ORIGINAL ARTICLE
European Journal of Cardio-Thoracic Surgery 45 (2014) 687–692 doi:10.1093/ejcts/ezt424 Advance Access publication 26 August 2013
Significance of the serum carcinoembryonic antigen level during the follow-up of patients with completely resected non-small-cell lung cancer† Naoki Ozekia,b, Takayuki Fukuia, Tetsuo Taniguchia, Noriyasu Usamia, Koji Kawaguchia, Simon Itoc, Yukinori Sakaob, Tetsuya Mitsudomib,d, Akihiro Hirakawae and Kohei Yokoia,* a b c d e
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Thoracic Surgery, Aichi Cancer Center, Nagoya, Japan Department of Thoracic Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan Division of Thoracic Surgery, Department of Surgery, Faculty of Medicine, Kinki University, Osaka-Sayama, Japan Biostatistics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
* Corresponding author. Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel: +81-52-7442376; fax: +81-52-7442383; e-mail:
[email protected] (K. Yokoi).
Abstract OBJECTIVES: The purpose of this study was to elucidate the detectability of recurrence and the prognostic significance of the serum carcinoembryonic antigen (CEA) levels in patients with completely resected non-small-cell lung cancer (NSCLC). METHODS: Five hundred and eighteen NSCLC patients who underwent complete resection at Aichi Cancer Center between April 2001 and March 2006 were enrolled in this study. The patient characteristics were as follows: the median age was 63 years; 331 tumours were classified as pathological stage I, 88 tumours were pathological stage II and 99 tumours were pathological stage III; 140 tumours were adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, 268 tumours were adenocarcinomas with EGFR wild-type mutations and 110 tumours were other NSCLCs. The patients were divided into three groups: those with a normal CEA level before and 1–3 months after surgery (N group, n = 380), those with an elevated CEA level before surgery and a normal CEA level 1–3 months after surgery (HN group, n = 105) and those with an elevated CEA level 1–3 months after surgery regardless of the preoperative CEA level (H group, n = 33). The correlations between the changes in the serum CEA levels and the clinical outcomes were analysed. RESULTS: Recurrence developed in 122 patients (32%) in the N group, 49 patients (47%) in the HN group and 19 patients (58%) in the H group (P = 0.001). The sensitivity and specificity of an elevated serum CEA level during the follow-up period for detecting recurrence were 30 and 98% in the N group and 82 and 73% in the HN group, respectively. Twenty-seven asymptomatic recurrent tumours combined with an elevated serum CEA level were detected in the HN group. In the multivariate Cox regression analysis, the serum CEA level 1–3 months after surgery had prognostic value for overall survival. CONCLUSIONS: In completely resected NSCLC patients, measuring the serum CEA level during the follow-up period is useful in patients in whom an elevated level normalizes after surgery, and the serum CEA level 1–3 months after surgery is considered to have prognostic significance regarding survival. Keywords: Lung cancer • Carcinoembryonic antigen • Follow-up • Surveillance
INTRODUCTION Non-small-cell lung cancer (NSCLC) is now the leading cause of cancer-related death worldwide. Due to cancer recurrence, the clinical outcomes of patients with NSCLC are not satisfactory, even when complete resection is performed. The purpose of surveillance following surgical resection is to detect recurrence and/or new primary lung cancer in order to apply appropriate treatment.
† Presented at the 21st European Conference on General Thoracic Surgery, Birmingham, UK, 26–29 May 2013.
The prognostic significance of intensive follow-up for detecting recurrence is debatable [1–3]. A certain population of NSCLC patients, first described in those with adenocarcinoma, produce carcinoembryonic antigens (CEAs) and have a high serum level at presentation. Among colon cancer patients, the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines recommend that the serum CEA level be measured during the followup period following surgery [4, 5]. Among NSCLC patients who undergo surgical treatment, there are currently no guidelines recommending the measurement of serum tumour markers, such as CEA, during the follow-up period to detect recurrence. Although
© The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
THORACIC
Received 18 May 2013; received in revised form 21 July 2013; accepted 24 July 2013
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each society, including the ASCO, NCCN and American College of Radiology (ACR), has established its own guidelines, no uniform method of surveillance following surgery has been established to date [6]. The serum CEA levels are sometimes assessed to monitor the progression of lung cancer following complete resection, although the prognostic significance of the perioperative serum CEA level and the detectability of recurrence during the follow-up period using this marker remain unclear. Therefore, this study was designed to evaluate the significance of measuring the serum CEA level from the preoperative state to the follow-up period for detecting recurrence and estimating survival in completely resected NSCLC patients.
MATERIALS AND METHODS This study was conducted with the Institutional Review Board of Aichi Cancer Center approval. Between April 2001 and March 2006, 529 patients underwent surgery for NSCLC with curative intent at Aichi Cancer Center. All the patients were without active concomitant malignancies and received regular postoperative follow-up, including measurement of the serum CEA level at every visit. Eleven patients who died or relapsed within 3 months of surgery were excluded from the analysis. Consequently, 518 patients constituted the study population. We retrospectively reviewed the medical records of all the patients and assessed the conditions of cancer recurrence and overall survival (OS). The seventh edition of the tumor node metastasis classification [7] was applied in this cohort, and the pathological diagnosis of the tumour was made based on the
World Health Organization classification [8]. An epidermal growth factor receptor (EGFR) mutational analysis of the surgical specimens was performed using one-step reverse transcription–polymerase chain reaction (RT–PCR) amplification with the QIAGEN One-Step RT–PCR Kit (Qiagen, Valencia, CA, USA). The patient characteristics were as follows: the median age was 63 years (range 22–82 years); 299 patients were male and 219 patients were female; 331 tumours were classified as pathological stage I, 88 tumours were classified as pathological stage II and 99 tumours were classified as pathological stage III; 140 tumours were adenocarcinomas (EGFR mutants), 268 tumours were adenocarcinomas (EGFR wild-type) and 110 tumours were of other histological types of NSCLC (Table 1). The follow-up programme included chest radiography, measurement of the serum CEA level and a physical examination and clinical interview at every visit. The frequency of visits was every 3 months up to 2 years from surgery and every 6 months thereafter. Chest and abdominal computed tomography (CT) scans were obtained annually and non-scheduled radiological examinations, including additional chest and abdominal CT, brain magnetic resonance imaging and positron emission tomography (PET) using 18 F-fluorodeoxyglucose combined with CT (PET-CT), were performed depending on the physicians’ decision, especially when prominent or continuous elevation of the serum CEA level was observed. With a cut-off value of 5.0 ng/ml, the serum CEA level was classified as elevated or normal. The patients were divided into three groups according to a preoperative serum CEA level ( preoperative CEA) and a serum CEA level 1–3 months after surgery ( postoperative CEA): those with a normal preoperative CEA and a normal postoperative CEA (N group, n = 380), those
Table 1: Clinicopathological characteristics of the patients H group (n = 33)
P-value
67 (8–115) 63 (39–79) 9.0 (5.1–286.0) 3.2 (0.6–4.9)
31 (4–110) 67 (56–81) 8.2 (2.6–160.0) 7.3 (5.3–147.5)
