Survival Impact of Primary Tumor Lymph Node Status and Circulating Tumor Cells in Patients with Colorectal Liver Metastases

Lars Thomas Seeberg, Cathrine Brunborg, Anne Waage, Harald Hugenschmidt, Anne Renolen, Ingunn Stav, Bjørn A Bjørnbeth, Elin Borgen, Bjørn Naume, Kristoffer W Brudvik, Gro Wiedswang, Lars Thomas Seeberg, Cathrine Brunborg, Anne Waage, Harald Hugenschmidt, Anne Renolen, Ingunn Stav, Bjørn A Bjørnbeth, Elin Borgen, Bjørn Naume, Kristoffer W Brudvik, Gro Wiedswang

Abstract

Objective: The aim of this study was to analyse the survival impact of primary tumor nodal status (N0/N+) in patients with resectable colorectal liver metastases (CLM), and to determine the value of circulating and disseminated tumor cells (CTCs/DTCs) in this setting.

Methods: In this prospective study of patients undergoing resection of CLM from 2008 to 2011, peripheral blood was analyzed for CTCs using the CellSearch System®, and bone marrow was sampled for DTC analyses just prior to hepatic resection. The presence of one or more tumor cells was scored as CTC/DTC-positive. Following resection of the primary tumor, the lymph nodes (LNs) were examined by routine histopathological examination.

Results: A total of 140 patients were included in this study; 38 patients (27.1%) were negative at the primary colorectal LN examination (N0). CTCs were detected in 12.1% of all patients; 5.3% of patients in the N0 group and 14.7% of patients in the LN-positive (N+) group (p = 0.156), with the LN-positive group (N+) consisting of both N1 and N2 patients. There was a significant difference in recurrence-free survival (RFS) when analysing the N0 group versus the N+ group (p = 0.007) and CTC-positive versus CTC-negative patients (p = 0.029). In multivariate analysis, CTC positivity was also significantly associated with impaired overall survival (OS) [p = 0.05], whereas DTC positivity was not associated with survival.

Conclusion: In this cohort of resectable CLM patients, 27% had primary N0 colorectal cancer. Assessment of CTC in addition to nodal status may contribute to improved classification of patients into high- and low-risk groups, which has the potential to guide and improve treatment strategies.

Trial registration: ClinicalTrials.gov NCT01919151.

Figures

Fig. 1
Fig. 1
Study selection process for the cohort of 194 CLM patients, selecting the actual study population of 140 patients with resectable CLM. CLM colorectal liver metastases
Fig. 2
Fig. 2
(a) Recurrence-free survival according to lymph node status (N+/N0) in 140 patients with resectable CLM (p < 0.01). (b) Recurrence-free survival according to CTC status in peripheral blood detected at liver surgery in 140 patients with resectable CLM (p = 0.029). (c) Overall survival analysing lymph node status (N+/N0) in 140 patients with resectable CLM (p = 0.267). (d) Overall survival according to CTC status in the peripheral blood at liver surgery in 140 patients with resectable CLM (p = 0.098). CLM colorectal liver metastases, CTC circulating tumor cells
Fig. 3
Fig. 3
Overall survival analyzing the combination of lymph node status (N+/N0) and CTC status at liver surgery in 140 patients with resectable CLM. CTC circulating tumor cells, CLM colorectal liver metastases

References

    1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–1502. doi: 10.1016/S0140-6736(13)61649-9.
    1. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27:872–877. doi: 10.1200/JCO.2008.19.5362.
    1. Karsa LV, Lignini TA, Patnick J, et al. The dimensions of the CRC problem. Best Pract Res Clin Gastroenterol. 2010;24:381–396. doi: 10.1016/j.bpg.2010.06.004.
    1. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th Edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–1474. doi: 10.1245/s10434-010-0985-4.
    1. Rees M, Tekkis PP, Welsh FKS, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer. Ann Surg. 2008;247:125–135. doi: 10.1097/SLA.0b013e31815aa2c2.
    1. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer. Ann Surg. 1999;230(3):309–318. doi: 10.1097/00000658-199909000-00004.
    1. Mala T, Bøhler G, Mathisen Ø, et al. Hepatic resection for colorectal metastases: can preoperative scoring predict patient outcome? World J Surg. 2002;26:1348–1353. doi: 10.1007/s00268-002-6231-x.
    1. Nordlinger B, Peschaud F, Malafosse R. Resection of liver metastases from colorectal cancer-how can we improve results? Colorectal Dis. 2003;5:515–517. doi: 10.1046/j.1463-1318.2003.00514.x.
    1. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–657. doi: 10.1097/01.sla.0000145964.08365.01.
    1. Veen T, Nedrebø BS, Stormark K, et al. Qualitative and quantitative issues of lymph nodes as prognostic factor in colon cancer. Dig Surg. 2013;30:1–11. doi: 10.1159/000349923.
    1. Veen T, Stormark K, Nedrebø BS, et al. Long-term follow-up and survivorship after completing systematic surveillance in stage I-III colorectal cancer: who is still at risk? J Gastrointest Cancer. 2015;46(3):259–266. doi: 10.1007/s12029-015-9723-2.
    1. Stoecklein NH. Klein CA Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer. 2010;126:589–598. doi: 10.1002/ijc.24916.
    1. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9:302–312. doi: 10.1038/nrc2627.
    1. Bork U, Grützmann R, Rahbari NN, et al. Prognostic relevance of minimal residual disease in colorectal cancer. World J Gastroenterol. 2014;20:10296–10304. doi: 10.3748/wjg.v20.i30.10296.
    1. Seeberg LT, Waage A, Brunborg C, et al. Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival. Ann Surg. 2015;261(1):164–171. doi: 10.1097/SLA.0000000000000580.
    1. Torino F, Bonmassar E, Bonmassar L, et al. Circulating tumor cells in colorectal cancer patients. Cancer Treat Rev. 2013;39(7):759–772. doi: 10.1016/j.ctrv.2012.12.007.
    1. Groot Koerkamp B, Rahbari NN, Büchler MW, et al. Circulating tumor cells and prognosis of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer: a meta-analysis. Ann Surg Oncol. 2013;20(7):2156–2165. doi: 10.1245/s10434-013-2907-8.
    1. Flatmark K, Borgen E, Nesland JM, et al. Disseminated tumour cells as a prognostic biomarker in colorectal cancer. Br J Cancer. 2011;104(9):1434–1439. doi: 10.1038/bjc.2011.97.
    1. Cancer in Norway 2013. Cancer Registry of Norway; 2015.
    1. Riethdorf S, Fritsche H, Müller V, 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;13:920–928. doi: 10.1158/1078-0432.CCR-06-1695.
    1. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10:6897–6904. doi: 10.1158/1078-0432.CCR-04-0378.
    1. Wiedswang G, Borgen E, Kåresen R, et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol. 2003;21:3469–3478. doi: 10.1200/JCO.2003.02.009.
    1. Haugland HK, Casati B, Dørum LM, et al. Template reporting matters: a nationwide study on histopathology reporting on colorectal carcinoma resections. Hum Pathol. 2011;42:36–40. doi: 10.1016/j.humpath.2010.06.009.
    1. Huang X, Gao P, Song Y, et al. Meta-analysis of the prognostic value of circulating tumor cells detected with the Cell Search System in colorectal cancer. BMC Cancer. 2015;30(15):202. doi: 10.1186/s12885-015-1218-9.
    1. Allen-Mersh TG, McCullough TK, Patel H, et al. Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma. Br J Surg. 2007;94:96–105. doi: 10.1002/bjs.5526.
    1. Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer. Arch Pathol Lab Med. 2000;124(7):979–994.
    1. Baxter NN, Virnig DJ, Rothenberger DA, et al. Lymph node evaluation in colorectal cancer patients: a population-based study. J Natl Cancer Inst. 2005;97:219–225. doi: 10.1093/jnci/dji020.
    1. Baxter NN. Is lymph node count an ideal quality indicator for cancer care? J Surg Oncol. 2009;99:265–268. doi: 10.1002/jso.21197.
    1. Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin. 2004;54:295–308. doi: 10.3322/canjclin.54.6.295.
    1. Sobin LH, Greene FL. TNM classification: clarification of number of regional lymph nodes for pNo. Cancer. 2001;92(2):452. doi: 10.1002/1097-0142(20010715)92:2<452::AID-CNCR1342>;2-B.
    1. Fleshman J. Should total number of lymph nodes be used as a quality of care measure for stage III colon cancer? Ann Surg. 2009;249(4):564. doi: 10.1097/SLA.0b013e3181a16d99.
    1. Søreide K, Nedrebø BS, Søreide JA, et al. Lymph node harvest in colon cancer: influence of microsatellite instability and proximal tumor location. World J Surg. 2009;33:2695–2703. doi: 10.1007/s00268-009-0255-4.
    1. Rahbari NN, Bork U, Motschall E, et al. Molecular 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-analysis. J Clin Oncol. 2011;30:60–70. doi: 10.1200/JCO.2011.36.9504.
    1. Gray R, Barnwell J, McConkey C, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–2029. doi: 10.1016/S0140-6736(07)61058-7.
    1. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC Trial. J Clin Oncol. 2009;27:3109–3116. doi: 10.1200/JCO.2008.20.6771.
    1. O’Connor ES, Greenblatt DY, LoConte NK. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol. 2011;29:3381–3388. doi: 10.1200/JCO.2010.34.3426.
    1. Dent S, Oyan B, Honig A, et al. HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials. Cancer Treat Rev. 2013;39:622–631. doi: 10.1016/j.ctrv.2013.01.002.
    1. Cohen SJ, Punt CJA, Iannotti N, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20:1223–1229. doi: 10.1093/annonc/mdn786.
    1. Sastre J, Maestro ML, Puente J, et al. Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol. 2008;19:935–938. doi: 10.1093/annonc/mdm583.
    1. Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138:1714–1726. doi: 10.1053/j.gastro.2010.01.008.
    1. Peach G, Kim C, Zacharakis E, et al. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer. 2010;102:1327–1334. doi: 10.1038/sj.bjc.6605651.
    1. Sastre J, Vidaurreta M, Gómez A, et al. Prognostic value of the combination of circulating tumor cells plus KRAS in patients with metastatic colorectal cancer treated with chemotherapy plus bevacizumab. Clin Colorectal Cancer. 2013;12:280–286. doi: 10.1016/j.clcc.2013.06.001.
    1. Brudvik KW, Seeberg LT, Hugenschmidt H, et al. Detection of circulating tumor cells at surgery and at follow-up assessment to predict survival after two-stage liver resection of colorectal liver metastases. Ann Surg Oncol. 2015;22(12):4029–4037. doi: 10.1245/s10434-015-4482-7.
    1. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14:623–631. doi: 10.1038/nrc3820.
    1. Gazzaniga P, Raimondi C, Gradilone A, et al. Circulating tumor cells in metastatic colorectal cancer: do we need an alternative cutoff? J Cancer Res Clin Oncol. 2013;139:1411–1416. doi: 10.1007/s00432-013-1450-0.
    1. Katsuno H, Zacharakis E, Aziz O, et al. Does the presence of circulating tumor cells in the venous drainage of curative colorectal cancer resections determine prognosis? A meta-analysis. Ann Surg Oncol. 2008;5:3083–3091. doi: 10.1245/s10434-008-0131-8.
    1. Giessen C, Fischer von Weikersthal L, Laubender RP, et al. Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial. Br J Cancer. 2013;109:1428–1436. doi: 10.1038/bjc.2013.475.
    1. Van Dalum G, Stam G-J, Scholten L, et al. Importance of circulating tumor cells in newly diagnosed colorectal cancer. Int J Oncol. 2015;46(3):1361–1368.
    1. McGowan PM, Kirstein JM, Chambers AF. Micrometastatic disease and metastatic outgrowth: clinical issues and experimental approaches. Future Oncol. 2009;5:1083–1098. doi: 10.2217/fon.09.73.
    1. Borgen E, Naume B, Nesland JM, et al. Use of automated microscopy for the detection of disseminated tumor cells in bone marrow samples. Cytometry. 2001;46:215–221. doi: 10.1002/cyto.1130.

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