The Importance of Quality Assurance in Radiation Oncology Clinical Trials.

Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.

Children's Oncology Group's 2023 blueprint for research: Radiation oncology.

Radiation oncology is an integral part of the multidisciplinary team caring for children with cancer. The primary goal of our committee is to enable the delivery of the safest dose of radiation therapy (RT) with the maximal potential for cure, and to minimize toxicity in children by delivering lower doses to normal tissues using advanced technologies like intensity-modulated RT (IMRT) and proton therapy. We provide mentorship for y ators and are actively involved in educating the global radiation oncology community. We are leaders in the effort to discover novel radiosensitizers, radioprotectors, and advanced RT technologies that could help improve outcomes of children with cancer.

Quality improvements in radiation oncology clinical trials.

Clinical trials have become the primary mechanism to validate process improvements in oncology clinical practice. Over the past two decades there have been considerable process improvements in the practice of radiation oncology within the structure of a modern department using advanced technology for patient care. Treatment planning is accomplished with volume definition including fusion of multiple series of diagnostic images into volumetric planning studies to optimize the definition of tumor and define the relationship of tumor to normal tissue. Daily treatment is validated by multiple tools of image guidance. Computer planning has been optimized and supported by the increasing use of artificial intelligence in treatment planning. Informatics technology has improved, and departments have become geographically transparent integrated through informatics bridges creating an economy of scale for the planning and execution of advanced technology radiation therapy. This serves to provide consistency in department habits and improve quality of patient care. Improvements in normal tissue sparing have further improved tolerance of treatment and allowed radiation oncologists to increase both daily and total dose to target. Radiation oncologists need to define a priori dose volume constraints to normal tissue as well as define how image guidance will be applied to each radiation treatment. These process improvements have enhanced the utility of radiation therapy in patient care and have made radiation therapy an attractive option for care in multiple primary disease settings. In this chapter we review how these changes have been applied to clinical practice and incorporated into clinical trials. We will discuss how the changes in clinical practice have improved the quality of clinical trials in radiation therapy. We will also identify what gaps remain and need to be addressed to offer further improvements in radiation oncology clinical trials and patient care.

Definitive Radiation Therapy for Medically Inoperable Endometrial Carcinoma.

Purpose: Upfront radiation therapy consisting of brachytherapy with or without external beam radiation therapy is considered standard of care for patients with endometrial carcinoma who are unable to undergo surgical intervention. This study evaluated the cancer-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS) of patients with endometrial carcinoma managed with definitive-intent radiation therapy. Methods and Materials: This was a single-institution retrospective analysis of medically inoperable patients with biopsy-proven endometrial carcinoma managed with up-front, definitive radiation therapy at UMass Memorial Medical Center between May 2010 and October 2021. A total of 55 cases were included for analysis. Patients were stratified as having low-risk endometrial carcinoma (LREC; uterine-confined grade 1-2 endometrioid adenocarcinoma) or high-risk endometrial carcinoma (HREC; stage III/IV and/or grade 3 endometrioid carcinoma, or any stage serous or clear cell carcinoma or carcinosarcoma). The CFS, CSS, OS, and grade ≥3 toxic effects were reported for patients with LREC and HREC. Results: The median age was 66 years (range, 42-86 years), and the median follow-up was 44 months (range, 4-135 months). Twelve patients (22%) were diagnosed with HREC. Six patients (11%) were treated with high-dose-rate brachytherapy alone and 49 patients (89%) were treated with high-dose-rate brachytherapy and external beam radiation therapy. Twelve patients (22%) were treated with radiation and chemotherapy. The 2-year CFS was 82% for patients with LREC and 80% for patients with HREC (log rank P = .0654). The 2-year CSS was 100% for both LREC and HREC patients. The 2-year OS was 92% for LREC and 80% for HREC (log P = .0064). There were no acute grade ≥3 toxic effects. There were 3 late grade ≥3 toxic effects owing to endometrial bleeding and gastrointestinal adverse effects. Conclusions: For medically inoperable patients with endometrial carcinoma, up-front radiation therapy provided excellent CFS, CSS, and OS. The CSS and OS were higher in patients with LREC than in those with HREC. Toxic effects were limited in both cohorts.

An Analysis of Major Target Deviations in Craniospinal Irradiation Treatment Plans for Patients With Intermediate-Risk Medulloblastoma Within a Phase 3 Clinical Trial (Children's Oncology Group Study ACNS0331).

Purpose: Craniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331). Methods and Materials: The principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was evaluated using the stratified Cox proportional hazards model. Results: Of the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113). Conclusions: Although intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution.

Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

A Review of Concurrent Chemo/Radiation, Immunotherapy, Radiation Planning, and Biomarkers for Locally Advanced Non-small Cell Lung Cancer and Their Role in the Development of ECOG-ACRIN EA5181.

ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial.

Practice Patterns of Pediatric Total Body Irradiation Techniques: A Children's Oncology Group Survey.

PURPOSE: The aim of this study was to examine current practice patterns in pediatric total body irradiation (TBI) techniques among COG member institutions. METHODS AND MATERIALS: Between November 2019 and February 2020, a questionnaire containing 52 questions related to the technical aspects of TBI was sent to medical physicists at 152 COG institutions. The questions were designed to obtain technical information on commonly used TBI treatment techniques. Another set of 9 questions related to the clinical management of patients undergoing TBI was sent to 152 COG member radiation oncologists at the same institutions. RESULTS: Twelve institutions were excluded because TBI was not performed in their institutions. A total of 88 physicists from 88 institutions (63% response rate) and 96 radiation oncologists from 96 institutions (69% response rate) responded. The anterior-posterior/posterior-anterior (AP/PA) technique was the most common technique reported (49 institutions [56%]); 44 institutions (50%) used the lateral technique, and 14 (16%) used volumetric modulated arc therapy or tomotherapy. Midplane dose rates of 6 to 15 cGy/min were most commonly used. The most common specification for lung dose was the midlung dose for both AP/PA techniques (71%) and lateral techniques (63%). Almost all physician responders agreed with the need to refine current TBI techniques, and 79% supported the investigation of new TBI techniques to further lower the lung dose. CONCLUSIONS: There was no consistency in the practice patterns, methods for dose measurement, and reporting of TBI doses among COG institutions. The lack of standardization precludes meaningful correlation between TBI doses and clinical outcomes including disease control and normal tissue toxicity. The COG radiation oncology discipline is currently undertaking several steps to standardize the practice and dose reporting of pediatric TBI using detailed questionnaires and phantom-based credentialing for all COG centers.

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.

Quality assurance in radiation oncology.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real-time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

Outcomes After Stereotactic Body Radiation Therapy as a Bridging Modality to Liver Transplantation for Hepatocellular Carcinoma.

PURPOSE: For patients with hepatocellular carcinoma awaiting liver transplantation (LT), stereotactic body radiation therapy (SBRT) has emerged as a bridging treatment to ensure patients maintain priority status and eligibility per Milan criteria. In this study, we aimed to determine the efficacy and safety of SBRT in such situations. METHODS AND MATERIALS: A retrospective analysis was conducted of the outcomes of 27 patients treated with SBRT who were listed for LT at 1 institution. Among these, 20 patients with 26 tumors went on to LT and were the focus of this study. Operative reports and postoperative charts were evaluated for potential radiation-related complications. The explant pathology findings were correlated with equivalent dose in 2 Gy fractions and tumor size. RESULTS: Median pretreatment tumor size was 3.05 cm. Median total dose of radiation was 50 Gy delivered in 5 fractions. Pathologic complete response (pCR) was achieved in 16 tumors (62%). Median interval from end of SBRT to transplant was 287 days. Of the 21 tumors imaged before transplant, 16 or 76% demonstrated a clinical complete response based on modified Response Evaluation Criteria in Solid Tumors criteria. There was no significant correlation between pCR rate and increasing tumor size (odds ratio [OR], 0.95; 95% confidence interval, 0.595-1.53) or pCR rate and equivalent dose in 2 Gy fractions (OR, 1.03; 95% confidence interval, 0.984-1.07.) No patients experienced radiation-related operative or postoperative complications. Of the 27 patients who were listed for transplant, the dropout rate was 22%. Two of the 5 patients with Child-Pugh score 10 died of liver failure. CONCLUSIONS: These data demonstrate that SBRT as a bridging modality is a feasible option, with a pCR rate comparable to that of other bridging modalities and no additional radiation-related operative or postoperative complications. There was no dose dependence nor size dependence for pCR rate, which may indicate that for the tumor sizes in this study, the radiation doses delivered were sufficiently high.

Stereotactic Body Radiotherapy for Palliation of Hematuria Arising From Urothelial Carcinoma of the Kidney in Unfavorable Surgical Candidates.

INTRODUCTION: Hematuria can be a distressing and debilitating complication of urothelial carcinoma (UC) of the kidney for patients who are not candidates for surgery or ureteroscopic ablation. We retrospectively assessed the efficacy, tolerability, and safety of stereotactic body radiotherapy (SBRT) for controlling gross hematuria in this patient population. MATERIALS AND METHODS: Institutional Review Board (IRB)-approved review of the records, laboratory values, pathology, and imaging of 8 consecutive patients treated with SBRT over a 5-year period for uncontrolled gross hematuria caused by UC of the renal pelvis or calyces. RESULTS: Therapy was delivered in 3 to 5 treatments over 1 to weeks. Individual treatments lasted an average of 17.2 minutes. No patient experienced treatment-related pain, vomiting, or diarrhea. All enjoyed cessation of bleeding within a week of completing therapy. Hematuria recurred in 2 patients in 4 and 22 months. Of the patients who have not re-bled, 3 expired of metastatic disease or co-morbidities, and 3 remain alive up to 6 years posttreatment. Of patients who have survived longer than a year, creatinine has changed by -0.05 to +0.35, and estimated glomerular filtration rate has fallen by an average of 22%. No patient has required dialysis. CONCLUSIONS: SBRT appears to be an effective and well-tolerated means of palliating gross hematuria secondary to UC of the renal pelvis or calyces in patients who are unfavorable candidates for nephrectomy or ureteroscopic ablation. Treatment was associated with a moderate decline in renal function.

A Review of Immunotherapy for Stage III and Metastatic Non-Small Cell Lung Cancer and the Rationale for the ECOG-ACRIN EA5181 Study.

ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA-NSCLC) to concomitant durvalumab or no additional therapy, with both arms receiving 1 year of consolidative durvalumab. Radiation dose escalation failed to improve overall survival in RTOG 0617. However, conventionally fractionated radiation to 60 Gy with concomitant chemotherapy is associated with a high risk of local failure (38%-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we review conventional chemo/radiation therapy for LA-NSCLC, as well as the quickly evolving world of immunotherapy in the treatment of non-small cell lung cancer and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: This article provides an up-to-date assessment of how immunotherapy is reshaping the landscape of metastatic non-small cell lung cancer (NSCLC) and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. This article reviews the recent publications of chemo/radiation as well as those combining immunotherapy with chemotherapy and chemo/radiation, and provides a strategy for improving overall survival of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Patients With Child-Pugh B or C Cirrhosis.

PURPOSE: Our purpose was to report outcomes in patients with Child-Pugh B or C (CP B/C) hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patients with HCC suitable for SBRT were prospectively enrolled in the study from 2012 to 2018. Outcomes in patients with CP B/C were analyzed. Cox proportional hazard models were used to compare survival outcomes between baseline CP score and post-SBRT CP score. RESULTS: Twenty-three patients with CP B/C with a total of 29 HCC tumors were treated with SBRT. Eighty-seven percent of patients were CP B8-C10. Median tumor size was 3.1 cm (range, 1-10 cm). Median dose delivered was 40 Gy in a median of 5 fractions. Eighteen of 23 patients (78.3%) had been previously treated with transarterial chemoembolization. Median follow-up was 14.5 months. Rates of 6- and 12-month local control were 100% and 92.3%, respectively. Six- and 12-month survival rates were 73.9% and 56.5%, respectively. Median survival was 14.5 months overall and 9.2, 22.5, 14.5, and 14.4 months for patients with CP B7, B8, B9, and C10, respectively. No patients exhibited symptoms of classic radiation-induced liver disease. However, 10 patients had CP score progression, with 4 patients (17%) having a ≥2-point increase in CP score by 6 months (or time of censor). There were 7 liver-related deaths, and based on independent review by a hepatologist, 1 of these deaths may have been attributable to SBRT-related liver injury. Fifteen of 23 patients were listed for liver transplant (LT) at the time of SBRT and 9 went on to receive LT with a pathologic complete response rate of 63.6%. Median survival, excluding patients who received LT, was 7.3 months. CONCLUSIONS: SBRT is a reasonable treatment option for carefully selected patients with CP B7-C10. In our small cohort, there was no detectable difference between local control or overall survival and baseline CP score.

Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report.

This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management.

Purpose: To identify the incidence, preoperative risk factors, and prognosis associated with pathologically positive lymph node (pN+) in patients undergoing a sub-lobar resection (SLR). Methods: This is a retrospective study using the National Cancer Database (NCDB) from 2004 to 2014 analyzing SLR excluding those with any preoperative chemotherapy and/or radiation, follow-up <3 months, stage IV disease, or >1 tumor nodule. Multivariable modeling (MVA) was used to determine factors associated with overall survival (OS). Propensity score matching (PSM) was used to determine preoperative risk factors for pN+ in patients having at least one node examined to assess radiation's effect on OS in those patients with pN+ and to determine whether SLR was associated with inferior OS as compared to lobectomy for each nodal stage. Results: A total of 40,202 patients underwent SLR, but only 58.3% had one lymph node examined. Then, 2,615 individuals had pN+ which decreased progressively from 15.1% in 2004 to 8.9% in 2014 (N1, from 6.3 to 3.0%, and N2, from 8.4 to 5.9%). A lower risk of pN+ was noted for squamous cell carcinomas, bronchioloalveolar adenocarcinoma (BAC), adenocarcinomas, and right upper lobe locations. In the pN+ group, OS was worse without chemotherapy or radiation. Radiation was associated with a strong trend for OS in the entire pN+ group (p = 0.0647) which was largely due to the effects on those having N2 disease (p = 0.009) or R1 resections (p = 0.03), but not N1 involvement (p = 0.87). PSM noted that SLR was associated with an inferior OS as compared to lobectomy by nodal stage in the overall patient population and even for those with tumors <2 cm. Conclusion: pN+ incidence in SLRs has decreased over time. SLR was associated with inferior OS as compared to lobectomy by nodal stage. Radiation appears to improve the OS in patients undergoing SLR with pN+, especially in those with N2 nodal involvement and/or positive margins.