What is the clinical evidence from this study?

Study design: Cohort. Population: Locally Advanced Non-Small-Cell Lung Cancer (n=125). Intervention: Pre-existing cardiac disease vs. No pre-existing cardiac disease. Primary outcome: Grade ≥ 3 cardiac event (HR 2.96, 95% CI 1.07-8.21, p=0.04).

March 16, 2017

Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non–Small-Cell Lung Cancer

Key Result

Pre-existing cardiac disease (HR 2.96) and higher mean heart dose (HR 1.07/Gy) were significantly associated with an increased risk of grade ≥ 3 cardiac events in patients with locally advanced NSCLC treated with definitive radiation.

Study Design

Type

Cohort (n=125)

Multicenter

Yes

Structured PICO

Does mean heart dose during radiation therapy increase the risk of grade ≥ 3 cardiac events in patients with locally advanced NSCLC?

Population

125 patients with stage II to III non-small-cell lung cancer (NSCLC) treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013, 27% with pre-existing cardiac disease.

Intervention

Definitive radiation therapy (median prescription dose 70 Gy), with 84% receiving concurrent chemotherapy.

Outcome

Development of a grade ≥ 3 cardiac event (per Common Terminology Criteria for Adverse Events v4.03).safety

Higher mean heart dose and pre-existing cardiac disease significantly increase the risk of severe cardiac events in patients receiving definitive radiation therapy for locally advanced NSCLC.

Main Result

Effect estimate: HR 2.96 (95% CI 1.07-8.21)

Absolute Event Rate: 21% vs 7%

p-value: p=0.04

Limitations

Possible that not all cardiac events were completely captured
Incidence of cardiac events will likely continue to rise with further follow-up
Others have estimated a slightly higher α/β ratio for heart than 2.5
Larger confirmatory studies with uniform fractionation and chemotherapy are required to confirm findings
Limited statistical power of the study

Abstract

Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio HR, 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.

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