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Gastrointestinal Cancer

Chemotherapy for Colorectal Cancer Liver Metastases

^aMayo Clinic, Rochester, Minnesota, USA; ^bSt. Joseph Hospital, Center for Cancer Prevention and Treatment, Orange, California, USA

Key Words. Chemotherapy • Colorectal cancer • Liver metastases • Oxaliplatin • 5-fluorouracil

Correspondence: Steven R. Alberts, M.D., M.P.H., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55901, USA. Telephone: 507-284-8965; Fax: 507-284-1803; e-mail: alberts.steven{at}mayo.edu

Received June 27, 2008; accepted for publication August 17, 2008; first published online in THE ONCOLOGIST Express on October 6, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Lawrence D. Wagman, Medwaves, Inc., San Diego, CA; Honoraria: Lawrence D. Wagman, Angiodynamics; Research funding: Steven R. Alberts, Bristol-Myers Squibb, Pfizer, Sanofi-Aventis; Ownership interest: None; Expert testimony: None; Other: None. The article discusses the neoadjuvant use of drugs manufactured or provided by Roche, Merck, and Sanofi-Aventis. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

	Learning Objectives

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
After completing this course, the reader should be able to:

1. Explain the role of chemotherapy in the treatment of liver metastases from colorectal cancer and the shifting goals of therapy—from palliation to prolongation of life.
   
2. Select among the evolving treatment options for patients with unresectable, not optimally resectable, and resectable liver metastases.
   
3. Discuss the unresolved research issues, including the optimal timing of perioperative chemotherapy and the role of biologic agents in the management of liver metastases from colorectal cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Colorectal cancer (CRC) is a highly prevalent malignant disease in industrialized nations. The annual incidence of invasive CRC in the U.S. is among the highest in the world, and the liver is the only metastatic site in approximately one third of patients. Without treatment, patients with metastatic disease have a poor prognosis; however, long-term survival benefits and even cure have been reported in patients undergoing surgical resection of metastases. In addition, advances in chemotherapy, imaging, and surgical techniques have increased the proportion of patients who are eligible for resection. Combination therapy with fluorouracil and leucovorin has been the mainstay of treatment for metastatic CRC; however, the introduction of newer agents, such as oxaliplatin and irinotecan, and targeted agents, such as cetuximab and bevacizumab, has yielded improvements in response rates (RRs) and survival. Maximizing the exposure of hepatic metastases to high target concentrations of cytotoxic drugs using hepatic arterial infusion (HAI) increases RRs further than with systemic chemotherapy; however, the impact of HAI on survival is unclear. As the goals of chemotherapeutic treatment for metastatic CRC increasingly shift from palliation to prolongation of survival, improvement in RRs, and downsizing of tumors in order to enable or optimize resection, treatment in a multidisciplinary environment involving a medical oncologist, radiologist, and surgical oncologist with hepatobiliary expertise will become central to deciding the best course of therapy and timing of surgery.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Colorectal cancer (CRC) is the second most prevalent malignant disease in industrialized countries, with approximately 2.8 million people alive who were diagnosed with the disease between 1997 and 2002 [1]. The annual incidence of invasive CRC in the U.S. remains among the highest in the world, with an age-adjusted rate of 50.6 per 100,000 population for the years 2001–2005 [2]. The major cause of death in patients with CRC is distant metastasis. Depending on the stage of the primary tumor, liver metastases are seen in 20%–70% of patients with CRC, and lung metastases are seen in 10%–20% of patients with CRC [3]. The liver is the only metastatic site in around one third of patients [4].

Without treatment, the outlook for patients with metastatic CRC is very poor, with a median survival time in the region of 1 year [5, 6]. However, surgical resection of metastases can produce long-term survival and cure in some patients. Large patient series have shown that liver resection is possible with reasonable mortality and morbidity, and may achieve 5-year survival rates of approximately 27%–41% [7]. In 1984, a series of 252 patients with biopsy-proven, unresected hepatic metastases from CRC was reported by Wagner and colleagues to achieve 5-year survival rates of 25% and 2% for patients with resected and unresected disease, respectively [8]. More recent data from Canada show a survival rate of 43% at 5 years after liver resection for metastatic CRC [9]. Furthermore, in well-selected patients, there is an estimated 17%–25% chance of cure after hepatectomy (survival >10 years after liver resection), even in the presence of poor prognostic factors [10].

Despite the clear benefits of surgery, conventionally only about 10%–20% of patients have had metastases that are considered to be resectable at presentation [11]. Fortunately, advances in chemotherapy, regional treatment, imaging, and surgical techniques are radically changing the management of liver metastases from CRC; patients who were eligible only for palliative chemotherapy a few years ago now have options that may improve their chances of long-term survival [11].

	WHICH PATIENTS HAVE RESECTABLE DISEASE?

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Recent opinion recommends that evaluation for resectability requires review by an expert team, which should include a skilled surgeon, a medical oncologist, and a radiologist [7]. Perceptions of resectability vary among surgeons, and this variability was highlighted by a multicenter study in which predefined criteria for unresectability were applied. Subsequent central review showed that 10% of patients who met the criteria for resection did not undergo surgery [7].

Broadly, patients without extrahepatic disease and those with good liver function and in good general condition may be eligible for hepatic resection [6]. Classic contraindications for surgery, such as more than four metastases, extrahepatic disease, and a resection margin <1 cm, have been revised in recent years. It has been suggested that the absolute contraindications should include unresectable extrahepatic disease, >70% liver involvement (six segments), liver failure, and insufficient fitness to undergo surgery [12]. Following a recent consensus conference, a definition of resectability was proposed that included the ability to achieve complete resection (negative margin), preserve two contiguous liver segments with adequate vascular inflow and outflow, and preserve an adequate future liver remnant (>20% healthy liver) [13]. Modifications of the required size of the remaining liver have been prepared and include the use of preoperative chemotherapy (30%) and underlying cirrhosis (40%).

The use of scoring systems may also help to identify patients likely to have recurrent metastatic disease after surgery [14, 15]. For example, analysis of records for 1,001 consecutive patients who underwent liver resection as a component of their treatment for metastatic CRC between 1985 and 1998 showed that a preoperative scoring system that included the negative factors of a node-positive primary tumor, a disease-free interval from primary to metastatic disease of <12 months, more than one hepatic metastasis, the largest hepatic metastasis >5 cm, and a carcinoembryonic antigen level >200 ng/l was highly predictive (p < .0001) of survival [14].

	DISEASE STAGING

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Accurate staging is required to rule out extrahepatic disease, select curable patients, and confirm the suitability of patients for surgery. Staging of metastatic disease includes radiologic (triple-phase computed tomography scan or magnetic resonance imaging) and functional (positron emission tomography scan) imaging. A review of imaging techniques is beyond the scope of this review, but has been well summarized elsewhere [16, 17].

	CHEMOTHERAPY FOR PATIENTS WITH LIVER METASTASES FROM CRC

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
For many years, fluorouracil (5-FU) in combination with leucovorin (LV) was the standard therapy for metastatic CRC, yielding a response rate (RR) of 20%–30% and median survival time of 11–12 months [4]. Newer systemic chemotherapy regimens incorporating the platinum agent oxaliplatin and the topoisomerase inhibitor irinotecan have increased both RRs and overall survival (OS) [18–28]. First-line chemotherapy regimens that include oxaliplatin or irinotecan have yielded RRs of 33%–62% [18–28]. The inclusion of targeted agents with chemotherapy has further improved outcomes. Cetuximab added to oxaliplatin or irinotecan regimens increased the RR from 33% to 49% [28], and the addition of bevacizumab to irinotecan increased the RR from 35% to 45% [22]. A median OS time >20 months is now seen [22, 27]. The objectives of chemotherapy in CRC with metastases to the liver have accordingly shifted from palliation to maximization of benefit through prolongation of survival, improving RRs, and downsizing tumors to enable or optimize resection. The recent recognition of the role of KRAS in predicting response to cetuximab will help to further select patients that may benefit from the use of an epithelial growth factor inhibitor such as cetuximab [29].

Initially Unresectable Disease
Increasing evidence supports the ability of chemotherapy to downsize tumors and enable surgery that was not initially possible. Three reports describe the ongoing experience of a group in France [30–32] and demonstrate that patients with initially unresectable disease who undergo curative liver surgery after a response to chemotherapy have a survival duration similar to that of patients who undergo primary resection.

The first report was a retrospective study in 330 initially inoperable chemotherapy-naïve patients, of whom 53 were able to undergo surgery after downsizing of metastases using a chronomodulated regimen of oxaliplatin plus 5-FU and LV [30]. The survival rate was 40% at 5 years, there was no operative mortality, and repeat surgery was possible for hepatic recurrence in 15 cases (Table 1).

Adam et al. [32] more recently reported data from a consecutive series of 1,439 patients managed over 11 years, of whom 1,104 initially had unresectable disease. After a mean of 10 courses of mostly oxaliplatin-based chemotherapy, resection was possible in 138 patients (12.5%) (Table 1); 75% of resections were major hepatectomies and 93% were potentially curative. The operative mortality rate was 0.7% at 2 months. The 10-year survival rate was 23%. Among the 335 patients who underwent primary surgery without chemotherapy, the 10-year survival rate was 30% (p = .01). Four preoperative risk factors predicting poor outcome were identified: rectal primary, three or more metastases, maximum tumor size >10 cm, and carcinoembryonic antigen level >100 UI/L.

Most recently, Baize et al. [33] identified 39 patients with unresectable metastases from 82 patients with advanced CRC, of whom 11 underwent surgery after oxaliplatin-based chemotherapy (Table 1). Among the patients who underwent surgery, the progression-free survival (PFS) duration was 14 months, compared with 6 months for the 28 patients who did not undergo surgery (p < .002). The median OS times were 60 months and 18.5 months in the two groups, respectively (p < .0001).

Subgroup analyses of recent phase III trials of oxaliplatin-containing regimens also show promising rates of secondary resection. In the OPTIMOX-1 (Optimized 5-FU-Oxaliplatin Strategy) study, which compared two first-line regimens of oxaliplatin plus 5-FU and LV (FOLFOX4 and "stop and go" FOLFOX7) in 620 patients with unresectable metastases from CRC, chemotherapy allowed resection in 101 patients (16%) [34]. An R0 (radical) resection was possible for 71 patients, and R1 and R2 resections were each performed in 15 patients. Patients who had an R0 or R1 resection had a median OS time of 51 months with FOLFOX4 and 38 months with FOLFOX7. In a retrospective analysis of data from the large Intergroup N9741 trial [35], the rate of curative resection was significantly higher with oxaliplatin-based regimens than with irinotecan in combination with 5-FU and LV (IFL) (FOLFOX4, 2.4%; irinotecan plus oxaliplatin, 2.9%; IFL, 0.9%; p = .02). In a study of 74 patients with unresectable metastatic CRC who were treated with FOLFOXIRI (oxaliplatin and irinotecan with LV and bolus plus infusional 5-FU), 19 patients (26%) were able to undergo a potentially curative resection [36]. The median OS time was 36.8 months for patients who underwent resection, compared with 22.2 months for the 34 patients who responded to chemotherapy but who did not undergo surgery (p = .0114). In a phase III study of 283 patients conducted by the Hellenic Oncology Research Group, the addition of oxaliplatin to FOLFIRI (irinotecan with LV and bolus plus infusional 5-FU) increased the resection rate of lung and liver metastases from 4% to 10% (p = .08); among patients who underwent surgery after FOLFOXIRI, 86% had an R0 resection [37]. FOLFOXIRI also conferred superior resection rates and survival over FOLFIRI in a phase III trial in 244 previously untreated patients with no prior chemotherapy [38, 39]. The overall RRs to FOLFIRI and FOLFOXIRI were 34% and 60%, respectively (p < .0001), enabling radical secondary resection in a greater proportion of patients in the FOLFOXIRI arm than in the FOLFIRI arm (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Radical (R0) resection rates in patients with initially unresectable metastatic colorectal cancer treated with FOLFIRI or FOLFOXIRI chemotherapy in a randomized phase III study [36, 37]. Differences between groups were significantly different for the overall (p = .033) and liver metastases only (p = .017) populations. Abbreviations: FOLFIRI, irinotecan with leucovorin and bolus plus infusional 5-fluorouracil; FOLFOXIRI, oxaliplatin and irinotecan with leucovorin and bolus plus infusional 5-fluorouracil.

However, when a decision is made to use an EGFR inhibitor it has become increasingly clear that the status of the KRAS gene within the tumor should be assessed first. Mutations of KRAS and its downstream signaling can adversely affect response to EGFR inhibitors. The currently available information shows that approximately 40%–45% of patients with advanced CRC have mutations within KRAS, making this a potential major determinant of treatment outcome for patients receiving EGFR inhibitors. Retrospective analyses of trials using either cetuximab or panitumumab have shown that there is essentially no response to treatment with one of these antibodies in patients with mutated KRAS, whereas those with wild-type KRAS are likely to respond. In a trial of 463 patients evaluating the potential efficacy of panitumumab in last line therapy, 427 had available KRAS data, of whom 43% had mutated KRAS [45]. For patients with wild-type KRAS, 17% responded and 34% had stable disease, compared with zero responders and 12% with stable disease in the mutated KRAS group. When the treatment arms were combined, the OS time was longer in patients with wild-type KRAS than in patients with mutated KRAS (hazard ratio, 0.67; 95% confidence interval [CI], 0.55–0.82).

The National Surgical Adjuvant Breast and Bowel Project (NSABP) is currently planning a trial of patients carefully selected specifically for "conversion" from unresectable to resectable using an EGFR inhibitor. With the newly gained knowledge on KRAS this trial will use analysis of KRAS status for treatment assignment.

While it is clear that progressive improvements are being made in downsizing tumors, this approach can negatively impact the quality of life of patients undergoing this approach. Given the potential greater toxicity of therapy to downsize metastases compared with what may be used in a palliative setting, it is important that patients be carefully evaluated for this type of approach. Patients should be assessed as to their ability to undergo chemotherapy as well as surgery.

Resectable Disease: Neoadjuvant Therapy
The potential benefits of neoadjuvant chemotherapy in patients with resectable disease include the opportunity to test for chemoresponsiveness [46], the potential elimination of micrometastatic disease [7], and the possibility of tumor downsizing with a higher likelihood of a complete resection and/or reduced extent of resection [47]. In addition, response to neoadjuvant chemotherapy has been highlighted as a potential prognostic indicator for survival, which may help to select suitable candidates for surgery [48]. Potential disadvantages of neoadjuvant chemotherapy include the possibility of hepatic damage (see below) and inducing a complete response that renders previously resectable patients unsuitable for surgery. In addition, Benoist et al. [49] described the high rate of recurrence of lesions (43 of 66, 65%) that were initially radiologically determined to be complete responses. Therefore, a mixed response of partial and complete responses may disrupt surgical planning for the complete resection or ablation of the originally identified lesions and result in a high rate of recurrence [49]. The ability to visualize the metastases at the time of surgery, either on a preoperative scan or directly in the operating room, permits a higher likelihood of a complete resection. A complete radiologic response may require that a large resection be performed to ensure all potential microscopic disease is resected and may also result in an incomplete resection through the lack of ability to visualize the metastases.

Neoadjuvant chemotherapy feasibility studies include two trials in which oxaliplatin-based chemotherapy was assessed in patients with resectable liver metastases [50, 51]. Good efficacy and manageable tolerability were noted with the MIROX strategy of giving six cycles of FOLFOX7 before surgery and six cycles of FOLFIRI thereafter in 22 patients (Table 3); the median OS time had not been reached at the time of reporting [51]. An intensive regimen of weekly high-dose 5-FU and LV with biweekly oxaliplatin also yielded high response and curative resectability rates in a small study of 20 patients [50] (Table 3).

View larger version (11K): [in this window] [in a new window]   Figure 2. Effect on progression-free survival (PFS) of perioperative FOLFOX4 versus surgery alone in patients with resectable colorectal cancer liver metastases [50]. Hazard ratios (95% confidence interval) corresponding to the absolute differences in PFS were 0.79 (0.62–1.02; p = .058), 0.77 (0.6–1.0; p = .041), and 0.73 (0.55–0.97; p = .025) for all, all eligible, and all resected patients, respectively. Abbreviations: FOLFOX, oxaliplatin plus 5-fluorouracil and leucovorin.

Hepatic Arterial Infusion
The rationale underlying HAI is the maximization of exposure of hepatic metastases to high target concentrations of cytotoxic drugs by localized infusion. Most randomized studies have shown higher RRs for HAI when compared with systemic chemotherapy, but the impact of HAI on survival is unclear, particularly when compared with optimal systemic regimens. A recent meta-analysis of seven randomized controlled trials in 1,098 patients showed median OS durations of 16.04 months and 12.64 months (p = .3) for HAI and systemic chemotherapy, respectively, in patients with unresectable liver metastases [56].

The Cancer and Leukemia Group B 9481 randomized trial compared floxuridine by HAI with systemic 5-FU and LV in 135 patients [57]. The median OS time (24.4 months versus 20.0 months; p = .0034), objective response rate (47% versus 24%; p = .012), and time to hepatic progression (9.8 months versus 7.3 months; p = .034) were all significantly better with HAI, and a quality of life assessment showed better physical functioning in the HAI group at 3 months and 6 months. Grade 3 or 4 neutropenia (2% versus 45%) and stomatitis (0% versus 24%) were significantly (p < .01) more frequent with systemic therapy, but elevated bilirubin was reported with HAI only (18.6% versus 0%; p < .01).

HAI of oxaliplatin with i.v. LV and bolus and infusional 5-FU appears to be feasible in patients with unresectable liver metastases after systemic chemotherapy failure [58]. After a median of nine cycles of treatment, there were 24 partial responses (62%) among 39 assessable patients, allowing R0 resection in seven patients and radiofrequency ablation in one patient. However, other trials have shown no survival benefit for 5-FU and LV HAI [59, 60]. Problems with HAI are most commonly linked with hepatic toxicity and gastric ulceration [4]. In early reports, HAI floxuridine was associated with biliary toxicity, manifested as elevated levels of aspartate transaminase, alkaline phosphatase, and bilirubin [61]. These toxicities have been managed with close attention to the development of "transaminitis" and hyperbilirubinemia. Immediate emptying of the residual floxuridine in the pump and subsequent dose reductions avoid the dangerous complications of sclerosing cholangitis. Careful skeletonization of the extrahepatic portion of the hepatic artery in the porta hepatis dramatically reduces, if not eliminates, common hepatic and bile duct strictures and gastroduodenal ulceration. Sclerosing cholangitis is also seen in patients undergoing HAI [4].

Two randomized trials of HAI following surgical resection of hepatic metastases from CRC previously reported evidence of clinical benefit. In a trial conducted at the Memorial Sloan–Kettering Cancer Center, patients were randomized to systemic chemotherapy alone versus systemic chemotherapy combined with HAI of floxuridine [62, 63]. Seventy-four patients were randomized to combined therapy and 82 were randomized to systemic therapy. A significant benefit was seen in patients receiving combined therapy, with a median survival time of 72.2 months in the combined therapy group, compared with 59.3 months for patients receiving systemic therapy alone. At 2 years, the rate of survival free of hepatic recurrence was 90% in the combined therapy group compared with 60% in the systemic therapy only group (p < .001). However, recurrence outside the liver was similar in both groups. In a separate study, patients with two to four resected hepatic metastases were randomized to resection alone versus HAI of floxuridine combined with systemic infusional 5-FU [64]. That trial also showed a markedly lower incidence of hepatic recurrence with HAI as well as a significantly longer recurrence-free survival time.

The potential benefit of a more active systemic regimen alternating with HAI was evaluated in a multicenter phase II trial (the North Central Cancer Treatment Group N9945 trial). Patients undergoing resection with or without ablation received four alternating cycles of HAI consisting of floxuridine and dexamethasone alternating with systemic capecitabine and oxaliplatin. Two additional cycles of systemic therapy were given. At the time of the initial analysis, the estimated 2-year survival rate was 86% (95% CI, 76%–97%) and the median time to progression was 32 months [65].

The clinical benefit of HAI in the setting of other available active systemic regimens requires further study. For the present time, the use of this modality should be restricted to experienced centers [66].

	OPTIMAL TIMING AND DURATION OF PERIOPERATIVE CHEMOTHERAPY

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
The issue of the optimal timing and duration of perioperative chemotherapy remains largely unresolved. The use of more than six cycles of preoperative chemotherapy has been associated with greater perioperative morbidity but not mortality [67]. Administration of >12 cycles has been associated with a longer postoperative hospital stay and a higher risk for repeat surgery [68]. In general, short courses of chemotherapy (up to six cycles) are recommended, with surgery being performed as soon as a response is observed [57]. The emerging paradigm is the close interaction of the medical oncologist and surgeon. In the absence of significant risk factors for the operation or recurrence, resectable patients should undergo surgery immediately. Borderline resectable patients should receive chemotherapy with planned 3-month/three-cycle restaging and evaluation of treatment toxicity and tumor response.

	SAFETY OF PERIOPERATIVE CHEMOTHERAPY

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Perioperative chemotherapy may cause liver damage, which has the potential to increase the risks of surgery, prevent liver resection, and impair functioning of the remaining hepatic tissue. Adverse effects of most concern in this setting are those causing vascular changes and chemotherapy-associated steatohepatitis. Vascular changes include sinusoidal dilation with erythrocytic congestion, sometimes accompanied by perisinusoidal fibrosis and fibrotic venular occlusion; this may result in sinusoidal obstruction syndrome, as seen in veno-occlusive disease [69].

Evidence suggests that oxaliplatin-based regimens are associated with a higher risk for hepatic vascular lesions [67, 69], whereas irinotecan-based regimens are associated with higher risks for steatosis and steatohepatitis [70]. Steatohepatitis tends to be seen more frequently in patients with a high body mass index [71] and is reported more frequently in U.S. studies [72], whereas vascular lesions are reported more commonly in Europe [66, 67]. It is therefore possible that chemotherapy does not cause steatosis as such but may aggravate it where it is already present.

Steatohepatitis has been associated with a higher 90-day mortality rate after surgery [70]. Pathologic review of 158 patients who received no preoperative chemotherapy and 248 patients who received neoadjuvant therapy for a median of 16 weeks showed more sinusoidal dilation with oxaliplatin-based regimens than with no chemotherapy (18.9% versus 1.9%), and more steatohepatitis with irinotecan-based regimens (20.2% versus 4.4%). A higher 90-day mortality rate was seen in patients with steatohepatitis (14.7% versus 1.6%; p = .001).

Although the association of perioperative chemotherapy with liver injury is accepted, the clinical significance of this effect remains uncertain. Safety data from the EORTC 40983 study, which compared surgery alone with perioperative chemotherapy comprising oxaliplatin plus 5-FU and LV in 364 patients, showed very low mortality rates (1%) in both treatment arms, with an acceptable rate of reversible complications [51].

Few data pertaining to the safety of targeted biologic agents in the perioperative setting are available, but there is concern that the use of bevacizumab may increase the risk for wound-related complications [73, 74]. Bevacizumab has been associated with a higher risk for organ perforation, bleeding, and decreased wound healing. VEGF is important in hepatic regeneration, and the use of VEGF inhibitors may therefore impair this process in patients undergoing surgery [74]. A review of wound-healing complications after cancer surgery in patients treated with 5-FU–containing chemotherapy showed complication rates of 1.3% (3 of 230 patients) when bevacizumab was added to chemotherapy and 0.5% (1 of 194 patients) with the control [73]. The authors concluded that the addition of bevacizumab to therapy caused no relevant increase in the rate of wound-healing complications.

	RADIOFREQUENCY ABLATION FOR LIVER METASTASES

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Nonsurgical ablative techniques are now being used more frequently for the treatment of liver metastases. Of the various techniques available, radiofrequency ablation (RFA) is the one most commonly used. However, long-term outcomes related to the use of RFA for potentially resectable liver metastases remain uncertain. In a recent review of the literature, no 5-year survival data could be identified in published studies for resectable liver metastases, while the 5-year survival rate for unresectable metastases was in the range of 14%–55% [75]. While RFA appears to have an important role in augmenting surgical resection or providing an option for patients unable to undergo surgical resection, it does not appear that RFA provides an outcome comparable with that of surgery overall. However, a subgroup of patients may exist in which RFA may provide outcomes similar to surgery, but with the lack of randomized trials this remains uncertain. Further work is needed to clarify the role of RFA in the treatment of liver metastases from CRC.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
The potential of chemotherapy to render unresectable liver metastases resectable is now a clinical reality. Studies have shown that oxaliplatin-based preoperative chemotherapy achieves high RRs and makes resection possible in a clinically relevant proportion of patients. Looking forward, further research is required to establish the best endpoint for new clinical trials in this setting [76]. OS is a long-term outcome and can be influenced by many factors. Possible alternatives include the best response, resection rate, and relapse-free survival rate after response [76]. As patients with metastatic CRC increasingly receive chemotherapy with curative intent, treatment in a multidisciplinary environment will become central to achieving optimal outcomes; a medical oncologist, radiologist, and skilled hepatobiliary surgeon should be involved in deciding the best course of therapy and timing of surgery. In this context, computerized decision models (including OncoSurge) are in development and will need to be validated for decision making [12, 77]. Emerging chemotherapeutic regimens, targeted biologic agents, and new surgical and radiation techniques create challenges for maintaining the timeliness of these tools. Clearly, there has been remarkable progress in therapy for CRC that has metastasized to the liver, and the prospect of long-term survival is becoming a reality for an increasing proportion of patients.

	AUTHOR CONTRIBUTIONS

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 
Manuscript writing: Steven Alberts, Lawrence Wagman

Final approval of manuscript: Steven Alberts, Lawrence Wagman

The authors take full responsibility for the content of the paper but thank Samantha Richer, Ph.D., from Adelphi Communications, supported by Sanofi-Aventis, US, for her assistance in preparing the initial draft of the manuscript and collating the comments of authors.

	REFERENCES

Top Learning Objectives Abstract Introduction Which Patients Have Resectable... Disease Staging Chemotherapy for Patients with... Optimal Timing and Duration... Safety of Perioperative... Radiofrequency Ablation for... Conclusions Author Contributions References

 

1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.[Abstract/Free Full Text]
2. Ries LAG, Melbert D, Krapcho M et al, SEER Cancer Statistics Review, 1975–2005, National Cancer Institute, Bethesda, MD, based on November 2007 SEER data submission, posted to the SEER Website in 2008. Available at http://seer.cancer.gov/csr/1975_2005/. accessed March 21, 2008.
3. Penna C, Nordlinger B. Colorectal metastases (liver and lung). Surg Clin North Am 2002;82:1075–1090.[CrossRef][Medline]
4. Kemeny N. Management of liver metastases from colorectal cancer. Oncology (Williston Park) 2006;20:1161–1176, 1179; discussion 1179–1180, 1185–1186.[Medline]
5. Stangl R, Altendorf-Hofmann A, Charnley RM et al. Factors influencing the natural history of colorectal liver metastases. Lancet 1994;343:1405–1410.[CrossRef][Medline]
6. Liu LX, Zhang WH, Jiang HC. Current treatment for liver metastases from colorectal cancer. World J Gastroenterol 2003;9:193–200.[Medline]
7. Mandalà M, Mosconi S, Quadri A et al. Neoadjuvant chemotherapy for patients with liver metastases from colorectal cancer. Expert Rev Anticancer Ther 2007;7:887–897.[CrossRef][Medline]
8. Wagner JS, Adson MA, van Heerden JA et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984;199:502–508.[Medline]
9. Shah SA, Bromberg R, Coates A et al. Survival after liver resection for metastatic colorectal carcinoma in a large population. J Am Coll Surg 2007;205:676–683.[CrossRef][Medline]
10. Tomlinson JS, Jarnagin WR, DeMatteo RP et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007;25:4575–4580.[Abstract/Free Full Text]
11. Vibert E, Canedo L, Adam R. Strategies to treat primary unresectable colorectal liver metastases. Semin Oncol 2005;32;(6) (suppl 8):33–39.[Medline]
12. Poston GJ, Adam R, Alberts S et al. OncoSurge: A strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 2005;23:7125–7134.[Abstract/Free Full Text]
13. Charnsangavej C, Clary B, Fong Y et al. Selection of patients for resection of hepatic colorectal metastases: Expert consensus statement. Ann Surg Oncol 2006;13:1261–1268.[CrossRef][Medline]
14. Fong Y, Fortner J, Sun RL et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 1999;230:309–318; discussion 318–321.[CrossRef][Medline]
15. Nordlinger B, Guiguet M, Vaillant JC et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996;77:1254–1262.[CrossRef][Medline]
16. Ong KO, Leen E. Radiological staging of colorectal liver metastases. Surg Oncol 2007;16:7–14.[Medline]
17. Martínez L, Puig I, Valls C. Colorectal liver metastases: Radiologic diagnosis and staging. Eur J Surg Oncol 2007;33(suppl 2):S5–S16.[Medline]
18. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914.[Abstract/Free Full Text]
19. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 2000;355:1041–1047.[CrossRef][Medline]
20. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.[Abstract/Free Full Text]
21. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004;22:229–237.[Abstract/Free Full Text]
22. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.[Abstract/Free Full Text]
23. Köhne CH, van Cutsem E, Wils J et al. 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 2005;23:4856–4865.[Abstract/Free Full Text]
24. Grothey A, Deschler B, Kroening H et al. Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2002;21:129a.
25. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136–147.[Abstract/Free Full Text]
26. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.[Abstract/Free Full Text]
27. Fuchs C, Marshall J, Mitchell E et al. A randomized trial of first-line irinotecan/fluoropyrimidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C). J Clin Oncol 2006;24;(18) (suppl):147s.
28. Venook A, Niedzwiecki, Hollis D et al. Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results. J Clin Oncol 2006;24;(18) (suppl):148s.
29. Lièvre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374–379.[Abstract/Free Full Text]
30. Bismuth H, Adam R, Lévi F et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;224:509–520; discussion 520–522.[CrossRef][Medline]
31. Giacchetti S, Itzhaki M, Gruia G 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;10:663–669.[Abstract/Free Full Text]
32. Adam R, Delvart V, Pascal G et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 2004;240:644–657; discussion 657–658.[Medline]
33. Baize N, Gerard B, Bleiberg H et al. Long-term survival of patients downstaged by oxaliplatin and 5-fluorouracil combination followed by rescue surgery for unresectable colorectal liver metastases. Gastroenterol Clin Biol 2006;30:1349–1353.[Medline]
34. Perez-Staub N, Lledo G, Paye F et al. Surgery of colorectal metastasis in the Optimox 1 study. A GERCOR study. J Clin Oncol 2006;24;(18) (suppl):3522.[Free Full Text]
35. Dy GK, Krook JE, Green EM et al. Impact of complete response to chemotherapy on overall survival in advanced colorectal cancer: Results from Intergroup N9741. J Clin Oncol 2007;25:3469–3474.[Abstract/Free Full Text]
36. Masi G, Cupini S, Marcucci L et al. Treatment with 5-fluorouracil/folinic acid, oxaliplatin, and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 2006;13:58–65.[CrossRef][Medline]
37. Souglakos J, Androulakis N, Syrigos K et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): A multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006;94:798–805.[CrossRef][Medline]
38. Falcone A, Masi G, Brunetti I et al. The triplet combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) vs the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.). J Clin Oncol 2006;24;(18) (suppl):149s.
39. Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25:1670–1676.[Abstract/Free Full Text]
40. Alberts SR, Horvath WL, Sternfeld WC et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 2005;23:9243–9249.[Abstract/Free Full Text]
41. Pozzo C, Basso M, Cassano A et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 2004;15:933–939.[Abstract/Free Full Text]
42. Díaz Rubio E, Tabernero J, van Cutsem E et al. Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: An international phase II study. J Clin Oncol 2005;23;(16) (suppl):254s.[CrossRef]
43. Gruenberger B, Tamandl D, Puhalla H et al. Bevacizumab plus XELOX as neoadjuvant chemotherapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2007;25;(18) (suppl):179s.
44. Adam R, Aloia T, Lévi F et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007;25:4593–4602.[Abstract/Free Full Text]
45. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626–1634.[Abstract/Free Full Text]
46. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2005;23:2038–2048.[Abstract/Free Full Text]
47. Tanaka K, Adam R, Shimada H et al. Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver. Br J Surg 2003;90:963–969.[CrossRef][Medline]
48. Allen PJ, Kemeny N, Jarnagin W et al. Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg 2003;7:109–115; discussion 116–117.[CrossRef][Medline]
49. Benoist S, Brouquet A, Penna C et al. Complete response of colorectal liver metastases after chemotherapy: Does it mean cure? J Clin Oncol 2006;24:3939–3945.[Abstract/Free Full Text]
50. Wein A, Riedel C, Brückl W et al. Neoadjuvant treatment with weekly high-dose 5-fluorouracil as 24-hour infusion, folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer. Oncology 2003;64:131–138.[CrossRef][Medline]
51. Taïeb J, Artru P, Paye F et al. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: Results of a phase II study. J Clin Oncol 2005;23:502–509.[Abstract/Free Full Text]
52. Nordlinger B, Sorbye H, Debois M et al. Feasibility and risks of pre-operative chemotherapy (CT) with FOLFOX4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 2005;23;(16) (suppl):3528.
53. Nordlinger B, Sorbye H, Collette L et al. Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. J Clin Oncol 2007;25;(18) (suppl):2s.
54. Mitry E, Fields A, Bleiberg H et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials. J Clin Oncol 2006;24;(18) (suppl):3524.[Free Full Text]
55. Portier G, Elias D, Bouche O et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006;24:4976–4982.[Abstract/Free Full Text]
56. Mocellin S, Pilati P, Lise M et al. Hepatic arterial infusion (HAI) compared to systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma: A systematic review and meta-analysis of randomized controlled trials. J Clin Oncol 2007;25;(18) (suppl):626s.
57. Kemeny NE, Niedzwiecki D, Hollis DR et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: A randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006;24:1395–1403.[Abstract/Free Full Text]
58. Boige V, Malka D, Elias D et al. Hepatic arterial infusion of oxaliplatin and intravenous LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol 2008;15:219–226.[CrossRef][Medline]
59. Kerr DJ, McArdle CS, Ledermann J et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: A multicentre randomised trial. Lancet 2003;361:368–373.[CrossRef][Medline]
60. Lorenz M, Müller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 2000;18:243–254.[Abstract/Free Full Text]
61. Kemeny N, Conti JA, Cohen A et al. Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 1994;12:2288–2295.[Abstract/Free Full Text]
62. Kemeny N, Huang Y, Cohen AM et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039–2048.[Abstract/Free Full Text]
63. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005;352:734–735.[Free Full Text]
64. Kemeny MM, Adak S, Gray B et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—an intergroup study. J Clin Oncol 2002;20:1499–1505.[Abstract/Free Full Text]
65. Alberts SR, Mahoney MR, Donohue J et al. Systemic capecitabine and oxaliplatin administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) following complete resection of colorectal metastases (M-CRC) confined to the liver: A North Central Cancer Treatment Group (NCCTG) phase II Intergroup Trial. J Clin Oncol 2006;24:152s.[CrossRef]
66. Biasco G, Derenzini E, Grazi GL et al. Treatment of hepatic metastases from colorectal cancer: Many doubts, some certainties. Cancer Treat Rev 2006;32:214–228.[CrossRef][Medline]
67. Karoui M, Penna C, Amin-Hashem M et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006;243:1–7.[CrossRef][Medline]
68. Aloia T, Sebagh M, Plasse M et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–4990.[Abstract/Free Full Text]
69. Rubbia-Brandt L, Audard V, Sartoretti P et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460–466.[Abstract/Free Full Text]
70. Vauthey JN, Pawlik TM, Ribero D et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–2072.[Abstract/Free Full Text]
71. Fernandez FG, Ritter J, Goodwin JW et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200:845–853.[CrossRef][Medline]
72. Bilchik AJ, Poston G, Curley SA et al. Neoadjuvant chemotherapy for metastatic colon cancer: A cautionary note. J Clin Oncol 2005;23:9073–9078.[Free Full Text]
73. Scappaticci FA, Fehrenbacher L, Cartwright T et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91:173–180.[CrossRef][Medline]
74. Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005;23:4853–4855.[Free Full Text]
75. Mulier S, Ni Y, Jamart J et al. Radiofrequency ablation versus resection for resectable colorectal liver metastases: Time for a randomized trial? Ann Surg Oncol 2008;15:144–157.[CrossRef][Medline]
76. Sobrero A, De Cian F, Andretta V et al. Objectives of chemotherapy for unresectable liver metastases: Best response or resection? Eur J Cancer 2007;5;(5) (suppl):317–321.
77. O'Reilly DA, Chaudhari M, Ballal M et al. The OncoSurge strategy for the management of colorectal liver metastases—an external validation study. Eur J Surg Oncol 2008;34:538–540.[Medline]

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