Randomized Phase 3, Double-Blind, Placebo-Controlled Study of Prophylactic Gabapentin for the Reduction of Oral Mucositis Pain During the Treatment of Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: The purpose of this paper is to determine whether prophylactic gabapentin usage in patients undergoing definitive concurrent chemotherapy and radiation therapy (chemoRT) for oropharyngeal cancer (OPC) improves treatment-related oral mucositis pain, opioid use, and feeding tube (FT) placement. METHODS AND MATERIALS: This double-blind, randomized phase 3 study for patients with locally advanced OPC undergoing chemoRT randomly allocated patients to prophylactic gabapentin (600 mg thrice daily) or placebo. The primary endpoint was change in Patient-Reported Oral Mucositis Symptom (PROMS) scores over the entire treatment period (baseline to 6 weeks post-radiation therapy [RT] follow-up) with higher scores indicating worse outcomes. Opioid requirements, FT placement, and other patient-reported quality of life (QOL) metrics (Functional Assessment of Cancer Therapy-Head and Neck [FACT-HN] and Patient-Reported Outcomes version of the National Cancer Institute Common Terminology Criteria for Adverse Events [PRO-CTCAE]) were assessed. Lower scores suggested poorer QOL with the FACT-HN questionnaire, and higher scores suggested worse outcomes with the PRO-CTCAE questionnaire. Questionnaires were administered at baseline, weekly during RT, and at 6 weeks post-RT follow-up. Repeated measures analysis of variance was used to detect differences in PROMS scores and change in opioid use from baseline. Wilcoxon rank sum tests were used to compare averages for the other secondary endpoints. A P value less than .05 was considered statistically significant. RESULTS: Treatment arms were well balanced overall, including T and N staging and dosimetric variables. There were 58 patients analyzed. No significant difference was found in PROMS scores (mean 29.1, standard deviation [SD] 22.5 vs 20.1, SD 16.8 for gabapentin vs placebo, respectively, P = .11). The FACT-HN functional well-being index had a significant decrease in scores from baseline to follow-up in the gabapentin arm (median -6, interquartile range [IQR] -10.0 to -0.5 vs -1, IQR -5.5 to 3.0, P = .03). PRO-CTCAE scores increased significantly at follow-up for gabapentin (median 6.5, IQR 3.5-11.8 vs 1, IQR -2.0 to 6.0, P = .01). There was no significant difference in average or change in opioid use. FT placement was significantly higher in the gabapentin arm (62.1% vs 20.7%, P < .01). CONCLUSIONS: This study suggests that prophylactic gabapentin is not effective in improving treatment-related oral mucositis symptoms in a select population of patients with OPC undergoing definitive chemoRT.

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

Does the Interval Between Hysterectomy and Start of Adjuvant Radiation Treatment Influence Survival in Women With Endometrial Carcinoma?: A National Cancer Database analysis.

OBJECTIVE: The objective of this study was to analyze the impact of the time interval (TI) between hysterectomy and initiation of adjuvant radiation treatment (ART) on overall survival (OS) among women with early stage endometrial carcinoma (EC) using the National Cancer Database (NCDB). MATERIALS AND METHODS: The NCDB was queried for women with the International Federation of Gynecology and Obstetrics (FIGO) stage I to II EC who underwent hysterectomy followed by ART. We examined the prognostic impact of TI on OS using the cutoff ≤8 or >8 weeks to initiate radiation treatment (RT). Two groups of patients were created. Kaplan-Meier curves were created for OS analysis. Predictors of OS were identified. RESULTS: A total 16,520 women were identified. The median follow-up time for the entire cohort was 59.1 months. Median age was 63 years, and 82% were FIGO stage I. Pelvic external beam RT alone was used in 9569 (58%) and vaginal brachytherapy alone in 4265 women (26%). In total, 10,040 women (61%) received RT ≤8 weeks. Delay in initiating RT >8 weeks was associated with shorter 5-year OS (P=0.048). Independent predictors of shorter OS includes older age, African American race, higher comorbidity burden, higher tumor grade, the presence of lymphovascular invasion and stage II tumors. Although TI in initiating RT was a significant predictor for OS in univariate analysis, its independent significance of OS was lost on multivariate analysis (P=0.28). CONCLUSION: Our study suggests that TI between hysterectomy and initiation of ART was not an independent predictor of OS in women with early stage EC.

Randomized prospective trial of fractionated stereotactic radiosurgery with chemotherapy versus chemotherapy alone for bevacizumab-resistant high-grade glioma.

PURPOSE: Outcomes for patients with recurrent high-grade glioma (HGG) progressing on bevacizumab (BEV) are dismal. Fractionated stereotactic radiosurgery (FSRS) has been shown to be feasible and safe when delivered in this setting, but prospective evidence is lacking. This single-institution randomized trial compared FSRS plus BEV-based chemotherapy versus BEV-based chemotherapy alone for BEV-resistant recurrent malignant glioma. MATERIALS AND METHODS: HGG patients on BEV with tumor progression after 2 previous treatments were randomized to 1) FSRS plus BEV-based chemotherapy or 2) BEV-based chemotherapy with irinotecan, etoposide, temozolomide, or carboplatin. FSRS was delivered as 32 Gy (8 Gy × 4 fractions within 2 weeks) to the gross target volume and 24 Gy (6 Gy × 4 fractions) to the clinical target volume (fluid-attenuated inversion recovery abnormality). The primary endpoints were local control (LC) at 2 months and progression-free survival (PFS). RESULTS: Of the 35 patients enrolled, 29 had glioblastoma (WHO IV) and 6 had anaplastic glioma (WHO III). The median number of prior recurrences was 3. Patients treated with FSRS had significantly improved PFS (5.1 vs 1.8 months, P < .001) and improved LC at 2 months (82% [14/17] vs 27% [4/15], P = .002). The overall median survival was 6.6 months (7.2 months with FSRS vs 4.8 months with chemotherapy alone, P = .11). CONCLUSIONS: FSRS combined with BEV-based chemotherapy in recurrent HGG patients progressing on BEV is feasible and improves LC and PFS when compared to treatment with BEV-based chemotherapy alone.

Real-time Magnetic Resonance-guided Liver Stereotactic Body Radiation Therapy: An Institutional Report Using a Magnetic Resonance-Linac System.

Background Stereotactic body radiation therapy (SBRT) is a proven and effective modality for treatment of hepatic primary and metastatic tumors. However, these lesions are challenging for planning and treatment execution due to natural anatomic changes associated with respiration. Magnetic resonance imaging (MRI) offers superior soft tissue contrast resolution and the ability for real-time image-guided treatment delivery and lesion tracking. Objective To evaluate the plan quality, treatment delivery, and tumor response of a set of liver SBRT cancer treatments delivered with magnetic resonance (MR)-guided radiotherapy on a MR-linear accelerator (MR-linac). Methods Treatment data from 29 consecutive patients treated with SBRT were reviewed. All treatments were performed using a step and shoot technique to one or more liver lesions on an MR-linac platform. Patients received 45 to 50 Gy prescribed to at least 95% of the planning target volume (PTV) in five fractions except for two patients who received 27-30 Gy in three fractions. Computed tomography and MRI simulation were performed in the supine position prior to treatment in the free-breathing, end exhalation, and end inhalation breath-hold positions to determine patient tolerability and potential dosimetric advantages of each technique. Immobilization consisted of using anterior and posterior torso MRI receive coils embedded in a medium-sized vacuum cushion. Gating was performed using sagittal cine images acquired at 4 frames/second. Gating boundaries were defined in the three major axes to be 0.3 to 0.5 cm. An overlapping region of interest, defined as the percentage volume allowed outside the boundary for beam-on to occur, was set between 1 and 10%. The contoured target was assigned a 5-mm PTV expansion. Organs at risk constraints adopted by the American Association of Physicists in Medicine Task Group 101 were used during optimization. Results Twenty-nine patients, with a total of 34 lesions, successfully completed the prescribed treatment with minimal treatment breaks or delays. Twenty-one patients were treated at end-exhale, and six were treated at end-inhale. Two patients were treated using a free-breathing technique due to poor compliance with breath-hold instructions. The reported mean liver dose was 5.56 Gy (1.39 - 10.43; STD 2.85) and the reported mean liver volume receiving the prescribed threshold dose was 103.1 cm3 (2.9 - 236.6; STD 75.2). Follow-up imaging at one to 12 months post treatment confirmed either stable or decreased size of treated lesions in all but one patient. Toxicities were mild and included nausea/vomiting, abdominal pain and one case of bloody diarrhea. Four patients died due to complications from liver cirrhosis unrelated to radiation effect. Conclusion SBRT treatment using a gated technique on an MR-linac has been successfully demonstrated. Potential benefits of this modality include decreased liver dose leading to decreased toxicities. Further studies to identify the benefits and risks associated with MR-guided SBRT are necessary.

Disparities in the Use of Single-fraction Stereotactic Radiosurgery for the Treatment of Brain Metastases From Non-small Cell Lung Cancer.

PURPOSE: Radiation treatment patterns in patients with brain metastases from non-small cell lung cancer (NSCLC) have not been well elucidated. The National Cancer Database (NCDB) was used to evaluate trends in the use of whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) for brain metastasis from NSCLC. METHODS: This NCDB study included patients > 18 years old with metastatic NSCLC treated with single-fraction SRS or WBRT between 2004 and 2014. Chi-square, t-test, and multivariable logistic regression analyses were used to identify predictors of SRS versus WBRT. RESULTS: Of 40,803 patients, 34,183 (83.8%) received WBRT and 6,620 (16.2%) received SRS. SRS utilization increased from 7% (157 cases) in 2004 to 37% (1,346 cases) in 2014 (p < .001). SRS was utilized more by academic than community facilities (22% versus 13%, p < .001). The strongest independent predictors of SRS included year of diagnosis in 2010-2014 versus 2004-2009 (odds ratio [OR] 2.62, 95% CI 2.46-2.79, p < .0001), metropolitan versus rural (OR 2.26, CI 1.79-2.85, p < .0001), distance from cancer-reporting facility of ≥ 30 versus < 30 miles (OR 2.36, CI 2.18-2.56, p < .0001), private insurance versus non-insured patients (OR 1.96, CI 1.68-2.29, p < .0001), and academic versus community facility (OR 1.76, CI 1.66-1.87, p < .0001). CONCLUSION: SRS for NSCLC brain metastases has steadily increased in the United States; however, WBRT remains the most commonly used. Wide geographic and socioeconomic variations exist in the utilization of SRS and WBRT for this patient population.

A Simplified Risk Stratification Method for Women With Stage I Endometrial Carcinoma.

OBJECTIVES: Available risk stratification methods for women with endometrial carcinoma are controversially defined. We sought to develop a simplified and an individualized prognostic index for cancer recurrence in women with International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial carcinoma, solely of endometrioid histology. MATERIALS AND METHODS: We identified 976 women who underwent a hysterectomy and did not receive any adjuvant therapy. Cox proportional hazards model was used to identify independent predictors of recurrence. Prognostic groups were created based on the number of independent predictors of recurrence (0, 1, or 2 or 3 risk factors). These groups were then validated using a separate cohort of 611 women treated at another academic institution. The model's performance for predicting cancer recurrence was measured by the concordance probability estimate along with a 95% confidence interval. RESULTS: Median follow-up was 65 months. The final recurrence model included 3 risk groups based on 3 independent predictors of recurrence (tumor grade 2 or 3, the presence of lymphovascular space invasion and stage IB). Five-year recurrence rates were 4%, 16%, and 44% for groups 0, 1, and 2 or 3, respectively. The performance of the model was very good with a concordance probability estimate of 0.72 and 0.80 for the development and validation cohorts, respectively. CONCLUSIONS: On the basis of 3 well-known prognostic factors, we have developed and externally validated a simplified prognostic model that accurately predicts cancer recurrence in women with stage I endometrial carcinoma. This simplified predictive tool may be helpful in estimating individualized risk of recurrence and guide counseling with regard to adjuvant treatment.

Does Age-Adjusted Charlson Comorbidity Score Impact Survival Endpoints in Women with Federation of Gynecology and Obstetrics-Stage III Endometrial Cancer?

OBJECTIVES: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC). METHODS AND MATERIALS: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score ≥5. Significant predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were analyzed. RESULTS: Median follow-up was 54 months and median age was 65 years. Stage IIIC was the most common stage (69%). The 3 groups were well-balanced except for less utilization of adjuvant chemotherapy in group 3 (p = 0.01). Five-year OS was significantly lower in group 3 compared to groups 1 and 2 (23 vs. 65 and 51%, respectively). Similarly, 5-year RFS was 54, 41, and 33% and DSS was 65, 54, and 35% for groups 1, 2, and 3 respectively. On multivariate analyses, AACCI group 3, cervical stromal involvement, positive peritoneal cytology, and higher tumor grade were predictors for shorter OS. Cervical stromal involvement and higher grade were independent predictors for worse RFS and DSS. Additionally, positive cytology, lymphovascular space invasion, and stage IIIC2 were significantly detrimental for RFS. CONCLUSIONS: Our study suggests that comorbidity burden is a strong predictor of worse OS in women with stage III EC. Women with higher AACCI are less likely to receive adjuvant chemotherapy. Comorbidity score can significantly impact survival endpoints for women with advanced EC.

Pediatric head and neck squamous cell carcinoma: Patient demographics, treatment trends and outcomes.

OBJECTIVES: To examine patient demographics, temporal and treatment trends, and survival outcomes of pediatric non-nasopharyngeal head and neck squamous cell carcinomas using the National Cancer Database. METHODS: The National Cancer Database was queried for pediatric patients (age 0-19 years) diagnosed with squamous cell carcinoma of the head and neck (including oral cavity, oropharynx, nasal cavity, larynx, hypopharynx, and salivary glands) from 2004 to 2013. RESULTS: Of 159 patients identified, the majority had oral cavity SCC (55%). There was no discernable change in incidence trends over the study period with the number of cases per year ranging from 10 to 20 (R2 = 0.174). The predominant treatment regimen for the nasal cavity was trimodality (surgery, radiation, and chemotherapy) treatment (29%), chemotherapy and radiation for the oropharynx (40%), and surgery alone for salivary gland (47%), oral cavity (44%), and larynx (22%). The 5-year overall survival for the entire cohort was 74% and by subsite: oral cavity (66%), oropharynx (68%), nasal cavity (75%), and larynx (95%). Laryngeal disease had statistically significant longer survival when compared to oral cavity (p = .031) or oropharynx (p = .029). CONCLUSION: Although pediatric non-nasopharyngeal head and neck squamous cell carcinomas are rare, practitioners should be aware of this entity and consider it in the differential diagnosis of pediatric malignancies.

What Is the Optimal Adjuvant Treatment Sequence for Node-Positive Endometrial Cancer? Results of a National Cancer Database Analysis.

OBJECTIVE: The optimal sequence of administering chemotherapy (CT) and radiation treatment (RT) in women with node-positive endometrial carcinoma (EC) remains controversial. We used the National Cancer Database to evaluate overall survival (OS) in women with advanced EC receiving different sequences of adjuvant therapy. METHODS: The National Cancer Database was queried for female adults with International Federation of Gynecology and Obstetrics 2009 stage IIIC1 to IIIC2 EC diagnosed from 2004 to 2012 treated with hysterectomy and adjuvant CT and RT. Overall survival was compared between sequential treatment (CT followed by RT) and concurrent treatment (CT and RT within 4 weeks). χ tests assessed differences by sequence and various clinical variables. Log-rank test and Cox proportional hazards models evaluated OS. Risk factors related to OS were identified by univariate and multivariate analyses. RESULTS: Of 1826 patients, 67% (1218) received sequential treatment and 33% (608) received concurrent treatment. The median follow-up was 49.2 months. The sequential treatment group had a better 5-year OS (67% [95% confidence interval = 64%-70%]) than the concurrent treatment group (62% [95% confidence interval = 57%-66%]) (P = 0.004). On multivariate analysis, the strongest predictors of worse OS were increasing age (hazard ratio [HR] = 1.04 [1.02-1.06], P = 0.0003), type 2 versus type 1 EC (HR = 1.60 [1.06-2.43], P = 0.03), grade 3 versus 1 (HR = 2.64 [1.23-5.67], P = 0.01), residual disease or positive margin versus negative margin (HR = 2.25 [1.43-3.56], P = 0.0005), and concurrent versus sequential treatment (HR = 1.67 [1.15-2.40], P = 0.006). CONCLUSIONS: This study suggests that upfront CT followed by RT may be a better treatment sequence for adjuvant therapy in women with advanced EC.

The impact of adjuvant vaginal brachytherapy in women with Stage II uterine endometrioid carcinoma: Results of a National Cancer Database analysis.

PURPOSE: To report survival outcomes in women with Stage II uterine endometrioid carcinoma who received adjuvant radiation therapy (RT) without chemotherapy using the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried for women with International Federation of Gynecology and Obstetrics Stage II uterine endometrioid carcinoma who underwent hysterectomy followed by adjuvant RT without chemotherapy. The χ2 tests were performed to compare differences in outcome by type of adjuvant RT (external beam radiation therapy [EBRT] alone, vaginal brachytherapy [VBT] alone, or combination of EBRT and VBT). Overall survival (OS) was assessed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed to identify predictors of OS. RESULTS: We identified 2681 women. Simple hysterectomy was performed on 2261 women (84%). Adjuvant EBRT, VBT, and combination RT were administered to 27%, 36%, and 37%, respectively. There was a statistically significant difference in OS by modality of adjuvant RT (p = 0.01) favoring women who received VBT alone or in combination with EBRT. The 5-year OS was 80%, 87%, and 83% for women who received EBRT, VBT, and combination RT, respectively (p = 0.001). On multivariate analysis, old age, African-American race, no or fewer number of examined lymph nodes, and higher tumor grade were independent predictors of worse OS. RT modality did not sustain its independent prognostic significance as a predictor of OS. CONCLUSIONS: In this nationwide hospital-based study of women with International Federation of Gynecology and Obstetrics Stage II uterine endometrioid carcinoma, adjuvant VBT alone provided excellent survival outcomes and may be a reasonable adjuvant RT modality for properly selected women with adequate lymph node dissection and low-grade tumors.

External pelvic and vaginal irradiation vs. vaginal irradiation alone as postoperative therapy in women with early stage uterine serous carcinoma: Results of a National Cancer Database analysis.

PURPOSE: Adjuvant treatment in early stage uterine serous carcinoma (USC) usually consists of chemotherapy with vaginal brachytherapy (VB), pelvic external beam radiation therapy (EBRT), or combination. We compared survival outcomes across these various radiation treatment modalities using the National Cancer Database. METHODS AND MATERIALS: The National Cancer Database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II USC diagnosed from 2003 to 2013 treated definitively with hysterectomy, adjuvant chemotherapy, and radiation therapy. χ2 tests were used to assess differences by radiation type (VB, pelvic EBRT, and EBRT + VB) and various clinical variables. Kaplan-Meier and log-rank test methods were used to evaluate survival outcomes. Risk factors related to overall survival were identified by univariate and multivariate analysis. RESULTS: We identified 1336 patients with USC who met our inclusion criteria. Most patients were treated with VB (66%) compared with EBRT (21%) or combination EBRT + VB (13%). The proportion of patients who received EBRT (including EBRT + VB) was higher for those who did not have a lymph node dissection or with fewer dissected lymph nodes. Patients treated with VB alone had longer 5-year survival rates (84% [95% confidence interval: 80, 90]) than those treated with EBRT (75% [95% confidence interval: 69, 80]) (p < 0.001). On multivariate analysis, the presence of lymphovascular space invasion (hazard ratio, 2.48; p < 0.001) and the absence of a lymph node dissection (hazard ratio, 2.24; p = 0.047) were independent predictors of overall survival. CONCLUSIONS: This large hospital-based study suggests that VB alone may be sufficient for adjuvant radiation treatment in women with USC treated with adjuvant chemotherapy and who underwent an adequate surgical staging.

Trends in the utilization of adjuvant vaginal brachytherapy in women with early-stage endometrial carcinoma: Results of an updated period analysis of SEER data.

PURPOSE: Adjuvant vaginal brachytherapy (VB) is a well-established and effective radiation treatment modality in women with early-stage endometrial carcinoma. We sought to evaluate and update published trends in the utilization of VB vs. other radiation therapy modalities (pelvic external beam radiation therapy (EBRT) or the combination of VB and pelvic EBRT using the National Cancer Institute's Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I-II endometrial carcinoma diagnosed from 1995 to 2012 and treated definitively with hysterectomy and adjuvant radiation therapy. Chi-square tests were used to assess differences by radiation type (VB, EBRT, and VB + EBRT) and various demographic and clinical variables. RESULTS: We identified 15,201 patients that met inclusion criteria. There was a significant overall increase in the use of VB was observed from 17.1% in 1995-2000 compared to 57.1% in 2007-2012 (p < 0.0001). Similarly, there was a proportional decrease in the use of EBRT from 54.0% to 25.5% (p < 0.0001) as well as in the use of VB + EBRT from 28.9% to 17.4% during the same period (p < 0.0001). The observed increase in utilization of VB was not limited to any variables (age, race, histological type, International Federation of Gynecology and Obstetrics stage, and the status of lymph node dissection [yes or no]) or the number of dissected lymph nodes. CONCLUSIONS: In this large national database set, there continues to be an increasing trend for the use of VB in the adjuvant setting in women with early-stage endometrial carcinoma.

Fatal complications after stereotactic body radiation therapy for central lung tumors abutting the proximal bronchial tree.

PURPOSE: Stereotactic body radiation therapy (SBRT) is associated with excess toxicity following treatment of central lung tumors. Risk-adapted fractionation appears to have mitigated this risk, but it remains unclear whether SBRT is safe for all tumors within the central lung zone, especially those abutting the proximal bronchial tree (PBT). We investigated the dependence of toxicity on tumor proximity to PBT and whether tumors abutting the PBT had greater toxicity than other central lung tumors after SBRT. MATERIALS AND METHODS: A total of 108 patients receiving SBRT for central lung tumors were reviewed. Patients were classified based on closest distance from tumor to PBT. Primary endpoint was SBRT-related death. Secondary endpoints were overall survival, local control, and grade 3+ pulmonary adverse events. We compared tumors abutting the PBT to nonabutting and those ≤1 cm and >1 cm from PBT. RESULTS: Median follow-up was 22.7 months. Median distance from tumor to PBT was 1.78 cm. Eighty-eight tumors were primary lung and 20 were recurrent or metastatic; 23% of tumors were adenocarcinoma and 71% squamous cell. Median age was 77.5 years. Median dose was 4500 cGy in 5 fractions prescribed to the 100% isodose line. Eighteen patients had tumors abutting the PBT, 4 of whom experienced SBRT-related death. No other patients experienced death attributed to SBRT. Risk of SBRT-related death was significantly higher for tumors abutting the PBT compared with nonabutting tumors (P < .001). Two patients with SBRT-related death received anti-vascular endothelial growth factor therapy and experienced pulmonary hemorrhage. Patients with tumors ≤1 cm from PBT had significantly more grade 3+ events than those with tumors >1cm from PBT (P = .014). CONCLUSIONS: Even with risk-adapted fractionation, tumors abutting PBT are associated with a significant and differential risk of SBRT-related toxicity and death. SBRT should be used with particular caution in central-abutting tumors, especially in the context of anti-vascular endothelial growth factor therapy.

Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study.

INTRODUCTION: We investigated the relationships between treatment characteristics and long-term outcomes in patients with locally advanced thymoma or thymic carcinoma. METHODS: We retrospectively reviewed 146 patients treated from 1980 to 2011 at 2 tertiary cancer care centers, 110 with Masaoka-Koga stages III to IVA invasive thymoma and 36 with stages I to IVA thymic carcinoma. Survival probabilities were estimated using the Kaplan-Meier method. Risk factors related to survival were identified by univariate and multivariate competing risk analysis, with overall survival (OS) as the competing risk. The Cox regression analysis was used to identify risk factors for OS. RESULTS: Median follow-up time for all patients was 64 months. At 5 and 10 years, rates of OS and freedom from recurrence (FFR) were 81% and 58% and 81% and 65%, respectively. Of the patients who underwent surgery, trimodality treatment produced better survival compared with less aggressive treatment among patients with stage III disease (P=0.03). Among patients who underwent trimodality treatment, patients with stage III disease had better OS (P=0.03) and FFR (P<0.001) than those with stage IVA disease. On Cox regression analysis, decreased OS was associated with thymic carcinoma (hazard ratio [HR], 7.36; 95% confidence interval [CI], 2.38-22.77; P=0.001), R2/unresectable disease (HR, 8.45; 95% CI, 1.44-49.42; P=0.02), and an Eastern Cooperative Oncology Group performance score of 1 (HR, 8.14; 95% CI, 1.55-42.75; P=0.01) or 2 to 3 (HR, 29.60; 95% CI, 4.0-218.98; P=0.001) versus 0. CONCLUSIONS: Aggressive treatment with chemotherapy, surgical resection, and postoperative radiation therapy can produce long-term survival for patients with invasive thymic malignancies.

Local control and toxicity in a large cohort of central lung tumors treated with stereotactic body radiation therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. METHODS AND MATERIALS: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonary toxicity. RESULTS: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT ("no-fly-zone" [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. CONCLUSIONS: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ and severe pulmonary toxicity. Esophageal toxicity may be an underappreciated risk, particularly when PTV overlaps the esophagus.

Dosimetric predictors of esophageal toxicity after stereotactic body radiotherapy for central lung tumors.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) to central lung tumors can cause esophageal toxicity, but little is known about the incidence or risk factors. We reviewed central lung SBRT patients to identify dosimetric factors predictive of esophageal toxicity. MATERIALS AND METHODS: We assessed esophageal toxicity in 125 SBRT patients. Using biological equivalent doses with α/ß=10 Gy (BED10), dose-volume histogram variables for the esophagus (Dv and Vd) were assessed for correlation with grade ⩾2 acute toxicity. RESULTS: Incidence of grade ⩾2 acute toxicity was 12% (n=15). Highly significant logistic models were generated for D5cc and Dmax (p<0.001). To keep the complication rate <20%, the model requires that D5cc⩽26.3 BED10. At 2 years, the probability of complication with BED10D5cc>14.4 Gy was 24%, compared to 1.6% if ⩽14.4 Gy. CONCLUSIONS: This novel analysis provides guidelines to predict acute esophageal toxicity in lung SBRT. Dose to the hottest 5cc and Dmax of the esophagus were the best predictors of toxicity. Converting the BED10 limits to physical doses, D5cc to the esophagus should be kept less than 16.8, 18.1 and 19.0 Gy for 3, 4, and 5 fractions, respectively, to keep the acute toxicity rate <20%.