Racial Differences in Treatments and Toxicity in Non-Small Cell Lung Cancer Patients Treated with Thoracic Radiation Therapy

Background: Racial disparities are of particular concern for lung cancer patients given historical differences in surgery rates for African-American lung cancer patients that resulted in lower overall survival and higher recurrence rates compared with rates in White patients. Objectives: The overall objective of this study was to examine racial differences in thoracic radiation therapy (RT) treatments and toxicities in a large cohort of patients from a multi-institutional consortium database of non-small cell lung cancer (NSCLC) patients. Methods: A large multi-institutional statewide prospectively collected patient-level database of locally advanced (stage II or III) NSCLC patients who received thoracic RT from March 2012 to November 2019 was analyzed to assess the associations between race and treatment and toxicity variables. Race (White or African-American) was defined by patient self-report or if not available then by the electronic medical record system classification. Race categories other than White or African-American comprised a small minority of patients and were excluded from this analysis. Patient-reported toxicity was determined by validated tools including the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Provider-reported toxicity was determined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Uni-variable and multi-variable regression models were then fitted to assess relationships between primary outcomes by race and indicators of high-quality treatment and secondary analysis of symptoms. Spearman rank correlation coefficients were calculated between provider reported toxicity and similar patient reported outcomes for each race category. Results: A total of 1441 patients from 24 institutions with mean age of 68 years (range 38-94) were evaluated; 226 patients were African-American, of whom 61% were treated at three facilities. Race was not significantly associated with RT treatment approach, use of concurrent chemotherapy, or the dose to the planning target volume (PTV) or organs at risk including the heart and lungs. However, there was increased patient-reported general pain in African-American patients (compared with White patients) at several time points including pre-RT (22% (vs 15%), P=0.02) and at the end of RT (30% (vs 17%), P=0.001). African-American patients were significantly less likely to have provider-reported grade 2+ radiation pneumonitis (odds ratio (OR) 0.36, P=0.03), despite similar levels of patient-reported respiratory toxicities such as cough and shortness of breath and even after controlling for known patient and treatment-related factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race categories. Conclusions: In this large multi-institutional observational study, we reassuringly found no evidence of differences in radiation treatment or chemotherapy approaches by race, in contrast to historical differences by race in surgical care that led to worse survival and outcomes in minority race patients. However, we did unexpectedly find that African-American race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis despite similar patient-reported toxicities of shortness of breath and cough. There are several possibilities for this finding including that pneumonitis is a multifactorial diagnosis that relies on clinical as well as radiologic information and clinical information alone may be insufficient. The Spearman correlation analysis also revealed stronger correlations between patient- and provider-reported toxicities in White patients compared with African-American patients, particularly for trouble swallowing/esophagitis. These findings together for pneumonitis and esophagitis discouragingly suggest possible under-recognition of symptoms in black patients. Further investigation is now warranted to better understand how these findings impact the care of racially diverse lung cancer patients

Long-Term Survival of a Patient with Metastatic Small-Cell Carcinoma of the Stomach Treated with Radiation Therapy

Small-cell carcinoma (SCC), or high-grade neuroendocrine carcinoma of the stomach, is a rare subtype of extra-pulmonary SCC which is almost invariably lethal. Gastric SCC often presents with local symptoms indistinguishable from other primary stomach cancers; however, both regional and distant spread are common at the initial presentation. Depending on symptoms and patient performance status, treatment typically consists of chemotherapy or resection followed by adjuvant chemotherapy, as even patients with limited stage gastric SCC likely have micrometastatic disease at the time of diagnosis. In this case report, we describe the long-term survival of a 75-year-old male with recurrent oligometastatic high-grade neuroendocrine carcinoma of the stomach treated with radiation therapy (RT) alone. He presented with abdominal pain and dyspepsia and was found to have a 6 cm locally invasive node-positive gastric SCC initially treated with extensive surgical resection. He was not a candidate for adjuvant chemotherapy, and surveillance imaging subsequently confirmed metachronous liver and local recurrences within 1 year after surgery, which were managed with stereotactic body RT and conventional radiation, respectively. An additional para-aortic nodal recurrence was treated with intensity-modulated radiotherapy 7 years after surgery with good response. He tolerated all RT courses without notable radiation-related toxicity and remains in complete remission 11 years after initial diagnosis

Radiotherapy for Oligometastatic Lung Cancer

Non-small cell lung cancer (NSCLC) typically presents at an advanced stage, which is often felt to be incurable, and such patients are usually treated with a palliative approach. Accumulating retrospective and prospective clinical evidence, including a recently completed randomized trial, support the existence of an oligometastatic disease state wherein select individuals with advanced NSCLC may experience historically unprecedented prolonged survival with aggressive local treatments, consisting of radiotherapy and/or surgery, to limited sites of metastatic disease. This is reflected in the most recent AJCC staging subcategorizing metastatic disease into intra-thoracic (M1a), a single extra thoracic site (M1b), and more diffuse metastases (M1c). In the field of radiation oncology, recent technological advances have allowed for the delivery of very high, potentially ablative, doses of radiotherapy to both intra- and extra-cranial disease sites, referred to as stereotactic radiosurgery and stereotactic body radiotherapy (or SABR), in much shorter time periods compared to conventional radiation and with minimal associated toxicity. At the same time, significant improvements in systemic therapy, including platinum-based doublet chemotherapy, molecular agents targeting oncogene-addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to improved control of micro-metastatic disease and extended survival sparking newfound interest in combining these agents with ablative local therapies to provide additive, and in the case of radiation and immunotherapy, potentially synergistic, effects in order to further improve progression-free and overall survival. Currently, despite the tantalizing potential associated with aggressive local therapy in the setting of oligometastatic NSCLC, well-designed prospective randomized controlled trials sufficiently powered to detect and measure the possible added benefit afforded by this approach are desperately needed

Cardiac and pulmonary dosimetric parameters in lung cancer patients undergoing post-operative radiation therapy across a state-wide consortium

PURPOSE/OBJECTIVES: The recently published Lung ART trial reported increased rates of cardiac and pulmonary toxicity in the post-operative radiation therapy (PORT) arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of contemporary real-world practice, which remains relevant for patients undergoing post-operative RT for positive surgical margins. The purpose of this study is to examine heart and lung dose exposure in patients receiving post-operative radiation therapy for non-small cell lung cancer (NSCLC) across a statewide consortium. MATERIALS/METHODS: From 2012 to 2022, demographic and dosimetric data were prospectively collected for 377 patients at 27 academic and community centers within [redacted] undergoing PORT for non-metastatic NSCLC. Dosimetric parameters for target coverage and Organ at Risk (OAR) exposure were calculated using data from dose volume histograms, and rates of 3D-CRT and IMRT utilization were assessed. RESULTS: Fifty-one percent of patients in this cohort had N2 disease at the time of surgery, 25% had a positive margin. Sixty-six percent of patients were treated with IMRT compared to 32% with 3D-CRT. Planning target volume (PTV) was significantly smaller in patients treated with 3D-CRT (149.2 cc vs. 265.4 cc, p\u3c0.0001). Median mean heart dose for all patients was 8.7 Gy (IQR 3.5, 15.3), median heart V5 was 35.2% (IQR 18.5, 60.2) and median heart V35 was 9% (IQR 3.2, 17.7). Median mean lung dose (MLD) was 11.4 Gy (IQR 8.1, 14.3), median lung V20 was 19.6% (IQR 12.7, 25.4). These dosimetric parameters did not significantly differ by treatment modality (IMRT vs. 3D-CRT) or in patients with positive vs. negative surgical margins. CONCLUSIONS: With increased rates of IMRT use, cardiac and lung dosimetric parameters in this state-wide consortium are slightly lower than those reported in Lung ART. These data provide useful benchmarks for treatment planning in patients undergoing post-operative RT for positive surgical margins

Effect of Education and Standardization of Cardiac Dose Constraints on Heart Dose in Patients With Lung Cancer Receiving Definitive Radiation Therapy Across a Statewide Consortium

PURPOSE: Cardiac radiation exposure is associated with an increased rate of adverse cardiac events in patients receiving radiation therapy for locally advanced non-small cell lung carcinoma (NSCLC). Previous analysis of practice patterns within the Michigan Radiation Oncology Quality Consortium (MROQC) revealed 1 in 4 patients received a mean heart dose \u3e20 Gy and significant heterogeneity existed among treatment centers in using cardiac dose constraints. The purpose of this study is to analyze the effect of education and initiation of standardized cardiac dose constraints on heart dose across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2020, 1681 patients from 27 academic and community centers who received radiation therapy for locally advanced NSCLC were included in this analysis. Dosimetric endpoints including mean heart dose (MHD), mean lung dose, and mean esophagus dose were calculated using data from dose-volume histograms. These dose metrics were grouped by year of treatment initiation for all patients. Education regarding data for cardiac dose constraints first occurred in small lung cancer working group meetings and then consortium-wide starting in 2016. In 2018, a quality metric requiring mean heart dose(D95) to the target was implemented. Dose metrics were compared before (2012-2016) versus after (2017-2020) initiation of interventions targeting cardiac constraints. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: After education and implementation of the heart dose performance metric, mean MHD declined from an average of 12.2 Gy preintervention to 10.4 Gy postintervention (P \u3c .0001), and the percentage of patients receiving MHD \u3e20 Gy was reduced from 21.1% to 10.3% (P \u3c .0001). Mean lung dose and mean esophagus dose did not increase, and target coverage remained unchanged. CONCLUSIONS: Education and implementation of a standardized cardiac dose quality measure across a statewide consortium was associated with a reduction of mean heart dose in patients receiving radiation therapy for locally advanced NSCLC. These dose reductions were achieved without sacrificing target coverage, increasing mean lung dose, or increasing mean esophagus dose. Analysis of the clinical ramifications of the reduction in cardiac doses is ongoing

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative

PURPOSE: National guidelines on limited stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy/30 fractions delivered twice-daily, however use of this regimen is uncommon compared to once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily RT regimens. METHODS AND MATERIALS: Demographic, clinical, and treatment data along with physician toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the [quality consortium] between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. Common Terminology Criteria for Adverse Events, version 4.0, incident Grade 2 or worse toxicity was longitudinally compared between regimens. RESULTS: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married/living with someone (65% vs 51%, p=0.019) and to have no major comorbidities (24% vs 10%, p=0.017). Once-daily RT fractionation toxicity peaked during RT and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had a 4.11 (95% confidence interval 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. CONCLUSION: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start utilizing hyperfractionated RT more frequently

Disease Control After Hypofractionation Versus Conventional Fractionation for Triple Negative Breast Cancer: Comparative Effectiveness in a Large Observational Cohort

PURPOSE: Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. METHODS AND MATERIALS: Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. RESULTS: The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). CONCLUSIONS: Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer

OBJECTIVES: The addition of adjuvant durvalumab improves overall survival in locally advanced nonsmall-cell lung cancer (NSCLC) patients treated with definitive chemoradiation, but the real-world uptake of adjuvant durvalumab is unknown. MATERIALS AND METHODS: We identified patients with stage III NSCLC treated with definitive concurrent chemoradiation from January 2018 to October 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers) and academic (n=5) across the state of Michigan. Use of adjuvant durvalumab was ascertained at the time of routine 3-month or 6-month follow-up after completion of chemoradiation. RESULTS: Of 421 patients with stage III NSCLC who completed chemoradiation, 322 (76.5%) initiated adjuvant durvalumab. The percentage of patients initiating adjuvant durvalumab increased over time from 66% early in the study period to 92% at the end of the study period. There was substantial heterogeneity by treatment center, ranging from 53% to 90%. In multivariable logistic regression, independent predictors of durvalumab initiation included more recent month (odds ratio [OR]: 1.05 per month, 95% confidence interval [CI]: 1.02-1.08, P=0.003), lower Eastern Cooperative Oncology Group score (OR: 4.02 for ECOG 0 vs. 2+, 95% CI: 1.67-9.64, P=0.002), and a trend toward significance for female sex (OR: 1.66, 95% CI: 0.98-2.82, P=0.06). CONCLUSION: Adjuvant durvalumab for stage III NSCLC treated with definitive chemoradiation was rapidly and successfully incorporated into clinical care across a range of community and academic settings in the state of Michigan, with over 90% of potentially eligible patients starting durvalumab in more recent months