Prediction of Distant Metastases After Stereotactic Body Radiation Therapy for Early Stage NSCLC: Development and External Validation of a Multi-Institutional Model.

INTRODUCTION: Distant metastases (DMs) are the primary driver of mortality for patients with early stage NSCLC receiving stereotactic body radiation therapy (SBRT), yet patient-level risk is difficult to predict. We developed and validated a model to predict individualized risk of DM in this population. METHODS: We used a multi-institutional database of 1280 patients with cT1-3N0M0 NSCLC treated with SBRT from 2006 to 2015 for model development and internal validation. A Fine and Gray (FG) regression model was built to predict 1-year DM risk and compared with a random survival forests model. The higher performing model was evaluated on an external data set of 130 patients from a separate institution. Discriminatory performance was evaluated using the time-dependent area under the curve (AUC). Calibration was assessed graphically and with Brier scores. RESULTS: The FG model yielded an AUC of 0.71 (95% confidence interval [CI]: 0.57-0.86) compared with the AUC of random survival forest at 0.69 (95% CI: 0.63-0.85) in the internal test set and was selected for further testing. On external validation, the FG model yielded an AUC of 0.70 (95% CI: 0.57-0.83) with good calibration (Brier score: 0.08). The model identified a high-risk patient subgroup with greater 1-year DM rates in the internal test (20.0% [3 of 15] versus 2.9% [7 of 241], p = 0.001) and external validation (21.4% [3 of 15] versus 7.8% [9 of 116], p = 0.095). A model nomogram and online application was made available. CONCLUSIONS: We developed and externally validated a practical model that predicts DM risk in patients with NSCLC receiving SBRT which may help select patients for systemic therapy.

Declining use of inguinofemoral lymphadenectomy in the treatment of clinically negative, pathologic node positive vulvar cancer.

PURPOSE: The management of vulvar cancer with clinically negative groin lymph nodes but with positive sentinel lymph node biopsy (SLNB) is controversial, with options including inguinofemoral lymphadenectomy (IFL) and/or adjuvant chemotherapy and radiotherapy. We used the National Cancer Database (NCDB) to examine trends in the management of clinically node negative, pathologically node positive (cN-/pN+) patients. METHODS: The NCDB was used to identify cN-/pN+ vulvar cancer patients. Demographic and clinical data were compared with chi-squared and Wilcoxon rank-sum tests. OS was analyzed with the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to determine factors associated with OS. RESULTS: A total of 885 cN-/pN+ vulvar cancer patients were identified between 2012 and 2016, during which the rate of SLNB alone increased from 3.6% to 11.7%, while the rate of IFL +/- SLNB decreased from 89.7% to 78.1% (p < 0.05). Radiation was used in 68.5% and 64.6% of the SLNB-alone and IFL +/- SLNB cohorts, respectively, with chemoradiation in 37.1% and 33.6%, respectively. OS was not different between patients who received SLNB-alone vs. IFL +/- SLNB (p = 0.644). Receipt of chemotherapy and radiation was associated with improved OS (p < 0.001). CONCLUSIONS: Among cN-/pN+ vulvar cancer patients in the NCDB, the practice of performing IFL decreased over time as SLNB-alone became more common and the majority received radiation +/- chemotherapy. There was no difference in OS between SLNB-alone vs. IFL +/- SLNB. Patients treated with adjuvant chemoradiation had improved survival. Whether the favorable outcomes in the SLNB-alone cohort may be attributed to radiotherapy dose escalation or use of chemotherapy warrants further study.

Benefit of Deep Inspiratory Breath Hold for Right Breast Cancer When Regional Lymph Nodes Are Irradiated.

BACKGROUND: Although deep inspiratory breath-hold (DIBH) is routinely used for left-sided breast cancers, its benefits for right-sided breast cancer (rBC) have yet to be established. We compared free-breathing (FB) and DIBH treatment plans for a cohort of rBC undergoing regional nodal irradiation (RNI) to determine its potential benefits. METHODS AND MATERIALS: rBC patients considered for RNI (internal mammary nodal chains, supraclavicular field, with or without axilla) from October 2017 to May 2020 were included in this analysis. For each patient, FB versus DIBH plans were generated and dose volume histograms evaluated the following parameters: mean lung dose, ipsilateral lung V20/V5 (volumes of lung receiving 20 Gy and 5 Gy, respectively); mean heart dose and heart V5 (volumes of heart receiving 5 Gy); liver V20 absolute /V30 absolute (absolute volume of liver receiving 20 Gy and 30 Gy, respectively), liver Dmax, and total liver volume irradiated (TVIliver). The dosimetric parameters were compared using Wilcoxon signed-rank testing. RESULTS: Fifty-four patients were eligible for analysis, comparing 108 FB and DIBH plans. DIBH significantly decreased all lung and liver parameters: mean lung dose (19.7 Gy-16.2 Gy, P < .001), lung V20 (40.7%-31.7%, P < .001), lung V5 (61.2%-54.5%, P < .001), TVIliver (1446 cc vs 1264 cc; P = .006) liver Dmax (50.2 Gy vs 48.9 Gy; P = .023), liver V20 (78.8-23.9 cc, P < .001), and liver V30 (58.1-14.6 cc, P < .001) compared with FB. DIBH use did not significantly improve heart parameters, although the V5Heart trended on significance (1.25-0.6, P = .067). CONCLUSIONS: This is the largest cohort to date analyzing DIBH for RNI-rBC. Our findings demonstrate significant improvement in all lung and liver parameters with DIBH, supporting its routine consideration for rBC patients undergoing comprehensive RNI.

Contemporary Topics in Radiation Medicine: Skin Cancer.

Radiation plays an important role in the management of a variety of skin cancers. This article discusses the role of radiation in the treatment of cutaneous squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, cutaneous T-cell lymphoma, and B-cell lymphomas.

Defining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis.

BACKGROUND: RTOG 9802 identified a cohort of patients with age less than 40 years and undergoing gross total resection as having low-risk, low-grade glioma (LR-LGG). European Organization for Research and Treatment of Cancer studies have demonstrated additional prognostic features in this group. The aim of this study was to analyze clinical factors associated with overall survival (OS), identify a potentially higher risk group within LR-LGG, and investigate patterns of care for adjuvant therapy. MATERIALS AND METHODS: Patients with LR-LGG diagnosed between 2010 to 2013 were identified in the National Cancer Database. Kaplan-Meier method was used to analyze OS. Propensity score matching and multivariate analysis were utilized to adjust for differences in cohorts. RESULTS: A total of 1,032 patients with LR-LGG were identified. Histological breakdown was 42.0% astrocytoma, 33.2% oligodendroglioma, and 25.8% mixed. Median follow-up was 3.9 years; median pre-operative tumor size was 4.0 cm. Overall, 834 (80.8%) underwent observation and 198 (19.2%) received adjuvant therapy. Tumor size >5 cm predicted for receipt of adjuvant therapy on regression analyses (OR=2.02, p=0.001). On multivariate analysis, tumor size >5 cm (hazard ratio=1.95) and non-oligodendroglioma histology (hazard ratio=2.50) were associated with inferior OS (both p<0.05). For patients with both poor prognostic features (a subset we consider "intermediate-risk"), 5-year OS was 78.4%, compared to 94.1% for all other low-risk patients (p<0.001). After propensity score matching, the intermediate-risk group continued to be associated with worse 5-year OS: 80.5% vs. 94.0%, p=0.004. CONCLUSION: Due to inferior OS for patients with LR-LGG with >5 cm, non-oligodendroglioma tumors, we propose an 'intermediate-risk' clinical classification for this subset.

Indications for invasive mediastinal staging in patients with early non-small cell lung cancer staged with PET-CT.

PURPOSE/OBJECTIVE(S): Appropriate use of invasive mediastinal staging in patients with clinically node-negative NSCLC staged by PET-CT is critical in selecting patients for curative-intent therapy such as surgery or SBRT, but little data exists to guide this decision-making. We examined a large population of patients with clinical stage I NSCLC referred for mediastinoscopy or EBUS to find risk factors for occult N2 lymph nodes and determine which patients benefit from invasive staging. MATERIALS/METHODS: We identified consecutive clinical T1-2N0 NSCLC patients being evaluated for curative-intent therapy between 2011 and 2015. None had evidence of nodal disease by PET-CT; the endpoint was pathologic confirmation of occult N2 disease by EBUS or mediastinoscopy. Tumor size, location, histology, SUVmax, and radiographic appearance were evaluated as determinants of occult N2 disease. Two group comparisons of continuous variables were done with independent t-tests and categorical variables were compared with χ2 or Fisher's exact test. RESULTS: In 284 patients with PET-CT-staged clinical T1-2N0 disease, the prevalence of occult N2 metastases was 7.0%. The negative predictive value of PET-CT was 92.9% and the negative predictive value of mediastinoscopy/EBUS was 96.3%. T2 tumors were more likely to have occult N2 disease than T1 tumors (11.8% v 3.6% p=0.009). Pure solid tumors had greater involvement of N2 nodes than tumors with any ground glass component (12.6% v 3.1%, p<0.001). 17.5% of central tumor cases were found to have occult N2 metastases while 4.4% of patients with peripheral tumors (P<0.001). 33.3% of patients with solid central T2 tumors had occult N2 metastases whereas 2.0% of patients with peripheral T2 tumors with a ground glass component, 1.2% of patients with peripheral T1 tumors with a ground glass component and 3.6% of patients with peripheral T1 solid tumors had N2 metastases. CONCLUSIONS: Invasive mediastinal staging should be strongly encouraged in central tumors and solid T2 tumors because the risk of occult nodal involvement is greater than 10% in these cohorts. However, for patients with peripheral T1 tumors or peripheral T2 tumors with a significant ground glass component, the yield of invasive staging after a negative PET-CT is very low and invasive staging may not be warranted.

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.

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.

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.

Postneoadjuvant adjuvant chemotherapy in resected N1 non-small cell lung cancer with residual nodal disease.

BACKGROUND AND OBJECTIVES: Nodal positivity following neoadjuvant chemotherapy in locally advanced non-small cell lung cancer (NSCLC) is considered a poor prognostic sign, but little data are available on the efficacy of adjuvant chemotherapy in these cases. This analysis sought to determine whether adjuvant chemotherapy was associated with increased survival in NSCLC patients with residual N1 disease at resection. METHODS: Patients from the National Cancer Database (NCDB) with cN1T1-2M0 NSCLC treated with neoadjuvant chemotherapy and definitive resection between 2006 and 2012 were identified. Treatment groups were defined as those receiving no additional therapy or adjuvant chemotherapy ± radiation after resection. Five-year overall survival (OS) was estimated for each group. Cox proportional hazard regression was used to estimate hazard ratios adjusting for demographic, clinical, and facility characteristics. RESULTS: Among 90 eligible patients, 5-year OS was 43% and 56% for patients receiving adjuvant chemotherapy and no additional treatment, respectively (P < 0.56). With multivariable analysis, the estimated hazard ratio was 0.61 (95% CI: 0.61-2.64, P = 0.51) for adjuvant chemotherapy compared to no additional therapy. CONCLUSION: This analysis suggests that adjuvant chemotherapy is not associated with increased survival in NSCLC patients with pathologic N1 NSCLC following neoadjuvant chemotherapy and resection.

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.