Clinical Investigation
Pulmonary Artery Invasion, High-Dose Radiation, and Overall Survival in Patients With Non-Small Cell Lung Cancer

https://doi.org/10.1016/j.ijrobp.2014.02.011Get rights and content

Purpose

To investigate whether high-dose radiation to the pulmonary artery (PA) affects overall survival (OS) in patients with non-small cell lung cancer (NSCLC).

Methods and Materials

Patients with medically inoperable/unresectable NSCLC treated with definitive radiation therapy in prospective studies were eligible for this study. Pulmonary artery involvement was defined on the basis of pretreatment chest CT and positron emission tomography/CT fusion. Pulmonary artery was contoured according to the Radiation Therapy Oncology Group protocol 1106 atlas, and dose-volume histograms were generated.

Results

A total of 100 patients with a minimum follow-up of 1 year for surviving patients were enrolled: 82.0% underwent concurrent chemoradiation therapy. Radiation dose ranged from 60 to 85.5 Gy in 30-37 fractions. Patients with PA invasion of grade ≤2, 3, 4, and 5 had 1-year OS and median survival of 67% and 25.4 months (95% confidence interval [CI] 15.7-35.1), 62% and 22.2 months (95% CI 5.8-38.6), 90% and 35.8 months (95% CI 28.4-43.2), and 50% and 7.0 months, respectively (P=.601). Two of the 4 patients with grade 5 PA invasion died suddenly from massive hemorrhage at 3 and 4.5 months after completion of radiation therapy. Maximum and mean doses to PA were not significantly associated with OS. The V45, V50, V55, and V60 of PA were correlated significantly with a worse OS (P<.05). Patients with V45 >70% or V60 >37% had significantly worse OS (13.3 vs 37.9 months, P<.001, and 13.8 vs 37.9 months, P=.04, respectively).

Conclusions

Grade 5 PA invasion and PA volume receiving more than 45-60 Gy may be associated with inferior OS in patients with advanced NSCLC treated with concurrent chemoradiation.

Introduction

Lung cancer is a leading cause of cancer-related death in the world (1). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with only 20% of these patients presenting with localized disease at diagnosis 2, 3. The standard treatment for stage I/II NSCLC is surgical resection, and 5-year overall survival (OS) ranges from 53% to 82% for stage I and from 29% to 51% for stage II 4, 5. In patients with medically inoperable early-stage NSCLC, stereotactic body radiation therapy (SBRT) and hypofractionated dose-intensified conventionally fractionated radiation therapy (RT) have provided outstanding disease control and are the standard of care 6, 7, 8. Unfortunately, approximately one-third of NSCLC patients present with locally advanced unresectable disease that cannot be safely treated with SBRT. In patients with good performance status in this group, concurrent chemotherapy and thoracic RT are the standard of care 8, 9, 10. A dose of 60 Gy or slightly higher is considered standard using a conventional schedule of 2.0-Gy daily fractions 9, 11, 12. High-dose RT may improve local tumor control, but it is often associated with increased risk of treatment toxicity 12, 13. However, preliminary results from the Radiation Therapy Oncology Group (RTOG) protocol 0617, a large randomized trial designed to determine whether a high dose of RT (74 Gy) with chemotherapy with or without cetuximab versus a standard dose of RT (60 Gy) with chemotherapy with or without cetuximab improved OS in patients with stage III, locally advanced, unresectable NSCLC, reported an inferior median OS (19.5 vs 28.7 months, P=.0007). Radiation Therapy Oncology Group 0617 also noted 2.3% and 3.9% increases in deaths from treatment-related adverse events at 12 and 18 months, respectively, including those from massive hemorrhage in the high-dose arm (74 Gy) (14). The reason for inferior survival from high-dose radiation is unclear. One reason may be the low local-regional control, and the local failure rates were 25.1% versus 34.3% at 18 months for 60 Gy and 74 Gy patients, respectively (P=.03). It was also notable that there were 2 more cases with reported massive bleeding in the 74-Gy arm. One would ask whether high-dose radiation to blood vessels contributes to such events. Cancer invading large vessels may also cause massive bleeding, which is sometimes not detected. The pulmonary artery (PA) is described as one of the most commonly invaded thoracic vessels in patients with advanced lung cancer and was reported to be a source of life-threatening massive bleeding from tumor progression 15, 16. We hypothesized that high-dose radiation applied to tumor-invaded PA may cause perforation or fistula and subsequently life-threatening hemoptysis or unattributable deaths in patients with advanced NSCLC. Our primary aim in this study was to investigate whether high-dose radiation to the PA is associated with a decrease in 1-year and median OS.

Section snippets

Eligibility

Patients with medically inoperable or unresectable NSCLC, enrolled in institutional review board–approved prospective clinical trials at University of Michigan and the VA Ann Arbor hospitals, were eligible for this study. All patients had a cytologic or histologic diagnosis of stage I-III NSCLC and Karnofsky performance status (KPS) score ≥60. All patients were treated with definitive fractionated RT with or without concurrent chemotherapy. Patients with malignant pleural effusion were excluded.

Patient characteristics

One hundred patients with pathologic stage I-III NSCLC with at least 1 year follow-up for surviving patients were eligible for this study. Patient characteristics are summarized in Table 2. Median patient age was 66 years (range, 43-85 years). Eighty-two patients (82%) were male, and 80 (80%) had stage III disease. Concurrent chemotherapy was administered in 82 patients (82%). The median radiation dose was 70 Gy (range, 60-85.5 Gy). As shown in Table 3, 53, 19, 5, 9, 10, and 4 patients had

Discussion

This study demonstrates that 1-year OS and median survival time were not significantly associated with the grade of PA invasion; however, a high percentage of our small sample size of grade 5 PA invasion cases died early from massive hemorrhage, suggesting that grade 5 PA invasion may carry a relatively higher risk of massive bleeding. Maximum and mean PA doses were not significantly associated with OS or 1-year OS, although PA volumes of 45-60 Gy were significantly correlated with OS.

Conclusions

Overall grade of PA invasion was not associated with OS in patients with inoperable NSCLC, although massive PA invasion may result in a high risk for severe hemoptysis and early mortality. Moderate-to-high PA dose volume was predictive of worse survival for patients with PA-involved NSCLC. Future prospective studies with larger numbers of patients are needed to validate these findings.

References (24)

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F.-M.(S.)K.'s present address is: Georgia Regent University, GRU Cancer Center, Radiation Oncology, Augusta, GA 30912.

Conflict of interest: none.

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