The influence of micrometastases on prognosis and survival in stage I-II colon cancer patients: the Enroute⊕ Study

Daniel J Lips, Boukje Koebrugge, Gerrit Jan Liefers, Johannes C van de Linden, Vincent T H B M Smit, Hans F M Pruijt, Hein Putter, Cornelis J H van de Velde, Koop Bosscha, Daniel J Lips, Boukje Koebrugge, Gerrit Jan Liefers, Johannes C van de Linden, Vincent T H B M Smit, Hans F M Pruijt, Hein Putter, Cornelis J H van de Velde, Koop Bosscha

Abstract

Background: The presence of lymph node metastases remains the most reliable prognostic predictor and the gold indicator for adjuvant treatment in colon cancer (CC). In spite of a potentially curative resection, 20 to 30% of CC patients testing negative for lymph node metastases (i.e. pN0) will subsequently develop locoregional and/or systemic metastases within 5 years. The presence of occult nodal isolated tumor cells (ITCs) and/or micrometastases (MMs) at the time of resection predisposes CC patients to high risk for disease recurrence. These pN0(micro+) patients harbouring occult micrometastases may benefit from adjuvant treatment. The purpose of the present study is to delineate the subset of pN0 patients with micrometastases (pN0(micro+)) and evaluate the benefits from adjuvant chemotherapy in pN0(micro+) CC patients.

Methods/design: EnRoute+ is an open label, multicenter, randomized controlled clinical trial. All CC patients (age above 18 years) without synchronous locoregional lymph node and/or systemic metastases (clinical stage I-II disease) and operated upon with curative intent are eligible for inclusion. All resected specimens of patients are subject to an ex vivo sentinel lymph node mapping procedure (SLNM) following curative resection. The investigation for micrometastases in pN0 patients is done by extended serial sectioning and immunohistochemistry for pan-cytokeratin in sentinel lymph nodes which are tumour negative upon standard pathological examination. Patients with ITC/MM-positive sentinel lymph nodes (pN0(micro+)) are randomized for adjuvant chemotherapy following the CAPOX treatment scheme or observation. The primary endpoint is 3-year disease free survival (DFS).

Discussion: The EnRoute+ study is designed to improve prognosis in high-risk stage I/II pN0(micro+) CC patients by reducing disease recurrence by adjuvant chemotherapy.

Trial registration: ClinicalTrials.gov: NCT01097265.

Figures

Figure 1
Figure 1
EnRoute+ study according to CONSORT
Figure 2
Figure 2
EnRoute+ flow chart
Figure 3
Figure 3
EnRoute+ follow up. OCV: outpatient clinic visit. CEA: carcinoma embryonic antigen abd. US: abdominal ultrasonography.

References

    1. van Steenbergen LN, Lemmens VE, Louwman MJ, Straathof JW, Coebergh JW. Increasing incidence and decreasing mortality of colorectal cancer due to marked cohort effects in southern Netherlands. Eur J Cancer Prev. 2009;18:145–152. doi: 10.1097/CEJ.0b013e32831362e7.
    1. Association of Comprehensive Cancer Centres. Guideline 'Colon cancer'. 2008. Ref Type: Electronic Citation.
    1. Nicastri DG, Doucette JT, Godfrey TE, Hughes SJ. Is occult lymph node disease in colorectal cancer patients clinically significant? A review of the relevant literature. J Mol Diagn. 2007;9:563–571. doi: 10.2353/jmoldx.2007.070032.
    1. Iddings D, Ahmad A, Elashoff D, Bilchik A. The prognostic effect of micrometastases in previously staged lymph node negative (N0) colorectal carcinoma: a meta-analysis. Ann Surg Oncol. 2006;13:1386–1392. doi: 10.1245/s10434-006-9120-y.
    1. Bilchik A, Nissan A, Wainberg Z, Shen P, McCarter M, Protic M. et al.Surgical quality and nodal ultrastaging is associated with long-term disease-free survival in early colorectal cancer: an analysis of 2 international multicenter prospective trials. Ann Surg. 2010;252:467–474.
    1. van der Zaag ES, Buskens CJ, Kooij N, Akol H, Peters HM, Bouma WH. et al.Improving staging accuracy in colon and rectal cancer by sentinel lymph node mapping: A comparative study. Eur J Surg Oncol. 2009;35:1065–1070.
    1. van Schaik PM, van der Linden JC, Ernst MF, Gelderman WA, Bosscha K. Ex vivo sentinel lymph node "mapping" in colorectal cancer. Eur J Surg Oncol. 2007;33:1177–1182.
    1. Stojadinovic A, Nissan A, Protic M, Adair CF, Prus D, Usaj S. et al.Prospective randomized study comparing sentinel lymph node evaluation with standard pathologic evaluation for the staging of colon carcinoma: results from the United States Military Cancer Institute Clinical Trials Group Study GI-01. Ann Surg. 2007;245:846–857. doi: 10.1097/01.sla.0000256390.13550.26.
    1. Wong JH, Johnson DS, Namiki T, Tauchi-Nishi P. Validation of ex vivo lymphatic mapping in hematoxylin-eosin node-negative carcinoma of the colon and rectum. Ann Surg Oncol. 2004;11:772–777. doi: 10.1245/ASO.2004.11.026.
    1. Nordgard O, Oltedal S, Korner H, Aasprong OG, Tjensvoll K, Gilje B. et al.Quantitative RT-PCR detection of tumor cells in sentinel lymph nodes isolated from colon cancer patients with an ex vivo approach. Ann Surg. 2009;249:602–607. doi: 10.1097/SLA.0b013e31819ec923.
    1. Sommariva A, Donisi PM, Gnocato B, Vianello R, Stracca PV, Zaninotto G. Factors affecting false-negative rates on ex vivo sentinel lymph node mapping in colorectal cancer. Eur J Surg Oncol. 2010;36(2):130–4.
    1. de BM, van Deurzen CH, van Dijck JA, Borm GF, van Diest PJ, Adang EM. et al.Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361:653–663. doi: 10.1056/NEJMoa0904832.
    1. Yun HR, Kim HC, Lee WY, Cho YB, Yun SH, Chun HK. The necessity of chemotherapy in T3N0M0 colon cancer without risk factors. Am J Surg. 2009;198:354–358. doi: 10.1016/j.amjsurg.2008.09.027.
    1. Morris M, Platell C, McCaul K, Millward M, van HG, Bayliss E. et al.Survival rates for stage II colon cancer patients treated with or without chemotherapy in a population-based setting. Int J Colorectal Dis. 2007;22:887–895. doi: 10.1007/s00384-006-0262-y.
    1. Association of Comprehensive Cancer Centres. Association of Comprehensive Cancer Centers. 2010. Ref Type: Electronic Citation.
    1. Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev. 2008. p. CD005390.
    1. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol. 1999;17:1356–63.
    1. Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG. et al.Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22:1797–1806. doi: 10.1200/JCO.2004.09.059.
    1. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420–1425. doi: 10.1093/jnci/djh275.
    1. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T. et al.Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351. doi: 10.1056/NEJMoa032709.
    1. Haller DG, Tabernero J, Maroun J, de Braud J, Price T, van cutsem E. et al.First efficacy findings from a randomized phase III trial of capecitabine + oxaliplatin vs. bolus 5-FU/LV for stage III colon cancer (NO16968/XELOXA study) Eur J Cancer Supplements. 2009;7:4.
    1. Taal BG, Van TH, Zoetmulder FA. Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer. 2001;85:1437–1443. doi: 10.1054/bjoc.2001.2117.
    1. Koyanagi K, Bilchik AJ, Saha S, Turner RR, Wiese D, McCarter M. et al.Prognostic relevance of occult nodal micrometastases and circulating tumor cells in colorectal cancer in a prospective multicenter trial. Clin Cancer Res. 2008;14:7391–7396. doi: 10.1158/1078-0432.CCR-08-0290.
    1. Bilchik AJ, DiNome M, Saha S, Turner RR, Wiese D, McCarter M. et al.Prospective multicenter trial of staging adequacy in colon cancer: preliminary results. Arch Surg. 2006;141:527–533. doi: 10.1001/archsurg.141.6.527.
    1. Saha S, Monson KM, Bilchik A, Beutler T, Dan AG, Schochet E. et al.Comparative analysis of nodal upstaging between colon and rectal cancers by sentinel lymph node mapping: a prospective trial. Dis Colon Rectum. 2004;47:1767–1772. doi: 10.1007/s10350-004-0661-5.
    1. Saha S, Seghal R, Patel M, Doan K, Dan A, Bilchik A. et al.A multicenter trial of sentinel lymph node mapping in colorectal cancer: prognostic implications for nodal staging and recurrence. Am J Surg. 2006;191:305–310. doi: 10.1016/j.amjsurg.2005.10.028.
    1. Cahill RA, Bembenek A, Sirop S, Waterhouse DF, Schneider W, Leroy J. et al.Sentinel node biopsy for the individualization of surgical strategy for cure of early-stage colon cancer. Ann Surg Oncol. 2009;16:2170–2180. doi: 10.1245/s10434-009-0510-9.
    1. Bembenek AE, Rosenberg R, Wagler E, Gretschel S, Sendler A, Siewert JR. et al.Sentinel lymph node biopsy in colon cancer: a prospective multicenter trial. Ann Surg. 2007;245:858–863. doi: 10.1097/01.sla.0000250428.46656.7e.
    1. Kelder W, Braat AE, Karrenbeld A, Grond JA, De Vries JE, Oosterhuis JW. et al.The sentinel node procedure in colon carcinoma: a multi-centre study in The Netherlands. Int J Colorectal Dis. 2007;22:1509–1514. doi: 10.1007/s00384-007-0351-6.
    1. Davies M, Arumugam PJ, Shah VI, Watkins A, Roger MA, Carr ND. et al.The clinical significance of lymph node micrometastasis in stage I and stage II colorectal cancer. Clin Transl Oncol. 2008;10:175–179. doi: 10.1007/s12094-008-0176-y.
    1. Kobayashi H, Mochizuki H, Morita T, Kotake K, Teramoto T, Kameoka S. et al.Timing of relapse and outcome after curative resection for colorectal cancer: a Japanese multicenter study. Dig Surg. 2009;26:249–255. doi: 10.1159/000226868.
    1. Saad ED, Katz A, Hoff PM, Buyse M. Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature. Ann Oncol. 2009;21(1):7–12.
    1. Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M. et al.Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23:8664–8670. doi: 10.1200/JCO.2005.01.6071.
    1. De GA, Hubbard J, Shi Q, O'Connell MJ, Buyse M, Benedetti J. et al.Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the 20,800 patient ACCENT data set. J Clin Oncol. 2010;28:460–465. doi: 10.1200/JCO.2009.23.1407.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅