Tumor Biol. DOI 10.1007/s13277-013-1327-5
RESEARCH ARTICLE
Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis Lu Han & Wei Chen & Qicheng Zhao
Received: 9 August 2013 / Accepted: 14 October 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Increasing scientific evidences suggest that circulating tumor cells (CTC) in peripheral blood may be a powerful predictor of survival in patients with pancreatic cancer. However, many existing studies have yielded inconclusive results. This meta-analysis aims to assess the prognostic value of CTC in patients with pancreatic cancer. An extensive literary search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CNKI, and CBM databases from their inception through July 1, 2013. The meta-analysis was then performed using the Stata 12.0 software. Crude hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated under a fixed or random effect model. Nine cohort studies were included in this metaanalysis with a total of 623 pancreatic cancer patients. This number included 268 CTC-positive patients and 355 CTCnegative patients. Our meta-analysis revealed that patients in the CTC-positive group were significantly associated with poor progression-free survival (PFS) (HR=1.89, 95 % CI= 1.25–4.00, P 0.05).
Discussion Evaluation of heterogeneity and publication bias Since CTC were first identified in peripheral blood, the detection of circulating tumor cells in patients with malignant tumors have become hot topics for biomedical researchers
Sensitivity analysis was performed to assess the influence of each individual study on the pooled HRs by omitting each Fig. 4 Subgroup analysis by ethnicity for the difference in OS between CTCs-positive and CTCs-negative pancreatic cancer patients
Overall Survival
Included studies
HR (95% CI)
Weight %
Asian populations Hu L 2013
7.69 (0.31, 10.00)
3.46
Hirooka S 2011
1.75 (1.11, 2.78)
26.64
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Uchikura K 2002
1.19 (0.40, 3.57)
6.69
1.79 (0.23, 3.23)
45.22
Bidard FC 2013
2.00 (0.72, 5.56)
15.18
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Z test (Z = 4.06, P < 0.001)
1.04 (0.53, 1.55)
54.78
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.39, P < 0.001) Caucasian populations
NOTE: Random effects model −12.00
0
12.00
Tumor Biol. Fig. 5 Subgroup analysis by detection method for the difference in OS between CTCspositive and CTCs-negative pancreatic cancer patients
Overall Survival
Included studies
HR (95% CI)
Weight %
RT-PCR Hu L 2013
7.69 (0.31, 10.00)
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Uchikura K 2002
1.19 (0.40, 3.57)
6.69
1.23 (0.69, 1.77)
34.02
Bidard FC 2013
2.00 (0.72, 5.56)
15.18
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Hirooka S 2011
1.75 (1.11, 2.78)
26.64
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Z test (Z = 5.20, P < 0.001)
1.69 (1.23, 2.70)
65.98
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.50, P < 0.001)
3.46
CellSearch
NOTE: Random effects model −12.00
12.00
This is the first meta-analysis evaluating the prognostic value of CTC in patients with pancreatic cancer. In this meta-analysis, nine independent cohort studies were included with a total of 268 CTC-positive patients and 355 CTCnegative patients. When all the eligible studies were pooled into the meta-analysis, the results showed that pancreatic patients in the CTC-positive group showed worser PFS and OS than those in the CTC-negative group, indicating that the prognosis of patients with pancreatic cancer was associated with the presence of CTC. Our findings were entirely consistent with previous studies which have suggested that CTC-positive patients had significantly shorter survival time than CTC-negative patients [6, 9–11, 18–20]. De
[21]. Previous studies have demonstrated that the detection of CTC has prognostic significance in lung, breast, colorectal, and prostate carcinomas [22–26]. CTC may have several valuable roles in monitoring tumor recurrence and predicting response to treatment and prognosis of patients with malignant tumors [27]. However, there are only a limited number of studies focused on the prognostic roles of CTC in pancreatic cancer. Some of these studies found the detection of CTC in patients with pancreatic cancer, but the results were still controversial [9, 11–13]. This discrepancy may result from the rather small sample size of patients included in these studies, as well as differences in detection and treatment methods.
Fig. 6 Subgroup analysis by treatment method for the difference in OS between CTCspositive and CTCs-negative pancreatic cancer patients
0
Overall Survival
Included studies
HR (95% CI)
Weight %
Surgery Hu L 2013
7.69 (0.31, 10.00)
3.46
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Uchikura K 2002
1.19 (0.28, 2.50)
6.69
1.11 (0.57, 1.65)
28.12
2.00 (0.72, 5.56)
15.18
1.75 (1.11, 2.78)
26.64
1.79 (1.25, 3.23)
41.82
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Z test (Z = 2.53, P = 0.011)
1.04 (0.59, 4.76)
30.05
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.02, P < 0.001) GEM−based chemotherapy Bidard FC 2013 Hirooka S 2011 Z test (Z = 4.44, P < 0.001) Surgery + GEM−based chemotherapy
NOTE: Random effects model −3.27
0
3.27
Tumor Biol.
Progression-free survival
Overall survival Hu L 2013
Khoja L 2012
Bidard FC 2013 Khoja L 2012 Sergeant G 2011 De Albuquerque AI 2012 Hirooka S 2011 Kurihara T 2008 Soeth E 2005 Uchikura K 2002 0.46
Sergeant G 2011 0.51
0.65
0.82
0.89
0.19
0.38
0.59
0.91
1.14
Fig. 7 Sensitivity analysis for the pooled HRs for the difference in OS and PFS between CTCs-positive and CTCs-negative pancreatic cancer patients
Albuquerque et al. have reported that the detection of CTC in peripheral blood was associated with decreased PFS and OS of pancreatic cancer patients [10]. Soeth et al. also showed a statistically significant relationship between CTC expression and the prognosis of pancreatic cancer patients [12]. Nevertheless, there is no consensus on the optimal cutoff of CTC for predicting the clinical outcome of pancreatic cancer. Bidard et al. have reported a CTC detection rate of 11 % (4.1~ 17.9 %) using the low cutoff of ≥1 CTC/7.5 ml of blood with the CellSearch system [9]. Khoja et al. also indicated that pancreatic cancer patients with CTC ≥1/7.5 ml blood, measured by CellSearch, had poorer clinical outcome than those without detectable CTC [6]. Maestro et al. have demonstrated that ≥2 CTC/7.5 ml might be a good prognostic biomarker for patients with solid tumors [28]. Therefore, additional clinical studies are still needed to establish the best cutoff point of CTC for predicting development and prognosis of pancreatic cancer. Begg’s funnel plot (Egger’s test: t = -0.97, P = 0.361)
2
ln[HR]
1
0
−1
−2 0
0.5
1.0
SE(ln[HR])
Fig. 8 Begg's funnel plots of the prognostic role of CTCs in patients with pancreatic cancer. Each point represents a separate study for the indicated association. Log[HR] natural logarithm of HR; horizontal line mean magnitude of the effect. Note: A funnel plot with pseudo 95 % confidence limits was used
In the current study, we also performed subgroup analyses based on ethnicity, detection methods, and treatment methods to further evaluate the prognostic value of CTC for pancreatic cancer. Subgroup analysis by ethnicity suggested that CTCpositive patients had a poor OS among both Asian and Caucasian populations. Further subgroup analyses by detection and treatment methods also suggested that CTC-positive patients showed worser OS than CTC-negative patients in the majority of subgroups. As publication bias is a major problem for literature reviews [29], we performed Begg's funnel plots and Egger's linear regression test to evaluate the potential for publication bias. However, no publication bias existed in this meta-analysis, indicating our statistically robust results. In interpreting our results of the current meta-analysis, some limitations need to be addressed. The first major limitation is the relatively small sample size of this metaanalysis, which may not have sufficient statistical power in estimating the prognostic role of CTC in pancreatic cancer. Therefore, more studies with larger sample sizes are still needed. In addition, as a type of a retrospective study that focuses on the summary of data from previously published studies, our meta-analysis may encounter recall or selection bias, thereby possibly influencing the reliability of the results. Most importantly, the lack of access to all data from the original studies limits further evaluations of the potential values of CTC expression. However, despite these statistical limitations, our study is the first comprehensive meta-analysis of all eligible studies concerning the prognostic role of CTC in patients with pancreatic cancer. In conclusion, our meta-analysis indicates that CTCpositive pancreatic cancer patients may have worser PFS and OS than CTC-negative patients. Detection of CTC in peripheral blood may be a promising biomarker for the detection and prognosis of pancreatic cancer. However, due to the limitations mentioned above, further detailed studies are still required to confirm these findings.
Tumor Biol. Acknowledgments This research is funded by Science and Technology Commission of Shanghai Municipality (No. 134119a6800). Conflicts of interest None.
References 1. Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an update. Dig Dis. 2010;28:645–56. 2. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6:699–708. 3. Li D, Abbruzzese JL. New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts. Clin Cancer Res. 2010;16: 4313–8. 4. Lucas AL, Chang MM, Lipsyc MD, Frucht H. The prevention and genetics of pancreatic cancer: a programmatic approach. Methods Mol Biol. 2013;980:205–14. 5. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16: 398–406. 6. Khoja L, Backen A, Sloane R, Menasce L, Ryder D, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106:508–16. 7. Coghlin C, Murray GI. Current and emerging concepts in tumour metastasis. J Pathol. 2010;222:1–15. 8. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84. 9. Bidard FC, Huguet F, Louvet C, Mineur L, Bouche O, et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 2013;24:2057–61. 10. de Albuquerque A, Kubisch I, Breier G, Stamminger G, Fersis N, et al. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology. 2012;82:3–10. 11. Hu L, Zhou JH, Yu ZQ, Yi YX, Ding H, et al. [Clinical significance of h-TERT and c-Met expression in the peripheral blood circulation of pancreatic cancer patients]. Chinese J Clin Oncol. 2013;40:208– 11. 12. Soeth E, Grigoleit U, Moellmann B, Roder C, Schniewind B, et al. Detection of tumor cell dissemination in pancreatic ductal carcinoma patients by CK 20 RT-PCR indicates poor survival. J Cancer Res Clin Oncol. 2005;131:669–76. 13. Uchikura K, Takao S, Nakajo A, Miyazono F, Nakashima S, et al. Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis. Ann Surg Oncol. 2002;9:364–70.
14. Stang A. Critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5. 15. Jackson D, White IR, Riley RD. Quantifying the impact of betweenstudy heterogeneity in multivariate meta-analyses. Stat Med. 2012;31:3805–20. 16. Biggerstaff BJ, Jackson D. The exact distribution of Cochran's heterogeneity statistic in one-way random effects meta-analysis. S Stat Med. 2008;27:6093–110. 17. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in metaanalysis. JAMA. 2006;295:676–80. 18. Hirooka S, Yanagimoto H, Satoi S, Yamamoto T, Toyokawa H, et al. The role of circulating dendritic cells in patients with unresectable pancreatic cancer. Anticancer Res. 2011;31:3827–34. 19. Kurihara T, Itoi T, Sofuni A, Itokawa F, Tsuchiya T, et al. Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result. J Hepatobiliary Pancreat Surg. 2008;15:189–95. 20. Sergeant G, Roskams T, van Pelt J, Houtmeyers F, Aerts R, et al. Perioperative cancer cell dissemination detected with a real-time RTPCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma. BMC Cancer. 2011;11:47. 21. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the Cell Search system. Clin Cancer Res. 2007;13:920–8. 22. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91. 23. Hou JM, Greystoke A, Lancashire L, Cummings J, Ward T, et al. Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy. Am J Pathol. 2009;175:808–16. 24. Sequist LV, Nagrath S, Toner M, Haber DA, Lynch TJ. The CTCchip: an exciting new tool to detect circulating tumor cells in lung cancer patients. J Thorac Oncol. 2009;4:281–3. 25. Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med. 2010;2:25ra23. 26. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20:1223–9. 27. Nakamura S, Yagata H, Ohno S, Yamaguchi H, Iwata H, et al. Multicenter study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer. 2010;17:199–204. 28. Maestro LM, Sastre J, Rafael SB, Veganzones SB, Vidaurreta M, et al. Circulating tumor cells in solid tumor in metastatic and localized stages. Anticancer Res. 2009;29:4839–43. 29. McGauran N, Wieseler B, Kreis J, Schuler YB, Kolsch H, et al. Reporting bias in medical research - a narrative review. Trials. 2010;11:37.
RESEARCH ARTICLE
Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis Lu Han & Wei Chen & Qicheng Zhao
Received: 9 August 2013 / Accepted: 14 October 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Increasing scientific evidences suggest that circulating tumor cells (CTC) in peripheral blood may be a powerful predictor of survival in patients with pancreatic cancer. However, many existing studies have yielded inconclusive results. This meta-analysis aims to assess the prognostic value of CTC in patients with pancreatic cancer. An extensive literary search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CNKI, and CBM databases from their inception through July 1, 2013. The meta-analysis was then performed using the Stata 12.0 software. Crude hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated under a fixed or random effect model. Nine cohort studies were included in this metaanalysis with a total of 623 pancreatic cancer patients. This number included 268 CTC-positive patients and 355 CTCnegative patients. Our meta-analysis revealed that patients in the CTC-positive group were significantly associated with poor progression-free survival (PFS) (HR=1.89, 95 % CI= 1.25–4.00, P 0.05).
Discussion Evaluation of heterogeneity and publication bias Since CTC were first identified in peripheral blood, the detection of circulating tumor cells in patients with malignant tumors have become hot topics for biomedical researchers
Sensitivity analysis was performed to assess the influence of each individual study on the pooled HRs by omitting each Fig. 4 Subgroup analysis by ethnicity for the difference in OS between CTCs-positive and CTCs-negative pancreatic cancer patients
Overall Survival
Included studies
HR (95% CI)
Weight %
Asian populations Hu L 2013
7.69 (0.31, 10.00)
3.46
Hirooka S 2011
1.75 (1.11, 2.78)
26.64
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Uchikura K 2002
1.19 (0.40, 3.57)
6.69
1.79 (0.23, 3.23)
45.22
Bidard FC 2013
2.00 (0.72, 5.56)
15.18
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Z test (Z = 4.06, P < 0.001)
1.04 (0.53, 1.55)
54.78
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.39, P < 0.001) Caucasian populations
NOTE: Random effects model −12.00
0
12.00
Tumor Biol. Fig. 5 Subgroup analysis by detection method for the difference in OS between CTCspositive and CTCs-negative pancreatic cancer patients
Overall Survival
Included studies
HR (95% CI)
Weight %
RT-PCR Hu L 2013
7.69 (0.31, 10.00)
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Uchikura K 2002
1.19 (0.40, 3.57)
6.69
1.23 (0.69, 1.77)
34.02
Bidard FC 2013
2.00 (0.72, 5.56)
15.18
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Hirooka S 2011
1.75 (1.11, 2.78)
26.64
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Z test (Z = 5.20, P < 0.001)
1.69 (1.23, 2.70)
65.98
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.50, P < 0.001)
3.46
CellSearch
NOTE: Random effects model −12.00
12.00
This is the first meta-analysis evaluating the prognostic value of CTC in patients with pancreatic cancer. In this meta-analysis, nine independent cohort studies were included with a total of 268 CTC-positive patients and 355 CTCnegative patients. When all the eligible studies were pooled into the meta-analysis, the results showed that pancreatic patients in the CTC-positive group showed worser PFS and OS than those in the CTC-negative group, indicating that the prognosis of patients with pancreatic cancer was associated with the presence of CTC. Our findings were entirely consistent with previous studies which have suggested that CTC-positive patients had significantly shorter survival time than CTC-negative patients [6, 9–11, 18–20]. De
[21]. Previous studies have demonstrated that the detection of CTC has prognostic significance in lung, breast, colorectal, and prostate carcinomas [22–26]. CTC may have several valuable roles in monitoring tumor recurrence and predicting response to treatment and prognosis of patients with malignant tumors [27]. However, there are only a limited number of studies focused on the prognostic roles of CTC in pancreatic cancer. Some of these studies found the detection of CTC in patients with pancreatic cancer, but the results were still controversial [9, 11–13]. This discrepancy may result from the rather small sample size of patients included in these studies, as well as differences in detection and treatment methods.
Fig. 6 Subgroup analysis by treatment method for the difference in OS between CTCspositive and CTCs-negative pancreatic cancer patients
0
Overall Survival
Included studies
HR (95% CI)
Weight %
Surgery Hu L 2013
7.69 (0.31, 10.00)
3.46
Soeth E 2005
1.34 (0.92, 1.94)
17.98
Uchikura K 2002
1.19 (0.28, 2.50)
6.69
1.11 (0.57, 1.65)
28.12
2.00 (0.72, 5.56)
15.18
1.75 (1.11, 2.78)
26.64
1.79 (1.25, 3.23)
41.82
Khoja L 2012
1.22 (0.63, 2.38)
15.73
Sergeant G 2011
1.96 (0.24, 2.64)
5.89
Kurihara T 2008
2.63 (0.51, 14.29)
8.43
Z test (Z = 2.53, P = 0.011)
1.04 (0.59, 4.76)
30.05
Heterogeneity test (I2 = 44.4%, P = 0.082)
1.23 (0.88, 2.08)
100.00
Z test (Z = 4.02, P < 0.001) GEM−based chemotherapy Bidard FC 2013 Hirooka S 2011 Z test (Z = 4.44, P < 0.001) Surgery + GEM−based chemotherapy
NOTE: Random effects model −3.27
0
3.27
Tumor Biol.
Progression-free survival
Overall survival Hu L 2013
Khoja L 2012
Bidard FC 2013 Khoja L 2012 Sergeant G 2011 De Albuquerque AI 2012 Hirooka S 2011 Kurihara T 2008 Soeth E 2005 Uchikura K 2002 0.46
Sergeant G 2011 0.51
0.65
0.82
0.89
0.19
0.38
0.59
0.91
1.14
Fig. 7 Sensitivity analysis for the pooled HRs for the difference in OS and PFS between CTCs-positive and CTCs-negative pancreatic cancer patients
Albuquerque et al. have reported that the detection of CTC in peripheral blood was associated with decreased PFS and OS of pancreatic cancer patients [10]. Soeth et al. also showed a statistically significant relationship between CTC expression and the prognosis of pancreatic cancer patients [12]. Nevertheless, there is no consensus on the optimal cutoff of CTC for predicting the clinical outcome of pancreatic cancer. Bidard et al. have reported a CTC detection rate of 11 % (4.1~ 17.9 %) using the low cutoff of ≥1 CTC/7.5 ml of blood with the CellSearch system [9]. Khoja et al. also indicated that pancreatic cancer patients with CTC ≥1/7.5 ml blood, measured by CellSearch, had poorer clinical outcome than those without detectable CTC [6]. Maestro et al. have demonstrated that ≥2 CTC/7.5 ml might be a good prognostic biomarker for patients with solid tumors [28]. Therefore, additional clinical studies are still needed to establish the best cutoff point of CTC for predicting development and prognosis of pancreatic cancer. Begg’s funnel plot (Egger’s test: t = -0.97, P = 0.361)
2
ln[HR]
1
0
−1
−2 0
0.5
1.0
SE(ln[HR])
Fig. 8 Begg's funnel plots of the prognostic role of CTCs in patients with pancreatic cancer. Each point represents a separate study for the indicated association. Log[HR] natural logarithm of HR; horizontal line mean magnitude of the effect. Note: A funnel plot with pseudo 95 % confidence limits was used
In the current study, we also performed subgroup analyses based on ethnicity, detection methods, and treatment methods to further evaluate the prognostic value of CTC for pancreatic cancer. Subgroup analysis by ethnicity suggested that CTCpositive patients had a poor OS among both Asian and Caucasian populations. Further subgroup analyses by detection and treatment methods also suggested that CTC-positive patients showed worser OS than CTC-negative patients in the majority of subgroups. As publication bias is a major problem for literature reviews [29], we performed Begg's funnel plots and Egger's linear regression test to evaluate the potential for publication bias. However, no publication bias existed in this meta-analysis, indicating our statistically robust results. In interpreting our results of the current meta-analysis, some limitations need to be addressed. The first major limitation is the relatively small sample size of this metaanalysis, which may not have sufficient statistical power in estimating the prognostic role of CTC in pancreatic cancer. Therefore, more studies with larger sample sizes are still needed. In addition, as a type of a retrospective study that focuses on the summary of data from previously published studies, our meta-analysis may encounter recall or selection bias, thereby possibly influencing the reliability of the results. Most importantly, the lack of access to all data from the original studies limits further evaluations of the potential values of CTC expression. However, despite these statistical limitations, our study is the first comprehensive meta-analysis of all eligible studies concerning the prognostic role of CTC in patients with pancreatic cancer. In conclusion, our meta-analysis indicates that CTCpositive pancreatic cancer patients may have worser PFS and OS than CTC-negative patients. Detection of CTC in peripheral blood may be a promising biomarker for the detection and prognosis of pancreatic cancer. However, due to the limitations mentioned above, further detailed studies are still required to confirm these findings.
Tumor Biol. Acknowledgments This research is funded by Science and Technology Commission of Shanghai Municipality (No. 134119a6800). Conflicts of interest None.
References 1. Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an update. Dig Dis. 2010;28:645–56. 2. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6:699–708. 3. Li D, Abbruzzese JL. New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts. Clin Cancer Res. 2010;16: 4313–8. 4. Lucas AL, Chang MM, Lipsyc MD, Frucht H. The prevention and genetics of pancreatic cancer: a programmatic approach. Methods Mol Biol. 2013;980:205–14. 5. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16: 398–406. 6. Khoja L, Backen A, Sloane R, Menasce L, Ryder D, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106:508–16. 7. Coghlin C, Murray GI. Current and emerging concepts in tumour metastasis. J Pathol. 2010;222:1–15. 8. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84. 9. Bidard FC, Huguet F, Louvet C, Mineur L, Bouche O, et al. Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. Ann Oncol. 2013;24:2057–61. 10. de Albuquerque A, Kubisch I, Breier G, Stamminger G, Fersis N, et al. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology. 2012;82:3–10. 11. Hu L, Zhou JH, Yu ZQ, Yi YX, Ding H, et al. [Clinical significance of h-TERT and c-Met expression in the peripheral blood circulation of pancreatic cancer patients]. Chinese J Clin Oncol. 2013;40:208– 11. 12. Soeth E, Grigoleit U, Moellmann B, Roder C, Schniewind B, et al. Detection of tumor cell dissemination in pancreatic ductal carcinoma patients by CK 20 RT-PCR indicates poor survival. J Cancer Res Clin Oncol. 2005;131:669–76. 13. Uchikura K, Takao S, Nakajo A, Miyazono F, Nakashima S, et al. Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis. Ann Surg Oncol. 2002;9:364–70.
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