Modeling of Tumor Control Probability in Stereotactic Body Radiation Therapy for Adrenal Tumors.

PURPOSE: Stereotactic body radiation therapy (SBRT) in the management of adrenal metastases is emerging as a well-tolerated, effective method of treatment for patients with limited metastatic disease. SBRT planning and treatment utilization are widely variable, and publications report heterogeneous radiation dose fractionation schemes and treatment outcomes. The objective of this analysis was to review the current literature on SBRT for adrenal metastases and to develop treatment guidelines and a model for tumor control probability of SBRT for adrenal metastases based on these publications. METHODS AND MATERIALS: A literature search of all studies on SBRT for adrenal metastases published from 2008 to 2017 was performed, and outcomes in these studies were reviewed. Local control (LC) rates were fit to a statistically significant Poisson model using maximum likelihood estimation techniques. RESULTS: One-year LC greater than 95% was achieved at an approximated biological equivalent dose with α/ß = 10 Gy of 116.4 Gy. CONCLUSIONS: While respecting normal tissue tolerances, tumor doses greater than or equal to a biological equivalent dose with α/ß = 10 Gy of 116.4 Gy are recommended to achieve high LC. Further studies following unified reporting standards are needed for more robust prediction.

Impact of Radiation Dose on Postoperative Complications in Esophageal and Gastroesophageal Junction Cancers.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established. Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with <50 Gy and ≥ 50 Gy, as well as to published CROSS study neoadjuvant chemoradiation group data (41.4 Gy). Results: Twenty-nine patients were treated with <50 Gy (range 39.6-46.8 Gy) and 53 patients were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Complication rates and CCI scores between our <50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS data, there was no significant difference in CCI scores between the CROSS study neoadjuvant chemoradiation, <50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS group (50%) than our <50 Gy (38%) or ≥ 50 Gy (30%) groups. Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50-50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4.

PURPOSE: Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity. EXPERIMENTAL DESIGN: Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity. RESULTS: A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4). CONCLUSIONS: The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.

Rising Rates of Upfront Surgery in Early Locally Advanced Cervical Cancer: What Factors Predict for This Treatment Paradigm?

OBJECTIVE: In this study, we analyzed patterns of care for patients with locally advanced cervical cancer to identify predictors for upfront surgery compared with definitive chemoradiation (CRT). METHODS: The National Cancer Database was queried for patients aged 18 years or older with Federation of Gynecology and Obstetrics IB2-IIB cervical cancer. All patients underwent either upfront hysterectomy with or without postoperative radiation therapy versus definitive CRT. Logistic regression was used to assess variables associated with modality of treatment (surgery vs CRT). RESULTS: Of the 9494 patients included, 2151 (22.7%) underwent upfront surgery. Of those undergoing surgery, 380 (17.7%) had positive margins, 478 (22.2%) had positive nodes, and 458 (21.3%) had pathologic involvement of the parametrium. Under multiple logistic regression, rates of surgery significantly increased from 2004 (12.2%) to 2012 (31.2%) (odds ratio [OR] per year increase, 1.15; confidence interval [CI], 1.12-1.17; P < 0.001). Upfront surgery was more commonly performed in urban (OR, 1.21; 95% CI, 1.03-1.41; P = 0.018) and rural counties (OR, 1.79; 95% CI, 1.24-2.58; P = 0.002), for adenocarcinoma (OR, 2.14; 1.88-2.44; P < 0.001) and adenosquamous (OR, 2.69; 2.11-3.43; P < 0.001) histologies, and in patients from higher median income communities (ORs, 1.19-1.37). Upfront surgery was less common at academic centers (OR, 0.73; 95% CI, 0.58-0.93; P = 0.011). CONCLUSIONS: Rates of upfront surgery relative to definitive CRT have increased significantly over the past decade. In the setting of level 1 evidence supporting the use of definitive CRT alone for these women, the rising rates of upfront surgery raises concern for both unnecessary surgical procedures with higher rates of treatment-related morbidity and greater health care costs.

Neural network dose models for knowledge-based planning in pancreatic SBRT.

PURPOSE: Stereotactic body radiation therapy (SBRT) for pancreatic cancer requires a skillful approach to deliver ablative doses to the tumor while limiting dose to the highly sensitive duodenum, stomach, and small bowel. Here, we develop knowledge-based artificial neural network dose models (ANN-DMs) to predict dose distributions that would be approved by experienced physicians. METHODS: Arc-based SBRT treatment plans for 43 pancreatic cancer patients were planned, delivering 30-33 Gy in five fractions. Treatments were overseen by one of two physicians with individual treatment approaches, with variations in prescribed dose, target volume delineation, and primary organs at risk. Using dose distributions calculated by a commercial treatment planning system (TPS), physician-approved treatment plans were used to train ANN-DMs that could predict physician-approved dose distributions based on a set of geometric parameters (vary from voxel to voxel) and plan parameters (constant across all voxels for a given patient). Patient datasets were randomly allocated, with two-thirds used for training, and one-third used for validation. Differences between TPS and ANN-DM dose distributions were used to evaluate model performance. ANN-DM design, including neural network structure and parameter choices, was evaluated to optimize dose model performance. RESULTS: Remarkable improvements in ANN-DM accuracy (i.e., from > 30% to < 5% mean absolute dose error, relative to the prescribed dose) were achieved by training separate dose models for the treatment style of each physician. Increased neural network complexity (i.e., more layers, more neurons per layer) did not improve dose model accuracy. Mean dose errors were less than 5% at all distances from the PTV, and mean absolute dose errors were on the order of 5%, but no more than 10%. Dose-volume histogram errors (in cm3 ) demonstrated good model performance above 25 Gy, but much larger errors were seen at lower doses. CONCLUSIONS: ANN-DM dose distributions showed excellent overall agreement with TPS dose distributions, and accuracy was substantially improved when each physician's treatment approach was taken into account by training their own dedicated models. In this manner, one could feasibly train ANN-DMs that could predict the dose distribution desired by a given physician for a given treatment site.

Patterns of fractionation for patients with T2N0M0 glottic larynx cancer undergoing definitive radiotherapy in the United States.

OBJECTIVES: Among patients with T2N0M0 glottic larynx cancer undergoing definitive radiotherapy, recent retrospective and prospective data have suggested improved outcomes with altered fractionation over conventional fractionation (CFxn). We sought to characterize national fractionation patterns and to compare outcomes among them. MATERIALS AND METHODS: We queried the National Cancer Database for T2N0M0 squamous cell carcinomas of the glottis diagnosed from 2004-2014 and managed with definitive radiotherapy. Dose-per-fraction and duration of radiotherapy were used to define cohorts undergoing CFxn, hypofractionation (HypoFxn), and hyperfractionation (HyperFxn). Logistic regression was performed to identify predictors of receiving altered fractionation. Cox regression and propensity-score matching (PSM) analyses were used to compare survival between schedules. RESULTS: We abstracted 2 006 CFxn patients, 1 166 HypoFxn patients, and 161 HyperFxn patients. Fractionation patterns changed significantly from 2004 to 2014, with use of HyperFxn decreasing from 6.3% to 1.8% and use of HypoFxn increasing from 23.9% to 54.1% (p<0.001). Receipt of altered fractionation was independently associated with later year of diagnosis and higher facility volume. On Cox regression, both HypoFxn (hazard ratio [HR] for mortality 0.84, 95% confidence interval [95%CI] 0.73-0.97) and HyperFxn (HR 0.74, 95%CI 0.56-0.99) were associated with improved survival over CFxn. The survival advantage of each altered fractionation schedule over CFxn was redemonstrated on comparison of PSM groups. CONCLUSION: Increasing utilization of HypoFxn for T2N0M0 glottic cancer is driving national practice patterns away from CFxn. Our findings support the use of altered fractionation, particularly HypoFxn, for patients undergoing definitive radiotherapy, although HyperFxn remains understudied in a prospective fashion.

Patterns of Care for Locally Advanced Pancreatic Adenocarcinoma Using the National Cancer Database.

OBJECTIVES: The role of radiotherapy (RT) in locally advanced pancreatic cancer (LAPC) is uncertain. This study examines patterns of care and survival outcomes of LAPC undergoing chemotherapy alone versus chemotherapy plus RT (C + RT). METHODS: The National Cancer Database was queried for nonmetastatic LAPC patients who received chemotherapy alone or C + RT. RESULTS: Of the 13,695 patients included, 5306 underwent chemotherapy alone and 4971, C + RT. Use of C + RT declined from 2003 to 2011 (73%-53%), whereas chemotherapy alone increased. Of those receiving RT, rates of intensity-modulated radiotherapy (IMRT) increased (27%-72%), whereas 3-dimensional (3D) RT decreased (73%-28%). Unadjusted 1-year overall survival (OS) was longer for versus chemotherapy (45.6% vs 38.7%), as was 2-year OS (12.9% vs 11.9%) (hazard ratio, 0.88; 0.85-0.91; P < 0.001). Under multivariate analysis, C + RT was associated with improved OS (hazard ratio, 0.84; 0.81-0.87; P < 0.001). On subgroup analysis comparing C + IMRT, C + 3D RT, and chemotherapy alone, 1-year OS was 49.1%, 45.1%, and 38.7%, and 2-year OS was 13.1%, 11.6%, and 11.9% accordingly. CONCLUSIONS: Utilization of RT in LAPC is decreasing, whereas chemotherapy alone is increasing. Of patients undergoing RT, rates of IMRT are increasing. Whereas C + IMRT appeared to be associated with improved OS compared with chemotherapy alone, 3D RT was not.

Adjuvant radiotherapy improves overall survival in patients with resected gastric adenocarcinoma: A National Cancer Data Base analysis.

BACKGROUND: For patients with resectable gastric adenocarcinoma, perioperative chemotherapy and adjuvant chemoradiotherapy (CRT) are considered standard options. In the current study, the authors used the National Cancer Data Base to compare overall survival (OS) between these regimens. METHODS: Patients who underwent gastrectomy for nonmetastatic gastric adenocarcinoma from 2004 through 2012 were divided into those treated with perioperative chemotherapy without RT versus those treated with adjuvant CRT. Survival was estimated and compared using univariate and multivariate models adjusted for patient and tumor characteristics, surgical margin status, and the number of lymph nodes examined. Subset analyses were performed for factors chosen a priori, and potential interactions between treatment and covariates were assessed. RESULTS: A total of 3656 eligible patients were identified, 52% of whom underwent perioperative chemotherapy and 48% of whom received postoperative CRT. The median follow-up was 47 months, and the median age of the patients was 62 years. Analysis of the entire cohort demonstrated improved OS with adjuvant RT on both univariate (median of 51 months vs 42 months; P = .013) and multivariate (hazard ratio, 0.874; 95% confidence interval, 0.790-0.967 [P = .009]) analyses. Propensity score-matched analysis also demonstrated improved OS with adjuvant RT (median of 49 months vs 39 months; P = .033). On subset analysis, a significant interaction was observed between the survival impact of adjuvant RT and surgical margins, with a greater benefit of RT noted among patients with surgical margin-positive disease (hazard ratio with RT: 0.650 vs 0.952; P for interaction <.001). CONCLUSIONS: In this National Cancer Data Base analysis, the use of adjuvant RT in addition to chemotherapy was associated with a significant OS advantage for patients with resected gastric cancer. The survival advantage observed with adjuvant CRT was most pronounced among patients with positive surgical margins. Cancer 2017;123:3402-9. © 2017 American Cancer Society.