Interplay of Cardiac and Pulmonary Toxicity: An Analysis of Prospective Trials for Locally Advanced Non-Small Cell Lung Cancer

Abstract

Purpose/Objective(s): Radiation is a key component in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). The surrounding normal lung tissue and heart are important organs-at-risk for treatment-related toxicity. Less is known about how damage to one organ can affect the other. We hypothesized that a significant overlap exists between those experiencing pulmonary and cardiac toxicity, and that early radiation induced lung toxicity (RILT) would predispose patients to future cardiac events (CEs). Materials/Methods: Patients with Stage II-III NSCLC who were treated with definitive RT as part of four IRB-approved prospective trials (median EQD2Gy:70 Gy) were included (n=125). Grade of radiation pneumonitis (RP) and clinical fibrosis (CF) (collectively RILT) were defined per individual trial. Cardiac events (CEs) were defined per CTCAE4.03. The cumulative incidence of toxicity was analyzed with death as a competing risk. The relationship between RILT (Grade 2+ and 3+) and time to Grade 3+ CEs was evaluated using time dependent variables in multivariable analysis (MVA). Toxicity effects on survival were also evaluated in MVA with age, sex, performance status, and time to any cancer progression. Results: Median age was 66 years. The majority of patients were male (76%), current/former smokers (94%), and received concurrent chemotherapy (84%). Baseline median FEV1 was 1.9L, 43% had COPD, and 32% had preexisting CAD/CHF. Median mean heart dose was 11 Gy (IQR: 7-19) and lung dose (MLD) was 15 Gy (IQR: 13-18). The 24 month cumulative incidence (median time to event (TOE)) of Grade 2+ RP was 16% (5 mos), CF was 11% (11 mos), and RILT was 22% (5 mos); corresponding Grade 3+ events were 6%, 4%, and 8% with similar median TOE. The 24 month CI of Grade 3+ cardiac events was 10% (15 mos). The majority (74%) of patients with Grade 3+ CEs did not have preceding Grade 2+ RILT. Of patients with Grade 2+ and 3+ RILT, 17% (n=5/29) and 20% (n=2/10) experienced future Grade 3+ CEs, respectively. In MVA, time dependent lung toxicity was not associated with future Grade 3 CEs when analyzing Grade 2+ RILT (HR 1.10, 0.41-2.96) or Grade 3+ RILT (HR 2.12, 0.27-16.88). Separate analysis of RP and CF had similar results. As a time dependent variable, Grade 3+ CEs was associated with lower survival in MVA (HR 1.74, 1.04-2.91). In contrast, neither Grade 2+ (HR 1.14, 0.75-1.74), nor 3+ RILT (HR 1.19, 0.53-2.63) was associated with lower survival. Conclusion: In a prospective cohort, RILT occurred earlier than Grade 3 CEs. By 24 months, however, rates of Grade 3+ RILT and CEs were similar. Patients with pulmonary and cardiac toxicity were largely distinct groups, and clinically apparent Grade 2+ or 3+ RILT was not associated with future cardiac events. Grade 3+ cardiac events were associated with decreased survival, but no such association was identified with Grade 2+ or 3+ RILT. We are investigating models that would permit us to choose an optimized dose that balances efficacy with RILT and CEs.