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.
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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)