Pre-Treatment Circulating Tumor Cell Levels Correlate with Regional and Distant Failure Rates Following Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancer

Abstract

Stereotactic body radiation therapy (SBRT) has become the standard of care for patients with medically inoperable early stage non-small cell lung cancer (NSCLC) due to good local control rates and minimal morbidity. However, of patients treated with SBRT, 10-15% patients fail regionally and 25% fail distantly. Our hypothesis underlying this prospective trial was that a high burden of circulating tumor cells (CTCs) prior to treatment is a useful prognostic marker for increased risk of recurrence following SBRT. 92 subjects with stage I NSCLC treated with SBRT were prospectively enrolled on an IRB-approved protocol. CTCs were enumerated by an assay utilizing a green fluorescent protein (GFP)-expressing adenoviral probe that detects the elevated telomerase activity in cancer cells. CTC “positivity” was defined as 1.3 GFP-positive cells per mL of peripheral blood samples. Pre-treatment samples were collected at the time of treatment consent for SBRT or at simulation. RT was delivered to a median dose of 50Gy (range, 40-60 Gy) in five fractions. Patient characteristics: female (58%), Caucasian (80%), and current (20%) or former (75%) smokers; median age was 71 years. Subjects had T1a (64%), T1b (23%), or T2a (13%) NSCLC with a median tumor size of 1.7 cm (range, 0.5-5.0 cm). Kaplan-Meier survival analysis and Cox multivariate regression analysis explored the relative effect of covariates on recurrence and survival outcomes, controlling for history of previous NSCLC, tumor size, and pre-treatment PET scan SUVmax. Receiver operating characteristic curves were generated for a series of baseline CTC values between 2 and 7 to identify if there were a threshold value prognostic of disease recurrence. With a median follow-up of 24 months (range, 2-62 months), the 2-year local, regional and distant control rates were 90.0%, 86.4%, and 86.5%, respectively. 38 of 92 subjects (40%) had a positive CTC test prior to treatment. Overall, a positive CTC test when compared to a negative test was not associated with local, nodal, or distant recurrence. A pre-SBRT cutoff of ≥5 CTCs/mL demonstrated the maximal area under the cure in predicting any event of recurrence (AUC=0.64, specificity=90.4%), therein defining favorable (n=78) and unfavorable (n=14) prognostic groups by baseline CTC. Increased risk of nodal and distant failure was observed in the unfavorable versus favorable cohorts, with 2-year freedom from nodal and distant failure of 83.9% and 75.7% versus 86.7% (HR 3.92, p=0.04) and 89.2%, (HR 4.29, p=0.03). Higher pre-treatment CTC counts appears to be predictive of increased risks of regional and distant recurrences following SBRT for early stage NSCLC, thus potentially identifying the subset of patients at highest risk of regional and distant recurrences who could benefit most from intensified or adjuvant systemic therapy.