Update on the optimal management of patients with colorectal liver metastases

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1 Critical Reviews in Oncology/Hematology 84 (2012) Review Update on the optimal management of patients with colorectal liver metastases Steven R. Alberts Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States Accepted 22 February 2012 Contents 1. Introduction Methods Local approaches Surgery Radiofrequency ablation Microwave ablation Surgery for recurrence after previous resection and/or RFA Selective internal radiation therapy Stereotactic body radiotherapy Hepatic artery infusions Multidisciplinary care Neoadjuvant/adjuvant therapy Downsizing initially unresectable disease Targeted therapy Bevacizumab Anti-EGFR Potential for liver damage after systemic chemotherapy Conclusions Conflict of interest statement Reviewers Acknowledgments References Biography Abstract Patients with colorectal liver metastases represent a distinct subset of metastatic colorectal cancer. Optimal management requires a multidisciplinary approach, local and systemic. Curative hepatic surgery is standard for resectable cases, but unfortunately, the majority of patients are not initially resectable due to the size, location, and/or extent of disease, inadequate remnant liver volume, or comorbidities. Other local approaches may be complementary (such as portal vein embolization) or alternative (such as ablation, hepatic arterial infusion, selective internal radiation therapy, and stereotactic body radiotherapy) to surgery. Systemic therapy can downsize disease, allowing surgical resection and, potentially, long-term survival, but it must be balanced against the potential for hepatotoxicity. Current standard approaches including Tel.: ; fax: address: alberts.steven@mayo.edu /$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 60 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) cytotoxics and biologics, such as bevacizumab and particularly anti-epidermal growth factor receptor therapy, improve response rates and may enhance downsizing and resection rates. Optimization of local therapies and systemic conversion strategies via controlled, randomized trials is still a pending question Elsevier Ireland Ltd. All rights reserved. Keywords: Colorectal cancer liver metastases; Portal vein embolization; Ablation; Hepatic arterial infusion; Stereotactic body radiotherapy; Bevacizumab; 1. Introduction Colorectal cancer (CRC) is the fourth most common malignancy, but second leading cause of cancer mortality in the US, with an estimated 49,380 annual deaths. [1] In approximately 75 80% of cases, patients have potentially resectable disease at the time of diagnosis [1]. The overall rate of recurrence following resection depends on disease stage, from 9% in stage I to 56% in stage III, with the liver being one of the most frequent sites of recurrence [2]. Metastatic disease (metachronous metastases) is confined to the liver in 44% of patients with distant recurrence following potentially curative resection [2], whereas liverconfined metastases (synchronous metastases) are found in 77% of patients presenting with stage IV disease at diagnosis [3]. Site-confined metastatic disease, particularly involving the liver, is a distinct clinical characteristic of metastatic colorectal cancer (mcrc) that offers the potential for curative approaches. The value of primary curative resection, particularly R0 resection (clean surgical margins), in extending survival of patients with colorectal liver metastases (CLM) has been demonstrated in multiple studies [4 6]. Many patients with CLM are not amenable to surgery initially, but may become surgical candidates following systemic interventions that downsize disease. Notably, secondary resection after downsizing may afford long-term outcomes similar to primary resection, and therefore warrants consideration as a therapeutic goal in appropriate patients. Multidisciplinary decisions for patients with CLM must balance the potential for long-term benefit after surgical management against perioperative risks, and several prognostic scores have been developed to better stratify patients according to their survival prospects after surgery (reviewed in [7]). Some of these scoring systems may be somewhat outdated, as they were based on surgical patient series from the 1970s or 1980s; in addition, subsequent studies attempting to validate them have yielded conflicting results about their usefulness in clinical practice. Nonetheless, some prognostic factors appear consistent across all scoring scales. Extra-hepatic disease is an unfavorable feature, and generally viewed as a contraindication to hepatectomy. The presence of nodepositive primary disease, as well as the size and number of hepatic metastases also have negative effects on outcomes, as do high CEA levels. More recent reports revisiting the clinical value of this type of patient stratification in the context of current practices indicate that prognostic scoring may hold relevance when done after the administration of neoadjuvant or downsizing therapy and before surgery, rather than at the initiation of treatment [8]. 2. Methods A literature search was performed, using the following databases: PubMed, ASCO Proceedings (ASCO Annual Meeting and Gastrointestinal Cancer Symposium) and ESMO Proceedings (Annals of Oncology ESMO Congress and Annals of Oncology World Congress on Gastrointestinal Cancers). The following keywords were used to find relevant entries: colorectal liver metastases combined with ablation, surgery, downstaging, adjuvant, neoadjuvant, and conversion. The resulting articles were assessed for relevance for inclusion in this systematic review. 3. Local approaches 3.1. Surgery Surgery is the standard treatment approach for resectable CLM [9,10]. Five-year overall survival (OS) exceeding 50% has been reported in contemporary cohorts following hepatic resection with curative intent [11,12], with a rate of 71% reported after resection of a solitary CLM [13]. Risk factors for poorer outcome include >3 tumor sites, tumor size 5 cm, and carcinoembryonic antigen level >200 ng/ml [6,11]. The most common recurrence pattern is intrahepatic, but many patients have recurrence at extrahepatic sites, or both intraand extrahepatic sites [14]. True local recurrence occurring in the treated Couinaud segment or at the surgical margin occurs in only 2% of patients [11]. A positive surgical margin with tumor found within 1 mm of the specimen edge is associated with increased risk of recurrence and decreased OS compared with a negative margin (>1 mm). The size of the negative margin is not predictive for outcome; only the fact that it is negative is important [6]. Wedge resection and anatomic resection yield similar positive surgical margin and recurrence rates, recurrence patterns, and 5-year OS rates, and therefore are considered equivalent for patients with CLM [15]. Synchronous presentation of liver metastases at diagnosis of mcrc is frequent, bringing to the forefront the question of optimal timing for the surgical management of the primary tumor vs. the liver metastases. The traditional approach is based on sequential surgeries, colectomy followed by hepatectomy; the practice of simultaneous resection, however,

3 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) appears not to compromise general perioperative safety and is becoming an accepted standard [16 18]. This approach deserves a note of caution when major hepatectomy (of 3 or more liver segments) is required, since in these cases, perisurgical morbidity and mortality may be significantly higher with simultaneous vs. sequential surgeries [19]. Finally, a liver first strategy may be valuable in borderline resectable cases, where hepatectomy (accompanied or not by perisurgical chemotherapy, see Section 4) is performed before managing the primary tumor. A single report [20] indicated high resection rates and a 5-year OS rate of 56%. However, patients with high symptom burden from their primary tumor may not be appropriate for this approach; in addition, the potential for complications as the liver treatment is taking place may need to be considered, such as primary tumor progression (or other) that may require unplanned procedures. In fact, it appears that liver-first approaches could reduce the likelihood of full treatment completion [21]. A complete resection requires that an adequate liver remnant remains after surgery. An adequate remnant volume for safe resection depends on the degree of underlying liver damage: it should be >20% in patients with normal liver, >30% in those with moderate liver disease, and >40% in those with well-compensated cirrhosis [22]. Portal vein embolization (PVE) to increase the volume and function of the remnant several weeks before hepatic resection is an option when the calculated remnant volume is inadequate [22]. A metaanalysis of 37 studies involving 1088 patients showed that PVE reduced risk of hepatic failure due to an inadequate remnant, with minimal morbidity and no mortality [23]. Moreover, multiple studies have shown that PVE increases the resectability rate in patients with initially unresectable CLM, with long-term outcomes comparable to resection without PVE [24 27] Radiofrequency ablation Radiofrequency ablation (RFA) is an option for patients with CLM who cannot undergo resection due to comorbidities, location of metastatic lesions, or inadequate liver remnant volume. RFA may be performed during open laparotomy either alone or with concomitant hepatic resection or other procedures; laparoscopically via 2 3 incisional ports; or percutaneously [28]. Ultrasound or another imaging modality is used to guide placement of the radiofrequency electrodes near the metastatic site. High-frequency alternating current delivered via the electrodes increases the temperature in the surrounding tissue, promoting protein denaturation, tissue coagulation, and desiccation as the tumor dissolves [29]. Most retrospective cohorts have shown RFA to be inferior to resection in terms of recurrence rates and OS [11 13,30,31]. For example, outcomes were compared retrospectively for 190 patients who underwent resection alone, 101 patients who had both resection and RFA, and 57 patients who had RFA alone [11]. Patients who underwent resection only compared with those who had RFA plus resection or RFA alone had significantly lower recurrence rates (52% vs. 64% and 84%; P < 0.001) and higher 4-year OS (65% vs. 36% and 22%; P < ). Moreover, intrahepatic recurrence occurred at a 4-times lower rate after resection than RFA (11% vs. 44%; P < 0.001). While these retrospective differences may reflect patient selection bias, technological limitations of the RFA method, or a combination of both, based on current data, RFA cannot replace surgery in patients with completely resectable disease [8]. RFA may become a viable option for those with unresectable liver metastases, pending more prospective research [28] Microwave ablation Based on results obtained from animal models, microwave ablation may allow for longer ablation zones and less bloodvessel deflection and heat-sink effect than RFA, resulting in consistently higher-temperature procedures [32]. Unfortunately, as with other emerging techniques, clinical data are still limited. Several retrospective or observational studies have shown that this approach is feasible in patients with CRC metastases by itself or combined with surgical hepatectomy in cases where complete resection is not possible [33 36]. However, the heterogeneity of those studies makes it challenging to determine whether outcomes with microwave ablation are on par with surgery or RFA. In a small randomized trial of 30 patients with multiple CLM, microwave ablation appeared to provide similar outcomes to surgery (3-year OS rates of 14% vs. 23% with hepatectomy) [37]. A larger, safety-based study of this procedure in patients with primary or metastatic liver disease (including 257 patients with CLM) demonstrated a mortality rate of 0.2% (no events in patients with CRC), and a major complication rate of 2.6%, including pleural effusion, tumor seeding and liver abscesses [38]; less severe (but more frequent) complications included fever, pain and asymptomatic pleural effusion Surgery for recurrence after previous resection and/or RFA Repeat curative intent surgery is being increasingly performed in patients who have recurrent CLM. A total of 246 patients were identified from a large multi-institutional database, who initially underwent curative intent hepatic resection and/or RFA, and then underwent a repeat curative intent procedure [39]. A subset of 46 patents underwent a third curative intent procedure, and 9 patients had a fourth such procedure. The mean intervals between the first and second procedures and between the second and third procedures were 19.1 months and 21.5 months, respectively. The extent of hepatic resection decreased with each subsequent procedure, with RFA used in approximately one-fourth of the repeat procedures. Mortality and morbidity rates were similar after each repeat procedure. Five-year OS was 47%,

4 62 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) %, and 24% after the first, second, and third curative intent hepatic surgery, respectively, with presence of extra-hepatic disease predictive of poorer survival (P = 0.01). A smaller retrospective analysis considered surgical resection of recurrent CLM in 28 patients who initially underwent RFA alone [40]. The median time from initial treatment to recurrence was 12 months, with most patients (79%) having recurrence only at the RFA site. In this cohort, 3-year OS and disease-free survival were 60% and 29%, respectively. Considered together, these retrospective analyses suggest that repeat curative surgery may be valuable for a meaningful percentage of patients with recurrent CLM Selective internal radiation therapy Selective internal radiation therapy (SIRT) and stereotactic body radiotherapy (SBRT) are newer local treatment options, but limited long-term information is available. SIRT, or radioembolization, delivers yttrium-90 microspheres via catheter into the hepatic artery to the CLM [41]. SIRT takes advantage of the fact that blood supply for much of the normal liver parenchyma arrives through portal circulation. The microsphere size precludes access to the venous circulation, therefore, a high radiation dose (>100 Gy) is delivered selectively to mostly metastatic sites while sparing normal liver parenchyma. The role of SIRT in treating CLM remains controversial; it may be an option for highly selected patients with unresectable metastases [10]. In a prospective study, SIRT was delivered at a median dose of 118 Gy to 72 patients with liver-dominant colorectal metastases, most of whom had received prior chemotherapy for mcrc [42]. The tumor response rate was 40%, with grade 3/4 bilirubin toxicity seen in 13%. Radiographic response predicted improved median OS (23.5 vs. 8.5 months; P = ). Other favorable predictors of survival were performance status 0, tumor burden 25% of the liver, and absence of extrahepatic disease. SIRT was evaluated as salvage therapy in a retrospective cohort of 208 patients with unresectable CLM, producing radiographic responses in 35% [43]. Median survival was 10.5 months for responders compared with only 4.5 months for non-responders. Comparable results have been reported in smaller cohorts that received SIRT as salvage therapy, with median OS ranging from 6.9 months to 11.6 months [44 47]. The feasibility of administering SIRT in conjunction with first-line chemotherapy was evaluated in a phase I trial involving 20 patients with CLM, of whom seven (35%) had liver-only metastases [48]. Patients received a modified FOLFOX4 regimen (reduced-dose oxaliplatin and full-dose 5-FU/LV during the first 3 cycles followed by full-dose FOL- FOX4 in subsequent cycles). SIRT was administered on day 3 or 4 of cycle 1. Eighteen patients (90%) had partial responses. Median progression-free survival (PFS) was 9.3 months for the entire cohort and 14.2 months for the subset with liveronly metastases Stereotactic body radiotherapy In SBRT, highly ablative radiation doses are delivered directly and accurately to the CLM in a limited number of fractions, with sharp dose gradients surrounding the target [49]. Outcomes following SBRT were assessed in a pooled tri-institutional analysis of 65 patients with CLM [50]. The patients had 1 4 metastases, received 1 6 SBRT fractions, and had radiologic imaging at least 3 months after treatment. Most patients (72%) had received chemotherapy before SBRT, including 42% with 2 previous regimens. During a median follow-up period of 1.2 years, 24 patients (37%) had local in-field recurrences and 44 patients (68%) had extrahepatic disease progression. The 2-year local control rate by lesion was 55%; the total radiation dose (P = ) and dose per fraction (P = 0.003) were independently associated with better local control. The 2-year OS was 38%; only the absence of active extrahepatic metastases was independently associated with improved OS (P = 0.046), although sustained local control showed borderline significance (P = 0.06). Using a tumor probability model, it was estimated that a dose range of Gy delivered in 3 fractions would be needed to achieve a 1-year local control rate of >90%. Other studies have investigated SBRT to the liver, or in patients with CRC, without focusing exclusively on CLM. For example, 40 of 68 patients (59%) in a phase I trial of individualized SBRT in liver had CLM, whereas the others had liver metastases due to breast cancer or other tumor types [51]. Prior treatments in the colorectal cohort included surgery (12%), RFA (15%), and chemotherapy (85%). Outcomes were presented for the entire cohort: the 1-year local control rate was 71% and median PFS and OS were 3.9 and 17.6 months, respectively. Only 1-year OS was reported for the subset with CLM; it was 63%. In another study in mcrc, 44 of 64 patients (69%) had liver-only colorectal metastases whereas the remaining patients had colorectal metastases at other sites [52]. SBRT was delivered in 3 fractions to a total dose of 45 Gy. Outcomes were presented for the entire cohort; the 2-year patient-based local control rate was 64%, and 2- year PFS and OS were 19% and 38%, respectively. Five-year OS was 13%. Outcomes were not presented for the CLM subset, although it was reported that extrahepatic metastases were associated with better survival in the multivariate analysis Hepatic artery infusions Hepatic artery infusions (HAI) permit delivery of high chemotherapy concentrations directly to tumor sites via a catheter or implantable pump connected to a subcutaneous port [53]. Floxuridine (FUDR), which is converted to 5-FU in the liver, is the preferred agent, since its high liver extraction rate and short systemic half-life allow for high drug concentrations in the liver [54]. HAI was compared with systemic chemotherapy in a meta-analysis of 10 randomized trials involving 1277 patients with unresectable CLM, of whom

5 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) patients (53%) were allocated to HAI [55]. HAI consisted of FUDR in 8 trials, either FUDR or 5-FU plus leucovorin in 1 trial, and 5-FU plus leucovorin in the other trial, whereas systemic chemotherapy consisted of 5-FU plus leucovorin in 7 trials and FUDR in the other 3 trials. HAI yielded significantly higher tumor response rates compared with systemic chemotherapy (42.9% vs. 18.4%; RR = 2.26; P < ), but it did not translate into a survival benefit. Median OS was 15.9 and 12.4 months, respectively (HR = 0.90; P = 0.24). Accordingly, HAI with FUDR is not used routinely for the treatment of unresectable CLM, particularly in light of improved systemic regimens that incorporate oxaliplatin, irinotecan, and targeted agents, and the specific technical expertise required for the procedure [10,53]. 4. Multidisciplinary care 4.1. Neoadjuvant/adjuvant therapy When small-sized CLM are initially amenable to resection, the use of neoadjuvant therapy offers the potential for better post-surgical outcomes (by presumably eradicating micrometastatic disease) and also allows assessment of response in order to better guide postsurgical treatment; this step, however, is not without controversy, due to the risk for tumor progression during systemic therapy (which is associated with a significant worsening of the prognosis [55]), and to the possibility that the achievement of a complete response will interfere with surgical feasibility. Adjuvant systemic therapy after surgery may also have an effect on micrometastatic disease and therefore reduce the risk of recurrence [56]. Initial evidence of the potential benefit of adjuvant therapy in this context came from a pooled analysis of 2 randomized trials (with a total of 278 patients). These trials investigated the administration of 6 cycles of bolus 5-FU after surgery (vs. no adjuvant treatment), and the pooled analysis showed trends nearing statistical significance in favor of the 5-FU treatment, for both PFS and OS [57]. A subsequent phase III trial (with 321 patients randomized) that compared protracted 5-FU infusion vs. FOLFIRI as adjuvant treatment in this same setting produced negative results, showing no advantage with the irinotecan regimen [58]. The effect of perioperative chemotherapy (pre- and postsurgery) versus surgery alone was evaluated in 364 patients with initially resectable CLM in the EORTC40983 trial [56]; this study, unfortunately, did not include an additional arm to evaluate adjuvant treatment only, which would have contributed to a deeper understanding of the relative merits of each therapeutic step. Patients allocated to the perioperative chemotherapy arm received 6 cycles of FOL- FOX4 before surgery and 6 cycles afterwards; surgery was performed at a median of 4.1 weeks after the last FOL- FOX4 administration [56]. A similar percentage of patients in both groups 83% in the chemotherapy arm and 84% in the surgery alone arm underwent potentially curative resection. In most other cases, the disease was more advanced than expected. One patient (0.5%) was not resected due to macroscopic liver damage that was most likely related to FOLFOX4. Perioperative chemotherapy improved 3-year PFS in the intent-to-treat population (35.4% vs. 28.1%; HR = 0.79; P = 0.058) and among surgery-eligible patients (36.2% vs. 28.1%; HR = 0.77; P = 0.041) [47]. Reversible postoperative complications occurred more frequently in the chemotherapy arm (25% vs. 16%; P = 0.04). This study shows that perioperative FOLFOX4 chemotherapy is compatible with major liver surgery and reduces disease progression in patients with initially resectable CLM. Further investigation is in progress by cooperative research groups. In the US, the NSABP is conducting the phase III C-11 trial, in which patients with resectable CLM (and no extra-hepatic disease) are randomized to receive 6 cycles of chemotherapy (FOLFOX6 or FOLFIRI) both before and after surgery. The incorporation of targeted therapy into adjuvant or neoadjuvant therapy is also of interest; in Europe, a small phase II study (56 patients) has already investigated the combination of bevacizumab, capecitabine and oxaliplatin as neoadjuvant therapy in patients at high risk of early recurrence, showing feasibility in terms of safety and lack of interference with liver regeneration [59]. The 3-arm phase II trial EORTC40091 (BOS2, recently activated) is comparing FOLFOX6 to FOLFOX6 plus bevacizumab and to FOLFOX6 plus panitumumab as adjuvant therapy for resectable CLM. Interestingly, while all these trials pursue the question of which regimen is superior, the question of the optimal duration of therapy before or after resection of liver metastases remains unresolved. The 6-cycle course was the first one studied, and there have been no comparisons with shorter or longer therapy plans, leaving this decision at the discretion of the treating physician Downsizing initially unresectable disease Some patients with initially unresectable CLM may become candidates for curative resection following tumor shrinkage with downsizing (or conversion) chemotherapy [10]. A systematic analysis of 5 prospective trials and 1 retrospective study found that the resection rate in patients with liver-limited metastases strongly correlated with the objective response rate (ORR) to chemotherapy (r = 0.96; P = 0.002) [60]. Combination regimens, such as FOLFOX and FOLFIRI, offer high response rates in the first-line treatment of mcrc: ORRs of 54 58% have been reported in phase III populations with metastases at any tissue site [61,62]. In these studies, secondary surgery to remove metastases was performed in 9 22% of patients, with R0 resection achieved in 7 13%. More importantly, patients who underwent surgery had favorable survival compared with the overall study population. Several phase II trials have evaluated combination regimens in patients with liver-limited metastases (Table 1) [63 67]. These trials reported ORRs of %, resection rates of %, and R0 resection

6 64 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) Table 1 Effect of combination regimens in downsizing chemotherapy of colorectal liver metastases [63 67]. Outcomes R0 rate (%) Study a Regimen Patients ORR (%) Resection rate (%) Resected patients: median time to recurrence: 19 months; 3-year OS: 67%. Entire cohort: median OS: 26 months Alberts et al. [63] FOLFOX4 N = 42; unresectable due to number (45%), location (7%), size (7%), or combination of these factors (35%) Median PFS/OS not reached after median f/u of 15 months De La Cámara et al. [64] Triplet therapy b N = 39; unresectable due to technical factors (56%) or poor prognosis for long-term survival after surgery (44%) Resected patients: median DFS: 14.3 months; all alive after median f/u of 19 months. Non-resected patients: median TTP: 5.2 months Pozzo et al. [65] FOLFIRI N = 40; unresectable due to number (35%), location (35%), size (25%), or insufficient liver reserve (5%) Resected patients: disease recurrence in 3 of 4 patients after median f/u of 33 months Ho et al. [66] FOLFIRI N = 40; unresectable due to bilobar disease (87%), size (8%), or location (5%) R0 resected patients: median RFS, 13.9 months. Entire cohort: median OS, 36 months; 2-year OS rate, 83% N = 34; unresectable based on technical inability to achieve R0 resection (due to location or size or metastases) Ychou et al. [67] Triplet therapy FOLFIRINOX DFS: disease-free survival; f/u: follow-up; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; RFS: relapse-free survival; TTP: time to progression. a Data are presented on an intent-to-treat basis for the entire cohort. b Oxaliplatin 120 mg/m 2 on day 1, irinotecan 150 mg/m 2 on days 1 and 14, and 5-fluorouracil 2600 mg/m 2 plus folinic acid 500 mg/m 2 on days 1 and 14 every 4 weeks. rates of 10 49%. In general, outcomes of resected patients were more favorable than those whose disease remained unresectable. These regimens include the triplet FOLFIRINOX, which would not be typically considered a standard regimen solely for palliative purposes. FOLFIRINOX is feasible and promising when the therapeutic goal is tumor shrinkage for resection, as indicated in the phase III trial by the Gruppo Oncologico Nord Ovest, which showed higher R0 resection rates with FOLFOXIRI compared to FOLFIRI in non-surgically selected patients (36% vs. 12%, P = 0.017) [68] Targeted therapy Three targeted agents have been shown to improve outcome in first-line mcrc when added to combination chemotherapy, including the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab [69,70], and the epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab [71 73] and panitumumab [74]. The anti-egfr agents are tailored for use in patients whose tumors express wild-type KRAS, whereas no molecular marker is available to identify patients most likely to benefit from bevacizumab. Addition of anti-egfr therapy to first-line chemotherapy has consistently increased ORR [71,73,74], whereas this was not evident in the NO16966 trial with bevacizumab [70] Bevacizumab First BEAT was an uncontrolled phase IV trial in which bevacizumab was added to the physician s choice of chemotherapy, with surgical data collected prospectively, and surgery with curative intent analyzed as a predefined secondary endpoint [75]. Surgery was recommended 6 8 weeks after the last dose of bevacizumab. Of the 1914 eligible patients, 225 (11.2%) underwent surgery with curative intent and 173 (9.0%) had R0 resections (Fig. 1). A total of R0 resection rate (%) First BEAT All pts 9 CT + Beva LLD 12.1 CT + Beva All patients CT CT + Beva NO LLD 12.3 CT CT + Beva (n=1914) (n=704) (n=701) (n=699) (n=207) (n=211) Fig. 1. R0 resection rates with bevacizumab plus chemotherapy (CT) in the entire study cohort and subset with liver-limited disease (LLD) in first BEAT and NO CT was the investigator s choice in first BEAT and either FOLFOX4 or XELOX in NO From Cassidy et al. [75].

7 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) patients had liver-only metastases, 107 (15.2%) underwent resection, and 85 (12.1%) had R0 resections [75]. In a preliminary analysis, 2-year OS was significantly greater among R0-resected patients compared with the overall study population (89% vs. 47%; P < ). NO16966 was a randomized controlled phase III trial, in which patients received bevacizumab or placebo in combination with either FOLFOX4 or XELOX. Addition of bevacizumab significantly improved the primary PFS endpoint (9.4 months vs. 8.0 months; HR = 0.83; P = ) and showed a weak trend for improving OS (21.3 months vs months; HR = 0.89; P = 0.077). However, bevacizumab did not improve ORR (47% vs. 49%; P = 0.31) [70]. Surgical information was collected retrospectively. The rate of R0 resection did not differ between the bevacizumab and placebo arms in the entire study cohort (6.3% vs. 4.9%) or in the subset with liver-only metastases (12.3% vs. 11.6%) (Fig. 1) [75]. In both arms, 2-year OS was higher among patients with R0 resection than those without it (82% vs. 38% in the placebo arm; 91% vs. 40% in the bevacizumab arm) [75].In both First BEAT and NO16966, the addition of bevacizumab was not associated with clinically meaningful increases in wound-healing complications or bleeding events compared with historical data [75]. Neoadjuvant therapy with bevacizumab and FOLFOX6 was evaluated in 21 patients with non-optimally resectable CLM in a recent phase II trial [76]. Six cycles of FOL- FOX6 and 5 cycles of bevacizumab were administered before surgery, producing an ORR of 57%. Thirteen patients (62%) underwent surgery with curative intent with 6 patients having minor postsurgical complications. The small BOXER trial (with 46 patients) investigated bevacizumab, capecitabine and oxaliplatin as a downsizing regimen for initially unresectable CLM, reporting a promising rate of conversion (40%) and no unexpected toxicities [77]. In summary, bevacizumab is a frequent de facto component of downsizing regimens, given its wide use as first-line targeted therapy. Two caveats, however, may be considered: the administration precautions necessary to ensure no increase in perisurgical risks (at least a 6-week nonbevacizumab period prior to surgery); and the inconsistent data supporting (or not) that resection rates, or even ORR, are increased with the addition of bevacizumab to chemotherapy Anti-EGFR In wild-type KRAS patients, addition of cetuximab to firstline FOLFIRI significantly improved PFS (9.9 months vs 8.4 months; HR = 0.696; P = ) and OS (23.5 months vs months; HR = 0.796; P = ) in the phase III CRYSTAL trial. addition to first-line FOLFOX4 significantly improved PFS (8.3 months vs. 7.2 months; HR = 0.567; P = ) in the phase II OPUS trial [59,60]. Moreover, cetuximab significantly increased ORR in both CRYSTAL (57% vs. 40%; P < 0.001) and OPUS (57% vs. 34%; P = ). A small minority of wild-type KRAS patients had liver-limited disease: 140 (21%) in CRYSTAL and 48 (27%) in OPUS [64]. significantly increased ORR in the liver-limited subset of both studies, to more than 70%, and produced numerically higher R0 resection rates compared with chemotherapy alone (Fig. 2). R0 resection was achieved by 13.2% and 16.0% of patients in the cetuximab arms of CRYSTAL and OPUS, respectively. The corresponding R0 resection rates in the chemotherapy arm were 5.6% and 4.3%. Despite the small size of the liverlimited subset, cetuximab addition significantly improved PFS in CRYSTAL (11.8 months vs. 9.2 months; HR = 0.56; P = 0.035) and produced a corresponding numerical improvement in OPUS (11.9 vs. 7.9 months; HR = 0.64; P = 0.39). In the PRIME trial, the addition of panitumumab to FOL- FOX improved overall PFS (9.6 months vs. 8.0 months; HR = 0.80; P = 0.02), and showed numeric increases in OS (23.9 months vs months; HR = 0.88; P = 0.17) and ORR (55% vs. 48%; P = 0.068) after extended follow-up. R0 resection rates were marginally higher with panitumumab plus FOLFOX4 compared with FOLFOX4 alone (8.3% vs. 7.0%) in the wild-type KRAS cohort [74]. However, R0 rates for the 116 wild-type KRAS patients (18% of study population) with liver-only metastases were not reported. Focusing specifically in the liver-limited disease setting, a limited study of 151 patients already refractory to chemotherapy and with unresectable disease by the time they received cetuximab-containing therapy, showed that for 27 of them, the disease was converted to resectable after a median of 6 cycles of either FOLFOX or FOLFIRI with cetuximab, reaching a median OS of 20 months, without noticeable increases in perioperative mortality or injury [79]. The randomized phase II CELIM trial evaluated first-line neoadjuvant therapy with cetuximab plus either FOLFOX6 or FOLFIRI in 109 patients with CLM that were unresectable due to technical reasons or the presence of 5 sites [80]. A multidisciplinary team reevaluated resectability after 16 weeks and then every 2 months for up to 2 years. Patients whose disease had become resectable were offered surgery within 4 6 weeks after the last treatment cycle. plus FOLFOX6 or FOLFIRI produced ORRs of 68% and 57%, respectively (differences not significant) [80]. Overall, 57 patients (54%) underwent resection, RFA, or exploratory laparotomy within a median of 5.1 months after receiving a median of 8 treatment cycles (Fig. 3). R0 resection was achieved in 38% and 30% of patients who received cetuximab plus FOLFOX6 or FOLFIRI, respectively, in 40% of those enrolled with 5 metastatic sites, and in 28% of those enrolled with technically unresectable lesions. Perioperative morbidity was reported in 36% of patients, with similar patterns between treatment groups except for a higher rate of wound infection among patients who had received FOLFIRI (17% vs. 0%) [80]. Two perioperative deaths were reported in patients who had received FOL- FOX6 (gram-negative sepsis and multiorgan failure occurring 8 and 75 days after surgery, respectively). This study lacked a non-cetuximab control arm, but showed high ORRs with cetuximab plus neoadjuvant chemotherapy [80].

8 66 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) CRYSTAL wt KRAS wt KRAS LLD OPUS wt KRAS wt KRAS LLD R0 resection rate (%) Response rate (%) FOLFIRI FOLFIRI + 2 OR=2.07 P<0.001 OR=2.65 P=0.027 FOLFIRI FOLFIRI OR=3.40 P< FOLFIRI FOLFIRI + OR=2.58 P= FOLFIRI FOLFIRI FOLFOX4 FOLFOX OR=2.55 P<0.003 OR=2.37 P= FOLFOX4 FOLFOX FOLFOX4 FOLFOX OR=4.57 P=0.016 OR=4.00 P= FOLFOX4 FOLFOX4 + (n=350) (n=316) (n=72) (n=68) (n=97) (n=82) (n=23) (n=25) Fig. 2. Effect of cetuximab on ORR (top panels) and R0 resection rate (bottom panels) with first-line FOLFIRI and FOLFOX4 in wild-type KRAS patients and in the subset with liver-limited disease (LLD) in the CRYSTAL and OPUS trials. From Köhne et al. [78]. Of interest in this study, the overall efficacy profile seemed comparable for FOLFOX or FOLFIRI combined with cetuximab. Recent phase III trials of cetuximab in combination with oxaliplatin therapy have produced negative results [81,82]; the COIN and NORDICVII studies, however, used non-folfox oxaliplatin platforms (XELOX and FLOX, respectively), which may have affected overall feasibility of administration and efficacy in combination with cetuximab, resulting in worse outcomes than those obtained with Fig. 3. Time to intervention (resection, RFA, or exploratory laparotomy) in CLM patients receiving neoadjuvant therapy with cetuximab plus either FOLFOX6 or FOLFIRI in the phase II CELIM trial. From Folprecht et al. [80]. the conventional protracted-infusion FOLFOX in OPUS or CELIM. 5. Potential for liver damage after systemic chemotherapy Chemotherapy produces a wide array of effects on the underlying liver parenchyma ranging from steatosis to steatohepatitis and sinusoidal obstruction syndrome (SOS). Steatosis is characterized by lipid-containing vesicles that alter hepatocyte function [83]. Steatohepatitis represents more severe liver damage, characterized by steatosis with lobular inflammation and hepatocyte ballooning, probably derived from chemotherapy-induced oxidative lipid peroxidation and cytokine release [83]. SOS is characterized by sinusoidal congestion and dilatation with discontinuity in the sinusoidal membranes and collagen deposition in the perisinusoidal spaces [84]. Hepatic steatosis is commonly seen on histological and radiographic analyses after 5-FU therapy [85]. The presence of moderate to severe steatosis (i.e., 33% of hepatocytes with lipid vesicles) is associated with higher postoperative morbidity, particularly infectious complications, although mortality does not appear to be elevated [83,86]. The addition of oxaliplatin or irinotecan results in higher levels of

9 S.R. Alberts / Critical Reviews in Oncology/Hematology 84 (2012) hepatic toxicity compared with 5-FU alone. Oxaliplatin has been specifically associated with SOS, the onset of which has been related to greater oxaliplatin exposure ( 6 cycles); oxaliplatin-related SOS reduces functional liver reserve and increases postoperative complications, but does not appear to increase mortality [84,87]. Irinotecan is associated with steatohepatitis, which increases both morbidity and mortality after liver resection [88]. The potential for liver damage with chemotherapy underscores the importance of limiting the number of treatment cycles. For example, in a cohort of 219 patients who underwent hepatic resection, treatment with FOLFOX-based therapy for 9 cycles did not affect pathological response rates compared with fewer treatment cycles, but increased the incidence of sinusoidal injury (42% vs. 26%; P = 0.017) and postoperative liver insufficiency (11% vs. 4%; P = 0.031) [89]. In turn, postoperative liver insufficiency led to higher complication rates and longer hospital stays, although 90- day mortality was not affected. The length, but not the type (with/without bevacizumab) of therapy was the determinant factor on the sinusoidal injury observed; in fact, the rate of injury seemed lower in patients who received bevacizumab. 6. Conclusions A multidisciplinary team approach is important for coordinating care of patients with CLM, particularly in borderline resectable cases. For initially operable cases, the inclusion of systemic therapy into the therapeutic plan improves outcomes, but any interference with the surgical component of treatment should be avoided, since it is the cornerstone of management. Individual patient characteristics must guide the decision about how many surgeries will be performed, and in which order. Multiple treatment options are available for initially unresectable disease, including local and systemic approaches. Surgeons are typically involved in the initial patient evaluation at larger academic institutions when the treatment plan is formulated, identifying which metastatic sites are truly resectable and which may be downsized to resectability with effective chemotherapy. In smaller practices, however, initiating systemic therapy is often prioritized, and a surgical consult may be delayed to a point where chemotherapy-related liver toxicity, or poor metastatic site visualization, may compromise surgery. Where a local approach is considered but surgery itself may be problematic, RFA is a widely used alternative. Newer radiation-based strategies may also be emerging as options, but their use is less common. The goals of treatment, whether best response, conversion to resectable disease, or palliation, must be the rationale when selecting the type and duration of systemic therapy. In borderline resectable cases, the goal is to choose a regimen with the greatest likelihood of a rapid treatment response to allow the patient to have surgery rather than a prolonged chemotherapy course that increases risk of liver toxicity. FOLFOX in combination with an active targeted drug is a common first choice for patients not treated previously with chemotherapy. An anti-egfr drug, if the tumor has wild-type KRAS, appears to offer a higher chance of response than bevacizumab. FOLFOX is also preferable to FOLFIRI in this setting, because oxaliplatin causes less liver toxicity than irinotecan, particularly with a limited number of treatment cycles. However, FOLFIRI is acceptable for patients previously treated with adjuvant FOLFOX. Patients should be re-evaluated every 6 weeks after 2 3 chemotherapy cycles, thereby allowing the surgeon to decide when tumor shrinkage is sufficient to proceed to surgery while limiting any chemotherapy-related liver toxicity. 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