Chemotherapy Before Liver Resection of Colorectal Metastases

Friend or Foe?

Kuno Lehmann, MD; Andreas Rickenbacher, MD; Achim Weber, MD; Bernhard C. Pestalozzi, MD; Pierre-Alain Clavien, MD, PhD, FACS

Disclosures

Annals of Surgery. 2012;255(2):237-247. 

In This Article

Abstract and Introduction

Abstract

Objective: We conducted a systematic review of the published literature to critically assess benefits and risks of the use of preoperative chemotherapy in patients presenting with colorectal liver metastases.
Background: In many centers, chemotherapy is used before hepatic resection of colorectal metastases, even in the presence of a single lesion. Application of chemotherapy requires clear conceptual distinction between patients presenting with resectable lesions (neoadjuvant) versus patients presenting with unresectable lesions, for which chemotherapy is used to reach a resectable situation (downsizing).
Methods: The literature (PubMed) was systematically reviewed for publications related to liver surgery and chemotherapy according to the methodology recommended by the Cochrane Collaboration.
Results: For unresectable liver metastases, combination regimens result in enhanced tumor response and resectability rates up to 30%, although the additional benefit from targeted agents such as bevacizumab or cetuximab is marginal. For resectable lesions, studies on neoadjuvant chemotherapy failed to convincingly demonstrate a survival benefit. Most reports described increased postoperative complications in a subset of patients due to parenchymal alterations such as chemotherapy-associated steatohepatitis or sinusoidal obstruction syndrome.
Conclusion: Preoperative standard chemotherapy can be recommended for downsizing unresectable liver metastases, but not for resectable lesions, for which adjuvant chemotherapy is preferred.

Introduction

In patients with colorectal cancer (CRC), the liver is the most common site of hematogenous metastases. Synchronous liver metastases occur in about 15% of the patients, whereas the overall risk of developing metachronous metastases after resection of the primary site is about 13%.[1] This risk increases to more than 30% in patients presenting with positive mesenteric lymph nodes (stage III disease).[1] In the absence of any treatment, the prognosis of patients with liver metastases is dismal with a 5-year survival rate approaching zero.[2] Liver surgery with complete resection of the metastases has markedly improved long-term survival ranging from 36% to 58% and from 23% to 36% at 5 and 10 years, respectively.[3–9] In addition, the safety of liver surgery has improved dramatically with current perioperative mortality rates of less than 5% in expert centers.[10–13]

The most significant advance regarding CRC over the past decade has been the introduction of several effective cytotoxic and targeted agents (Table 1). Until the mid-1990s, 5-fluorouracil (5FU) was the only drug available for the treatment of metastatic CRC, yielding response rates below 20% without survival advantage. Then, two potent cytotoxic drugs, oxaliplatin and irinotecan, were introduced.[14] Irinotecan increased the response rates up to 39% in combination with 5FU therapy.[15,16] Similarly, oxaliplatin improved the response rate from 22% to 51% compared to 5FU alone.[17,18] Further benefits were achieved by the addition of newly developed targeted agents such as the monoclonal antibodies cetuximab or panitumumab directed against EGFR (Erbitux, Bristol-Myers Squibb, USA; Vectibix, Amgen, Netherlands, Avastin, Roche, Switzerland)[19] or bevacizumab directed against VEGF (Avastin, Roche).[20] Combinations of oxaliplatin- or irinotecan-based chemotherapy with such antibodies resulted in tumor response rates in up to 60% of the evaluated populations. Several large studies (Table 1) provide evidence that in patients with metastatic CRC treated in a palliative intention, the combination of two cytotoxic drugs with an antibody increased the median overall survival from 20 to 22 months. In contrast to the palliative situation, there is much less evidence about the effect of chemotherapy on survival in the perioperative setting. For example, there are only few studies looking at the use of adjuvant chemotherapy after complete (R0) resection of liver metastases. One recently published multicenter RCT of 5FU monotherapy demonstrated an increased disease-free survival and a trend toward increased overall survival compared to resection alone.[21] Although such a single agent regimen is currently obsolete, this unique RCT suggests that better results are possible with modern regimens.

In contrast to adjuvant chemotherapy, preoperative regimens may influence the surgeon's decision on the timing and the type of operation. Preoperative chemotherapy might be considered in two distinct settings: (a) in patients presenting with unresectable liver metastases with the aim to permit a complete resection by preoperative shrinking of the tumor. Such a strategy is referred to as "downsizing chemotherapy"[13,22] and (b) in patients with primarily resectable disease with the aim to improve long-term survival by reducing postoperative relapse; this strategy is called "neoadjuvant chemotherapy." To justify the routine use of neoadjuvant chemotherapy, the benefits should clearly outweigh the risk. Potential disadvantages are the inherent risk of disease progression before surgery and the burden of liver toxicity. This review is focusing on the current evidence for benefits and risks of preoperative (downsizing or neoadjuvant) chemotherapy before liver surgery for colorectal metastases.

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