The Tower of Babel of liver metastases from colorectal cancer: Are we ready for one language?

Critical Reviews in Oncology/Hematology 85 (2013) 332–341

The Tower of Babel of liver metastases from colorectal cancer: Are we ready for one language? Alessandro Bittoni a,∗ , Mario Scartozzi b , Riccardo Giampieri b , Luca Faloppi a , Elena Maccaroni a , Michela Del Prete a , Maristella Bianconi a , Stefano Cascinu b b

a Scuola di Specializzazione in Oncologia, Università Politecnica delle Marche, Via Tronto 10/A, 60100 Ancona, Italy Clinica di Oncologia Medica, AO Ospedali Riuniti-Università Politecnica delle Marche, Ancona, Via Conca, 71, 60126 Ancona, Italy

Accepted 9 August 2012

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Selection of patients for perioperative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potentially resectable liver metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Perioperative chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unresectable metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant chemotherapy after liver resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Duration of treatment and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

332 333 333 334 334 336 337 338 339 339 339 339 341

Abstract Advances in surgical and medical treatments have significantly changed the management of colorectal cancer liver metastases (CRCLMs). In particular, new drugs and modern combination chemotherapy regimens, together with the improvement of surgical techniques, allow a potentially curative approach in an increasing number of patients. Nevertheless, there is no strong evidence for an optimal treatment strategy for CRCLMs, mainly because of the extensive heterogeneity in the patients. In fact, although we consider them a population, they represent different clinical and biological subtypes requiring different approaches. Furthermore, results from different studies in this setting may be difficult to interpret, also because the definitions of different patient subgroups are unclear and overlapping. In this review we discuss the results of clinical trials evaluating the role of chemotherapy in the multimodal management of CRCLMs, in either the pre- or postoperative setting. Then we identify three main categories of CRCLM patients, providing clinical recommendations for each. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Colorectal cancer; Liver metastases; Chemotherapy; Surgery; Targeted therapy

1. Introduction

∗

Corresponding author. Tel.: +39 0715964611; fax: +39 0715964192. E-mail address: [email protected] (A. Bittoni).

1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.08.005

Significant advances have been achieved in the treatment of metastatic colorectal cancer (mCRC) in the last decade, and median survival of patients currently exceeds 20 months.

A. Bittoni et al. / Critical Reviews in Oncology/Hematology 85 (2013) 332–341

Notably, in the subset of patients with liver-only metastases, 5-year survival rates of 30–40% have been reported after surgical resection of the metastases [1,2], and therefore surgery of liver metastases offers the best chance of long-term survival, or even cure, to mCRC patients. Unfortunately, only a small percentage (about 10–20%) of patients present with initially resectable liver metastases [3]. Moreover, 60–75% of patients will relapse after liver resections, with the majority of the recurrences again in the liver [4,5]. There has therefore been great interest in the development of new multimodal strategies – including chemotherapy, surgery and locally ablative procedures – for the treatment of colorectal cancer liver metastases (CRCLMs) with the aim of increasing resectability, reducing recurrences, and improving overall survival. Nevertheless, there is no strong evidence for an optimal treatment strategy. This could be due to the heterogeneity of patients’ CRCLMs. In fact, although we consider them a homogeneous population, they represent different clinical and biological situations, each probably requiring a different treatment approach. Furthermore, results from different studies in this setting may be difficult to interpret, also because the definitions of different patient subgroups are unclear and overlapping, and studies include heterogeneous populations of patients. In this review we will focus our attention on how it is possible to define the optimal treatment for each patient with CRCLMs, according to tumor and host features. 1.1. Selection of patients for perioperative treatment Considering the significant benefit yielded by resection of liver metastases in the management of mCRC, the definition of resectability of hepatic metastases has gained increasing importance. Although several attempts have been made, there are still no clear and uniformly defined criteria for resectability of liver metastases. Historically, liver metastases were considered unresectable if they were large, multinodular, or poorly located, or if there was evidence of extrahepatic disease. In the last few years there has been a paradigm shift in the definition of resectability, from being defined by the extent of the disease removed to the current focus on the liver reserve remaining after resection. In particular, the number and/or size of hepatic nodules are not considered limiting, and it is now accepted that surgeons with specific expertise can carry out any kind of resection providing that there is sufficient liver remaining (>30%) and that the resection is complete, with no residual disease (R0). Even the presence of extrahepatic disease is no longer deemed to be an absolute contraindication to surgery, as long as it is radically resectable. Improvements in surgical techniques have increased the number of patients who can undergo resection of liver metastases during the course of their disease. In such a scenario, the availability of predictors of outcome to help in the selection of patients who may actually benefit from an invasive treatment such as hepatic surgery is increasingly important. Several scoring system have been created to predict survival after

333

resection of colorectal liver metastases. One of the most used scores was elaborated by Fong et al. [6] on 1001 patients who underwent resection of liver metastases. This scoring system incorporates five risk factors: node-positive primary, diseasefree interval < 12 months, more than one lesion, size >5 cm, and carcinoembryonic antigen (CEA) >200 ng/ml. Patients with five risk factors had a 5-year survival rate (5ySR) of 14% with a median of 22 months compared with a 5ySR of 44% and a median of 51 months in the case of one risk factor and a 60% 5yrSR with no risk factor. The accuracy of this score in the prediction of outcome for colorectal cancer patients undergoing surgery for liver metastases has been confirmed also with a longer follow-up by Tomlinson et al. [7]: after a 10-year follow-up the survival rate was 21% for patients with a low score (0–2) and 10% for patients with a high risk score (3–5). In the management of CRCLMs, clinicians typically have to deal with three main categories of patient. The first group is represented by patients with readily resectable liver metastases and a low risk of relapse. This group, accounting for about 10% of the patients in clinical practice, includes patients with a few liver metastases (four or fewer), adequate radiological margins, and no major poor prognostic factors. In this group of patients, upfront surgery is often the preferred option. The second group, which we will define as “potentially resectable”, is a heterogeneous class of patients with resectable liver disease but with a high risk of relapse, including: patients where liver resection is possible but technically difficult because metastases are close to all hepatic veins or to both portal branches (technically challenging), or patients with major indicators of short progression-free survival (PFS), such as synchronous presentation, multiple metastases, or a large (>5 cm) single lesion or high CEA (biologically challenging). The third group is represented by patients with liver metastases considered to be unresectable. This group includes patients with extensive liver involvement (>70% liver invasion or all three hepatic veins involved) or with major liver insufficiency, but also patients with extrahepatic unresectable disease and those unfit for surgery. In this group we can distinguish patients in whom surgery is potentially achievable after significant tumor shrinkage with chemotherapy (ultimately resectable) and patients whose metastases are never likely to be resectable. Treatment strategy and aims are different for each of the above classes, and the choice of the best therapy should take in account not only the characteristics of the tumor but also the characteristics of the patient, such as age, comorbidities, and performance status.

2. Potentially resectable liver metastases The role of chemotherapy in the management of patients with resectable liver metastases is still controversial. Indeed, in patients with resectable liver metastases and good prognostic features (as in patients with small and solitary lesions),

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upfront surgery is often the preferred option. However, it is widely accepted that systemic treatment plays a key role in most patients with liver metastases in clinical practice: in particular, in patients with poor prognostic factors that we have previously defined as biologically challenging, and in patients with liver metastases close to major hepatic vessels, where the achievement of radical resection is technically difficult, that we have identified as technically challenging. Nevertheless, the optimal timing of chemotherapy (preoperative versus postoperative) and the optimal regimen have still not been defined. 2.1. Perioperative chemotherapy The use of preoperative chemotherapy has been proposed also in patients with resectable liver disease, with several aims: to increase the complete resection rate, to facilitate limited hepatectomies, and to treat micrometastatic disease. Moreover, neoadjuvant chemotherapy provides a test of chemoresponsiveness and allows identification of aggressive disease and then selection of patients who may actually benefit from surgery. This approach has been tested in the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial [8] that randomized 364 patients with resectable liver metastases to two treatment arms: surgery alone, or 6 months of perioperative chemotherapy with 5-fluorouracil and oxaliplatin (modified FOLFOX4) administered 3 months before and 3 months after surgery. Patients had to be technically resectable, with a maximum of four liver metastases, and not previously treated with oxaliplatin. The primary aim of the study was PFS. In the chemotherapy arm, resection was possible in 159 patients (87.4%) compared with 170 in the surgery arm (97.3%), but the rates of R0 resections were almost identical (83.0 versus 83.5%). In the perioperative chemotherapy group there was an increase in PFS of 7.3% (from 28.1% to 35.4%) in all randomized patients (HR = 0.79; P = 0.058); the benefit reached 9.2% for patients actually undergoing resection (from 33.2% to 42.4%; HR = 0.73; P = 0.025) (Table 1). In a subsequent update of the results, presented in 2009, the benefit in PFS for perioperative chemotherapy was found to be statistically significant (median PFS 20.1 versus 14.3 months, HR = 0.76; P = 0.026). About 80% of patients in the experimental arm completed the preoperative part of the treatment, while only 52% of patients also completed the postoperative six cycles. These observations, together with the somehow disappointing results of most of the adjuvant trials, suggest the importance of the neoadjuvant part of the treatment in the outcome of patients. The toxicity observed during the preoperative chemotherapy was consistent with the previous experiences with FOLFOX. A slight increase in reversible postoperative complications was observed in the experimental arm (25% versus 16%; P = 0.04), but there was no impact on postoperative death rate (1% in both arms). On the basis of these results, upfront chemotherapy has become the standard of care for most patients with resectable

liver metastases and is recommended by international consensus conferences [9]. Recently, results of overall survival (OS) analysis, representing a secondary endpoint of the study, have been presented [10]. After a median follow-up of 8.5 years, and 221 reported deaths (61% of all randomized patients), there was no statistically significant difference in OS between the patients in the chemotherapy arm and the patients who underwent only surgery (HR = 0.88; 95%CI, 0.68–1.14; P = 0.34). In particular, the 5-year OS rate was 51.2% in the chemotherapy arm versus 47.8% in the surgery arm in all randomized patients, and 52.4% versus 48.3%, respectively, in all eligible patients. This lack of a benefit in OS for chemotherapy may be related to the influence of subsequent treatment lines but also to an increase in death unrelated to cancer in the chemotherapy arm. Data about the use of target therapies in the perioperative treatment of resectable CRCLMs are still scarce. A recent single-arm phase-II study [11] assessed a perioperative treatment with capecitabine, oxaliplatin and bevacizumab in 56 patients with resectable liver metastases and at least one risk factor according to the Fong risk score. Radical resections were performed in 52 out of 56 patients, with 11 synchronous resections of primary tumor and metastases; bevacizumab, which was stopped 5 weeks before surgery, did not increase postoperative morbidity significantly. The study showed a high response rate (73.2%) and disease control rate (94.6%) with 11 complete pathological responses (8.9%). The trial confirmed the safety and feasibility of bevacizumab in the preoperative treatment of liver metastases. Currently, different studies are evaluating the role of target therapies in the treatment of colorectal cancer liver metastases. The EORTC BOS-2 trial, a randomized phase-II trial, is comparing FOLFOX alone, FOLFOX plus bevacizumab, and FOLFOX plus panitumumab in the perioperative treatment of patients with resectable liver metastases from K-RAS wild-type colorectal cancer. Another ongoing trial in this setting is the New EPOC trial, an English phase-III randomized trial comparing chemotherapy with oxaliplatin/irinotecan plus fluorouracil versus oxaliplatin/irinotecan plus fluorouracil and cetuximab pre- and postoperatively in patients with resectable, KRAS wild-type CRCLMs. The primary endpoint of the study is PFS. Other clinical trials are comparing the perioperative strategy with the adjuvant strategy in the treatment of liver metastases. In the NSABP C-11 phase-III trial, patients are randomized to perioperative chemotherapy with FOLFOX/FOLFIRI plus bevacizumab or adjuvant postoperative chemotherapy with the same regimen. An ongoing phase-III Chinese study has a similar design, comparing perioperative FOLFOX and adjuvant FOLFOX in the same setting.

3. Unresectable metastases In initially uresectable patients, currently available combination chemotherapy regimens – such as FOLFOX or FOLFIRI with the possible addition of targeted agents – can

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Table 1 Perioperative chemotherapy for resectable colorectal cancer liver metastases. Results from the EORTC 40983-EPOC trial (first publication). Patients

Perioperative chemotherapy

Surgery

All Eligible Resected

182 171 151

182 171 152

Absolute difference for 3-year PFS +7.3% (28.1–35.4%) +8.1% (28.1–36.2%) +9.2% (33.2–2.4%)

HR

P-value

0.79 0.77 0.73

0.058 0.041 0.025

PFS, progression-free survival.

allow, in case of response, radical resection of liver metastases, offering to the patients a chance of long survival or even cure. In this subgroup of patients a significant tumor shrinkage is necessary to “convert” unresectable metastases to resectability; the use of a highly active treatment is therefore warranted. Indeed, the importance of tumor response has been clearly outlined in a pooled analysis showing a significant correlation between response rate to front-line chemotherapy and resection rate of liver metastases [12]. According to the GERCOR trial, standard doublet chemotherapy regimens used in the first line, such as FOLFOX and FOLFIRI, offer response rates of around 50% with resection rates of 9–22% and R0 resection rates of 7–13%, with no significant differences between the two regimens [13]. On the basis of these data, both the doublets are considered equivalent in efficacy in the preoperative setting. The intensification of chemotherapy with the addition of a third agent to these regimens has been shown to increase the response rates and the resection rates in this subset. In a phase-III trial by GONO (Gruppo Oncologico Nord-Ovest) [14], the FOLFOXIRI regimen significantly increased the response rate and radical resection of metastases compared to FOLFIRI (15% versus 6% all patients; P = 0.0033; 36% versus 12% in livermetastases-only patients; P = 0.017). The feasibility of this approach was confirmed by a small single-arm French study [15] which evaluated a similar chemotherapy combination, called FOLFIRINOX, in 34 colorectal cancer patients with potentially resectable liver metastases. The activity of the regimen was high, with a response rate of 70.6%; 82% of the patients underwent liver surgery after chemotherapy, and nine patients (26.5%) achieved radical resection (R0). The not negligible toxicity profile of these “intensified” chemotherapy regimens, in particular the relatively high rate of severe hematological and gastrointestinal side effects, suggest that care should be taken in the selection of patients suitable for this strategy. The integration of combination chemotherapy with targeted agents, namely bevacizumab and cetuximab, has recently become the standard treatment for most advanced colorectal cancer patients considering the improvement in patients’ outcome observed in clinical trials. Data about increase in conversion rates with targeted agents come mainly from phase-II studies or secondary analysis of randomized trials which evaluated these drugs in broader metastatic populations (Table 2). The largest set of data about the anti-VEGF (vascular endothelial growth factor) monoclonal antibody

bevacizumab comes from the first BEAT trial, a phase-IV trial evaluating the addition of bevacizumab to chemotherapy given at the investigator’s choice in mCRC patients. Among the 1914 patients enrolled, hepatic resection was carried out in 225 patients (11.8%), with radical resection (R0) achieved in 173 patients (9%). In the liver-only disease population (704 patients), metastasectomy was performed in 15.2% (107 patients) with an R0 rate of 12.1% (85 patients). Two-year OS rates in patients with liver-only disease reached 94% in patients undergoing R0 hepatic resection compared with 54% in the whole population [16]. Resection rates were apparently higher with the use of oxaliplatin-based regimens compared to irinotecan-based chemotherapy, but this difference was not statistically significant. Another large analysis comes from the NO16966 study, which assessed the addition of bevacizumab to FOLFOX (or XELOX) in advanced colorectal cancer patients [17]. Secondary resection rates were not an endpoint of the study, but these data were retrospectively collected and analyzed. In the bevacizumab arm, 44 patients out of 699 (6.3%) underwent R0 resection compared with 34 out of 701 (4.9%) in the placebo arm; this difference was not statistically significant (P = 0.24). Similarly, in the subgroup of liver-only disease at baseline, 26 out of 211 patients (12.3%) of those receiving bevacizumab underwent curative surgery compared with 24 out of 207 (11.6%) patients receiving placebo (P = 0.81). It is noteworthy, however, that the number of patients undergoing resection in this trial was small; thus the ability of this trial to detect a difference in resection rates would be quite limited. Encouraging results in the preoperative setting have been observed also in clinical trials evaluating the anti-EGFR (epidermal growth factor receptor) antibody cetuximab. Notably, in the first studies with cetuximab the population was not selected for KRAS status, and the influence of this biomarker was assessed in retrospective analysis. The large phaseIII CRYSTAL trial [18], which randomized 1198 patients to FOLFIRI plus cetuximab or FOLFIRI alone as firstline treatment for unresectable mCRC, showed an increased response rate in K-RAS wild-type patients treated with cetuximab compared to patients treated with chemotherapy alone (57.3% versus 39.7%). Resectability rate, evaluated in the whole population, reached 7.0% in cetuximab-treated patients versus 3.7%. Radical resection was achieved in 4.8% of patients in the cetuximab arm versus 1.7%; P = 0.002. Similar results in terms of response rates and resection rates were observed in the OPUS trial, a randomized phase-II trial comparing FOLFOX plus cetuximab with FOLFOX alone [19].

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173 (9.0%) 85 (12.1%) 44 (6.3%) 24 (11.6%) 34 (4.9%) 24 (11.6%) 4.8% 1.7% 4.7% 2.4% 20 (38%) 16 (30%) 57.3% (WT) 39.7% (WT) 57% (WT) 34% (WT) 68% 57% 599 599 169 168 56 55 II

II

OPUS

CELIM

WT, KRAS wild-type.

III CRYSTAL

FOLFIRI + cetuximab FOLFIRI FOLFOX + cetuximab FOLFOX FOLFOX + cetuximab FOLFIRI + cetuximab

III NO16966

FOLFOX/XELOX + bevacizumab FOLFOX/XELOX + placebo

38% 38%

7% 3.7%

225 (11.8%) 107 (15.2%) 1914 704 (liver only) 699 211 (liver only) 701 207 (liver only) IV First BEAT

Chemotherapy + bevacizumab

Response rate Number of patients Phase

Regimen

Resection rates in a more selected population have been reported in the recent phase-II CELIM trial [20]. This trial randomized 114 patients with unresectable liver metastases to receive either FOLFOX or FOLFIRI in association with cetuximab. Non-resectability was defined as having five or more liver metastases or metastases that were viewed as technically non-resectable by the local liver surgeon and radiologist (based on inadequate future liver remnant, or vascular infiltration). Treatment was administered for 16 weeks and then resectability was reassessed by the multidisciplinary team. Afterwards, resectability was reassessed every 2 months, and patients deemed to be resectable underwent surgery within 4–6 weeks from the last chemotherapy cycle. The primary endpoint of the study was response rate. A 62% response rate was observed in the whole population with a non-significant difference between FOLFOX (36 out of 53 patients, 68%) and FOLFIRI (30 out of 53 patients, 57%). In the KRAS wild-type population a 70% response rate was achieved compared to 41% in KRAS mutant patients (P = 0.008). R0 resections were achieved in 38% of patients in the FOLFOX arm and 30% of patients in the FOLFIRI arm. A retrospective review of resectability was performed by seven surgeons on 68 patients; following review, 41 of 68 patients (60%) were judged to be resectable after chemotherapy, compared with 22 of 68 patients (32%) at baseline. This difference was statistically significant (P < 0.0001), leading to an apparent increase in resectability of 28%.

4. Adjuvant chemotherapy after liver resection

Study

Table 2 Conversion rates in unresectable colorectal cancer liver metastases patients treated with bevacizumab or cetuximab containing regimens.

Resection rate

R0 rate

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Recurrence after liver resection is a significant problem, with about 70% of patients developing recurrence after surgery. Most treatment failures are due to local hepatic recurrences, lung recurrences or both, and most develop within the first 2 years after surgery. Therefore, the use of an adjuvant systemic chemotherapy has a strong rationale in this setting, and in Europe and United States postoperative chemotherapy is usually administered after liver resection, even if data from randomized trials are limited. Four randomized trials compared adjuvant systemic chemotherapy with observation after liver resection; only two of them were adequately powered and included more than 100 patients. The Canadian–European ENG (EORTC/NCICTG/GIVIO) trial showed a non-significant trend toward a longer recurrence-free survival (RFS) (median RFS 39 versus 20 months; P = 0.35) and an increase in OS (median OS 53 versus 43 months; P = 0.39) for postoperative 5fluorouracil/folinic acid compared to surgery alone [21]. Notably, the study included not only patients with liver metastases but also patients with resected lung metastases. Another study with a similar design was performed by the FFCD (Federation Francophone de Cancerologie Digestive) and published in 2006 [22]. The study randomized 173 patients to liver resection alone or liver resection followed by 6 months of adjuvant chemotherapy with bolus 5-FU/FA. The

A. Bittoni et al. / Critical Reviews in Oncology/Hematology 85 (2013) 332–341

5-year disease-free survival (DFS) rates, the primary endpoint of the study, were 26.7% and 33.5% for observation versus chemotherapy, respectively. The difference was not statistically significant in univariate analysis, and only after adjusting for negative prognostic factors (e.g. synchronous and multiple metastases) was a significant positive effect for chemotherapy seen (OR for recurrence or death, 0.66; 95%CI, 0.46–0.96; P = 0.028). A trend for an increased OS was also observed for chemotherapy. A pooled analysis of the 278 patients from the two trials was performed; a trend for improved PFS was observed, with a median PFS of 27.9 versus 18.8 months (P = 0.058) for adjuvant chemotherapy versus surgery alone, while median OS was 62.2 and 47.3 months, respectively (P = 0.095). Adjuvant chemotherapy was independently associated with PFS (P = 0.036) and OS (P = 0.046) in multivariate analysis, along with the number of metastases (≥2) [23]. The use of 5-FU-based adjuvant chemotherapy after liver resection is further supported by the results of large retrospective analyses carried out in Europe and North America [24,25] showing significant associations between chemotherapy and improved survival. The intensification of the postoperative treatment has been recently investigated in a randomized phase-III trial comparing infused 5-FU/FA versus FOLFIRI following R0 resection of colorectal liver metastases [26]. The trial showed no benefit in the addition of irinotecan to 5-FU alone in DFS, the primary endpoint of the study (median DFS: 24.7 versus 21.6 months for FOLFIRI versus 5-FU/FA respectively; P = 0.44). Actually, the results were consistent with the lack of benefit from the use of irinotecan in the adjuvant treatment of stageIII colorectal cancer [27]. The FOLFOX regimen, commonly used as adjuvant treatment in colorectal cancer, is currently being assessed in randomized trials in this setting. The use of hepatic arterial infusion (HAI) with 5-FU derivates has been extensively evaluated as adjuvant treatment after liver resection [28–30]. Despite the interesting results coming from clinical trials, this strategy has not been universally accepted, mainly because of technical difficulties and specific toxicities, and it is not commonly used.

5. Duration of treatment and toxicity Despite the advantages of preoperative chemotherapy, systemic treatment can result in severe liver damage and may result in increased perioperative morbidity and mortality in the neoadjuvant setting. Different chemotherapeutic agents have been associated with specific toxicities. In particular, sinusoidal injury can be observed after oxaliplatin treatment, while irinotecan treatment has been associated with an increased risk of steatohepatitis. While sinusoidal lesions have not been correlated with increased mortality after surgery, irinotecan-related steatohepatitis has been associated with an increased 90-day mortality due to liver failure after surgery [31]. Nevertheless, this has not been confirmed

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in other studies and is probably related to the duration of treatment. Indeed, several studies have shown the association between the duration of preoperative chemotherapy and the risk of hepatic injury or postoperative morbidity [32]. Considering the important role of VEGF in woundhealing processes, concerns about a possible influence of bevacizumab in perioperative morbidity have been raised. On the basis of available clinical data, and given the half-life of bevacizumab (11–50 days), it is currently recommended that bevacizumab be stopped at least 6 weeks before surgery. Clinical experiences have shown that even shorter intervals could not increase the rate of complications [10]. In the phaseII study of preoperative chemotherapy with XELOX and bevacizumab cited above, there was no increase in wound healing or bleeding complications compared to those in historical controls. Interestingly, recent evidence suggests a protective role for bevacizumab against oxaliplatin-related sinusoidal injury [33]. To date there are no suggestions about an increase in postoperative complications or changes in liver parenchyma for cetuximab-containing regimens. On the basis of these considerations, the duration of neoadjuvant chemotherapy should be limited to reduce the risk of liver toxicity, and response should be evaluated at short intervals during the treatment. In patients with potentially or marginally resectable liver disease, surgical resection should be considered as soon as radical surgery is deemed to be achievable. As described above, reduction in tumor size facilitates the possibility of curative resection, and tumor shrinkage is essential in patients with potentially resectable disease. However, the complete disappearance of liver metastases after neoadjuvant treatment, while rarely associated with a complete pathological response, may impact on the chances of achieving a radical resection during surgery. In a series of 66 liver metastases [34] that disappeared after chemotherapy, it was shown that persistent macroscopic disease was present at surgery at the site of 20 lesions (30.3%), despite the radiological complete response. Considering also microscopic residual disease and early recurrence in situ, residual disease was present in 55 of 66 lesions (83%) having a complete response on imaging. By contrast, complete tumor eradication is observed in some cases, whether the initial tumor sites have disappeared (CCR, complete clinical response) or still persist (no CCR) radiologically. From an oncological perspective, the complete tumor destruction (CPR, complete pathological response) has more clinical relevance than CCR. It has been demonstrated that a CPR is associated with improved prognosis in patients undergoing resection of liver metastases and with uncommonly high survival rates [35,36]. To this end, some authors have assessed pathological analysis of viability of liver metastases after preoperative chemotherapy as a tool to evaluate response to treatment. In particular, Ribero et al. [33] assessed this new histological tool on 105 mCRC patients who underwent resection of liver metastases after chemotherapy with or without bevacizumab. Response to chemotherapy was evaluated by pathological

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Colorectal cancer liver metastases

Potentially resectable

Resectable

Unresectable

Low risk

Biologically challenging

Technically challenging

Ultimately resectable

Never resectable

-Single M+ -Size ≤5 cm -N0 at primary tumor -Metachronous metastases or long DFS (>12 months) -CEA ≤100 ng/mL

-Multiple metastases -Size >5 cm -N+ at primary tumor -Synchronous metastases or short DFS (<12 months) -CEA >100 ng/mL

-Close to hepatic veins or portal branches -Major hepatectomy required

>70–80% of liver involvement <25% remnant after resection -6 segments involved

Unresectable extrahepatic disease

Surgery

Perioperative chemotherapy + surgery

Conversion chemotherapy + surgery (if sufficient response)

Palliative chemotherapy

Fig. 1. Treatment strategies for colorectal cancer patients with liver metastases.

analysis of tumor viability, and in particular, as the percentage of viable tumor in relation to tumor surface area. Then patients were stratified into four groups according to the magnitude of their tumor viability (<25%, 25–49%, 50–75%, and >75% of total tumor surface area). This study showed that a higher proportion of patients treated with bevacizumab had <25% residual tumor cells than patients who did not receive bevacizumab (45% versus 23%; P = 0.02), providing pathological support for the effectiveness of bevacizumab in combination with standard chemotherapy in patients with colorectal cancer liver metastases. These results have been confirmed by another retrospective analysis that showed higher CPR for bevacizumab-containing regimens compared to chemotherapy alone [37]. Another issue in the definition of the best regimen in the preoperative treatment of liver metastases is the assessment of tumor response with the use of targeted agents. It is well known that the RECIST criteria, developed for the evaluation of response to cytotoxic agents, may be of limited value in the assessment of response to biological agents such as bevacizumab. In a

series of 234 liver metastases from colorectal cancer patients treated with bevacizumab-containing regimens, new tumor response criteria, based on morphological changes of the lesions on CT scan, were evaluated [38]. The CT-based morphological criteria proved to be significantly associated with pathological tumor response and overall survival of the patients, confirming that in bevacizumab-treated patients the response to treatment is often displayed by changes in the radiographic morphological pattern more than in tumor size reduction.

6. Conclusions Multimodal treatment strategies can significantly improve the outcome of patients with liver-confined metastatic colorectal cancer. Liver resection offers to the patient a chance of long-term survival or cure. Despite a strong rationale, data from clinical trials on adjuvant chemotherapy after liver metastases resection are not convincing. Possible reasons

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include small trials, long accrual periods, methodological problems, and the use of outdated chemotherapy regimens. Nevertheless, in clinical practice the common practice of administering an “adjuvant” treatment with FOLFOX or fluoropyrimidines to stage-IV resected colorectal cancer patients seems to be reasonable. The role and timing of chemotherapy in the management of resectable liver metastases are still debatable. The results of EORTC-EPOC trial, demonstrating a DFS benefit for perioperative chemotherapy in the treatment of resectable liver disease, make chemotherapy a standard option in this setting. The use of 3 months of preoperative chemotherapy followed by another 3 months after surgery has been shown to be safe and effective in this setting by EPOC trial. The risk of progressive disease, leading to unresectability, during the preoperative part of treatment is low with the currently used regimens. Retrospective data suggest that progression during neoadjuvant chemotherapy predicts poor outcome after resection [39]; in these cases, a multidisciplinary assessment is recommended to decide whether to offer second-line chemotherapy or to proceed to surgery, given that lesions are still resectable. In the EPOC trial, 12 patients (7%) in the chemotherapy arm had progression during the treatment and eight (4%) were no longer deemed resectable. Half of them developed new lesions during the treatment, and in these patients an upfront resection would probably not have been beneficial. Patients with resectable liver metastases and without high-risk features – such as patients with small (<5 cm), solitary, metachronous metastases – should probably proceed to upfront surgery, particularly if there is a risk of disappearance of the lesion, which may compromise surgical resection (Fig. 1). In patients with technically challenging liver metastases or ultimately resectable metastases, the use of highly active chemotherapy regimens can allow conversion to resectability in selected patients, and therefore increasing response rate is an important issue. In this setting consideration should be given to the use of three-drug regimens (such as FOLFOXIRI) or doublet combined with targeted agents. In patients with KRAS mutant tumors the choice is limited to bevacizumab, while in KRAS wild-type tumors cetuximab and panitumumab may be the preferred options. As already discussed, the addition of cetuximab to chemotherapy has been demonstrated to significantly increase response rates and resection rates in patients with colorectal cancer liver metastases, and the improvement in response rates is apparently greater than that observed in trials with bevacizumab. Nevertheless, several studies have shown that pathological responses are increased with the use of bevacizumab in the preoperative setting. Moreover, when choosing a treatment strategy for liver metastases, consideration should be given to the fact that a delay period is required after treatment with bevacizumab before surgery. Globally, in this setting the anti-EGFR (epidermal growth factor receptor) antibodies in combination with chemotherapy may represent the preferred option in KRAS wild-type tumors, while in KRAS

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mutant colorectal cancer the choice is limited to bevacizumab plus chemotherapy or, in selected patients, chemotherapy triplets. The duration of preoperative chemotherapy should be limited and radical surgery should be considered as soon as resectability is achieved. A postoperative treatment should follow for 3–6 months with a regimen chosen considering response and tolerance to preoperative therapy. Finally, a multidisciplinary assessment and management of patients with liver metastases from colorectal cancer is the way forward to improve patients’ prognosis. The choice of treatment for each patient should take account of the biology of the tumor, surgical technical aspects, and patient’s characteristics and preferences.

Conflict of interest statement All the authors have declared that they have no conflict of interest.

Funding sources No sponsors were involved in the writing of the manuscript or in the decision to submit the manuscript for publication.

Reviewers Axel Grothey, M.D., Mayo Clinic, Division of Medical Oncology, 200 First St SW, Rochester, MN 55905, United states. Alberto Zaniboni, M.D., Fondazione Poliambulanza, Oncology Department, Via Gabriele Rosa, 3, I-25121 Brescia, Italy.

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Biography Dr Alessandro Bittoni has been a fellow of the Postgraduate School of Oncology, Medical Oncology Unit of the Università Politecnica delle Marche, since 2008. He got his M.D. degree in 2007 with a dissertation on the prognostic role of IGF-1 and IGF-2 in GISTs (gastrointestinal stromal tumors), obtaining 110/110 cum laude. At present he is involved in clinical research and trials on

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treatment of solid tumors, especially on gastrointestinal cancer. In particular he participated as sub-investigator in about ten trials in good clinical practice, also taking care of the enrolled patients in clinic and day hospital. He worked at the Department of Medicine of the Royal Marsden Hospital, UK (Gastrointestinal and Lymphoma Unit) from February to July 2011 as Honorary Clinical Fellow. He is an author of several scientific publications and chapters in books.