Cardiac Toxicity After Radiotherapy for Stage III Non–Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy

Radiotherapy (RT) –associated heart toxicity has long been recognized in patients with breast cancer or Hodgkin lymphoma, with increases in cardiovascular events and deaths typically noted 10 or more years after treatment.^1-6 However, the clinical relevance of RT-associated heart disease for patients with stage III non–small-cell lung cancer (NSCLC) is unclear. Conventional wisdom holds that there are few long-term survivors to experience toxicity, given the typically long latency of RT-associated heart injury and poor prognosis. On the other hand, though most RT-associated cardiac events in patients with breast cancer or lymphoma occur many years after RT, there may also be an increased rate at earlier intervals.^6-9 In addition, patients with lung cancer are more likely to have comorbid risk factors such as smoking and pre-existing cardiac disease that lower their reserve and predispose them to earlier events.

Several studies report increased cardiac deaths with postoperative RT after surgery for stage I to III NSCLC.^10-12 Evidence for cardiac injury after definitive RT is more limited.^13,14 Recently, the Radiation Therapy Oncology Group (RTOG) 0617 (A Randomized Phase III Comparison of Standard-Dose [60 Gy] Versus High-Dose [74 Gy] Conformal Radiotherapy With Concurrent and Consolidation Carboplatin Plus Paclitaxel ± Cetuximab {IND #103444} in Patients With Stage IIIA and IIIB Non–Small-Cell Lung Cancer) trial reported inferior overall survival (OS) with dose-escalated chemoradiation to 74 Gy compared with standard 60 Gy for stage III NSCLC. Heart radiation dose was associated with worse OS with a median follow-up of 2 years, suggesting a contribution of radiation-induced cardiac morbidity relatively soon after treatment.¹⁵

From 1996 to 2009, the University of North Carolina (UNC) participated in six single or multi-institution prospective phase I and II trials that investigated various chemotherapeutic regimens with dose-escalated RT in the definitive treatment of stage III NSCLC.^16-22 Here we review these studies to assess the impact of cardiac doses on subsequent cardiac events.

Patient characteristics are listed in Table 2. Median follow-up for the 11 surviving patients was 8.8 years (range, 2.3 to 17.3 years). Median follow-up for the 39 patients without disease progression was 6.3 years (range, 0.3 to 17.3 years). Most patients (72%) received 74 Gy. All patients received induction chemotherapy, 90% received concurrent chemotherapy, and 25% received consolidation chemotherapy.

In 112 patients with stage III NSCLC treated on six prospective dose-escalation trials with long follow-up, there was an association between clinically significant cardiac events and both radiation doses to the heart and baseline cardiac risk. Although cardiac events were likely multifactorial, the association with heart dose was strong, and it persisted when controlling for baseline cardiac risk. These data may inform researchers and clinicians regarding the potential significance of cardiac toxicity in this setting and also have implications for RT technique and estimates of risk based on heart dosimetry.

The major question we addressed is whether cardiac toxicity is important in the definitive treatment of stage III NSCLC. A common perception is that significant RT-associated heart toxicity occurs 10 or more years after treatment on the basis of studies in breast cancer and Hodgkin lymphoma.^1-6 Those patients are comparably younger with more favorable prognosis, and thus RT practices have evolved toward cardiac avoidance for these diagnoses. This is not the case for patients with stage III NSCLC in whom median survival is generally less than 2 years and for whom pneumonitis and esophagitis are considered the major toxicities. This is reflected by the lack of cardiac constraints for most of the trials included in our study, as well as by the RTOG 0617 protocol itself, which allowed up to 100% of the heart to receive 40 Gy (V40Gy < 100%) and which states “Normal tissue constraints shall be prioritized in the following order for treatment planning: 1 = spinal cord, 2 = lungs, 3 = esophagus, 4 = brachial plexus, and 5 = heart.”¹⁵

Like RTOG 0617, our findings challenge the perception that minimizing heart dose is not important in the treatment of patients with stage III NSCLC. Although prognosis is poor in these patients, they generally receive higher heart doses and may also have more comorbidities and smoking history, thus increasing risk and perhaps shortening the latency between RT and resultant heart disease. In this study, 23% of patients had symptomatic cardiac events, most within 5 years of treatment. Mean heart dose was 20 Gy and V30Gy was 29% in patients with events—well within the RTOG 0617 limit (V40Gy < 100%), and those of other modern protocols including V40Gy < 100% in RTOG 1306 (A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non–Small-Cell Lung Cancer [NSCLC]), and V30Gy < 50% in RTOG 1308 (Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II to IIIB NSCLC).^15,28,29 Even with adjustment for the competing risk of death, patients with mean heart doses ≥ 20 Gy had a 21% 2-year event rate. We did not find an association between heart dose and survival, perhaps because of the small sample size and the overpowering competing risk of death from lung cancer. Nevertheless, our data support minimization of heart radiation exposure whenever possible to doses lower than commonly recommended^9,15,28,29 in patients with stage III NSCLC to reduce risks of toxicity.

Several studies report increased cardiac toxicity with postoperative RT for lung cancer.^10-12 However, these studies did not show a dose-toxicity relationship and might not apply to patients managed nonoperatively with chemoradiation; evidence is limited in this setting. Allan et al³⁰ recently presented data indicating a possible association between cardiac events and heart dose in patients treated to approximately 63 Gy. Hardy et al¹⁴ also showed an association between RT and cardiac toxicity, but patients with stage IV disease were included and nearly half had surgery. In contrast, Schytte et al¹³ found no association between heart doses and cardiac events or survival in patients with stage I to III disease treated with RT with or without chemotherapy. Similarly, Tucker et al³¹ also reported no association between heart doses and survival in patients with stage III disease undergoing chemoradiation but did not report toxicity. Most of the patients in those studies received conventional doses of 60 to 66 Gy and were not enrolled in prospective trials. Patients included in this analysis all received ≥ 70 Gy and had protocol-specified follow-up. Thus, our findings and those from RTOG 0617 support the notion that RT-associated heart injury may be relevant, particularly in the setting of dose escalation.

It is unclear how radiation may increase the risk of early cardiac toxicity, but given the diversity of event types, the mechanism is likely multifactorial. As described by Darby et al,⁷ RT may cause both accelerated late atherosclerosis of major vessels and early microvascular changes. Evidence suggesting early microvascular changes comes from animal models^32,33 and from clinical studies. Marks et al³⁴ reported a 27% rate of new perfusion defects detected with nuclear imaging only 6 months after RT. Similar findings have been reported by others.^35-37 Hatakenaka et al³⁸ also reported early LV dysfunction on cardiac magnetic resonance imaging scanning after chemoradiation for esophageal cancer. Although early microvascular changes may increase susceptibility to late coronary artery disease, they could also contribute to early cardiac toxicity. Another possible mechanism is the development of pericardial effusions that occurred in 36% of patients at a median 11 months after treatment, consistent with prior reports.³⁹ Effusions that are initially insignificant may eventually become symptomatic or contribute to the later development of other cardiac toxicities. Finally, there was a high rate of significant arrhythmia. Although these events are perhaps more likely to be precipitated by concurrent medical illnesses, the effect of RT on nervous system structures is well documented in other settings⁴⁰; injury to cardiac nerve pathways could conceivably lead to aberrant conduction and increase the risk of arrhythmia. This is supported by a recent article on almost 2,000 long-term survivors of Hodgkin lymphoma in whom ischemia and arrhythmia were the two most common initial cardiac events.⁴¹

Our study suggests a dose dependence for RT-associated cardiotoxicity. The growing dose, volume, and outcome data from our study and similar studies provide additional information to guide RT treatment planning. Ideally doses are delivered only to the target, but the physical nature of radiation beams makes this impossible. Incidental irradiation of surrounding normal tissues is unavoidable. Thus, the planning process essentially balances where this incidental dose is delivered. Risk of cardiac toxicity likely increases continuously with heart dose, but the degree to which heart dose can be minimized is limited by competing priorities of tumor control and doses to other organs, especially the lung. Further studies are needed to determine the ideal balance between these priorities. In our opinion, tumor coverage should rarely be compromised to meet a heart dose constraint. However, it would be reasonable to try to limit heart mean dose to < 20 Gy (lower if possible) on the basis of the high event rate we observed in patients exceeding this dose (21% at 2 years and 41% at 4 years). Sophisticated radiation treatment planning techniques (eg, IMRT) and charged particle therapy with protons or carbon ions may provide increased flexibility to generate more conformal treatment plans and reduce heart dose, which could potentially improve the clinical outcomes in patients with stage III NSCLC.^42-44

Our study has several limitations. First, toxicity end points were retrospectively assessed. However, patients were followed prospectively on protocols, which may increase the completeness of post-treatment evaluations.⁴⁵ Nevertheless, there may have been undocumented cardiac events, and our results may therefore actually underestimate their frequency. Second, the number of events was low, which limits the examination of multiple covariates, but this is still one of the largest studies of its type to address this important clinical question. Third, assessing baseline cardiac risk via the WHO/ISH risk score and baseline CAD is imperfect, but it is still a reasonable and practical approach similar to those used by others.^3,8 Fourth, patients were treated over many years on multiple trials, which introduces treatment heterogeneity. Different chemotherapy regimens may contribute differentially to cardiac toxicity, although we did not find associations between specific trials (and therefore chemotherapy regimens) and events. Furthermore, agents used in these trials are not considered particularly cardiotoxic,⁴⁶ although they could potentially enhance radiation-induced cardiotoxicity. Fifth, patients were treated using high-dose RT (≥ 70 Gy), often without cardiac constraints, and thus our findings might not be applicable for patients treated to conventional doses or with IMRT in the modern era. Nevertheless, our findings support the presence of a relationship between dose-volume and toxicity, and our data can assist in redefining reasonable cardiac constraints (which for lung cancer have not changed appreciably for many years). Sixth, multiple types of events were included in the primary end point, and some (such as arrhythmia) may be more subject to confounding by concurrent illnesses. However, when excluding arrhythmia from the primary end point, the results were essentially unchanged. Finally, the high competing risk of death as a result of cancer is a significant confounder when analyzing a comparably rare toxicity, but this issue plagues essentially all similar studies in patients with such serious illnesses.

In conclusion, clinically significant cardiac events after high-dose thoracic RT for stage III NSCLC were associated with heart dose and cardiac risk and occurred fairly early after treatment. Consistent with the current emphasis on reducing radiation heart exposure for other malignancies, heart doses should be similarly minimized in patients with stage III NSCLC.