ANTICANCER RESEARCH 33: 253-260 (2013) CEA Fluctuation During a Single Fluorouracil-based Chemotherapy Cycle for Metastatic Colorectal Cancer KETHE HERMUNEN1, CAJ HAGLUND1* and PIA OSTERLUND2* 1Department of Gastroenterological Surgery and 2Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland Abstract. Background: Carcinoembryogenic antigen (CEA) limited value for primary diagnosis of CRC (3, 4), but should is useful in the evaluation of chemotherapy response of be determined before treatment to obtain a baseline value metastatic colorectal cancer (CRC). We studied weekly CEA (5-9). CEA adds valuable information when evaluating during one fluorouracil-based chemotherapy cycle, correlated prognosis (10, 11), in postoperative surveillance (12, 13), and with long-term (8-12 week interval) computed tomography when monitoring treatment efficacy during systemic therapy (CT) and CEA responses. Patients and Methods: CEA, liver for metastatic CRC (14). function tests and inflammatory parameters were measured During treatment for metastatic CRC, CEA should be prospectively at baseline, day 7, day 14, and after the cycle measured at the start of treatment and then every 8 to 12 weeks (day 21/28), in 60 patients with metastatic CRC. Results: during active treatment according to the American Society of CEA non-significantly decreased at day 7 and was increased Clinical Oncology (ASCO) guidelines (14). Two values above on day 14. In progressive disease, CEA increased significantly baseline are adequate evidence of progressive disease, even in during the evaluation cycle (55.4 μg/l vs. 148.2 μg/l; the absence of corroborating radiographs. Two reports question p=0.024), but the level was stable in patients with disease the ASCO definition of progressive disease (15, 16), both control (10.6 μg/l vs. 17.8 μg/l; p=0.58). CEA fluctuation showing that initial elevation of CEA during chemotherapy for correlated neither with liver function test nor with metastatic CRC does not always indicate disease progression. inflammatory parameters. Correlation of long-term response This transient CEA elevation is considered a tumour flare was most evident in progressive disease. Conclusion: CEA reaction or CEA surge, defined as an increase from baseline of should not be measured during 5-fluorouracil-based oral >20% followed by a more than 20% drop in CEA levels (15). chemotherapy nor within two weeks from intravenous The ASCO GI Tumour Marker Guideline Update 2006 chemotherapy administration recommends caution when interpreting CEA elevations during the first 4 to 6 weeks of a new therapy, since spurious early Colorectal cancer (CRC), the third most common rises may occur, especially after oxaliplatin use (2). In the malignancy in the Western world, represents the second guidelines no recommendation on the timing of CEA leading cause of cancer-related mortality. Worldwide in measurement during chemotherapy administration is given. 2008, of some 1,234 million new patients with colorectal 5-FU chemotherapy is generally administered every one, cancer 609,000 died from metastatic disease (1). two or four weeks as intravenous boluses (Roswell Park, Carcinoembryonic antigen (CEA), a tumour-associated Nordic FLv, Mayo), every one to two weeks in continuous rather than a tumour-specific marker, is the only widely infusion (AIO, LV5FU2) and every three weeks in oral recommended serum tumour marker for CRC (2). CEA is of administration (capecitabine, carmofur, UFT). Modern combination chemotherapy with irinotecan, oxaliplatin, bevacizumab, cetuximab and panitumumab is based on these 5-FU chemotherapy backbones. *These Authors contributed equally to this study. Tumour marker levels are often measured in the middle of the chemotherapy administration, in conjunction with nadir Correspondence to: Pia Osterlund, MD, Ph.D., Department of blood counts, in order to have relevant values available for Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN- evaluation at follow-up visits. To the best of our knowledge, 00029 HUS, Finland. Tel: +35 894711, Fax +35 8947174201, e-mail: [email protected] the pattern of CEA fluctuation and optimal timing of measurement during a 3- to 4-week 5-FU-based chemotherapy Key Words: CEA, chemotherapy, fluctuation, metastatic colorectal cycle has received little attention and has not been correlated cancer, tumor flare. with repeated CEA or CT responses at 8- to 12-week intervals. 0250-7005/2013 $2.00+.40 253 ANTICANCER RESEARCH 33: 253-260 (2013) Figure 1. Chemotherapy regimens and evaluation time points in the study. Patients and Methods agent carmofur was administered in 3-week cycles, in which carmofur at 300 mg/m2, divided into three daily doses, was given orally for 14 days, followed by one week of rest. CEA evaluation was a secondary endpoint in an open, prospective non-randomized study, which included 60 consecutive patients with metastatic CRC patients at a single institution (Helsinki University Data collection. Collected data included type of treatment, treatment Central Hospital), the primary end-point being the inflammatory response, patient demographics, location of primary tumour, response, which has been published previously (17). The protocols location of metastatic sites, performance status according to WHO, of the study were approved by the local Ethics Committee and the and serial weekly levels of laboratory tests, including CEA National Agency for Medicines, Helsinki, Finland, and informed (AutoDELFIA®, HUSLAB, Helsinki, Finland), C-reactive protein consent was required from all patients. The patients were divided (CRP), aspartate aminotransferase (AST), alanine aminotransferase into three groups depending on the type of chemotherapy they (ALT), alkaline phosphatase (ALP), bilirubin (BIL), gamma- received, with 20 patients in each group (Figure 1). The first group glutamyltransferase (GT), interleukin-6 (IL-6), interleukin-8 (IL-8), received a combination of raltitrexed and carmofur; the second and tumour necrosis factor-α (TNF-α). The laboratory tests were group raltitrexed as a single-agent therapy; and the third group a 5- run during one cycle of chemotherapy treatment and were taken at FU-based therapy, with 5-FU in combination with leucovorin (either baseline (on day 0), day 7, day 14, and after the treatment cycle the Mayo 5-day bolus injection regimen or the De Gramont (generally on day 21, n=52; but in the Mayo and De Gramont infusional regimen), or the 5-FU prodrug carmofur. regimen on day 28, n=8). Whole-body CT and CEA were performed before the Chemotherapy regimens. Raltitrexed at 3.0 mg/m2 was given as a chemotherapy treatment cycle and repeated after 8 to 12 weeks. CT 15- to 30-min infusion three times weekly. When given in response was coded according to WHO criteria (Figure 1) (19). In combination with carmofur, raltitrexed at 1.5 to 3.0 mg/m2 was this study, CT response served as the gold standard for evaluation administered on cycle day 1 and carmofur at 300 to 400 mg/m2 of treatment response. Tumour marker progression was defined as orally was divided into three daily doses on cycle days 2-14, a 20% or greater increase in CEA level. CEA values were missing followed by a week of rest (18). The Mayo regimen was for two patients on day 0 (n=58), for four on day 7 (n=56), five on administered as bolus injections of leucovorin at 20 mg/m2 and at 5- day 14 (n=55), one on day 21 (n=59), and for six on both pre- and FU 425 mg/m2 on days 1 to 5 of the cycle, repeated every four post-therapy (n=54). weeks. The simplified De Gramont regimen was given every two Statistical analysis. All analyses were performed by the StatView weeks with leucovorin at 400 mg/m2 as a 2-h infusion, followed by software, version 5.0.1 (SAS Institute, Abacus Concepts Inc., 5-FU at 400 mg/m2 given as a bolus, followed by a continuous Berkeley, CA, USA) or SPSS (PASW statistics version 18.0 Inc.; infusion of 5-FU at 3.6 g/m2 for 48 h using a portable pump. Single- Chicago, IL, USA). Descriptive data are given as the median (range) 254 Hermunen et al: CEA Fluctuation During 5-Fluorouracil Chemotherapy Table I. Patients’ characteristics by chemotherapy regimen. All patients Raltitrexed + carmofur Raltitrexed 5-FU-based (n=60) (n=20) (n=20) (n=20) Median age, years (range) 62 62 62 62 (40-77) (48-73) (40-77) (45-77) Gender Male 32 (53%) 9 (45%) 12 (60%) 11 (55%) Female 28 (47%) 11 (55%) 8 (40%) 9 (45%) Primary tumour Colon 29 (48%) 5 (25%) 11 (55%) 13 (65%) Rectum 31 (52%) 15 (75%) 9 (45%) 7 (35%) Metastatic sites Liver 45 (75%) 16 (80%) 14 (70%) 15 (75%) Lung 34 (57%) 16 (80%) 11 (55%) 7 (35%) Other 24 (40%) 8 (40%) 6 (30%) 10 (50%) Performance status WHO 0 7 (12%) 2 (10%) 0 (0%) 5 (25%) 1 41 (68%) 15 (75%) 12 (60%) 14 (70%) 2 12 (20%) 3 (15%) 8 (40%) 1 (5%) Treatment response PR 22 (37%) 11 (55%) 6 (30%) 5 (25%) SD 18 (30%) 2 (10%) 7 (35%) 9 (45%) PD 20 (33%) 7 (35%) 7 (35%) 6 (30%) for skewed distributions. CEA alteration was calculated as the Chemotherapy regimens. The CEA levels categorized by difference (Δ) between days 21 and 0, as well as between post- chemotherapy regimen are presented in Table II. No therapy and pre-therapy values. The χ-squared test served for significant CEA difference was apparent between analysis of categoric data. The Wilcoxon signed-rank test served for chemotherapy regimens. The five largest fluctuation quotients paired comparisons and the Mann Whitney U-test or the Kruskall Wallis test for non-paired comparisons. Non-parametric correlation of the CEA levels during one chemotherapy cycle according to chemotherapy regimens are presented in Figure 2A. was calculated with Spearman’s rho (Rs). A p-value less than 0.05 was regarded as statistically significant.