When Failure is Final: Subsequent Outcomes of Patients with Stage I NSCLC who Fail Initial Stereotactic Body Radiation Therapy Monitored with Circulating Tumor Cells

Abstract

Stage I non-small cell lung cancer (NSCLC) is increasingly treated with stereotactic body radiation therapy (SBRT), but regional and distant disease progression frequently occur. In a pilot trial of stage I NSCLC patients treated with SBRT accompanied by sequential circulating tumor cell (CTC) assays, we previously found that pretreatment CTCs > 5 /ml and persistent CTCs after SBRT were associated with a significantly higher risk of regional or distant disease progression. To better understand the disease history and impact of salvage treatment on this cohort, we extended analysis of patients with disease progression. Among 92 consecutive patients with clinical stage I NSCLC treated with definitive SBRT prospectively enrolled on an IRB-approved protocol with serial telomerase-based CTC assays, 19 subjects (21%) developed disease progression while on study. Medical records were assessed for new clinical events, treatment details, and status at last follow-up. Initial SBRT was delivered to a median dose of 50 Gy (range, 40-60 Gy) in 4-5 fractions. No patient received chemo- or immunotherapy prior to first disease progression. Median follow-up was 29 months (range, 14-69 mo.) from time of initial SBRT. Additional follow-up was obtained in all but 2 patients (1 withdrew and 1 was lost to follow-up). Four, 5, and 8 patients had local, regional, or distant recurrences, respectively, as the first site of progression. Five (29%) patients who progressed after initial definitive SBRT are alive, of which 4 (24%) were successfully treated with a 2nd course of SBRT without systemic therapy (2 for local recurrences and 2 for oligometastatic distant) at a median of 32.8 months after initial SBRT (range: 32.7 to 35.3 mo.). The remaining 12 patients were deceased, with mean and median time to death following initial SBRT of 26.6 (14-52 mo.) and 24 months, respectively. Of the deceased, the mean and median time to disease progression following initial SBRT were 14.5 (3.2-44.2) and 11.4 months, and all but four received chemo-, immuno-, and/or targeted therapy before succumbing (only one received SBRT). Pre-SBRT or 3 months post-SBRT CTCs were elevated in 9 (or 75%) of the 12 deceased patients, versus only 5 (or 8.3%) of the 62 patients confirmed to be still alive, a significant difference (p < 0.001). Less than a third of patients who fail initial SBRT for stage I NSCLC in this study received a 2nd course of SBRT and remain alive. In contrast, the majority of patients who progressed rapidly succumbed to disease progression, most within 2 years after initial SBRT. The window for intervention with salvage treatment is, therefore, surprisingly narrow. These results support the usefulness of CTC assays for rapidly denoting the subset of patients who may benefit from adjuvant systemic therapy, added to SBRT, for maximizing survival.