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. Early or late timing of the evaluation cycle. Dividing the Results evaluation cycles into two groups, early within CEA surge period (chemotherapy cycles 1 to 2, n=38) and later (cycles Patients’ characteristics. Patients’ characteristics were 3 to 15, n=22), showed no significant difference in the generally well-balanced (Table I). Regarding the location of wavelike pattern (Table II). the primary tumour, there was a higher frequency of patients with rectal cancer in the group treated with raltitrexed and CEA in relation to treatment efficacy. Median CEA levels were carmofur. A slight imbalance with more patients with WHO nearly four-fold higher in patients with progressive disease performance status 2 was noted in the group treated with (PD) on CT than in patients with stable disease (SD) or partial single-agent raltitrexed. response (PR) (Table II). The wavelike pattern was not as evident in the PD group. When the CEA level before and at the CEA fluctuation during one chemotherapy cycle. Weekly CEA end of the cycle was compared according to treatment measurements often showed a wavelike variation, with lower response, a correlation was found for the PD group (p=0.024), values at day 7 and increased values at day 14, when compared but no correlation was apparent for the PR (p=0.72) and the with CEA on baseline day 0 or at day 21 (Table II). We found SD groups (p=0.72). Comparing the CEA level on day 0 with the CEA level to be significantly higher at day 21 than at day day 7 in the three response groups, the differences were not 0 (p=0.037), whereas the differences for the other comparisons significant, nor were they significant between day 0 and day were non-significant (CEA day 0 to day 7 p=0.36, CEA day 0 14. Figure 2B shows data for five patients from each treatment to 14 p=0.59). At cycle day 0, 84% of patients had an elevated response group, with the largest quotient between the highest CEA level (median 60 μg/l, range 5.2-2960 μg/l). and the lowest CEA values during the chemotherapy cycle.
255 ANTICANCER RESEARCH 33: 253-260 (2013)
Table II. Median (range) CEA values in μg/l during one chemotherapy cycle by chemotherapy regimen, timing of evaluation cycle, and chemotherapy response.
CEA (μg/l)
Pretherapy Day 0 Day 7 Day14 Day 21 Posttherapy
All n=60 35.2 (1.3-3320) 38.8 (1.3-2960) 34.4 (1.4-3070) 54.3 (1.4-3670) 50.0 (1.5-3760) 39.6 (1.8-6170) Chemotherapy regimen Raltitrexed + carmofur n=20 96.0 (1.3-3320) 73.4 (2.1-1320) 59.7 (2.6-1150) 92.9 (1.9-1880) 129.7 (2.7-710) 76.2 (2.7-3710) Raltitrexed n=20 167 (5.7-2960) 139.8 (5.7-2960) 59.0 (5.6-3070) 110.0 (5.7-3670) 96.5 (4.7-3760) 50.7 (2.8-6170) 5-FU n=20 9.3 (1.6-1840) 8.2 (1.3-1840) 7.2 (1.4-2140) 18.9 (1.4-2310) 9.1 (1.5-3150) 9.3 (1.8-4040) Evaluation cycle Cycle 1-2 n=38 29.2 (1.6-2960) 31.3 (1.3-2960) 33.0 (1.4-3070) 41.9 (1.4-3670) 39.5 (1.5-3760) 34.2 (1.8-6170) Cycle 3-15 n=22 71 (1.3-3320) 76.5 (2.1-1840) 46.2 (2.6-2140) 124 (2.8-2310) 137.5 (3.2-3710) 50.2 (3.2-4040) Radiological therapy response PD n=20 77.0 (6.3-1840) 55.4 (6.3-1840) 56.6 (4.1-2140) 119 (6.4-2310) 148.2 (7.1-3710) 190 (9.1-4040) SD n=18 17.5 (1.6-1080) 12.8 (1.3-1080) 15.0 (1.4-785) 23.1 (1.4-852) 17.8 (1.5-1010) 17.8 (1.8-2320) PR n=22 26.4 (1.3-3320) 10.6 (1.5-2960) 9.4 (1.5-3070) 18.8 (1.6-3670) 18.5 (1.8-3760) 11.4 (2.4-6170) Non-PD (PR/SD) n=40 24.8 (1.3-3320) 10.6 (1.3-2960) 10.9 (1.4-3070) 21.15 (1.4-3670) 17.8 (1.5-3760) 11.8 (1.8-6170)
In 19 patients with a true PD response on CT evaluation, performance status, primary location, sex, chemotherapy 10 had a more than 20% increase in CEA levels from regimen, early or later evaluation cycle and number of baseline to the end of the cycle. Thus, sensitivity for CEA metastatic sites were not explanatory. Patients with liver was 53%. In 39 patients with disease control (PR or SD) on metastases more often had a radiologically PD and at least a CT evaluation, 28 did not have a more than 20% increase in 20% CEA increase from baseline to the end of the cycle. the CEA level from before the cycle to the end of the cycle. Thus, specificity for CEA was 72%. Correlation between CEA and liver function tests and inflammatory parameters. Liver function tests had a similar Correlation of long-term CEA values with the one-cycle CEA wavelike pattern to that of CEA, with a decrease at day 7 and value. Long-term CEA values were available for 54 patients an increase at day 14 and normalization at the end of the in conjunction with CT evaluation, performed at 8- to 12-week cycle. Median and 95% confidence intervals (CI 95%) for intervals (Table II). The median pre-therapy CEA was CEA and liver function tests are presented in Figure 3A. 35.2 μg/l and that post-therapy CEA was 39.6 μg/l (p=0.079). Pairwise day 0 to day 21 comparisons show no significant CEA increased significantly in patients with PD response correlations between CEA and liver function test (Rs=0.046- (77.0 μg/l vs. 190.0 μg/l; p=0.004), but was stable in SD 0.225). No liver function tests predicted radiological (17.5 μg/l vs. 17.8 μg/l; p=0.21) and decreased non- response. significantly in PR (26.4 μg/l vs. 11.4 μg/l; p=0.20). In 17 Inflammatory parameters showed a wave-like pattern patients with a true PD response on CT evaluation, 14 had a different from that of CEA, with an increase at day 7 and a more than 20% increase in long-term CEA levels. Thus, decrease at day 14 (Figure 3B). Pairwise day 0 to day 21 sensitivity for CEA was 82%. In 37 patients with disease comparisons show a weak but statistically significant control (PR or SD) on CT evaluation, 23 did not have a more correlation between CEA and CRP (Rs=0.276, p=0.034), but than 20% increase in long-term CEA level. Thus, specificity no other significant correlations were found (Rs-0.051-0.074). for CEA was 62%. No inflammatory parameters predicted treatment response. Correlation of single-cycle CEA alteration (Δ CEA day 21 to 0) with long-term CEA alteration (Δ CEA post-therapy Discussion and pre-therapy at 8- to 12-week intervals) was highly significant for patients with PD (median Δ was 19.5 μg/l vs. Two successive elevated CEA values, at least two months 83 μg/l, R=0.804; p<0.001), significant for SD (0.2 μg/l vs. apart may be indicative of tumour progression, but radiology 0.6μg/l, R=0.677; p=0.006), and non-significant for PR (0.3 remains the gold standard for determining tumour status/ μg/l vs. –1.6 μg/l, R=0.402; p=0.063). response. When response evaluation with CEA measurement Explanatory factors. Table III shows explanatory factors for is planned every 8 to 12 weeks, very little is known about treatment response in the radiological response evaluation the optimal timing of CEA measurement during the actual 3- and a CEA increase of at least 20%. Baseline WHO to 4-week chemotherapy administration cycle.
256 Hermunen et al: CEA Fluctuation During 5-Fluorouracil Chemotherapy
Figure 2. The greatest percentual CEA fluctuation quotients with three different chemotherapy regimens (panel A) and the three response categories (panel B).
In most tumour marker studies, the measurements have been weeks (range=2-10 weeks) from the start of chemotherapy (16). repeated at 4- to 15-week intervals, showing decent correlation A CEA surge with initial tumour marker elevation has been with chemotherapy response (14). The study with the most evidenced for both metastatic CRC and other tumour types, frequent CEA measurement, every 14 days, was performed by namely non-seminomatous germ cell tumours (18), and in Sorbye and Dahl but only for the first two months of prostate and breast cancer with bone metastasis (20, 21). chemotherapy, with oxaliplatin combined with bolus 5-FU In our study, the wavelike pattern of the CEA alteration during (n=27) (15). Sorbye found a transient CEA increase in four one cycle was similarly independent of whether the assessment patients (15%) and the time from start of chemotherapy to the was carried out during early treatment cycles (within the CEA CEA peak ranged from two to eight weeks. In another study, surge period of six weeks from chemotherapy initiation) or 10 out of 89 patients with metastatic CRC (nine with oxaliplatin during later cycles (6-45 weeks). The initial surge phenomenon, and 5-FU), had a CEA surge, with the median peak at four thus, does not explain the CEA fluctuation pattern.
257 ANTICANCER RESEARCH 33: 253-260 (2013)
Table III. Explanatory factors for radiological response categories (PD or PR/SD on whole-body CT) and CEA response categories (increased CEA ≥20% from day 0 to day 21 or stabile/decreased during the same time period). Patients with liver metastases more often had disease progression when assessed with CT (*p=0.014) or with tumour marker CEA increase (**p=0.042). All other factors were n.s.
Radiological CT response n(%) Tumour marker response n(%)
PR/SD PD Increased ≥20% Stable or decreased
Patients n(%) 40 (67.0) 20 (33.0) 21 (35) 39 (65) WHO PS day 0 0 5 (12.5) 2 (10.0) 3 (14.3) 4 (10.3) 1-2 35 (87.5) 18 (90.0) 18 (85.7) 35 (89.7) Location of primary tumour Colon 19 (47.5) 10 (50.0) 9 (42.9) 20 (51.3) Rectum 21 (52.5) 10 (50.0) 12 (57.1) 19 (48.7) Gender Male 19 (47.5) 13 (65.0) 10 (47.6) 22 (56.4) Female 21 (52.5) 7 (35.0) 11 (52.4) 17 (43.6) Metastatic site Liver 26 (65.0)* 19 (95.0)* 19 (90.5)** 26 (66.7)** Lung 22 (36.7) 12 (60.0) 10 (47.6) 24 (61.6) Other 18 (45.0) 6 (30.0) 11 (52.4) 13 (33.3) No. of mestastatic sites 1 19 (47.5) 6 (30.0) 7 (33.3) 18 (46.2) 2 12 (30.0) 11 (55.0) 7 (33.3) 16 (41.0) 3+ 9 (22.5) 3 (15.0) 7 (33.3) 5 (12.8) Chemotherapy regimen Raltitrexed + carmofur 13 (32.5) 7 (35.0) 6 (28.6) 14 (35.9) Raltitrexed 13 (32.5) 7 (35.0) 8 (38.1) 12 (30.8) 5-FU-based 14 (35.0) 6 (30.0) 7 (33.3) 13 (33.3) Evaluation cycle no. 1 24 (60.0) 8 (40.0) 11 (52.4) 21 (53.9) 2 3 (7.5) 3 (15.0) 1 (4.8) 5 (12.8) 3-15 13 (32.5) 9 (45.0) 9 (42.8) 13 (33.3) Tumour burden Small 8 (20.0) 1 (5.0) 1 (4.8) 8 (20.5) Moderate 21 (52.5) 9 (45.0) 12 (57.1) 18 (46.2) Bulky 11 (27.5) 10 (50.0) 8 (38.1) 13 (33.3)
The evaluation was carried out for patients receiving three to baseline (day 0) correlated with treatment response. The different chemotherapy regimens for metastatic CRC with an 53% sensitivity and 72% specificity were disappointingly anti-metabolite mode of action. Forty patients received 5-FU- low. The CEA at days 7 and 14, however, did not predict based regimens (the Mayo, infusional and oral 5-FU response. Patients with SD and PR could not be assessed prodrug), which are still the cornerstone in CRC reliably within this short evaluation period. A longer time- chemotherapy. The wavelike patterns of variation were frame for CEA assessment with the ASCO recommended 8- similar under all 5-FU regimens, as well as with the to 12-week interval was also performed but showed similar antimetabolite raltitrexed. This phenomenon has not been correlation only in patients with PD, with 82% sensitivity; studied in patients receiving modern combination regimens, specificity was dissappointingly low (62%). but since such regimens are all based on 5-FU, either Baseline-elevated ALP and lactate dehydrogenase (LDH) intravenously or orally, it is probable that a similar CEA are associated with worse prognosis in many studies (22, 23). fluctuation will occur using these combinations. We did not analyze LDH here, but ALP in conjunction with Tumour markers are measured because they are other liver function tests was performed weekly. ALP was considered to reflect chemotherapy efficacy. In this study, the only marker that correlated with CEA in patients with CEA alterations were correlated with response based on PD. No other liver function tests correlated either with radiology, and in the four weekly CEA measurements during treatment response or with CEA alterations. the chemotherapy cycle, only the difference between CEA at Inflammatory parameters, especially CRP, have been the end of each therapy cycle (day 21 or 28), when compared evaluated in response prediction and prognostic evaluation
258 Hermunen et al: CEA Fluctuation During 5-Fluorouracil Chemotherapy
Conclusion
The timing for tumour marker assessment is crucial in evaluation of response to therapy of metastatic CRC. CEA should not be measured during 5-FU-based oral chemotherapy, nor within two weeks of intravenous chemotherapy administration, because significant variation may occur. This variation showed a wavelike pattern in patients with disease control. Significantly increasing values at the end of the cycle were seen in patients whose disease was progressing in both short- (3-week) and in long-term (8- to 12-week) evaluation intervals. CEA alteration was not significant in patients with PR or SD.
Acknowledgements
This work was supported by grants from Finska Läkaresällskapet, The Kurt och Doris Palander Foundation, The Dorothea Olivia, Karl Walter och Jarl Walter Perklén Foundation, The Sigrid Jusélius Foundation and Medicinska understödsföreningen Liv och Hälsa. Special thanks are due to Antti Hermunen for assistance with graphics and to Carol Norris for language editing.
References
1 Jemal A, Bray F, Center M, Ferlay J, Ward E and Foreman D: Global cancer statistics, 2008. CA Cancer J Clin 61: 69-90, 2011. 2 Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF, Bast RC Jr., Asco: ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24: 5313-5327, 2006. 3 Macdonald JS: Carcinoembryonic antigen screening: Pros and cons. Semin Oncol 26: 556-560, 1999. 4 Palmqvist R, Engaras B, Lindmark G, Hallmans G, Tavelin B, Weekly median and CI 95% values for CEA, liver-function Figure 3. Nilsson O, Hammarstrom S and Hafstrom L: Prediagnostic tests (ALP, ALT, GT, BIL) and, inflammatory parameters (CRP, IL-6, IL- levels of carcinoembryonic antigen and CA 242 in colorectal 8, TNFα) during one chemotherapy cycle. cancer: A matched case-control study. Dis Colon Rectum 46: 1538-1544, 2003. 5 Chen CC, Yang SH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS and Chang SC: Is it reasonable to add preoperative serum (24). IL-6 and -8, together with TNF-α, reflect inflammation, level of CEA and CA19-9 to staging for colorectal cancer? J liver damage, and tumour necrosis, but did not correlate with Surg Res 124: 169-174, 2005. treatment response in our limited analysis, nor with 6 Kim JC, Lee KH, Yu CS, Kim HC, Kim JR, Chang HM, Kim alterations in the CEA level. Cytostatic agents, especially JH, Kim JS and Kim TW: The clinicopathological significance drugs that are inflammatory-reaction inducers, such as of inferior mesenteric lymph node metastasis in colorectal cancer. Eur J Surg Oncol 30: 271-279, 2004. bleomycin, raltitrexed, oxaliplatin, and cytarabine, may affect 7 Weissenberger C, Von Plehn G, Otto F, Barke A, Momm F and tumour marker levels. Geissler M: Adjuvant radiochemotherapy of stage II and III CEA is metabolized in the liver and it is well-known that rectal adenocarcinoma: Role of CEA and CA 19-9. Anticancer increased CEA levels may occur in different liver diseases Res 25: 1787-1793, 2005. (25). Since chemotherapy is frequently associated with an 8 Park YJ, Youk EG, Choi HS, Han SU, Park KJ, Lee KU, Choe increase in liver function test levels, one possibility could be KJ and Park JG: Experience of 1446 rectal cancer patients in that a transient increase in CEA level reflects liver damage. korea and analysis of prognostic factors. Int J Colorectal Dis 14: 101-106, 1999. It is also possible that behind the tumour marker fluctuation 9 Park YJ, Park KJ, Park JG, Lee KU, Choe KJ and Kim JP: lay shedding of antigen or tumour necrosis. The reason for Prognostic factors in 2230 korean colorectal cancer patients: tumour marker variation during single-chemotherapy cycle Analysis of consecutively operated cases. World J Surg 23: 721- remains unknown. 726, 1999.
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10 Fong Y, Fortner J, Sun RL, Brennan MF and Blumgart LH: 20 Sonoo H and Kurebayashi J: Serum tumor marker kinetics and Clinical score for predicting recurrence after hepatic resection the clinical course of patients with advanced breast cancer. Surg for metastatic colorectal cancer: Analysis of 1001 consecutive Today 26: 250-257, 1996. cases. Ann Surg 230: 309-318; discussion 318-321, 1999. 21 Loprinzi CL, Tormey DC, Rasmussen P, Falkson G, Davis TE, 11 Nordlinger B, Guiguet M, Vaillant JC, Balladur P, Boudjema K, Falkson HC and Chang AY: Prospective evaluation of Bachellier P and Jaeck D: Surgical resection of colorectal carcinoembryonic antigen levels and alternating chemotherapeutic carcinoma metastases to the liver. A prognostic scoring system to regimens in metastatic breast cancer. J Clin Oncol 4: 46-56, 1986. improve case selection, based on 1568 patients. association 22 Kohne CH, Cunningham D, Di CF, Glimelius B, Blijham G, francaise de chirurgie. Cancer 77: 1254-1262, 1996. Aranda E, Scheithauer W, Rougier P, Palmer M, Wils J, Baron B, 12 Graham RA, Wang S, Catalano PJ and Haller DG: Postsurgical Pignatti F, Schoffski P, Micheel S and Hecker H: Clinical surveillance of colon cancer: Preliminary cost analysis of determinants of survival in patients with 5-fluorouracil-based physician examination, carcinoembryonic antigen testing, chest treatment for metastatic colorectal cancer: Results of a multivariate x-ray, and colonoscopy. Ann Surg 228: 59-63, 1998. analysis of 3825 patients. Ann Oncol 13: 308-317, 2002. 13 Pietra N, Sarli L, Costi R, Ouchemi C, Grattarola M and 23 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Peracchia A: Role of follow-up in management of local Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, recurrences of colorectal cancer: A prospective, randomized Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, study. Dis Colon Rectum 41: 1127-1133, 1998. Wilson C, Morvan F and Bonetti A: Leucovorin and fluorouracil 14 Bast RC Jr., Ravdin P, Hayes DF, Bates S, Fritsche H,Jr, Jessup with or without oxaliplatin as first-line treatment in advanced JM, Kemeny N, Locker GY, Mennel RG, Somerfield MR, colorectal cancer. J Clin Oncol 18: 2938-2947, 2000. American Society of Clinical Oncology Tumor Markers Expert 24 Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Panel: 2000 update of recommendations for the use of tumor Glimelius B, Frodin JE, Masucci G and Kiessling R: A short-term markers in breast and colorectal cancer: Clinical practice dietary supplementation of high doses of vitamin E increases T guidelines of the American Society of Clinical Oncology. J Clin helper 1 cytokine production in patients with advanced colorectal Oncol 19: 1865-1878, 2001. cancer. Clin Cancer Res 8: 1772-1778, 2002. 15 Sorbye H and Dahl O: Transient CEA increase at start of 25 Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder oxaliplatin combination therapy for metastatic colorectal cancer. E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C and Topolcan Acta Oncol 43: 495-498, 2004. O: Tumour markers in colorectal cancer: European Group on 16 Ailawadhi S, Sunga A, Rajput A, Yang GY, Smith J and Fakih M: Tumour Markers (EGTM) guidelines for clinical use. Eur J Chemotherapy-induced carcinoembryonic antigen surge in patients Cancer 43: 1348-1360, 2007. with metastatic colorectal cancer. Oncology 70: 49-53, 2006. 17 Osterlund P, Orpana A, Elomaa I, Repo H and Joensuu H: Raltitrexed treatment promotes systemic inflammatory reaction in patients with colorectal carcinoma. Br J Cancer 87: 591-599, 2002. 18 Horwich A and Peckham MJ: Transient tumor marker elevation following chemotherapy for germ cell tumors of the testis. Cancer Treat Rep 70: 1329-1331, 1986. Received October 15, 2012 19 Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting Revised November 9, 2012 results of cancer treatment. Cancer 47: 207-214, 1981. Accepted November 12, 2012
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