Full Dose SBRT in Combination With Mediastinal Chemoradiation for Locally Advanced, Non-Small Cell Lung Cancer: A Practical Guide for Planning, Dosimetric Results From a Phase 2 Study, and a Treatment Planning Guide for the Phase 3 NRG Oncology LU-008 Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS: We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS: Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS: SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

The Association Between Radiation Therapy Dose and Overall Survival in Patients With Intracranial Infiltrative Low-Grade Glioma Treated With Concurrent and/or Adjuvant Chemotherapy.

PURPOSE: Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. METHODS AND MATERIALS: We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. RESULTS: The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. CONCLUSIONS: Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.

Implementation, adherence, and results of systematic SARS-CoV-2 testing for asymptomatic patients treated at a tertiary care regional radiation oncology network.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus is a current pandemic. We initiated a program of systematic SARS-CoV-2 polymerase chain reaction (PCR) testing in all asymptomatic patients receiving radiotherapy (RT) at a large radiation oncology network in the Charlotte, NC metropolitan region and report adherence and results of the testing program. METHODS: Patients undergoing simulation for RT between May 18, 2020 and July 10, 2020 within the Levine Cancer Institute radiation oncology network who were asymptomatic for COVID-19 associated symptoms, without previous positive SARS-CoV-2 testing, and without recent high-risk contacts were included. PCR testing was performed on nasal cavity or nasopharyngeal swab samples. Testing was performed within 2 weeks of RT start (pre-RT) and at least every 4 weeks during RT for patients with prolonged RT courses (intra-RT). An automated task based process using the oncology electronic medical record (EMR) was developed specifically for this purpose. RESULTS: A total of 604 unique patients were included in the cohort. Details on testing workflow and implementation are described herein. Pre-RT PCR testing was performed in 573 (94.9%) patients, of which 4 (0.7%) were positive. The adherence rate to intra-RT testing overall was 91.6%. Four additional patients (0.7%) tested positive during their RT course, of whom 3 were tested due to symptom development and 1 was asymptomatic and identified via systematic testing. A total of 8 (1.3%) patients tested positive overall. There were no known cases of SARS-CoV-2 transmission from infected patients to clinic staff and/or other patients. CONCLUSIONS: We detailed the workflows used to implement systematic SARS-CoV-2 for asymptomatic patients at a large radiation oncology network. Adherence rates for pre-RT and intra-RT testing were high using this process. This information allowed for appropriate delay in initiating RT, minimizing the occurrence of RT treatment interruptions, and no known cases of transmission from infected patients to clinic staff and/or other patients.

The effect of adjuvant radiotherapy on overall survival in adults with intracranial ependymoma.

BACKGROUND: Adult intracranial ependymoma is rare, and the role for adjuvant radiotherapy (RT) is not well defined. METHODS: We used the National Cancer Database (NCDB) to select adults (age ≥ 22 years) with grade 2 to 3 intracranial ependymoma status postresection between 2004 and 2015 and treated with adjuvant RT vs observation. Four cohorts were generated: (1) all patients, (2) grade 2 only, (3) grade 2 status post-subtotal resection only, (4) and grade 3 only. The association between adjuvant RT use and overall survival (OS) was assessed using multivariate Cox and propensity score matched analyses. RESULTS: A total of 1787 patients were included in cohort 1, of which 856 patients (48%) received adjuvant RT and 931 (52%) were observed. Approximately two-thirds of tumors were supratentorial and 80% were grade 2. Cohorts 2, 3, and 4 included 1471, 345, and 316 patients, respectively. There was no significant association between adjuvant RT use and OS in multivariate or propensity score matched analysis in any of the cohorts. Older age, male sex, urban location, higher comorbidity score, earlier year of diagnosis, and grade 3 were associated with increased risk of death. CONCLUSIONS: This large NCDB study did not demonstrate a significant association between adjuvant RT use and OS for adults with intracranial ependymoma, including for patients with grade 2 ependymoma status post-subtotal resection. The conflicting results regarding the efficacy of adjuvant RT in this patient population highlight the need for high-quality studies to guide therapy recommendations in adult ependymoma.

Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery.

INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate (4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression modeling, melanoma histology (ß: 10.10, SE: 1.89, p < 0.0001) and number of initial brain metastases (ß: 1.52, SE: 0.34, p < 0.0001) remained predictive of BMV (adjusted R2 = 0.06). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair.

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.

Association Between Radiation Dose and Outcomes With Postoperative Radiotherapy for N0-N1 Non-Small Cell Lung Cancer.

PURPOSE: To review trends in the use of postoperative radiotherapy (PORT) in the modern era for N0-N1 margin-negative non-small cell lung cancer (NSCLC) following surgical resection and evaluate the association between PORT dose and overall survival. MATERIALS AND METHODS: We performed a retrospective study of nonmetastatic stage II and III N0-N1 margin-negative NSCLC surgically treated patients within the National Cancer Data Base from 2003 to 2011. Cox proportional hazards regression was performed for multivariable analyses of overall survival and PORT dose. Radiation modalities included nonconformal beam radiation, 3-dimensional conformal radiation (3D-CRT), and intensity-modulated radiation therapy. RESULTS: We identified 2167 (6.7%) and 30,269 (93.3%) patients with surgically resected stage II or III N0-N1 margin-negative NSCLC who were treated with and without PORT, respectively. The proportion of patients treated with PORT (dose range, 45 to 74 Gy) decreased from 8.9% in 2003 to 2006 to 4.1% in 2010 to 2011. Among patients receiving PORT, the use of high-dose (60 to 74 Gy) PORT rose throughout the study period, starting at 34.8% in 2003 to 2006 and rising to 49.3% in 2010 to 2011.Overall, patients who received PORT had worse survival (hazards ratio=1.30; 95% confidence interval, 1.20-1.40) compared with those not receiving PORT. This association was unchanged when limited to patients receiving modern treatment with 3-CRT or intensity-modulated radiation therapy (hazards ratio=1.35; 95% confidence interval, 1.10-1.65). CONCLUSIONS: The use of PORT for N0-N1 margin-negative NSCLC decreased from 2003 to 2011. We found no evidence of benefit from PORT for resected N0-N1 margin-negative NSCLC, regardless of dose or technique. PORT should be approached with caution in this group of patients, regardless of radiotherapy technique.

Patterns of care and outcomes for use of concurrent chemoradiotherapy over radiotherapy alone for anaplastic gliomas.

BACKGROUND AND PURPOSE: The role of concurrent chemoradiotherapy (CRT) for anaplastic gliomas is undefined and patterns of care are under-reported. To address the knowledge gap, we examined use of CRT for grade III gliomas compared to radiotherapy (RT) alone. MATERIAL AND METHODS: In an observational study design cohort from the National Cancer Database, we identified 4437 adult patients receiving surgery followed by either CRT or RT for supratentorial anaplastic glioma in 2003-2011. Univariable and multivariable logistic regression analyses were used to assess factors associated with use of CRT. Overall survival (OS) was assessed by the Kaplan-Meier analysis with log-rank tests, Cox proportional hazards regression modeling, and propensity score matching. RESULTS: Receipt of CRT (vs. RT) was associated with recent year of diagnosis (OR for 2011 (vs. 2003) 3.36, 95% CI 2.49-4.54) and having astrocytoma (vs. oligodendroglioma) (OR 1.37, 95% CI 1.15-1.63). Patients receiving CRT had a lower adjusted hazard of death (hazard ratio 0.72, 95% CI 0.65-0.79). Outcomes were worse for patients ≥60 (HR 6.94, 95% CI 6.09-7.91) and astrocytomas (HR 2.08, 95% CI 1.85-2.34). CONCLUSION: Use of concurrent CRT is associated with more recent year of diagnosis and improved survival relative to RT alone.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas.

High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood-brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456-69. ©2017 AACR.

Role of Adjuvant Treatment in Esophageal Cancer With Incidental Pathologic Node Positivity.

BACKGROUND: The optimal adjuvant treatment for cT1-2 N0 esophageal cancer patients found to have pathologic nodal involvement after an upfront operation is unclear. This study investigated the effects of postoperative chemotherapy and chemoradiation therapy on overall survival in cT1-2 N0 patients with incidental pN+ disease stratified by margin status. METHODS: We identified cT1-2 N0 M0 esophageal carcinoma patients from 2004 to 2012 from the National Cancer Data Base. Patients were categorized as having received surgical resection alone, surgical resection followed by chemotherapy (S+CT), and surgical resection followed by concurrent chemoradiation therapy (S+CRT). Subset analyses were conducted on margin-negative and margin-positive patients. Overall survival was compared by Kaplan-Meier estimation, the log-rank test, and multivariable Cox regression analysis. RESULTS: Among 443 patients, 52.6% received surgical resection alone, 18.7% received S+CT, and 28.6% received S+CRT. Significantly more adenocarcinoma patients received adjuvant treatment (50.8%) than squamous cell carcinoma patients (27.7%, p = 0.001). On multivariable analysis, S+CT (hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; p = 0.014) and S+CRT (hazard ratio, 0.73; 95% confidence interval,. 0.55 to 0.98; p = 0.038) both were associated with significantly increased overall survival. These findings persisted among margin-negative patients. However, in margin-positive patients, S+CRT (hazard ratio, 0.29; p = 0.002) was the only treatment arm that was associated with significantly improved survival compared with surgical resection alone. CONCLUSIONS: Among cT1-2 N0 pN+ esophageal cancer patients, adjuvant chemotherapy may be sufficient for margin-negative patients, whereas adjuvant chemoradiation therapy appears necessary for margin-positive patients. Further prospective studies are needed to confirm the results.

The role of radiation in treating glioblastoma: here to stay.

Despite numerous efforts over the past several decades, few therapeutic breakthroughs in the treatment of GBM have been realized, and even these have yielded only incrementally modest gains. Radiotherapy remains a crucial component in the management of this disease. In this review, the historical basis for inclusion of radiotherapy as part of the therapeutic regimen for GBM is examined. Additionally, an overview of the evidence supporting the modern role of radiotherapy is provided along with a discussion of standard and emerging combined modality therapies. Finally, GBM management guidelines from three professional societies are reviewed.

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

Stage I Lung SBRT Clinical Practice Patterns.

OBJECTIVES: Stereotactic body radiation therapy (SBRT) has become increasingly utilized over the last decade in the treatment of inoperable stage I non-small cell lung cancer (NSCLC) patients, although no standardized dosing guidelines exist. In this retrospective study, we investigated the dose prescription pattern use in the United States for patients receiving SBRT. METHODS: Patients with stage I NSCLC treated with SBRT between 2004 and 2011 were identified within the National Cancer Database (NCDB). Trends in SBRT use and dose prescriptions were analyzed. RESULTS: A total of 5246 patients met criteria as receiving SBRT. The overall mean and median BED10 were 134.5 and 132 Gy, respectively. Of these patients, 94.5% were prescribed a regimen with a BED10≥100 Gy. The most common prescriptions overall were 60 Gy in 3 fractions (24.1%), 48 Gy in 4 fractions (17.8%), 50 Gy in 5 fractions (13.0%), and 54 Gy in 3 fractions (12.8%). Analysis of prescription trends revealed decreased utilization of 54 to 60 Gy in 3 fractions (47.9% in 2006 to 27.9% in 2011, combined) and increased utilization of 50 Gy in 5 fractions (3.1% in 2006 to 20.4% in 2011). CONCLUSIONS: Our findings suggest increasing use of SBRT over the last decade with a majority of patients being treated with regimens employing a BED10≥100 Gy. Since 2006, there has been a decline in the use of 54 to 60 Gy in 3 fractions, with an increase in the use of 50 Gy in 5 fractions. Possible explanations include concern for increased toxicity with higher BED regimens and increasing treatment of centrally located tumors.

Post-operative radiotherapy is associated with improved survival in esophageal cancer with positive surgical margins.

BACKGROUND: The optimal treatment for early-stage esophageal cancer with positive surgical margins after an upfront esophagectomy is not well-defined. This study investigates the effect of post-operative radiotherapy (PORT) on overall survival (OS) in clinical stage I-II patients with positive margins. METHODS: We identified patients diagnosed between 2004 and 2012 with clinical stage I-II esophageal carcinoma from the National Cancer Data Base (NCDB) who underwent an upfront esophagectomy. For those patients with positive margins, administration of PORT was recorded, and OS was compared by the Kaplan-Meier estimator and log-rank test. Multivariable Cox regression analysis was performed to identify variables associated with improved survival. RESULTS: Among the 3,490 patients identified, 209 (5.8%) had positive margins. One hundred forty-two (67.9%) patients did not receive PORT while 67 (32.1%) did receive PORT. Compared to those receiving PORT, patients who did not receive PORT were significantly older (68.5 vs. 64.0 years, P=0.003), more likely to have pN0 disease (50.7% vs. 35.4%, P=0.026), and less likely to receive postoperative chemotherapy (21.1% vs. 86.6%, P<0.001). On multivariable logistic regression, only receipt of chemotherapy predicted for receipt of PORT (OR: 25.6, 95% CI: 9.9-65.8, P<0.001). OS was significantly higher for patients receiving PORT compared to those who did not (median OS: 32.2 vs. 16.9 months, log-rank P=0.008). Multivariable analysis confirmed an association with PORT and improved OS (HR: 0.39, 95% CI: 0.27-0.60, P<0.001). Subset analysis demonstrated that the OS benefit of PORT persisted in those patients who received adjuvant chemotherapy (HR: 0.33, 95% CI: 0.19-0.57, P<0.001). CONCLUSIONS: PORT is associated with improved OS in clinical stage I-II esophageal cancer patients after an upfront esophagectomy with positive margins. In the absence of prospective randomized data, our findings suggest that PORT should be strongly considered in the setting of early-stage esophageal cancer resected with positive margins.

Trends in stereotactic body radiation therapy for stage I small cell lung cancer.

OBJECTIVES: We aimed to report trends in stereotactic body radiation therapy (SBRT) utilization, dose prescriptions, and chemotherapy administration for stage I small cell lung cancer (SCLC) in the United States. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to identify patients with cT1-2 N0 SCLC treated with SBRT between 2004 and 2013. Trends in SBRT use and dose prescription were analyzed over time. Multivariable logistic regression was used to determine factors associated with the administration of chemotherapy with SBRT. The Kaplan-Meier method was used to estimate overall survival. RESULTS: Of 9265 patients with clinical stage I SCLC who were examined for initial treatment allocation, 285 were treated with SBRT and represented the subject of the primary analysis. SBRT utilization increased from 2004 (0.4% of all stage I patients diagnosed that year) to 2013 (6.4%). During this same time period, definitive surgical management also increased from 14.9% of all patients in 2004 to 28.5% in 2013. The median SBRT biologically effective dose (BED10) was 112.5Gy (range, 72-290) and only 33 out of 285 (11.6%) received a BED10<100Gy. Nearly half of all patients (130/285, 45.6%) received chemotherapy, with 42.7% of those patients receiving their chemotherapy prior to SBRT. On multivariable logistic regression, only age<75 (the median) vs. ≥75years (OR 4.97, 95% CI 2.96-8.35, p<0.001) and year of diagnosis 2004-2008 vs. 2009-2013 (OR 2.58, 95% CI 1.27-5.26, p=0.009) were predictive of chemotherapy use with SBRT. After median follow up of 45 months, the median survival was 23.5 months. CONCLUSIONS: Our findings suggest that SBRT utilization for stage I SCLC has increased between 2004 and 2013, highlighting the need for additional research to validate the feasibility of this management approach for inoperable patients.

Role of Adjuvant Therapy for Node-Negative Lung Cancer Invading the Chest Wall.

INTRODUCTION: The present study investigated the effect of adjuvant chemotherapy and radiation on survival among patients undergoing chest wall resection for T3N0 non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with T3N0 NSCLC who underwent chest wall resection were identified in the National Cancer Data Base in 2004 to 2012. The cohort was divided into patients who had received adjuvant chemotherapy, radiation therapy, chemoradiation therapy, or no adjuvant treatment. Kaplan-Meier and log-rank tests were used to compare overall survival, and a bootstrapped Cox proportional hazards model was used to determine the significant contributors to survival. A subset analysis was performed with stratification by margin status and tumor size. RESULTS: Of 759 patients identified, 42.0% underwent surgery alone, 23.3% underwent surgery followed by chemotherapy, 22.3% underwent surgery followed by chemoradiation therapy, and 12.3% underwent surgery followed by radiotherapy alone. Tumors > 4 cm benefited from adjuvant chemotherapy and radiation therapy in the multivariable analysis, and those ≤ 4 cm benefited only from adjuvant chemotherapy. The subgroup analysis by margin status identified that margin-positive patients with tumors > 4 cm benefited significantly from either adjuvant chemoradiation therapy or radiation therapy alone. CONCLUSION: T3N0 NSCLC with chest wall invasion requires unique management compared with other stage IIB tumors. An important determinant of management is tumor size, with tumors ≤ 4 cm benefiting from adjuvant chemotherapy and tumors > 4 cm benefiting from adjuvant chemotherapy if margin negative and adjuvant chemoradiation therapy or radiotherapy if margin positive.

Timing of Surgery after Neoadjuvant Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: A subset of patients with potentially resectable clinical stage IIIA NSCLC are managed with trimodality therapy. However, little data exist to guide the timing of surgery after neoadjuvant therapy. This study examined whether the time interval between neoadjuvant chemoradiation (NCRT) and surgical resection affects overall survival. METHODS: Patients with clinical stage IIIA disease (T1-3 N2) NSCLC who underwent NCRT were identified in the National Cancer Data Base (NCDB) between 2004 and 2012 and categorized on the basis of the interval between chemoradiation and surgery (0 to ≤3, >3 to ≤6, >6 to ≤9, and >9 to ≤12 weeks). Other clinical stages were excluded. The Kaplan-Meier method and log-rank tests were used to compare overall survival rates, and a bootstrapped Cox proportional hazards model was used to determine significant contributors to overall survival. RESULTS: Of the 1623 patients identified, 7.9% underwent an operation 0 to 3 weeks or less after NCRT, 50.5% underwent an operation greater than 3 and less than or equal to 6 weeks after NCRT, 31.9% underwent an operation greater than 6 and less than or equal to 9 weeks after NCRT, and 9.6% underwent an operation greater than 9 and less than or equal to 12 weeks after NCRT. Multivariate survival analysis demonstrated no significant difference in survival in those who underwent an operation within 6 weeks of NCRT. However, significant drops in overall survival were observed in those who had an operation greater than 6 and less than or equal to 9 weeks after NCRT (hazard ratio = 1.33, 95% confidence interval: 1.01-1.76, p = 0.043) and greater than 9 and less than or equal to 12 weeks after NCRT (hazard ratio = 1.44, 95% confidence interval: 1.04-2.01, p = 0.030). CONCLUSIONS: The findings from this retrospective study suggest that overall survival may be significantly lower in patients with clinical stage IIIA N2 NSCLC who undergo an operation later than 6 weeks after NCRT. These results discourage unnecessary delays in surgery.

A Comparison of Prognostic Ability of Staging Systems for Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

IMPORTANCE: The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system, developed for human papillomavirus (HPV)-unrelated disease, discriminates poorly when applied to HPV-related oropharyngeal squamous cell cancer (OPSCC), leading to calls for a new staging system. OBJECTIVE: To compare the prognostic ability of the AJCC/UICC seventh edition staging system; a recently proposed system, the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S); and a novel objectively derived system for HPV-related OPSCC using a national database of patients primarily treated with either radiation or surgery. DESIGN, SETTING, AND PARTICIPANTS: In this observational study, patients with HPV-related nonmetastatic OPSCC were identified in the National Cancer Database between 2010 and 2012. Recursive partitioning analysis (RPA) was used to derive the proposed-RPA staging system. The data were analyzed from March to May 2016. MAIN OUTCOMES AND MEASURES: Overall survival was calculated using the Kaplan-Meier method. The performance of the 3 systems was compared using published criteria, and internal validation using bootstrap methods was performed. Survival differences between stage groups were evaluated using the log-rank test. RESULTS: A total of 5626 patients (86.0% male; median [range] age, 58 [21-90] years) were identified. The median (range) follow-up was 28.5 (0.1-58.8) months. A novel staging system (proposed-RPA) consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; stage III, T4a-bN0-3 resulted in 3-year overall survival rates of 91%, 87%, 81%, and 70%, respectively. This system, as well as the ICON-S, significantly prognosticated for survival when either primary surgery or primary radiation subgroups were examined (log-rank P < .001 for all). The AJCC/UICC system, ICON-S, and proposed-RPA all significantly predicted survival outcomes when analyzed globally (log-rank P < .001 for all). The AJCC/UICC system could not differentiate between survival when stages I and IVA were compared, however (log-rank P = .17). On comparative performance evaluation for survival prediction, the proposed-RPA provided superior prognostication compared with the other systems. CONCLUSIONS AND RELEVANCE: We validated the ICON-S staging as prognostic, overall, and in primary radiation therapy and surgery subgroups, but ultimately found that a staging system consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; and stage III, T4a-bN0-3 (with stage IV representing M1 disease) outperformed the others. The proposed-RPA is an alternative staging system that should be evaluated for potential adoption as part of the next AJCC/UICC staging system.

Success and Failures of Combined Modalities in Glioblastoma Multiforme: Old Problems and New Directions.

Glioblastoma multiforme (GBM) is an aggressive intracranial tumor characterized by local and distant brain relapse despite aggressive therapy. Current standard treatment includes surgical resection followed by radiation with concurrent and adjuvant temozolomide as part of a combined modality approach. In this review, the historical basis for the current standard treatment is discussed as well as other recent combined modality successes and failures. An overview of emerging combined modality therapies for GBM is presented including immunotherapy, and rationally designed radiosensitizers. Unanswered questions facing the oncology community regarding the treatment of GBM are also discussed.