A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker in patients with extensive small-cell lung cancer

Abstract

Background: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC.

Methods: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6-8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs.

Results: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0-3430) and 2 (range 0-526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range -100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival.

Conclusion: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients' clinical responses to therapy.

Keywords: biomarkers; circulating tumor cells; extensive stage; prognosis; small-cell lung carcinoma.

Figure 1

Plot of individual patient-level CTC change data (log scale). The x-axis is number of days post-treatment at which the CTC measurement was collected for patient, y-axis is the percent change from baseline at that time for each patient, each patient has a line representing his or her change.

Figure 2

Kaplan–Meier survival estimates of subjects who showed partial response (green, n = 12, two censored), progressive disease (red, n = 1), and those not evaluable for response due to early death (blue, n = 5). Three subjects with stable disease are not shown due to missing survival data. Significant differences in survival were found (log-rank χ² = 25.3, p < 0.0001). Partial responders survived, on average, 321 days (95% CI: 189, 385). Subject with progressive disease survived 38 days. Subjects not evaluated for response had median survival of 65 days (95% CI: 14, 89).

Figure 3

Kaplan–Meier survival estimates of subjects with measurable CTCs at baseline (>5, red, n = 17, one censored) and without (<5. blue, n = 9, three censored). Subjects with >5 CTCs at baseline survived, on average, 223 days (95% CI: 65, 321). Subjects with <5 CTCs at baseline had median survival of 358 days (95% CI: 58, 358). Differences in survival were significant at the 10% level (log-rank χ² = 1.99, p = 0.1).

Figure 4

Receiver operating characteristic (ROC) curves for CTCs at baseline (red, AUC = 0.7308, 95% CI: 0.36, 1.0) and change in CTCs from pre- to post-treatment (blue, AUC = 0.6795, 95% CI: 0.33, 1.0).