and peripheral tumors although the absolute rate was low for peripheral tumors. While limited by low sample size and event rate, there was no correlation observed between interval or sequence of VEGFI and SABR and rate of high-grade hemorrhage.

Background The addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (≥40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy. Methods A decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters. Results Modeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY. Conclusion The addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.

Background Radiation therapy (RT) remains a critical component of multimodality treatment for medulloblastoma. Traditionally, clinicians strive to start RT within 4-5 weeks of surgery, but the optimal timing after surgery remains unclear. Methods Using the National Cancer Database, we identified pediatric and adolescent patients with medulloblastoma treated with curative-intent surgery, RT, and chemotherapy. Factors associated with early or delayed RT were identified using Pearson chi-squared tests. Overall survival (OS) differences based on RT timing were compared using the Kaplan-Meier estimator with log-rank tests. Patient, tumor, and treatment characteristics associated with OS were analyzed with univariate and multivariate Cox proportional hazards models. Results Among the 1338 patients analyzed, early RT (defined as initiation ≤3 wk after surgery) was associated with younger age, M1-3 disease, and subtotal resection. Patients who initiated RT early had decreased 5-year OS compared with patients who initiated RT 3.1-4, 4.1-5, or >5 weeks after surgery (72.5% vs. 80.5%, 79.4%, and 77.8%, respectively; P = 0.019), but there was no significant difference in OS among the latter 3 groups (P = 0.788). On multivariate analysis, early RT versus the 3.1- to 4-week interval was significantly associated with poorer OS (adjusted hazard ratio, 1.72; 95% CI: 1.19-2.48; P = 0.004), while time to RT of >5 weeks but within 90 days of surgery did not adversely impact OS (P = 0.563). Conclusions In this large national database analysis, delaying RT within 90 days of surgery was not associated with inferior outcomes. Although clinical judgment remains paramount, postoperative RT timing should allow for healing and the development of an optimal treatment plan.

Nonoperative management of rectal cancer is an emerging treatment approach that aims to enable carefully selected patients to avoid the morbidity of radical surgical resection, while benefiting from the same excellent rates of tumor control achieved with radical surgery-based combined-modality therapy. The success of nonoperative management in this setting is based on the accurate assessment of tumor eradication after chemoradiotherapy, without pathologic verification. Therefore, clinical evidence of complete response-based on physical examination, endoscopic procedures, and imaging-must be utilized as a marker to predict for pathologic complete response and thus help select the patients who are most appropriate for nonoperative management. Initial evidence from retrospective and prospective single-arm and cohort studies has demonstrated high rates of local control and disease-free survival with nonoperative management of rectal cancer, compared with historical results of combined-modality therapy. Several trials and registries are prospectively investigating nonoperative management vs standard treatment of rectal cancer. At this time, combined-modality therapy with total mesorectal excision remains the standard of care for patients with locally advanced rectal cancer; nonoperative management should not be routinely offered outside of clinical trials.

Purpose: Drivers of variation in the cost of care after chemoradiotherapy for the management of anal squamous cell carcinoma (SCC) have not been fully elucidated. We sought to characterize the direct and indirect impact of radiotherapy modality on health care costs among patients with anal SCC. Patients and Methods: A retrospective cohort study was performed using the 2014 linkage of the SEER-Medicare database. We identified 1,025 patients with anal SCC diagnosed between 2001 and 2011 and treated with chemoradiotherapy. Propensity score matching was used to balance baseline differences between patients treated with intensity-modulated radiotherapy (IMRT) and those treated with three-dimensional conformal radiotherapy (3D-CRT). Differences in total, cancer-attributable, and procedure-specific costs between groups were measured. Results: Radiation-related, patient out-of-pocket, and total costs in the 1-year period after radiotherapy start were all higher for the IMRT group than the 3D-CRT group (median total cost, $35,890 v $27,262, respectively; P < .001). Patients who received IMRT had lower cumulative costs associated with urgent hospitalizations and emergency department visits at both 9 months and 1 year after treatment start compared with a matched cohort of patients who received 3D-CRT (median, $711 v $4,957 at 1 year, respectively; P = .021). Conclusion: Although total costs of care were higher for IMRT compared with 3D-CRT, primarily as a result of higher radiotherapy-specific costs, IMRT was associated with decreased unplanned health care utilization costs starting at 9 months after treatment start. Radiotherapy-centered episodes of care may need to encompass a longer time horizon to capture the full cost savings associated with more advanced radiation modalities.

Background Emerging data support aggressive local treatment of oligometastatic non–small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker. Materials and Methods We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS). Results On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014). Conclusion The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

Head and neck cancers centered at the base of skull are better visualized on MRI than on CT. The purpose of this investigation was to investigate the accuracy of bulk density assignment in head and neck intensity‐modulated radiation therapy (IMRT) treatment plan optimization. Our study investigates dose calculation differences between density‐assigned MRI and CT, and identifies potential limitations related to dental implants and MRI geometrical distortion in the framework of MRI‐only‐based treatment planning. Bulk density assignment was performed and applied onto MRI to generate three MRI image sets with increasing levels of heterogeneity for seven patients: 1) MRIW: all water‐equivalent; 2) MRIW + B: included bone with density of 1.53 g/cm3; and 3) MRIW + B + A: included bone and air. Using identical planning and optimization parameters, MRI‐based IMRT plans were generated and compared to corresponding, forward‐calculated, CT‐based plans on the basis of target coverage, isodose distributions, and dose‐volume histograms (DVHs). Phantom studies were performed to assess the magnitude and spatial dependence of MRI geometrical distortion. MRIW‐based dose calculations overestimated target coverage by 16.1%. Segmentation of bone reduced differences to within 2% of the coverage area on the CT‐based plan. Further segmentation of air improved conformity near air–tissue interfaces. Dental artifacts caused substantial target coverage overestimation even on MRIW + B + A. Geometrical distortion was less than 1 mm in an imaging volume 20 × 20 × 20 cm3 around scanner isocenter, but up to 4 mm at 17 cm lateral to isocenter. Bulk density assignment in the framework of MRI‐only IMRT head and neck treatment planning is a feasible method with certain limitations. Bone and teeth account for the majority of density heterogeneity effects. While soft tissue is well visualized on MRI compared to CT, dental implants may not be visible on MRI and must be identified by other means and assigned appropriate density for accurate dose calculation. Far off‐center geometrical distortion of the body contour near the shoulder region is a potential source of dose calculation inaccuracy. PACS numbers: 87.61.‐c, 87.55.‐D

To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting.We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ≥3 months after surgery. We used logistic regression models to assess the association between age (70, 70-79, and ≥80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ≥70 years.A total of 25,829 patients were included in the study. Compared with those aged70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79).In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy.

The effect of race on cognitive test performance in the evaluation of Alzheimer's disease (AD) remains controversial. One factor that may contribute substantially to differences in cognitive test performance in diverse populations is education. The current study examined the extent to which quality of education, even after controlling for formal years of education, accounts for differences in cognitive performance between African Americans and White Non-Hispanics (WNHs). The retrospective cohort included 244 patients diagnosed with AD who self-identified as African Americans (n= 51) or WNHs (n= 193). The Wechsler Test of Adult Reading (WTAR) was used as an estimate of quality of education. In an analysis that controlled for traditional demographics, including age, sex, and years of formal education, African Americans scored significantly lower than WNHs on the Mini-Mental State Examination, as well as on neuropsychological tests of memory, attention, and language. However, after also adjusting for reading level, all previously observed differences were significantly attenuated. The attenuating effect remained even after controlling for disease severity, indicating that reading scores are not confounded by severity of dementia. These findings suggest that quality, and not just quantity, of education needs to be taken into account when assessing cognitive performance in African Americans with AD. (JINS, 2012,18, 277–285)

Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98–99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10−6 M; IC50 = 3.7 × 10−8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT1 (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT1 transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.

132 Background: Sinoatrial node (SAN) injury following stereotactic ablative radiation therapy (SABR) in the chest has not been reported in the literature. We report SAN dysfunction as a potential toxicity of SABR in the chest. Methods: We examined the clinical courses and SABR plans of 47 patients treated for T1 or T2 non-small cell lung cancer of the right upper lobe, middle lobe, lower lobe, or hilum. After developing a contouring atlas for the SAN, based upon the junction between the superior vena cava and the right atrium, dose to the SAN was retrospectively determined for each patient. We identified 13 patients whose treatment imparted significant dose to the SAN, as defined by the SAN encompassed within the 10% prescription isodose (IDL) line. Biologically effective doses (BED), acute and chronic, were correlated with SAN toxicity. Results: Patients underwent SABR to the right lung to a dose of 40-50 Gy in 4 or 5 fractions, with mean acute BED (alpha/beta ratio = 10) of 100.2 Gy and late BED (alpha/beta ratio = 3) of 222.7 Gy. Mean volume of the GTV and PTV were 26.1 and 75.1 mL, respectively. Mean follow-up was 25.5 months. The mean volume of the SAN was 0.37 mL. Average max dose and mean dose to the SAN were 24.7 and 70.7 Gy, respectively. Of the 13 patients whose treatment imparted significant dose to the SAN, one patient without prior arrhythmia developed symptomatic SAN dysfunction requiring pacemaker placement at 6 months after completion of treatment. The sinoatrial node of the patient received a maximum dose of 44.8 Gy in 4 fractions, correlated with an acute BED (alpha/beta ratio = 10) of 90 Gy and late BED (alpha/beta ratio = 3) of 194.1 Gy, and a mean dose of 35.5 Gy in 4 fractions, correlated with an acute BED (alpha/beta ratio = 10) of 71 Gy and late BED (alpha/beta ratio = 3) of 153.8 Gy. This was the third highest max dose and second highest mean dose to SAN in the cohort. Conclusions: We report sinoatrial node dysfunction as a potential toxicity of SABR in the chest for non-small cell lung cancer. Caution is advised when treatment imparts significant dose to the sinoatrial node.

Debate exists regarding differences in the prevalence of Alzheimer disease (AD) in African Americans and Hispanics in the United States, with some evidence suggesting that the prevalence of AD may be considerably higher in these groups than in non-Hispanic whites. Despite this possible disparity, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment for dementia. This review investigates these disparities by conceptualizing the dementia disease process as a product of both biological and cultural factors. Ethnoracial differences in biological risk factors, such as genetics and cardiovascular disease, may help to explain disparities in the incidence and prevalence of AD, whereas race-specific cultural factors may impact diagnosis and treatment. Cultural factors include differences in perceptions about what is normal aging and what is not, lack of adequate access to medical care, and issues of trust between minority groups and the medical establishment. The diagnosis of AD in diverse populations may also be complicated by racial biases inherent in cognitive screening tools widely used by clinicians, but controlling for literacy level or using savings scores in psychometric analyses has the potential to mitigate these biases. We also suggest that emerging biomarker-based diagnostic tools may be useful in further characterizing diverse populations with AD. Recognizing the gap in communication that exists between minority communities and the medical research community, we propose that education and outreach are a critical next step in the effort to understand AD as it relates to diverse populations.