Urgent need for a new staging system in advanced colorectal cancer.

Despite recent advances in the medical treatment of metastatic colorectal cancer (mCRC), which include irinotecan- and oxaliplatin-based first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the increasing use of targeted monoclonal antibodies, 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with CRC liver metastases, liver resection remains the only chance of cure, with 5-year survival rates ranging from 25% to 40%. However, 80% to 85% of patients with stage IV CRC have liver disease which is considered unresectable at presentation. The rapid expansion in the use of improved combination chemotherapy regimens plus or minus biologics, to render initially unresectable metastases resectable has increased the percentage of patients eligible for potentially curative surgery. However, the current staging criteria for CRC patients with metastatic disease do not reflect these recent changes or the fact that there is also a large variation in the survival of patients with stage IV CRC. For example the survival for a patient with a solitary, resectable liver metastasis is better than that for a patient with stage III disease. A new staging system is therefore needed that acknowledges both the improvements that have been made in surgical techniques for resectable metastases and the impact of modern chemotherapy on rendering initially unresectable CRC liver metastases resectable, while at the same time distinguishing between patients with a chance of cure at presentation and those for whom only palliative treatment is possible.

[1]  Daniel J Sargent,et al.  A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  M. Ychou,et al.  Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases , 2008, Cancer Chemotherapy and Pharmacology.

[3]  A. Carrato,et al.  Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study , 2008, Acta oncologica.

[4]  E. Van Cutsem,et al.  Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Yuman Fong,et al.  Actual 10-year survival after resection of colorectal liver metastases defines cure. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  M. Ducreux,et al.  Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  F. Giuliante,et al.  Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases , 2007, British Journal of Cancer.

[8]  A. Carrato,et al.  Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. , 2007, European journal of cancer.

[9]  J. Figueras,et al.  Surgical treatment of liver metastases from colorectal carcinoma in elderly patients. When is it worthwhile? , 2007, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[10]  J. Figueras,et al.  Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  L. Crinò,et al.  Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  T. Serrano,et al.  Surgical Resection of Colorectal Liver Metastases in Patients with Expanded Indications: A Single-Center Experience with 501 Patients , 2007, Diseases of the colon and rectum.

[13]  M. Ychou,et al.  Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. , 2006, European journal of cancer.

[14]  Catherine Julié,et al.  Complete response of colorectal liver metastases after chemotherapy: does it mean cure? , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  D. Berger,et al.  RFA for liver tumors: does it really work? , 2006, The oncologist.

[16]  J. Vauthey,et al.  Downstaging or downsizing: time for a new staging system in advanced colorectal cancer? , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  M. Basso,et al.  Long-term follow-up of colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy with irinotecan and fluorouracil plus folinic acid (5-FU/FA) for unresectable liver metastases. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  T. Seufferlein,et al.  Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[19]  D. Sargent,et al.  Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  E. Beckner,et al.  STANDING ON THE SHOULDERS OF GIANTS , 2005 .

[21]  S. Curley,et al.  OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Pignon,et al.  Hepatic and Extrahepatic Colorectal Metastases: When Resectable, Their Localization Does Not Matter, But Their Total Number Has a Prognostic Effect , 2005, Annals of Surgical Oncology.

[23]  C. Köhne,et al.  Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  F. Lévi,et al.  Three-drug chronotherapy via hepatic artery as salvage treatment for patients with liver-only metastases from colorectal cancer , 2005 .

[25]  H. Hayat,et al.  Alternating hepatic artery chronotherapy with CPT-11 and systemic chronotherapy with 5-FU/FA + carboplatin for metastatic colorectal cancer confined to the liver: A phase II study , 2005 .

[26]  F. Lordick,et al.  A phase I/II study of cetuximab in combination with 5-fluorouracil (5-FU)/folinic acid (FA) plus weekly oxaliplatin (L-OHP) (FUFOX) in the first-line treatment of patients with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR). Preliminary results , 2005 .

[27]  A. Carrato,et al.  Resectability of liver metastases (LM) in patients with advanced colorectal cancer (ACRA) after treatment with the combination of oxaliplatin (OXA), irinotecan (IRI) and 5FU. Final results of a phase II study , 2005 .

[28]  L. Rimassa,et al.  Definitive results of hybrid chemotherapy with intravenous (iv) oxaliplatin (OXA) and folinic acid (FA), and intra-hepatic infusion (HAI) of 5-fluorouracil (5-FU) in patients with colorectal liver metastases , 2005 .

[29]  P. Ballardini,et al.  Phase II randomized trial on protracted 5-fluorouracil infusion plus oxaliplatin (FOX) versus capecitabine plus oxaliplatin (XELOX) as first-line treatment in advanced colorectal cancer (ACRC): Preliminary results of the Italian FOCA Study , 2005 .

[30]  W. Hiddemann,et al.  Hepatic artery infusion of 5-fluorouracil, folinic acid plus oxaliplatin for liver metastasis from colorectal cancer. Final analysis of a phase I/II studay , 2005 .

[31]  R. Stupp,et al.  Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[32]  M. Weiser,et al.  An increasingly common challenge: management of the complete responder with multi-focal metastatic colorectal cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  G. Poston Radiofrequency ablation of colorectal liver metastases: where are we really going? , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  F. Lévi,et al.  Tumor Progression While on Chemotherapy: A Contraindication to Liver Resection for Multiple Colorectal Metastases? , 2004, Annals of surgery.

[35]  Bernard Paule,et al.  Rescue Surgery for Unresectable Colorectal Liver Metastases Downstaged by Chemotherapy: A Model to Predict Long-term Survival , 2004, Annals of surgery.

[36]  J. García-Foncillas,et al.  Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  R. Advani,et al.  A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  W. Scheithauer,et al.  Neoadjuvant chemotherapy for resectable colorectal cancer liver metastases: Impact on magnitude of liver resection and survival , 2004 .

[39]  L. Schwartz,et al.  Liver resection after hepatic arterial infusion (HAI) plus systemic oxaliplatin (Oxal) combinations in pretreated patients with extensive unresectable colorectal liver metastases , 2004 .

[40]  P. Hérait,et al.  Dose-finding study of weekly 24-h continuous infusion of 5-fluorouracil associated with alternating oxaliplatin or irinotecan in advanced colorectal cancer patients. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[41]  Kenneth Hess,et al.  Recurrence and Outcomes Following Hepatic Resection, Radiofrequency Ablation, and Combined Resection/Ablation for Colorectal Liver Metastases , 2004, Annals of surgery.

[42]  D. Sargent,et al.  Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  M. Ducreux,et al.  Evolution of missing colorectal liver metastases following inductive chemotherapy and hepatectomy , 2004, Journal of surgical oncology.

[44]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  J. Pignon,et al.  Results of R0 Resection for Colorectal Liver Metastases Associated With Extrahepatic Disease , 2004, Annals of Surgical Oncology.

[46]  C. Tournigand,et al.  FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Tomoyuki Kato,et al.  Preoperative probability model for predicting overall survival after resection of pulmonary metastases from colorectal cancer , 2004, The British journal of surgery.

[48]  L. Zelek,et al.  Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial). , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[49]  L. Chiche [When is first-line resection of hepatic metastasis indicated?]. , 2003, Gastroenterologie clinique et biologique.

[50]  M. Rivoire,et al.  Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma , 2002, Cancer.

[51]  M. Yasuno,et al.  Evaluation of Aggressively Treated Patients With Unresectable Multiple Liver Metastases From Colorectal Cancer , 2002, Diseases of the colon and rectum.

[52]  Michael A. Choti,et al.  Trends in Long-Term Survival Following Liver Resection for Hepatic Colorectal Metastases , 2002, Annals of surgery.

[53]  U. Baum,et al.  Impact of surgery on survival in palliative patients with metastatic colorectal cancer after first line treatment with weekly 24-hour infusion of high-dose 5-fluorouracil and folinic acid. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[54]  F. Lévi,et al.  Five-Year Survival Following Hepatic Resection After Neoadjuvant Therapy for Nonresectable Colorectal [Liver] Metastases , 2001, Annals of Surgical Oncology.

[55]  W. Lees,et al.  Neo-adjuvant therapy improves resectability rates for colorectal liver metastases. , 2001, Annals of the Royal College of Surgeons of England.

[56]  D. Khayat,et al.  Prospective Phase II Trial of Irinotecan, 5-Fluorouracil, and Leucovorin in Combination as Salvage Therapy for Advanced Colorectal Cancer , 2001 .

[57]  L H Blumgart,et al.  Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. , 1999, Annals of surgery.

[58]  J. Ledermann,et al.  Neoadjuvant therapy improves resectability rates for colorectal liver metastases , 1999 .

[59]  F. Lévi,et al.  Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[60]  T. Takayama,et al.  A pilot study of multimodality therapy for initially unresectable liver metastases from colorectal carcinoma: hepatic resection after hepatic arterial infusion chemotherapy and portal embolization. , 1997, Japanese journal of clinical oncology.

[61]  F. Lévi,et al.  Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. , 1996, Annals of surgery.

[62]  B. Nordlinger,et al.  Surgical resection of colorectal carcinoma metastases to the liver: A prognostic scoring system to improve case selection, based on 1568 patients , 1996, Cancer.

[63]  W. Johnson,et al.  Lung recurrence after curative surgery for colorectal cancer , 1987, Diseases of the colon and rectum.

[64]  F. A. Coller,et al.  THE PROGNOSTIC SIGNIFICANCE OF DIRECT EXTENSION OF CARCINOMA OF THE COLON AND RECTUM , 1954, Annals of surgery.

[65]  C. Dukes The Surgical Pathology of Rectal Cancer , 1949, American journal of surgery.

[66]  Ma Dong,et al.  Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer , 2006 .

[67]  Z. Hua Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer , 2006 .

[68]  P. Rougier,et al.  Cetuximab in combination with irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) in the first-line treatment of metastatic colorectal cancer (mCRC) , 2005 .

[69]  T. Mok,et al.  Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases , 2005, Medical oncology.

[70]  Richard Stang,et al.  Resection of colorectal liver metastases , 1997, Journal of Gastrointestinal Surgery.

[71]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[72]  C. Balch,et al.  AJCC Cancer Staging Manual. 6th ed , 2002 .

[73]  D. Khayat,et al.  Prospective phase II trial of iriontecan, 5-fluorouracil, and leucovorin in combination as salvage therapy for advanced colorectal cancer. , 2001, American journal of clinical oncology.

[74]  L. Ellis,et al.  Surgery After Downstaging of Unresectable Hepatic Tumors With Intra-Arterial Chemotherapy , 2000, Annals of Surgical Oncology.

[75]  K. Hughes Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of indications for resection. Registry of Hepatic Metastases. , 1988, Surgery.

[76]  Peter Schlag,et al.  Resection of the liver for colorectal carcinoma metastases , 1988, Diseases of the colon and rectum.