MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos 10.3892/mco.2013.116 mco-01-04-0582 Review Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies AKAGIYOSHITO KINUGASATETSUSHI ADACHIYOSUKE SHIROUZUKAZUO Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan Correspondence to: Dr Yoshito Akagi, Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan, E-mail: yoshisg@med.kurume-u.ac.jp 07 2013 09 05 2013 1 4 582 592 01 11 2012 18 04 2013 Copyright © 2013, Spandidos Publications 2013 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

Circulating tumor cells (CTCs) that detach from the primary tumor and move into the circulation are detected in patients with metastatic cancer. The discovery of such cancer cells has been used as a predictor of recurrence and prognosis, although a consensus regarding such applications has not been reached. Peritoneal cytology may be used for identifying high risk of recurrence or mortality, whereas the intraoperative presence of tumor cells in drainage veins, bone marrow, or the liver is not always useful for evaluating the prognosis. The reported positive rate for tumor cells in the peripheral blood of patients with colorectal cancer, including metastasis, has varied from 10 to 80%; however, numerous studies have demonstrated significant differences in the recurrence and mortality rates between patients with and without isolated tumor cells (ITCs) in the peripheral blood. However, the clinical significance of CTCs as an absolute prognostic factor has not been elucidated, since the measurement methodologies and/or the number of cases differed between the studies. Future prospective studies including larger patient populations may elucidate the utility of routine detection of ITCs in daily practice.

 colorectal cancer isolated tumor cells circulating tumor cells disseminated tumor cells prognosis Contents

Introduction

Tumor cells in lymph nodes

Tumor cells in the peritoneal cavity

Tumor cells in the peripheral blood

Tumor cells in drainage veins

Tumor cells in the bone marrow

Isolated tumor cells in stage IV patients

Conclusion

 Introduction

Biomarkers predictive of the prognosis of colorectal cancer have been investigated using various materials and methods. With advances in immunohistochemistry (IHC) and molecular biology, occult tumor cells, including micrometastases in lymph nodes and circulating tumor cells (CTCs) in the peripheral blood, have been detected in patients with gastrointestinal and breast cancers (1–5). By applying highly sensitive and specific diagnostic techniques, several prospective studies suggested that the presence of isolated tumor cells (ITCs) in peripheral areas, drainage veins and the bone marrow is associated with poor outcomes in colorectal cancer patients (6–9). ITCs are single tumor cells or small clusters of cells, ≤0.2 mm in greatest dimension, detectable by routine hematoxylin and eosin staining or IHC. Several reviews and meta-analyses evaluated clinical studies on ITCs in lymph nodes, peripheral blood, bone marrow and liver and suggested the prognostic significance of such cells in colorectal cancer patients (10–15).

To elucidate the findings of previous clinical studies assessing the prognostic value of disseminated tumor cells (DTCs) in patients with colorectal cancer, we investigated English literature over the past 10 years, using computer searches of PubMed with the following key words: ‘colorectal cancer’, ‘micrometastasis’, ‘occult metastasis’, ‘circulating tumor cell’, ‘disseminated tumor cell’, ‘isolated tumor cell’, ‘lymph node’, ‘peritoneal cavity’, ‘peripheral blood’, ‘drainage vein’, ‘bone marrow’, ‘liver’, ‘prognosis’, and ‘survival’. After reading all the abstracts and reviewing the available studies, a total of 87 studies were collected and included in this review.

 Tumor cells in lymph nodes

Between January, 2002 and March, 2012, a total of 31 studies assessed the prognostic value of tumor cells in histologically negative lymph nodes of patients with colorectal cancer (Table I) (16–46). The studies investigated a total of 4,080 patients with colorectal (n=20), colon (n=7) and rectal (n=4) cancer, with a median cohort size of 105 patients. The majority of the studies detected tumor cells using a marker of cytokeratin (CK) and IHC techniques.

Positive rates for tumor cells in histologically negative lymph nodes varied considerably among these studies, ranging from 5 to 88% (median, 30%). With median follow-up periods of 24–128 months (median, 60 months), 16 out of the 31 studies (52%) demonstrated a significant difference in recurrence and/or mortality rates between patients with and without ITCs in lymph nodes.

 Tumor cells in the peritoneal cavity

During the same period, 13 studies assessed the prognostic value of tumor cells in the peritoneal cavity of patients with colorectal cancer (Table II) (34,47–58). The studies investigated a total of 2,434 colorectal cancer patients (median, 125 patients). The majority of these studies used standard cytological methods to detect tumor cells in peritoneal lavage samples.

Positive rates for tumor cells in the peritoneal cavity varied among studies, ranging from 2 to 33% (median, 17%). The median follow-up period was 47 months (range, 25–103 months) and 9 out of the 13 studies (69%) demonstrated significant differences in recurrence and/or mortality rates between patients with and without ITCs in the peritoneal cavity.

 Tumor cells in the peripheral blood

A total of 22 studies assessed the prognostic value of tumor cells in the peripheral blood of patients with colorectal cancer (Table III) (38,59–79). The studies included a total of 2,857 patients (median, 103 patients), most of whom had colorectal cancer, with the exception of 2 patients with colon and 1 with rectal cancer only. A total of 13 studies included patients with stage I/II/III disease (Dukes’ A/B/C), whereas 9 included patients with stage IV disease (Dukes’ D). The majority of the studies detected tumor cells using a carcinoembryonic antigen (CEA) or CK marker and reverse transcriptase-polymerase chain reaction (RT-PCR), IHC, immunomagnetic assay (IMA), or membrane assay (MA) techniques.

Positive rates for tumor cells in the peripheral blood ranged from 10 to 62% (median, 38%). Following the exclusion of 9 studies on stage IV patients, the positive rate for tumor cells among the studies was 22–62% (median, 36%). With a median follow-up period of 40 months (range, 24 to >70 months), 15 out of the 22 studies (68%) demonstrated significant differences in recurrence and/or mortality rates between patients with and without ITCs in the peripheral blood. Among the 14 studies including only stage I/II/III patients, 12 (86%) demonstrated a prognostic value of ITCs.

 Tumor cells in drainage veins

Six studies assessed the prognostic value of tumor cells in drainage veins sampled from the mesenteric or portal vein during surgery (Table IV) (63,65,80–83). The studies investigated patients with colorectal cancer, including a total of 638 patients (median, 94 patients). Tumor cells were detected using a CEA marker and RT-PCR.

The positive rate for tumor cells in the drainage vein varied from 11 to 49% (median, 43%). With a median follow-up period of 46 months (range, 30 to ≥60 months), 4 out of the 6 studies (67%) demonstrated a significant difference in recurrence and/or mortality rates between patients with and without ITCs in the drainage veins.

 Tumor cells in the bone marrow

Four studies assessed the prognostic value of tumor cells in the bone marrow (Table V) (34,66,84,85). The studies included a total of 514 colorectal cancer patients (median, 115 patients). These studies detected tumor cells using a CK marker and immunocytochemistry (ICC) or RT-PCR techniques.

Positive rates of tumor cells in the bone marrow varied from 17 to 64% (median, 29%). With a median follow-up of 60 months (range, 55–112 months), only 1 in 4 studies (25%) demonstrated a significant difference in recurrence and/or mortality rates between patients with and without ITCs in the bone marrow.

 Isolated tumor cells in stage IV patients

We identified 9 studies assessing the prognostic value of tumor cells in the peripheral blood of patients with metastatic colorectal cancer (Table VI) (86–94). The positive rate of tumor cells in the peripheral blood varied from 15 to 80% (median, 30%). Median follow-up was 25 months (range, 11 to ≥38 months) and 7 studies (78%) demonstrated a significant difference in recurrence and/or mortality rates between patients with and without ITCs in the peripheral blood.

Seven studies assessed the prognostic value of tumor cells in the bone marrow of patients with liver metastasis (Table VII) (86,88,95–99). The median positive rate for tumor cells in peripheral blood was 22% (range, 7–50%). The median follow-up period was 35 months (range, 18 to ≥43 months) and 4 studies (57%) demonstrated a significant difference in recurrence and/or mortality rates between patients with and without ITCs in the bone marrow.

Five studies assessed the prognostic value of tumor cells in the normal liver tissue of patients with liver metastasis, excluding 1 study comprising only stage I/II/III patients (Table VIII) (89,100–103). The positive rate for tumor cells in the peripheral blood varied considerably among the studies (10–70%; median, 37%). With a median follow-up period of 44 months (range, 1 to ≥5 months), 3 studies (60%) demonstrated significant differences in recurrence and/or mortality rates between patients with and without ITCs in the normal liver tissue.

 Conclusion

Although IHC and molecular techniques are useful for detecting tumor cells in histologically negative lymph nodes, the prognostic significance of such cells is equivocal among recent 10-year studies (104). Peritoneal cytology during curative resection ocasionally detects tumor cells and may be useful in identifying a high risk of recurrence or mortality, whereas the presence of tumor cells during surgery in the drainage vein, bone marrow, or liver is not always useful for evaluating the prognosis (105).

Recent studies demonstrated that identifying ITCs in the peripheral blood is useful for estimating the outcome of patients with localized as well as metastatic cancer (106,107). ITCs in the peripheral blood may be measured using the CellSearch system (4,5,108–112) and future prospective studies based on large patient samples and long-term follow-up may elucidate the utility of routine examination for ITCs in the daily practice of colorectal cancer surgery.

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Buxhofer-AuschVAuschCKitzwegerEMollikMReiner-ConcinAOgrisEStampflMHamiltonGSchiesselRHinterbergerWSpontaneous changes in tumour cell dissemination to bone marrow in colorectal cancerColorectal Dis127767822010 HinzSBockholstJRoderCEgbertsJHSchafmayerCKüchlerTBeckerTKalthoffHDisseminated tumor cells in the bone marrow negatively influence survival after resection of colorectal liver metastasesAnn Surg Oncol19253925462012 YokoyamaNShiraiYAjiokaYNagakuraSSudaTHatakeyamaKImmunohistochemically detected hepatic micrometastases predict a high risk of intrahepatic recurrence after resection of colorectal carcinoma liver metastasesCancer94164216472002 SchimanskiCCLinnemannUGallePRArbogastRBergerMRHepatic disseminated tumor cells in colorectal cancer UICC stage IV patients: Prognostic implicationsInt J Oncol237917962003 LinnemannUSchimanskiCCGebhardtCBergerMRPrognostic value of disseminated colorectal tumor cells in the liver: results from follow-up examinationsInt J Colorectal Dis193803862004 KochMKienlePLoganEAntolovicDGalindoLSchmitz-WinnenthalFHSchmidtJHerfarthCWeitzJDetection of disseminated tumor cells in liver biopsies of colorectal cancer patients is not associated with a worse prognosisAnn Surg Oncol148108172007 RahbariNNBorkUMotschallEThorlundKBüchlerMWKochMWeitzJMolecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysisJ Clin Oncol3060702012 BraunSVoglFDNaumeBJanniWOsborneMPCoombesRCSchlimokGDielIJGerberBGebauerGPiergaJYMarthCOruzioDWiedswangGSolomayerEFKundtGStroblBFehmTWongGYBlissJVincent-SalomonAPantelKA pooled analysis of bone marrow micrometastasis in breast cancerN Engl J Med3537938022005 RahbariNNAignerMThorlundKMollbergNMotschallEJensenKDienerMKBüchlerMWKochMWeitzJMeta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancerGastroenterology138171417262010 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Tumor cells in negative lymph nodes.

Author (year) Cases Tumor Stage Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Rosenberg, et al (2002) 85 CRC I/II CK20 RT-PCR 52 86a R: 34 vs. 7%; M: 22 vs. 5% Yes (16)
Choi, et al (2002) 93 CRC II MNF116 IHC 31 66 R: 17 vs. 14% No (17)
Noura, et al (2002) 64 CRC II CEA RT-PCR 30 80 R: 39 vs. 12%; M: 22 vs. 5% Yes (18)
Merrie, et al (2003) 141 CC II CK20 RT-PCR 34 42 M: HR 2.7 Yes (19)
Shimoyama, et al (2003) 57 RC I/II CK7/8/CAM5.2 IHC 19 NA R: 45 vs. 22% Yes (20)
Palma, et al (2003) 38 CRC II AE1/AE3 IHC 16 75 R: 71 vs. 76b No (21)
Fisher, et al (2003) 399 CRC I/II AE1/AE3 IHC 18 NA R: HR 1.19; M: HR 0.94 No (22)
Bukholm, et al (2003) 156 CC II CAM5.2 IHC 38 NA M: HR 4.4 Yes (23)
Kronberg, et al (2004) 90 CRC I/II AE1/AE3 IHC 29 91 R: 23 vs. 20%; M: 19 vs. 10% No (24)
Laso, et al (2004) 21 CRC I/II AE1/AE3 IHC 38 57 M: 55 vs. 77b No (25)
Rosenberg, et al (2004) 85 CRC I/II CEA/CK20 IHC 27 86 M: 28 vs. 9% Yes (26)
Mukai, et al (2005) 124 CRC II AE1/AE3 IHC 17 >60 R: 65 vs. 10%; M: 38 vs. 8% Yes (27)
Lee, et al (2006) 121 CRC I/II MNF116 IHC 50 57 R: 17 vs. 15% No (28)
Garcia-Saenz, et al (2006) 105 CRC II AE1/AE3 IHC 25 60 R: 23 vs. 20% No (29)
Messerini, et al (2006) 395 CRC II A CK20 IHC 38 128 R: 22 vs. 22% No (30)
Wang, et al (2007) 55 RC I/II CK20 IHC 18 56 R: 50 vs. 20% Yes (31)
Hara, et al (2007) 144 RC I/II AE1/AE3 IHC 24 81 R: 24 vs. 17% No (32)
Fleming, et al (2007) 56 RC I/II CAM5.2 IHC 18 98 R: 10 vs. 17% No (33)
Steinert, et al (2008) 90 CRC I/II CK18 IHC 46 61 R: NS No (34)
Davies, et al (2008) 105 CRC I/II AE1/AE3 IHC 47 48 R: 16 vs. 18% No (35)
Park, et al (2008) 160 CC I/II CK20 IHC 5 46 R: 20 vs. 15%; M: 8 vs. 7% No (36)
Bosch-Roig, et al (2008) 39 CC II AE1/AE3 IHC 10 82a R: 50 vs. 17%; M: 50 vs. 6% Yes (37)
Koyanagi, et al (2008) 67 CRC I/II CK20/cMET RT-PCR 40 34 R: 37 vs. 61; M: 43 vs. 57b Yes (38)
Waldman, et al (2009) 257 CRC I/II GUCY2C RT-PCR 88 24 R: 21 vs. 6% Yes (39)
van Schaik, et al (2009) 72 CC I/II LU5 IHC 24 68 R: 49 vs. 28%; M: 38 vs. 21% Yes (40)
Uribarrena-Amezaga, et al (2010) 85 CRC I/II AE1/AE3 IHC 36 NA R: 32 vs. 22% No (41)
Haince, et al (2010) 123 CC I/II GUCY2C RT-PCR 20 53 R: 33 vs. 16% Yes (42)
Faerden, et al (2011) 126 CC I/II CAM5.2 IHC 31 60 R: 23 vs. 7% Yes (43)
Oh, et al (2011) 124 CRC II AE1/AE3 IHC 27 36 R: 14 vs. 7%; M: 4 vs. 2% No (44)
Hyslop, et al (2011) 291 CRC I/II GUCY2C RT-PCR 40 24 R: 41 vs. 2% Yes (45)
Mescoli, et al (2012) 312 CRC I/II MNF116 IHC 59 63 R: 14 vs. 5% Yes (46)

Mean,

survival (months). CRC, colorectal cancer; CC, colon cancer; RC, rectal cancer; CK, cytokeratin; CEA, carcinoembryonic antigen; GUCY, guanylate cyclace HR, hazard ratio; IHC, immunohistochemistry; RT-PCR, reverse transcriptase-polymerase chain reaction; NA, not available; R, recurrence rate; M, mortality rate; NS, not significant.

Tumor cells in the peritoneal cavity.

Author (year) Cases Tumor Stage or depth of invasion Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Guller, et al (2002) 39 CRC I–III CEA/CK20 RT-PCR 28 31 R: 82 vs. 7%.. Yes (47)
Yamamoto, et al (2003) 189 CRC T3/T4 TC CYT 6 103 R: 55 vs. 26% Yes (48)
Kanellos, et al (2003) 110 CRC T1–T3 TC CYT 20 >60 M: 32 vs. 20% No (49)
Bosch, et al (2003) 53 CRC I–III CK20 CYT/ICC 25 37 R: 62 vs. 28% Yes (50)
Baskaranathan, et al (2004) 281 CRC I–IV TC CYT 9 49a R: 35 vs. 14% Yes (51)
Lloyd, et al (2006) 125 CRC I/II CEA/CK20 RT-PCR 33 25 R: 29 vs. 4%.. Yes (52)
Kanellos, et al (2006) 95 CRC I–III TC CYT 26 >60 M: 36 vs. 30% No (53)
Gozalan, et al (2007) 67 CRC I–IV TC CYT 9 >24 R: 50 vs. 31% No (54)
Steinert, et al (2008) 132 CRC I–III CK18 CYT/ICC 22 61 R: NS No (34)
Katoh, et al (2009) 91 CRC III TC CYT 11 >24. R: 30 vs. 9%b; M: 86 vs. 21%. Yes (55)
Noura, et al (2009) 697 CRC 0-III TC CYT 2 91a R: 63 vs. 17%; M: 50 vs. 13% Yes (56)
Nishikawa, et al (2009) 410 CRC T3/T4 TC CYT 8 36 R: 60 vs. 30%; M: 79 vs. 32% Yes (57)
Temesi, et al (2012) 145 CRC T1–T4 TC CYT 17 47 R: 56 vs. 23% Yes (58)

Mean,

local/peritoneal recurrence. CRC, colorectal cancer; CEA, carcinoembryonic antigen; CK, cytokeratin; TC, tumor cell; RT-PCR, reverse transcriptase-polymerase chain reaction; CYT, cytology; ICC, immunocytochemistry; R, recurrence rate; M, mortality rate; NS, not significant.

Tumor cells in the peripheral blood.

Author (year) Cases Tumor Stage Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Bessa, et al (2003) 66 CRC I–III CEA RT-PCR 55 36 R: 22 vs. 23% No (59)
Giacomelli, et al (2003) 41 CRC I–IV EGFR RT-PCR 39 36 R: 94 vs. 4% Yes (60)
Chen, et al (2004) 42 CRC II–IV GCC RT-PCR 29 36 R: 50 vs. 7% Yes (61)
Zhang, et al (2005) 58 CRC I–III CK20 RT-PCR 45 >12 M: 55 vs. 33% Yes (62)
Sadahiro, et al (2005) 93 CRC I–III CEA RT-PCR 39 59 R: 6 vs. 19% No (63)
Douard, et al (2006) 121 CRC I–IV CGM2 RT-PCR 48 NA R: 28 vs. 29% No (64)
Iinuma, et al (2006) 167 CRC I–IV CEA/CK20 RT-PCR 10 30 R: NS No (65)
Koch, et al (2006) 90 CRC II CK20 RT-PCR 25 58 R: 28 vs. 10% Yes (66)
Katsumata, et al (2006) 57 CC I–IV CK20 RT-PCR 42 >70 R: 25 vs. 12% No (67)
Allen-Mersh, et al (2007) 113 CRC I–III CEA/VK20 RT-PCR 31 46 R: HR 8.66 Yes (68)
Sadahiro, et al (2007) 200 CRC I–III CEA RT-PCR 22 52 R: 45 vs. 22% Yes (69)
Koch, et al (2007) 45 RC I–IV CK20 RT-PCR 38 51 M: 34 vs. 13% No (70)
Wang, et al (2007) 157 CRC I–III CEA/CK19/20 MA 57 36 M: 50 vs. 12% Yes (71)
Friederichs, et al (2007) 37 CRC I–IV CK20 RT-PCR 30 40 M: 45 vs. 15% No (72)
Uen, et al (2007) 194 CRC II CEA/CK19/20 MA 27 40 R: 85 vs. 8% Yes (73)
Uen, et al (2008) 438 CRC I–III CEA/CK19/20 MA 31 44 R: 68 vs. 16% Yes (74)
Yie, et al (2008) 51 CRC I–IV Survivin RT-PCR 41 36 R: 48 vs. 17% Yes (75)
Koyanagi, et al (2008) 34 CRC I–III CK20/cMET RT-PCR 47 34 M: 36 vs. 50b Yes (38)
Wong, et al (2009) 132 CRC I–III CK20 IMA 62 24 M: 52 vs. 17% Yes (76)
Vardakis, et al (2011) 265 CRC II–III CEA RT-PCR 37 34 R: 37 vs. 12%; M: 24 vs. 12% Yes (77)
Lu, et al (2011) 141 CC II/III CEA/CK19/20 MA 36 62 R: 73 vs. 12% Yes (78)
Iinuma, et al (2011) 315 CRC II/III CEA/CK19/20 RT-PCR 24 37a R: HR 3.04; M: HR 3.20 Yes (79)

Mean,

survival (months). CRC, colorectal cancer; CC, colon cancer; RC, rectal cancer; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; GCC, guanylyl cyclase C; CGM2, carcinoembryonic gene member 2; CK, cytokeratin; RT-PCR, reverse transcriptase-polymerase chain reaction; IMA, immunomagnetic assay; MA, membrane assay; HR, hazard ratio; NA, not available; R, recurrence rate; M, mortality rate; NS, not significant.

Tumor cells in drainage veins.

Author (year) Cases Tumor Stage Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Sunouchi, et al (2003) 37 CRC I–IV CEA RT-PCR 43 33 R: 25 vs. 5%b ; M: 31 vs. 5% Yes (80)
Akashi, et al (2003) 80 CRC I–III CEA RT-PCR 44 52a R: 20 vs. 5% No (81)
Sadahiro, et al (2005) 49 CRC I–III CEA RT-PCR 49 59 R: 7 vs. 21% No (63)
Iinuma, et al (2006) 167 CRC I–IV CEA/CK20 RT-PCR 34 30 R: HR 1.744; M: HR 1.517 Yes (65)
Kanellos, et al (2006) 108 CRC I–III CEA RT-PCR 11 >60 R: 50 vs. 15% Yes (82)
Shimada, et al (2012) 197 CRC II/III CEA/CK/CD133 RT-PCR 62 37 R: HR 1.13/1.25c; M: HR 2.28/1.49c Yes (83)

Mean,

liver and lung,

Dukes’ B/C. CRC, colorectal cancer; CEA, carcinoembryonic antigen; CK, cytokeratin; CD113, cluster of differentiation 113; RT-PCR, reverse transcriptase-polymerase chain reaction; R, recurrence rate; M, mortality rate; HR, hazard ratio.

Tumor cells in the bone marrow.

Author (year) Cases Tumor Stage Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
O’Connor, et al (2005) 49 CRC I–III CK18 ICC 29 55 R: 29 vs. 31% No (84)
Koch, et al (2006) 90 CRC II CK20 RT-PCR 28 58 R: 5 vs. 17% No (66)
Steinert, et al (2008) 140 CRC I–III CK18 CYT/ICC 64 61 M: 17 vs. 20% No (34)
Flatmark, et al (2011) 235 CRC I–III EpCAM IMA/ICC 17 112 R: HR 3.0 Yes (85)

CRC, colorectal cancer; CK, cytokeratin; EpCAM, epithelial cell adhesion molecule; ICC, immunocytochemistry; RT-PCR, reverse transcriptase-polymerase chain reaction; IMA, immunomagnetic assay; CYT, cytology; R, recurrence rate; M, mortality rate; HR, hazard ratio.

Tumor cells in the peripheral blood of stage IV patients.

Author (year) Cases Tumor Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Vlems, et al (2003) 22 CRC CK20 RT-PCR 15 18 R: 75 vs. 64% No (86)
Fruhauf, et al (2005) 18 CRC A45B/B3 IHC 56 31a R: 76 vs. 10% Yes (87)
Koch, et al (2005) 37 CRC CK20 RT-PCR 30 38 M: 71 vs. 50% Yes (88)
Topal, et al (2005) 20 CRC CEA/CK20 RT-PCR 80 37 NA No (89)
Cohen, et al (2008) 413 CRC CK8/18/19 CSS 26 11 R: 5 vs. 8b; M: 9 vs. 19c Yes (90)
Cohen, et al (2009) 413 CRC CK8/18/19 CSS 26 26 R: 4 vs. 8b; M: 9 vs. 21c Yes (91)
Tol, et al (2010) 451 CRC CK8/18/19 CSS 29 17 R: 8 vs. 10b; M: 13 vs. 22c Yes (92)
Rahbari, et al (2011) 63 CRC CK20 RT-PCR 57 23 R: 58 vs. 44% Yes (93)
Pilati, et al (2012) 50 CRC CD133 RT-PCR 50 36 R: 88 vs. 24%; M: HR 2.611 Yes (94)

Mean,

relapse-free survival (months),

overall survival (months). CRC, colorectal cancer; CK, cytokeratin; CD113, cluster of differentiation 113; CEA, carcinoembryonic antigen; RT-PCR, reverse transcriptase-polymerase chain reaction; IHC, immunohistochemistry; CSS, CellSearch system; R, recurrence rate; M, mortality rate; NA, not available; HR, hazard ratio.

Tumor cells in the bone marrow of patients with liver metastasis.

Author (year) Cases Tumor Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Bjørnland, et al (2003) 29 CRC MOC31 IMA 7 18 M: 50 vs. 12% Yes (95)
Vlems, et al (2003) 22 CRC CK20 RT-PCR 23 18 R: 80 vs. 65% No (86)
Koch, et al (2005) 37 CRC CK20 RT-PCR 16 38 R: 75 vs. 51% Yes (88)
Schoppmeyer, et al (2006) 30 CC CK ICC 50 43 M: 47 vs. 53% No (96)
Vogelaar, et al (2010) 44 CRC CK20 RT-PCR 20 24 R: HR 4.11; M: HR 6.40 Yes (97)
Buxhofer-Ausch, et al (2010) 45 CRC A45B/B3 ICC 22 35 R: 30 vs. 22% No (98)
Hinz, et al (2012) 71 CRC CK20 RT-PCR 23 41 R: 22 vs. 45a Yes (99)

Recurrence-free survival (months). CRC, colorectal cancer; CC, colon cancer; CK, cytokeratin; IMA, immunomagnetic assay; RT-PCR, reverse transcriptase-polymerase chain reaction; ICC, immunocytochemistry; M, mortality rate; R, recurrence rate; HR, hazard ratio.

Tumor cells in the normal liver tissue of patients with liver metastasis.

Author (year) Cases Tumor Marker Method Positive rate (%) Follow-up (months) Recurrence/mortality rate Prognostic value (Refs.)
Yokoyama, et al (2002) 46 CRC CK20 IHC 70 44 R: 69 vs. 16%; M: 78 vs. 36% Yes (100)
Schimanski, et al (2003) 16 CRC K-ras RT-PCR 50 NA M: 165 vs. 240a Yes (101)
Linnemann, et al (2004) 54 CRC K-ras RT-PCR 26 >1 R: 71 vs. 30%; M: 64 vs. 25% Yes (102)
Topal, et al (2005) 19 CRC CEA/CK20 RT-PCR 37 37 NA No (89)
Koch, et al (2007) 100 CRC CK20 RT-PCR 10 55 R: 11 vs. 23%; M: 20 vs. 23% No (103)

Overall survival (months). CRC, colorectal cancer; CK, cytokeratin; CEA, carcinoembryonic antigen; IHC, immunohistochemistry; RT-PCR, reverse transcriptase-polymerase chain reaction; NA, not available; R, recurrence rate; M, mortality rate.