Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor

Annals of Oncology, Nov 2012

Background Initial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy.

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Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor

T. J. N. Hiltermann M. M. Pore A. van den Berg 0 W. Timens 0 H. M. Boezen 4 J. J. W. Liesker 3 J. H. Schouwink 2 W. J. A. Wijnands 1 G. S. M. A. Kerner F. A. E. Kruyt H. Tissing 6 A. G. J. Tibbe 6 L. W. M. M. Terstappen 5 H. J. M. Groen 0 Pathology and Medical Biology 1 Department of Pulmonary Diseases, Deventer Hospital , Deventer , The Netherlands 2 Department of Pulmonary Diseases , Medisch Spectrum Twente, Enschede 3 Department of Pulmonary Diseases, Scheper Hospital , Emmen 4 Medical Epidemiology, University of Groningen, University Medical Center Groningen , Groningen 5 Faculty of Science and Technology, University of Twente , Enschede , The Netherlands 6 Immunicon Corporation , Huntingdon Valley, Veridex LCC, Raritan , USA Background: Initial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy. Patients and methods: In this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch systems. Results: At baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14 040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P 0.001). CTCs decreased after one cycle of chemotherapy; this decrease was not associated with tumor response after four cycles of chemotherapy. CTC count after the first cycle of chemotherapy was the strongest predictor for overall survival (HR 5.7; 95% CI 1.7-18.9; P = 0.004). Conclusion: Absolute CTCs after one cycle of chemotherapy in patients with SCLC is the strongest predictor for response on chemotherapy and survival. Patients with low initial CTC numbers lived longer than those with higher CTCs. - introduction Small-cell lung cancer (SCLC) is a disease with high propensity for hematogenously spread metastases, often already present in early-stage disease. Classically, SCLC is divided into limited disease stage (LD, localized disease) and extensive disease stage (ED, metastasized disease). Mortality of SCLC remains high; even in patients with LD, 5-year survival is only 10% [1] (maximum 26%) [2]. This is due to metastases in many organs and perhaps to circulating tumor cells (CTCs) that originate from detachment of the primary tumor mass and migration of tumor cells to secondary sites via the lymphatic and blood system. The presence of CTCs has been demonstrated in the blood of patients with various solid tumors [3]. Their presence has been associated with poor outcome in metastatic breast, colorectal, prostate, gastric, and non-SCLC [48]. In SCLC, the presence of 2 CTCs/7.5 ml of peripheral venous blood was found in 75% of patients with both LD and ED [9, 10]. A problem in the analysis of CTCs may be the low number of CTCs encountered in whole blood, potentially affecting the reproducibility of counting these tumor cells. An additional aim of this study was to assess the repeatability of two independent measurements at each time point. The presence of CTCs may rather be a reflection of the metastatic potential of the tumor and therefore may correlate better with survival than the bulk of disease as reflected by tumor imaged with computed tomography (CT) [11, 12]. In this study, the predictive value of CTCs for progression-free survival (PFS) and overall survival (OS) was studied. Furthermore, we hypothesize that the resistant CTCs present after one cycle of chemotherapy are those that determine the fate of SCLC patients in terms of OS. The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: . patients and methods study design This is a prospective study from four medical centers in consecutive patients with SCLC. Patients were evaluated with laboratory tests, CT of the chest and upper abdomen and when indicated with magnetic resonance imaging of the brain and radionuclide bone scan or positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG). Patients were staged according to the new Tumor, Node, Metastasis classification (TNM 7th edition), and for comparison with older studies, they were reclassified them into LD and ED [13]. CTs were made after two and four cycles of chemotherapy for tumor response assessments and thereafter imaging was carried out every 12 weeks. Tumor size and response to therapy were independently reevaluated according to RECIST version 1.1 [14]. If a patient progressed before a second CT scan had been made, this patient was denoted as progressive. PFS was determined from the start of chemotherapy u (...truncated)


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T. J. N. Hiltermann, M. M. Pore, A. van den Berg, W. Timens, H. M. Boezen, J. J. W. Liesker, J. H. Schouwink, W. J. A. Wijnands, G. S. M. A. Kerner, F. A. E. Kruyt, H. Tissing, A. G. J. Tibbe, L. W. M. M. Terstappen, H. J. M. Groen. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor, Annals of Oncology, 2012, pp. 2937-2942, 23/11, DOI: 10.1093/annonc/mds138