ReviewDoes 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
Introduction
Despite the recent advances in first-line chemotherapy strategies for the treatment of patients with advanced colorectal cancer (CRC),1, 2, 3, 4, 5 liver resection offers the only chance of cure for patients with colorectal liver metastases.6 Until recently, the 5-year survival rates following liver resection typically ranged between 25% and 40% compared with between 0% and 5% for patients from the same institute who did not undergo liver resection.6, 7, 8, 9, 10, 11, 12 These are consistent with the 5-year survival rates reported for most large series where liver resection has been performed.13, 14, 15, 16 The major challenge however comes from the fact that approximately 85% of patients with stage IV CRC, referred to specialist centres, have metastatic liver disease which is considered to be unresectable at presentation17 (see Fig. 1).
Over the last 5 years there has been the recognition that preoperative, neoadjuvant, combination chemotherapy regimens, namely, 5-fluorouracil/folinic acid (5-FU/FA) in combination with either irinotecan or oxaliplatin, can facilitate the downsizing of colorectal liver metastases and render initially unresectable metastases resectable,15, 17, 18, 19, 20 and that the addition of targeted therapies21, 22, 23, 24, 25, 26 and a third cytotoxic to these standard combination therapy regimens27, 28, 29, 30 might render them even more effective in this clinical setting (Table 1). Over the same time period, advances in surgical techniques have led to changes in the criteria for resectability. Today, the requirement for the remaining liver remnant to be equivalent to 30% of the original liver volume is considered to be the most critical factor.31 Even the presence of disease outside the liver no longer automatically excludes surgery provided that it is also resectable.32 As a consequence, the percentage of patients eligible for potentially curative liver resection is increasing. The published resection rates, however, are very much biased towards specialist treatment centres. The goal of the European Colorectal Metastases Treatment Group (ECMTG) has been to advocate a multidisciplinary treatment approach to patients with metastatic colorectal disease, confined principally to the liver, which can be adopted by all treatment centres. The first manuscript of the ECMTG focussing on current treatment strategies and on criteria for resection was published in the Eur J Cancer in 2006.31 The intention of this expert group is to increase the number of patients who achieve long-term survival by increasing the number of patients who undergo resection of their liver metastases.31 Today, resection rates in excess of 20% are not unusual in patients with initially unresectable liver metastases following neoadjuvant chemotherapy (Table 1), with 5-year survival rates of 50% now being reported. This manuscript reviews the current recommendations of the ECMTG resulting from their two recent workshops, in Paris in May 2006 and at the 31st ESMO Congress in September 2006.
Section snippets
Patient selection
A recent retrospective analysis of objective response rates and rates of resection for patients with initially unresectable liver metastases has demonstrated a strong correlation between the response rate (RR) to chemotherapy and the resection rate for liver metastases in patients with metastatic CRC (mCRC).20 This correlation was stronger (0.96; p = 0.002) in selected patients, with isolated, liver-only metastases, than in non-selected patients (0.74; p < 0.001).20 Indeed, the resection rate in
New staging system
Currently stage IV is a ‘catch all’ classification/term that includes all colorectal tumours with liver metastases (and metastases outside of the liver), irrespective of the potential resectability of those metastases. A new staging system is needed that acknowledges not only the improvements that have been made in surgical techniques for resectable metastases but also the impact that neoadjuvant chemotherapy has had on rendering initially unresectable CRC liver metastases resectable. It should
A new end-point for trials involving resection
Resectability could become a new end-point for assessing the efficacy of neoadjuvant (pre-operative) chemotherapy, prior to hepatic resection.20 Overall survival, although the most objective end-point, is a long-way down the line from the neoadjuvant treatment setting for stage IV disease and can be influenced by many other factors. However, the indications for resection itself are also subjective, dependent not only on the patient and the metastases, but also on the skill and aggressiveness of
Optimal neoadjuvant chemotherapy
Since the recognition that neoadjuvant therapy could render initially unresectable metastases resectable, the use of neoadjuvant chemotherapy has expanded rapidly. However this has highlighted a divergence in the treatment strategies for those patients with initially unresectable but potentially resectable metastases and those patients whose liver metastases will never be resectable. Patients whose liver metastases may be rendered resectable by chemotherapy are looking for a chemotherapy
Monitoring patients during neoadjuvant therapy
The monitoring of patients during neoadjuvant therapy was identified as a major challenge, bearing in mind the limitations of spiral CT and ultrasound scans. From the surgeon’s point of view a complete response is undesirable as they can no longer locate tumors for resection, and there is already evidence from one study that 83% of patients (55 out of 66), assessed to be disease-free by CT scan, had either persistent disease or early recurrence.53 FDG-PET scanning has been shown to detect
Effects of chemotherapy on liver
Increasingly, concerns are being raised about the effects of long-term neoadjuvant therapy on the liver, especially chemotherapy-induced steatohepatitis (CASH).34, 55, 56, 57, 58 However, this appears to be particularly related to obese patients.55 A recent analysis of 45 patients who received preoperative, neoadjuvant chemotherapy and 22 who did not receive any chemotherapy prior to resection for colorectal liver metastases showed that although prolonged neoadjuvant chemotherapy changed the
Treatment of synchronous metastases
CRC liver metastases may present synchronously with the primary tumour or at a different (later) time (metachronous). Although only approximately 20% of patients present with synchronous metastases and only 15% of these are potentially resectable (accounting for approximately 3% of patients overall), these patients now have a better chance of long-term survival. Today, the question is one of timing of the surgical removal of the primary and the administration of adjuvant/neoadjuvant
The consensus and position statement
- 1.
The ECMTG propose that resectability should always be considered either directly or after neoadjuvant chemotherapy except when:
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Less than 30% of the liver would remain post-surgery even after portal vein embolisation.
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Involved coeliac lymph nodes are present or where there is evidence of disease outside of the liver or in the liver that cannot be cleared.
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There is invasion of the two branches of the liver pedicle or of the inferior vena cava or invasion of the three hepatic veins.
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- 2.
The ECMTG
Conflict of interest statement
None declared.
Acknowledgements
The ECMTG acknowledge financial support from Pfizer and editorial support from Dr. Anne Kinsella.
References (66)
- et al.
Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial
Lancet
(2000) Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases
Ann Oncol
(2003)- et al.
Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery
Ann Oncol
(1999) - et al.
Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates
Ann Oncol
(2005) - 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
Ann Oncol
(2006) - et al.
Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study
Ann Oncol
(2005) - et al.
Towards a pan-European consensus on the treatment of patients with colorectal liver metastases
Eur J Cancer
(2006) - et al.
Radiofrequency ablation in liver tumours
Ann Oncol
(2004) - et al.
Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients
Ann Oncol
(2004) - et al.
Liver resection for primarily unresectable colorectal metastases downsized by chemotherapy
J Gastrointest Surg
(2007)
First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer
Ann Oncol
Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases
J Am Coll Surg
Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer
Ann Oncol
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
Ann Oncol
Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer
J Clin Oncol
Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer
J Clin Oncol
Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group
N Engl J Med
Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986
J Clin Oncol
Factors influencing the natural history of colorectal liver metastases
Lancet
Resection of liver metastases – When is it worthwhile?
World J Surg
Resection of colorectal liver metastases
World J Surg
[Resection of colorectal liver metastases. What prognostic factors determine patient selection?]
Chirurg
Long-term survival following resection of colorectal hepatic metastases. Association Francaise de Chirurgie
Br J Surg
Liver resection for colorectal metastases
J Clin Oncol
Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal
Ann Surg Oncol
Resection rate and effect of postoperative chemotherapy on survival after surgery for colorectal liver metastases
Br J Surg
Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy
Ann Surg
Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie
Cancer
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study
J Clin Oncol
Cetuximab plus oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) for the epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) in the first-line setting: a phase II study
Eur J Cancer Suppl
A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer
J Clin Oncol
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
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- q
Both contributed equally.
- r
Georges Chalkiadakis, University General Hospital of Heraklion, Greece. Alfredo Falcone, University of Pisa, Italy. Joan Figueras, Hospital Josep Trueta, Girona, Spain. Jean-Francois Gigot, Saint-Luc, University Hospital, Brussels, Belgium. Rob Glynne-Jones, Mount Vernon Hospital, UK. Bernard de Hemptinne, Ghent University, Belgium. John Papadimitriou, Athens University, Greece. Carmelo Pozzo, Catholic University of the Sacred Heart, Rome, Italy.