Cardiac and Pulmonary Dosimetric Parameters in Lung Cancer Patients Undergoing Post-Operative Radiation Therapy in the Real-World Setting

Purpose/Objective(s): The recently published Lung ART trial reported increased rates of cardiac and pulmonary toxicity in the post-operative radiation therapy arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of real-world practice. 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 2020, 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium (MROQC) underwent surgical resection followed by post-operative radiation therapy for non-metastatic NSCLC. Demographic and dosimetric data were prospectively collected for these patients. Rates of 3D-CRT and IMRT use were analyzed. Mean heart dose (MHD), heart V5, heart V35, mean lung dose (MLD), lung V20, target volume and minimum dose to 95% PTV were calculated for these patients and the reported dosimetric parameters were stratified by treatment modality. Results: 51% of patients in this cohort had N2 disease at the time of surgery, 18% had a positive margin. 65.8% of patients were treated with IMRT compared to 32.1% treated with 3D-CRT. Average MHD for all patients was 10.3 Gy, mean Heart V5 was 40.3% and mean heart V35 was 12.6%. Average MLD was 11.2 Gy and mean lung V20 was 18.9%. These dosimetric parameters did not significantly differ based on treatment modality, with MHD and MLD 9.9 Gy and 10.1 Gy, respectively, for patients treated with 3D-CRT compared to 10.6 Gy and 11.8 Gy for patients treated with IMRT. Conclusion: Cardiac and lung dosimetric parameters for patients receiving post-operative radiation therapy for NSCLC are similar to the dosimetric characteristics reported in Lung ART. The mean heart and mean lung doses observed are slightly lower (MHD 10.3 Gy, MLD 11.2 Gy) compared to Lung ART (MHD 13 Gy, MLD 13 Gy), possibly owing to increased use of IMRT. These data support application of Lung ART\u27s findings outside of the clinical trial setting

Predictors of Early Death or Hospice in Curative Inoperable Lung Cancer Patients

Purpose/Objective(s): The current treatment approach for inoperable stage II-III non-small cell lung cancer (NSCLC) involves aggressive chemo/radiotherapy (CRT). While outcomes have improved with immunotherapy, some patients transition to hospice or die early into their treatment. To help identify these patients and tailor treatment interventions, we developed a predictive model for early poor outcomes in this population. Materials/Methods: We included patients who received definitive CRT for stage II-III lung cancer from April 2012 - November 2019. Patient information was collected prospectively as part of a statewide consortium involving 27 sites. We defined an early poor outcome as termination of treatment due to hospice enrollment or death within 5 months of initiating radiation therapy. Potential predictors included patient and disease characteristics, patient reported outcomes (PROs), and treatment variables. Generalized linear models were used to describe the relationships between single predictors and outcomes of interest. Due to missing data, we imputed 25 datasets to fit multivariable models. We used Lasso regression on all 25 datasets to select variables of interest. Using these selected variables, we fit generalized linear models on all 25 imputed data sets and present pooled results. Results: A total of 2127 patients met criteria, of which 96 patients discontinued treatment early due to hospice enrollment or death. Of the 96 patients, 59% received concurrent chemotherapy and the mean age was 71 years old. When modeled individually, age, ECOG performance status, PTV volume, distance to critical structures, mean heart dose, insurance status, functional and physical well-being scale, and lung cancer symptom scale were all significant predictors of early hospice or death. Additionally, specific PRO questions, including “I have a lack of energy”, “I have been coughing”, and “I have been short of breath” were significant univariable predictors. Gender, marital status, baseline FEV1, treatment center, lung radiation dose (V5, V20, mean), and esophageal dose (D2cc) were not significant univariable predictors. Our Lasso procedure selected the following predictors for multivariable analysis: age, ECOG performance status, PTV volume, patient reported lack of energy, patient reported cough, mean heart dose, and patient insurance status. The pooled estimate of AUC for this multivariable model was 0.71. Conclusion: Our models identified a combination of initial patient, disease and treatment characteristics, and PROs that may help identify individuals undergoing curative CRT who are at high risk of early hospice enrollment or death. Further research to determine if interventions for this group (e.g. treatment modifications, supportive care) may help improve patients’ outcomes

Association between Adverse Events and Quality of Life in Patients Treated with Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer

Purpose/Objective(s): Clinician-reported adverse events (AEs) and declines in patient-reported quality of life (QOL) are common during and after definitive radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC), but associations between these two outcomes are not well known. The purpose of this study was to assess associations between AEs and patient reported outcomes (PROs) including QOL at different time points during and after definitive radiotherapy for LA-NSCLC in a state-wide consortium. Materials/Methods: Eligible patients included those treated with definitive RT for LA-NSCLC at 24 institutions within the Michigan Radiation Oncology Quality Consortium (MROQC) between 2012-2018 (n=1367). The Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI) was collected at baseline, end of treatment, and at 1, 3 and 6 months post-RT. The FACT-TOI includes 3 QOL components: Physical Well Being (PWB), Functional Well Being (FWB), and Lung Cancer Subscale (LCS). Clinicians graded AEs using CTCAE weekly during RT and at the same follow-up visits. An AE score was calculated as the sum of AE grades for pneumonitis, pleuritic pain, cough, dyspnea, esophagitis and esophageal pain at each time point. Spearman correlation coefficients were calculated for AEs and similar PROs, and between AEs and change in each QOL component from baseline. Changes in QOL were compared at different time points for patients with grade ≥ 2 esophagitis (versus grade ≤ 1) and grade ≥ 2 pneumonitis (versus grade ≤ 1) using Student’s t-tests. Results: All QOL domains declined from baseline to the end of RT then recovered at different rates up to 6 months after RT. Mean AE scores at end of RT and 1, 3, and 6 months post-RT were 3.3, 2.3, 2.2, and 2.3, respectively. Correlation coefficients ranged from 0.36 to 0.66 for AEs and similar PROs. Among AEs, esophagitis had the strongest correlation with change in PWB (r=-0.32), while dyspnea had the strongest correlation with change in FWB (r=-0.21) and LCS (r=-0.31). Correlations for AE score were slightly greater, with r=-0.39 for PWB, r=-0.25 for FWB, and r=-0.36 for LCS. The difference in average change in QOL from baseline between the two esophagitis groups was clinically meaningful and statistically significant during the last week of RT for PWB, and at 1 month post-RT for PWB and FWB but not for LCS (statistically significant only). Differences between the pneumonitis groups were clinically meaningful at 6 months post-RT for PWB and LCS, but they were not statistically significant. Conclusion: Patients with higher quantity and severity of clinician-reported AEs have greater average declines in self-reported QOL during and after RT for LA-NSCLC. The associations between AEs and QOL were modest, however, suggesting that treatment-related AEs account for only a portion of QOL changes that patients experience, and reinforce the complementary nature of PROs and AEs

Are We Missing Acute Toxicities Associated with Hypofractionated Breast Irradiation? A Report from a Large Multi-Center Cohort Study

Purpose/Objective(s): The efficacy and long-term safety of hypofractionated whole breast irradiation (HF-WBI) has been established through multiple randomized trials. However, data on acute toxicities associated with HF-WBI remain more limited. Since 2013, our group has prospectively collected data on acute toxicities associated with HF-WBI based on weekly evaluation during treatment and assessment at 1 month after completion of radiotherapy. In October 2015, we intentionally shifted the post-treatment assessment time-point from 1 month to 2 weeks post-completion of treatment. This change was intended to evaluate whether a closer follow-up (f/u) might result in the detection of otherwise unobserved acute toxicities for patients receiving HF-WBI. In this study we report whether 2-week f/u has resulted in increased sensitivity for detecting acute toxicity as compared with 4-wk f/u. Materials/Methods: We prospectively compared acute toxicity for patients treated with HF-WBI at 25 participating institutions. We compared patients treated between 1/1/2013 and 8/31/2015 (before 2-week f/u up was adopted – “4 wk f/u cohort”) to patients treated between 1/1/2016 – 8/31/2018 (after adoption of a 2-week f/u – “2 wk f/u cohort”). Acute toxicity was considered the maximum reported composite toxicity from 7 days prior to the completion of radiotherapy until 42 days (6 weeks) following completion. Composite toxicity was defined as self-reported or physician-assessed moderate or severe breast pain, and/or physician-assessed presence of moist desquamation. Multivariable logistic regression models were used to assess difference in toxicity by cohort using ASTRO HF-WBI 2018 Guideline v. 2011 Guideline, and further adjusted for BMI, breast volume, race, presence of comorbidity, smoking status, and use of IMRT. Results: 2243 patients who received post-lumpectomy radiation and boost were analyzed, 1369 patients in the 2-wk f/u cohort and 874 in the 4-wk f/u cohort. Occurrence of composite acute toxicity was similar between the 2 cohorts, 28.4% for 2-wk f/u cohort vs 26.9% for the 4-wk f/u cohort, adjusted p=0.66. When analyzing only patients who met all ASTRO HF-WBI Guideline v. 2011 criteria, no difference in acute toxicity was noted; 26.5% with 2-wk f/u vs 25.0% with 4-wk f/u, adjusted p=0.83. Finally, with 2 wk f/u compared with 4 wk f/u, additional acute toxicities were not detected for patients who were younger \u3c50 years (p=0.72), received chemotherapy (p=0.93), had ductal carcinoma in-situ (p=0.13), or had separation \u3e25 cm, (p=0.43), yet otherwise guideline compliant. Conclusion: A closer post-treatment follow-up for patients receiving HF-WBI did not reveal a significant increased incidence of acute toxicities at 2 weeks compared to 4 weeks. This study provides physicians and patients with additional data on the safety and tolerability of HF-WBI and the appropriateness of the interval of follow-up

Factors Associated with Patient-Reported and Physician-Assessed Acute Toxicity after Hypofractionated Breast Radiotherapy, a Report from a Large Multi-Center Cohort Study

Purpose/Objective(s): In 2018 ASTRO published an update to the 2011 evidence-based guideline for the use of hypofractionated whole breast irradiation (HF-WBI), increasing the patient populations for whom expert consensus supports the use of HF-WBI. While individualized decision making is encouraged, this updated guideline has been expanded to support HF-WBI for patients \u3c50 years, receipt of chemotherapy, larger separation distance, and a diagnosis of DCIS. For some of these indications, however, only moderate data exist. Thus, we now assess patient and physician reported toxicity data in a large prospective registry for populations not well represented on the trials and in whom there is less experience with this approach. Materials/Methods: Prospective data were evaluated from 2,083 patients receiving HF-WBI plus boost, treated between 1/1/2016 – 8/31/2018 at 24 academic and community centers participating in a statewide consortium. A composite toxicity endpoint was defined as occurrence of self-reported (4-10 modified brief pain inventory) or physician-assessed moderate or severe breast pain (CTCAE v. 4.0 grade 2-3) when patient report absent, and/or physician-assessed presence of moist desquamation. Logistic regression models were constructed isolating the effect of specific criteria from the 2011 HF-WBI guidelines, specifically age \u3c50 years, separation distance \u3e25cm, chemotherapy use, and DCIS. This was further adjusted for patient BMI, breast volume, race, comorbidity, smoking status, and IMRT. Results: Mean age was 62 years, mean separation was 22cm. Twenty-two percent of patients were treated for DCIS with the remaining 78% treated for invasive cancer; 17% of patients received chemotherapy. Of the 2,083 patients, 376 patients had more than one 2011 guideline discordance (for ex. \u3c50 years with chemotherapy), therefore 1707 patients were included in this analysis. On multivariable analysis, patients age \u3c 50 years were estimated to be 82% more likely to experience toxicity than older patients (OR=1.82, 95% CI: 1.11-2.97, p=0.02). While unadjusted difference on univariate analysis showed increased toxicity with separation \u3e 25 cm, multivariable analysis revealed no significant difference in toxicity for separation \u3e 25 cm(p=0.25), DCIS (p=0.6753), or treatment following chemotherapy p=0.10). Conclusion: Young breast cancer patients may be at increased risk of acute toxicity compared with other patients when receiving HF-WBI. Additional work is needed to determine why patients \u3c50 years, who were notably underrepresented in the prospective trials establishing the safety and efficacy of HF-WBI, may experience increased breast pain and dermatitis. Work is underway in our group to determine if this same increased risk is appreciated for patients \u3c50 years receiving conventionally fractionated radiotherapy