Presurgical Chemotherapy in Patients Being Considered forLiver Resection

NANCY KEMENY

Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Key Words. Neoadjuvant chemotherapy • Liver resection • Hepatotoxicity from chemotherapy

LEARNING OBJECTIVES

1. Describe the approach to patients with unresectable liver metastases from colorectal cancer.

2. Identify the hepatotoxicities associated with chemotherapy.

3. Explain what happens to metastatic sites when there is a response.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.comCMECME

ABSTRACT

The liver is a frequent site of metastatic disease forcolorectal cancer patients. Approximately 15% of pa-tients have liver metastases at diagnosis and another50% develop metastatic disease to the liver over thecourse of their disease. Advances in systemic chemo-therapy and surgical techniques for hepatic resectionhave led to longer survival times for these patients.There is no doubt that unresectable patients benefitfrom systemic chemotherapy. For patients who haveresectable disease, the timing of chemotherapy is stillnot clear. This review addresses the pros and cons ofpresurgical chemotherapy. The benefits of preopera-tive chemotherapy include decreasing tumor size,

controlling micrometastatic disease, assessing activ-ity of chemotherapy, improving chemotherapy toler-ance, and perhaps allowing some prediction of thesuccess of liver resection. The risks for presurgicalchemotherapy include liver toxicity, the risk for pro-gression or growth of new sites, secondary spleno-megaly, selection of resistant clones, and thepossibility of leaving behind active tumor that is nolonger seen because of a complete radiographic re-sponse. The challenge for the future is to develop amultidisciplinary team approach that can design thebest treatment plan for patients with liver metastases.The Oncologist 2007;12:825–839

Disclosure of potential conflicts of interest is found at the end of this article.

INTRODUCTION

There will be approximately 130,000 new cases of coloncancer in the U.S. in 2007. Fifteen percent of these patientswill have liver metastases at diagnosis, and another 50%will develop liver metastases during the course of their dis-

ease [1]. With advances in adjuvant therapy after primarycolon resection, there is hope that the number of cases withmetastatic disease will decrease [2].

For those who develop metastatic disease, there are newchemotherapy agents (irinotecan [3] and oxaliplatin [4, 5])

Correspondence: Nancy Kemeny, M.D., Memorial Sloan-Kettering Cancer Center, Gastrointestinal Oncology Service, 1275 York Av-enue, Suite H916, New York, New York 10021, USA. Telephone: 212-639-8068; Fax: 212-794-7186. Received February 2, 2007; ac-cepted for publication April 13, 2007. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.12-7-825

TheOncologist®

Hepatobiliary

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and new targeted agents (cetuximab [6] and bevacizumab[7]) that have improved response rates and survival times.Unfortunately, even with these new agents, the 2-year sur-vival rate remains about 40% for patients with metastaticdisease. Therefore, the development of other treatment mo-dalities is important.

Surgeons have demonstrated that resection of liver me-tastases increases survival [1, 8]. Several reports documenta 30% 5-year survival rate for patients who undergo cura-tive resection of their liver metastases [1, 8]. Although thereare no randomized studies of surgery versus no surgery,there are natural history studies of patients who had resect-able disease and did not undergo resection. In a review byScheele et al. [9], of 902 patients with unresected liver me-tastases, only 21 patients survived 3 years, and none werealive at 5 years. Sixty-two patients had resectable diseasebut were not resected, and none were alive at 5 years. Thosewho were resected had a 5-year survival rate of 40%. Un-fortunately, only 10%–25% of patients with liver metasta-ses are candidates for liver resection.

New effective chemotherapeutic agents have increasedresponse rates and also the possibility of resection. In 1996,Bismuth et al. [10] reported that patients who were initiallyunresectable could be treated with systemic chemotherapy,and if a good response was obtained, resection was possiblein 16% (53 of 330 patients). These patients had a survivalduration similar to those who were initially resectable.Thus, in patients who are clearly unresectable, few woulddispute the utility of chemotherapy. However, in patientswho are initially resectable, the benefit of preoperative che-motherapy is uncertain. This review covers some of the ad-vantages and disadvantages of neoadjuvant therapy.

HOW TO DEFINE RESECTABLE DISEASE

In the early history of surgery for liver metastases, it wasfelt that patients with more than three metastatic liver le-sions or bilobar disease were not appropriate for liver resec-tion. However, newer data have demonstrated that evenpatients with poor prognostic characteristics can survive 5years after curative liver resection [11–13]. Trials lookingfor prognostic indicators have devised a variety of clinicalrisk scores. A French review [12] of 1,568 patients foundthat age, number of metastases, size of the largest metasta-sis, carcino-embryonic antigen (CEA) level, primary tumorstage, disease-free interval, and positive resection marginswere all significant prognostic factors. Giving one point toeach of these factors, they divided patients into three riskgroups, with corresponding 2-year survival rates of 79%,60%, and 43% for groups with scores of 0–2, 3–4, and 5–7,respectively. At Memorial Sloan-Kettering Cancer Center(MSKCC), a multivariate analysis of many factors found

that the size of the tumor (�5 cm), disease-free interval(�12 months), number of tumors (�1), positive lymphnodes from the primary, and preoperative CEA level �200ng/ml were the most significant indicators of poor progno-sis [11]. If one point is assigned for each of these factors, ascore can be obtained that correlates with survival. Thus, aclinical risk score (CRS) of 0, 1–2, 3, or 4 –5 predicted5-year survival rates of 60%, 42%, 20%, and 18%, respec-tively. While poor characteristics definitely decrease sur-vival, survival was still better than in those withoutresection, who rarely survive 5 years. An internationalgroup (LiverMetSurvey) looking at 2,122 patients undergo-ing liver resection, found overall 5- and 10-year survivalrates of 42% and 26%, respectively, and showed that pa-tients with greater or less than three metastases had 5-yearsurvival rates of 48% and 24%, respectively (p � .001)[13]. In none of these series do the authors suggest that sur-gery should not be done in the patients with poor prognosticcharacteristics.

A computer program was developed to aid in selectingpatients for resection (OncoSurge model) [14]. A panel of16 experts decided that absolute contraindications for re-section were extrahepatic disease, �70% liver involve-ment, liver failure, and/or being surgically unfit. Otherfactors such as age, primary tumor stage, and time to thedevelopment of metastases were not contraindications forresection. Today, even extrahepatic disease is not a clear in-dicator of unresectable disease [15]. There are now reportsof resecting liver metastases in patients with positive lymphnodes [16] and small lung or ovarian metastases [15]. In arecent report, the 5-year survival rate was 28% for patientswho had extrahepatic disease resected as well, with thenumber of metastases being a stronger indication of pro-gression than location of disease [15].

With recent advances in surgery, more patients are be-ing considered for resection [17]. One preoperative tech-nique involves portal vein embolization, to remove theblood supply to the affected liver and thus induce hypertro-phy of the nondiseased portion of the liver, allowing formore radical liver resections [18]. Better vascular clampingtechniques [19], controlled anatomic resection [20], and theuse of radiofrequency ablation [21] to small lesions of theremaining liver also expand the options for liver resection.The definition of resectable disease varies greatly. A largerconsensus is needed to clearly define what is unresectabledisease.

INITIAL CHEMOTHERAPY IN

UNRESECTABLE DISEASE

For patients who do not have resectable disease, initial ther-apy, often called neoadjuvant therapy, may be a way to re-

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duce tumor size and facilitate resection. Early retrospectivestudies from France [10, 22] were updated in a report of1,439 patients with colorectal cancer managed from 1988–1999, where 1,104 patients were considered to have ini-tially unresectable disease. After receiving chemotherapy(70% received 5-fluorouracil, leucovorin, and oxaliplatin[FOLFOX]), 12.5% became resectable, with 5-year sur-vival and disease-free survival rates in the resected patientsof 33% and 22%, respectively, with a median follow-uptime of 48.7 months [23]. Eighty percent had had a tumorrecurrence, of which 71% recurred in the liver. Four preop-erative factors were associated with shorter survival times:(a) rectal primary, (b) three or more metastases, (c) tumorsize �10 cm, and (d) cancer antigen (CA)19–9 level �100u/l [23]. The mean adjusted 5-year survival rate with zero,one, two, three, or four of the above factors was 59%, 30%,7%, 0%, and 0%, respectively.

Recent trials have prospectively evaluated neoadjuvantchemotherapy. Comparisons are somewhat difficult be-cause of diverse reasons for patient unresectability. Someinclude the number of lesions or bilobar disease, while oth-ers look at technical reasons for why patients are unresect-able, such as involvement of all three hepatic veins, bothportal veins, or the retrohepatic vena cava, or that a resec-tion would leave less than two hepatic segments or leaveinadequate hepatic reserve. Many of these trials are listed inTable 1. In the trial by Pozzo et al. [24], patients were con-sidered unresectable if they had six metastases with threeper lobe; one lesion �5 cm if six metastases were present;or continuity with two hepatic veins, the inferior vena cava,or the liver hilum. The response rate to neoadjuvant chemo-therapy was 47.5%, and 13 patients (32.5%) went on to re-section. Although further systemic chemotherapy wasgiven, the median disease-free interval was 14.3 months. Inthe Mayo Clinic trial [25], unresectability was defined as(a) involvement of three major hepatic veins, the portal veinbifurcation, or the retrohepatic vena cava; (b) involvementof the main right or left portal vein and the main hepaticvein of the opposite lobe; (c) disease requiring more than aright or left trisegmentectomy; and (d) six or more meta-static lesions distributed diffusely to both lobes of the liver.Twenty-five patients (60%) had a tumor reduction, and 17(40%) underwent surgery. Retrospective review of thesedata demonstrated that 10% were actually resectable priorto neoadjuvant chemotherapy. There is no description ofwhich patients became resectable, that is, patients with sixor more lesions or patients with central lesions. With a me-dian follow-up of 22 months, 11 patients have had recur-rence, mostly in the liver. In the study by Ho et al. [26] ofliver resection after 5-fluorouracil, leucovorin, and irinote-can (FOLFIRI), 40 patients were treated, 55% had a re-

sponse, and four patients underwent liver resection.However, of these four patients, one had stable disease,again suggesting that resection could have been possiblewithout the preoperative chemotherapy in some patients.

In order to increase resectability, a combination of iri-notecan, oxaliplatin, and 5-fluorouracil/leucovorin (5-FU/LV) has been attempted. A randomized study of irinotecan,oxaliplatin, and 5-FU/LV versus FOLFIRI in patients whowere unresectable and had no prior chemotherapy had as itssecondary endpoint the ability to perform surgical resec-tion. There was a 15% resection rate with the irinotecan/oxaliplatin/5-FU/LV regimen and a 6% resection rate withFOLFIRI [27]. If patients with just liver metastases onlywere evaluated, the resection rates were 36% and 12%, re-spectively.

Chronomodulation of FOLFOX versus standard FOL-FOX did not increase resectability [28]. In the EuropeanOrganization for Research and Treatment of Cancer(EORTC) 05963 study, including 554 patients, 50 were re-sectable in each arm. However, we do not know yet whetherthe chronomodulation may have decreased hepatic toxicity.

The use of targeted agents may increase response ratesand resectability. Rougier et al. [29] treated 23 patients withcetuximab and FOLFIRI, and seven (30%) became resect-able. Another approach to maximize response in the liver isto use hepatic arterial infusion (HAI), because hepatic tu-mors are perfused by the hepatic artery [30]. Because flox-uridine (FUDR) has an extraction rate of 94%–99% duringthe first pass [31], it is an ideal drug to use in treating livermetastases, and HAI may be combined with almost fulldoses of systemic therapy. Even in previously treated pa-tients, high response rates can be achieved with the use ofHAI therapy coupled with systemic therapy. A trial usingHAI FUDR and dexamethasone with systemic irinotecanproduced a 73% response rate in 38 patients (all previouslytreated), with responses in 13 of 15 patients who had re-ceived previous irinotecan [32]. Another study using HAIFUDR/dexamethasone with systemic oxaliplatin producedan 88% response rate in 36 patients (89% of whom werepreviously treated with systemic chemotherapy) [33]. In anupdated analysis, 44 patients with clearly unresectable livermetastases were treated with combined HAI FUDR/dexa-methasone and systemic oxaliplatin/irinotecan, and 35%were able to undergo liver resection after treatment (per-sonal observation). Clavien et al. [34] treated 23 previouslytreated patients with HAI FUDR plus bolus cisplatin anddoxorubicin and achieved a 23% resection rate.

The main toxicity from HAI FUDR is to the bile ductsrather than the liver parenchyma. Bile ducts, as well as livermetastases, are perfused by the hepatic artery, thus the maintoxicity of HAI is biliary, which, when severe, is known as

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sclerosing cholangitis [35]. The toxicity usually occurs af-ter multiple treatments. Therefore, if a response occurs rap-idly, biliary toxicity should be less of an issue. In a studycomparing the time needed to achieve a maximum responsewith HAI plus systemic therapy versus systemic therapyalone, the mean tumor shrinkage after 2 months of treat-ment was 60% with HAI plus systemic therapy, and 20%with systemic therapy alone. Thus, conversion to resect-ability after therapy may occur more quickly with HAI ther-apy [36]. More studies are needed to define how best todecrease liver metastases and enable resection.

SYNCHRONOUS LIVER METASTASES

The question of whether liver metastases can safely be re-sected at the time of resection of the primary colorectal car-cinoma is still uncertain. Small metastases seen at the timeof laparotomy for the primary lesion can easily be resected.When patients are evaluated for their primary and are foundto have a large burden of metastatic disease, a question maybe whether a simultaneous resection of the primary tumorand the metastases should be done, or whether preoperativechemotherapy should be offered. Bolton and Fuhrman [37]reported a 12% operative mortality rate with simultaneoussurgeries that increased to 24% if the surgery included amajor liver resection. Nordlinger et al. [12] reported a 7%mortality rate for simultaneous resections compared with2% for staged resections (p � .01). Tanaka et al. [38], Mar-tin et al. [39], and Weber et al. [40], on the other hand, re-ported that operative mortality and morbidity werecomparable whether staged or simultaneous procedureswere done. Tanaka et al. [38] reported that the resected livervolume was the only factor associated with postoperativecomplications of simultaneous colorectal and liver resec-

tion. It is the practice in many institutions to do a simulta-neous resection with right colon primaries or when singlesynchronous metastases are found in the liver, and stagedresections for rectal primaries or for patients with multipleliver metastases [41].

NEOADJUVANT THERAPY FOR PATIENTS WHO

ARE RESECTABLE

The following sections discuss the pros and cons of neoad-juvant therapy for patients who are resectable (Table 2).

Pros

Decrease Tumor SizeIt is known that large liver tumor size (�5 cm) indicates aworse prognosis [11, 12]. Although one might reason thatdecreasing the tumor size with chemotherapy would im-prove survival, this has not yet been demonstrated. De-creasing the size may make the surgery easier, but thequestion is whether residual microscopic disease remains.Resection of a smaller volume of disease may not improveprognosis if residual disease remains.

Control Micrometastatic DiseaseWhen patients present with liver metastases, there is thepossibility that there is undetectable disease in other parts ofthe body, and therefore it would be appropriate to controlthis disease before attempting liver resection. Also, if thepatient is on chemotherapy for a period of time before re-section, one can then eliminate patients who develop extra-hepatic disease while on treatment and avoid the risksassociated with major hepatic resection. Supporting thisconcept, the LiverMetSurvey group found that patients

Table 1. Evaluating neoadjuvant systemic chemotherapy regimens for unresectable disease

Study Chemotherapy regimen n of patients Resectability rate

Wein et al. (2001) [87] 5-FU/LV 53 11%

Gaspar et al. (2003) [88] FOLFOX 37 27%

Wein et al. (2003) [89] Oxaliplatin � 5-FU/LV 53 11%

Quenet et al. (2004) [90] Oxaliplatin/irinotecan/5-FU/LV 34 37.5%

Alberts et al. (2005) [25] FOLFOX 42 33%

Abad et al. (2005) [91] Oxaliplatin/irinotecan/5-FU/LV 47 30%

Ho et al. (2005) [26] FOLFIRI 40 10%

Pozzo et al. (2006) [24] FOLFIRI 40 27.5%

Falcone et al. (2006) [92] Oxaliplatin/irinotecan/5-FU/LV 122 15%

Falcone et al. (2006) [92] FOLFIRI 122 6%

Masi et al. (2006) [93] 5-FU/LV/Oxaliplatin � irinotecan 74 26%

Abbreviations: 5-FU, 5-fluorouracil; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOX, 5-fluorouracil,leucovorin, and oxaliplatin; LV, leucovorin.

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with more than five metastases survived longer if they weregiven neoadjuvant chemotherapy, with 5-year survivalrates of 22% and 12% (p � .07) for the preoperatively andnonpreoperatively treated groups, respectively. However,for all patients, the group receiving preoperative chemo-therapy had a 5-year survival rate of 38%, versus 50% forthose without preoperative chemotherapy.

In another retrospective review at MSKCC, preopera-tive chemotherapy did not improve survival. In a review of230 patients who received HAI plus systemic therapy afterliver resection [42], the median survival times in patientswho did and did not receive preoperative (neoadjuvant)therapy were 63 and 115 months, respectively (p � .26).The group who received neoadjuvant therapy had a higherCRS and a greater number of metastases, which may ex-plain the longer survival in those without preoperative che-motherapy. In order to determine if neoadjuvant therapybenefits patients with poor prognostic indicators (CRS,3–5), these patients were separated from those with a goodCRS (0–2). Among patients with a poor CRS (3–5), the me-dian survival times were 60 and 55 months, respectively,for those who received preoperative chemotherapy andthose who did not (p � .79). Among patients with a CRS of0 –2, in those who received neoadjuvant therapy versusthose who did not, the median survival times were 67 versus114 months, respectively (p � .41). The results in this re-port may have been influenced by the addition of postoper-ative therapy after the liver resection. It is not clear thatpreoperative chemotherapy is helpful in resectable patients,but this concept requires further study.

Assessment of Chemotherapy ActivityAnother advantage of preoperative chemotherapy is that itcan be used to assess response to chemotherapeutic agentsprior to resection. By knowing if certain drugs produce aresponse, postresection therapy can be designed more effi-ciently.

Better Chemotherapy ToleranceAfter liver resection, patients may not be able to tolerate fulldoses of chemotherapy. Two adjuvant studies using sys-temic irinotecan [32] or oxaliplatin/5-FU/LV [43] demon-strated that full doses of systemic chemotherapy could notbe administered postresection with HAI therapy. Higherdoses of preoperative chemotherapy may impact the abilityto treat microscopic disease. In trials evaluating preopera-tive chemotherapy and radiation for rectal cancer, toxicitywas less when treatment was given in the preoperative pe-riod [44]. However, at this time, whether preoperative che-motherapy for colorectal liver metastases is better toleratedthan postoperative therapy is unknown.

Surrogate Markers for Success of Liver SurgerySome reports suggest that tumor progression while onchemotherapy predicts worse survival after liver resec-tion. Adam et al. [45] reviewed 131 consecutive patientswho underwent liver resection for multiple lesions (�4lesions) after systemic chemotherapy. This representedapproximately 30% of the patients undergoing resection attheir institution. They divided the patients into threegroups: those who had an objective response (group 1),those who had tumor stabilization (group 2), and those withtumor progression (group 3). The 5-year survival rates forgroups 1, 2, and 3 were 37%, 30%, and 8%, respectively(p � .0001). However, there were imbalances among thegroups. For example, group 1 (the response group) had alower preoperative and postoperative CEA level and therewere fewer patients with rectal carcinoma, characteristicsthat would lead to a higher survival rate. The disease-freesurvival rates were 21%, 20%, and 3%, respectively (p �.02). In the entire group of 131 patients, 78% had liver re-currence after resection. In a multivariate analysis, tumorprogression on chemotherapy, elevated preoperative serumCA19 –9, number of resected metastases, and number ofregimens of chemotherapy were independently associatedwith a shorter survival duration.

Allen and colleagues looked at patients with synchro-nous liver metastases from January 1995–2000 at MSKCC.Neoadjuvant chemotherapy was given to 52 of the 106 pa-tients. The 5-year survival rates were similar in those whodid and did not receive neoadjuvant chemotherapy, 43%and 35%, respectively (p � .49). Patients whose tumors did

Table 2. Pros and cons of preoperative chemotherapy

Pros

Decrease size

Control micrometastatic disease

Assessment of activity of chemotherapy

Better chemotherapy tolerance

Surrogate marker for success of liver surgery

Cons

Liver toxicity

Steatosis

Sinusoidal dilatation

Steatohepatitis

Risk for progression or growth of new sites

Complete response may make surgery more difficult

Secondary splenomegaly

Selection of resistant clones

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not progress while receiving chemotherapy had an in-creased survival compared to those who did not receive pre-operative therapy (p � .03) [46]. An updated analysisshowed no significant difference, with median survivaltimes of 48 and 39 months (p � NS) for patients whose tu-mor did not progress on preoperative chemotherapy andthose who did not receive neoadjuvant therapy, respec-tively (personal observation).

When analyzing patients who are considered unresect-able, Folprecht et al. [47] found a strong relationship (r �0.96, p � .002) between tumor response to neoadjuvantchemotherapy and resection in an analysis of five retrospec-tive studies of patients with unresectable hepatic metasta-ses. Considering only phase III studies, the correlation wasnot as significant (r � 0.67, p � .024).

Cons

Liver ToxicityIn treating patients with resectable hepatic disease, onemust consider the clinical impact of hepatotoxicity fromsystemic chemotherapy. Hepatotoxicity has been reportedwith 5-FU, and this was increased when levamisole wasadded [48]. Additional reports of liver toxicity have beenpublished, which may reflect the use of new drugs such asirinotecan and oxaliplatin, or new ways of administering5-FU. Types of liver toxicity include steatosis [49], sinusoi-dal changes [50], steatohepatitis [51], and hemorrhagic cen-tral lobular necrosis (HCN) [52].

Steatosis represents fatty changes in the liver, as dem-onstrated by the presence of fat droplets within the hepato-cytes (Fig. 1). Why would steatosis interfere with hepaticresection? It has been shown that steatosis may interferewith circulation through sinusoids and impair regeneration.The liver’s protective mechanism against oxidative stressappear to be impaired by steatosis [53, 54], observed in livertransplantation. Figure 2 shows how normal liver paren-chyma after preoperative chemotherapy–induced steatosisbecomes less dense and therefore darker on computed to-mography scans.

The morbidity following liver resection associated withsteatosis has been reported in three trials. Belghiti et al. [55]noted that, in 747 patients, the mortality rate was higher inpatients having steatosis than in those with no steatosis,22% versus 8%, respectively (p � .003). In the Behrns et al.[56] study, of 135 patients, morbidity was seen in 29% and10% of the patients with steatosis and without steatosis, re-spectively. Kooby et al. [49] evaluated 325 patients atMSKCC who had steatosis at the time of resection. Liverspecimens were evaluated by two pathologists and classi-fied as mild, moderate, or severe steatosis. The level of ste-

atosis was compared with the rate of complications seenafter liver resection. Twenty-three percent of patients withimpaired wound healing had marked steatosis versus only1% of patients with no steatosis (Table 3). Biliary compli-cations and infection were also more frequent in patientswith marked steatosis, as was any postoperative complica-tion. If all complications were tabulated, the rates were35%, 48%, and 62% in the groups with no steatosis, mildsteatosis, and marked steatosis, respectively. The study alsodemonstrated that there were baseline characteristics thatincreased the chance for developing severe steatosis. Malegender, higher body mass index (BMI), and preoperativechemotherapy all were associated with a higher incidenceof hepatic steatosis. In patients with abnormal liver pathol-ogy, only 38% had received preoperative chemotherapy,while in those with severe steatosis, 66% had received pre-operative chemotherapy (Table 4).

Fernandez et al. [57] examined 37 patients who under-went resection for colorectal metastases. Thirteen had noprior chemotherapy and 10 received prior 5-FU, irinotecan,or oxaliplatin. The specimens from these patients weregraded for nonalcoholic steatohepatitis (NASH) or liver in-jury score (LIS). The NASH score was significantly worsefor patients who had received irinotecan or oxaliplatin thanfor patients with no prior chemotherapy or 5-FU alone (p �.003). The LIS was also worse for this group (p � .057).There was a direct relationship between BMI and NASHscore. They also found that women tended to have a higherNASH score (p � .08). Patients receiving irinotecan or ox-aliplatin had a higher LIS (p � .005). These investigatorsrecommended that, if patients receive chemotherapy preop-eratively, and particularly if they have a high BMI, thereshould be an evaluation of the liver parenchyma prior toliver resection. They suggested that, in cases with hepato-toxicity from chemotherapy, preoperative portal vein em-

Figure 1. Steatosis. Fatty change, represented by the pres-ence of fat droplets (arrow) within hepatocytes.

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bolization of the involved liver should be used to increase thesize of the uninvolved liver before liver resection [58, 59].

Benoist et al. [60] examined the results of 60 patientswho underwent large liver resections, which required portaltriad clamping or hepatic vascular exclusion, after receiv-ing six cycles of preoperative chemotherapy. The morbidityrate was 18% with triad clamping and 43% after vascularexclusion (p � .044). Transfusion rates were high in bothgroups: 50% and 40%, respectively, which is higher thanthose reported by others after major liver resections [55].Their conclusion, however, was that vascular occlusion can

be used with acceptable morbidity in patients who need amajor liver resection after prolonged chemotherapy.

Preoperative chemotherapy can also lead to vascularchanges, including sinusoidal dilatation, which involvescongestion of the liver tissue surrounding the centralvenules (Fig. 3). Rubbia-Brandt et al. [50] reviewed patho-logic slides from 153 patients who underwent liver resec-tion in 1994–2002 at their institutions. They noted that 51%of those who had preoperative chemotherapy developed si-nusoidal dilatation, which was not seen in those who did notreceive preoperative chemotherapy. For those who had re-

Figure 2. Computed tomography (CT) scans of the liver demonstrating preoperative chemotherapy–induced steatosis. (A): Nor-mal liver with tumor. (B): The tumor has decreased in size, but the liver now has fatty changes that make it less dense, and thereforedarker on CT and darker than the spleen.

Table 3. Impact of steatosis on perioperative outcome (n � 325)

Complication No steatosis Mild steatosis Marked steatosis p-value

Wound 1% 9% 23% �.01

Biliary 13% 22% 25% .01

Any complication 35% 48% 62% �.01

Infection 14% 24% 43% �.01

From Kooby DA, Fong Y, Suriawinata A et al. Impact of steatosis on perioperative outcome following hepatic resection. JGastrointest Surg 2003;7:1034–1044.

Table 4. Patient characteristics and relationship to steatosis in those undergoing liver resection (n � 325)

Normal(n � 160)

Severe Steatosis(n � 102) p-value

Age (mean � SD) 61 � 11 60 � 12 NS

Gender (male) 43% 59% .01

BMI 26 � 5 30 � 6 �.01

Diabetes mellitus 9% 13% NS

Heavy alcohol use 5% 8% NS

Preoperative chemotherapy 38% 66% �.01

Abbreviations: BMI, body mass index; NS, not significant; SD, standard deviation.From Kooby DA, Fong Y, Suriawinata A et al. Impact of steatosis on perioperative outcome following hepatic resection. JGastrointest Surg 2003;7:1034–1044.

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ceived previous oxaliplatin, 78% had striking sinusoidalchanges. The authors hypothesized that the chemotherapymay have caused an injury to the endothelial cells that re-sulted in sinusoidal disruption. The observed sinusoidal le-sions were similar to those seen in veno-occlusive disease.Sebagh et al. [61] reported on a series of 52 patients treatedwith oxaliplatin-based chemotherapy and found that only38% had vascular lesions; they did not observe the veno-occlusive disease described by Rubbia-Brandt et al. [50]. Intheir series, the patients were given a chronomodulated in-fusion of chemotherapy, which they postulate could possi-bly have explained the difference in toxicity.

Vascular alterations can result in changes in the liversimilar to cirrhosis and can make the liver appear blue(“blue liver”) [62]. In a recent report, vascular lesions werecategorized by what the authors felt were increasing gradesof severity—sinusoidal vasodilation, peliosis, HCN, andregenerative nodular hyperplasia. From a cohort of 144 pa-tients who had prior chemotherapy, 75 were randomly se-lected and compared with 17 patients from a group of 159chemotherapy-naive patients [63]. In the treated group, 53of 75 patients had received chronomodulated oxaliplatin/5-FU/LV, while 23 had received 5-FU/LV alone. Althoughthe preoperative chemotherapy group had a similar numberof major resections or liver segments resected, the meantransfusion rate was fourfold higher, 1.9 versus 0.5, respec-tively (p � .03), in those who had received preoperativechemotherapy. The incidence of all hepatic vascular lesionswas greater in the chemotherapy group (p � .01; Table 5),while the incidence of steatosis was similar in the groupswith or without prior chemotherapy. A multivariate analy-

sis revealed that preoperative chemotherapy was the onlyprognostic factor that predicted the need for intraoperativetransfusion. Patients who received preoperative chemother-apy were 2.26 times more likely to receive more than oneunit of transfused blood intraoperatively, and patients withmore blood loss experienced a more difficult recovery.When the 5-FU/LV group was compared with those receiv-ing oxaliplatin/5-FU/LV, the incidence of steatosis was26% versus 8% (p � .09), while the incidence of HCN inthese groups was 4% versus 35% (p � .003), respectively.Transfusions were more commonly performed in patientswith HCN. The greater morbidity seen in this trial has beenseen in other trials. The EORTC 40983 trial, which com-pared preoperative chemotherapy with immediate surgery,had a complication rate of 24% in the treatment group and13% in the surgery-alone group. However, the length ofhospital stay did not differ [63].

The complication rate may increase with the length oftime chemotherapy is administered. Karoui et al. [64] as-sessed the risk of preoperative chemotherapy by examiningthe patients who required total vascular exclusion to per-form a major liver resection. The complication rate was54% for those receiving six or more cycles of chemotherapyversus 19% for those receiving fewer than six cycles (p �.047). The overall morbidity rate was higher in those receiv-ing preoperative chemotherapy than in those receiving notherapy, 38% versus 13.5%, respectively (p � .03). Thenumber of patients with associated gastrointestinal proce-dures was higher in the chemotherapy group. Hepatic fail-ure rates were 11% and 0%, respectively. Karoui et al. [64]reported that 49% of patients treated with preoperative che-motherapy demonstrated sinusoidal dilatation.

A potentially more severe form of liver toxicity is ste-atohepatitis, depicted in Figure 4, with balloon degenera-tion and Mallory body formation. In a retrospective reviewof 406 patients who underwent resection in 1992–2005,Vauthey et al. [51] divided the patients into groups depen-dent on the type of preoperative chemotherapy or no che-motherapy and described the nontumor liver pathology inthese groups. Four pathologists examined the liver andscored the degree of steatosis, steatohepatitis, and sinusoi-dal injury. One hundred fifty-eight patients had no priorchemotherapy, 63 had 5-FU alone, 94 had 5-FU plus irino-tecan, and 79 had 5-FU plus oxaliplatin. Table 6 lists thetype of hepatic injury stratified by the type of chemother-apy. Steatohepatitis was seen most often in patients whohad received preoperative irinotecan (20%). The incidenceof steatohepatitis was greater in patients with a BMI �25kg/m2. In those treated with preoperative irinotecan, the in-cidences were 12.1% and 24.6%, and in those treated withpreoperative oxaliplatin, the incidences were 0% and

Figure 3. Sinusoidal dilatation. Liver tissue around the cen-tral venule (black arrows) shows congestion and dilatation ofsinusoidal spaces (red arrows outline a dilated sinusoid). Thesinusoids are filled with red blood cells.

Source: Courtesy of Dr. Jinru Shia, Memorial Sloan-Ket-tering Cancer Center, New York.

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11.9%, for patients with a BMI �25 kg/m2 versus thosewith a BMI �25 kg/m2, respectively. In patients who hadreceived preoperative oxaliplatin, 18.9% had sinusoidal di-latation, and only 6.3% had steatohepatitis. The 90-daymortality rates were 14.7% and 1.6% for patients with orwithout steatohepatitis (p � .001), respectively, and thepostoperative liver failure rates were also higher, 5.8% and0.8%, respectively (p � .01). Death within 90 days wasseen in 6.5% of patients with steatohepatitis and in 1.6%without steatohepatitis (p � .01). No patient died from si-nusoidal injury.

Hepatotoxicity observed after preoperative HAI therapyis dependent on the drugs that are used. Tanaka et al. [65]examined 41 consecutive patients with five or more bilobarliver metastases from colorectal cancer who underwent ma-jor liver resections with or without prior HAI therapy. TheHAI therapy was 5-FU/LV and cisplatin. The complicationrates were about the same, 27% and 21%, respectively, inthe groups with and without preoperative HAI therapy. Thecomplications in the HAI group included wound abscess,liver stump abscess, biliary fistula, and intestinal obstruc-tion. Severe steatosis was seen in 1 of 19 patients and 6 of22 patients in the non-HAI and HAI groups, respectively(p � .197), while fibrosis of the centrilobular veins wasseen in 5 of 19 and 8 of 22 patients, respectively. The sig-nificant differences were a lower platelet count (p � .01)and a higher alkaline phosphatase level on postoperativeday 3 (p � .01) in the HAI group. The authors concludedthat preoperative HAI therapy did not increase morbidity[65]. These were the toxicities with HAI 5-FU/LV and cis-platin. The toxicities with HAI FUDR are usually biliary(narrowing of bile ducts) and not parenchymal liverchanges [1, 66].

Does Perioperative Bevacizumab Increase Morbidity?The question of whether bevacizumab increases toxicity ifgiven prior to or after liver resection is being investigated.There have been reports of elevated factor VIII and vonWillebrand factor with bevacizumab and chemotherapytreatment [67]. Anti–vascular endothelial growth factor(VEGF) antagonism could also decrease wound healing[68] and, in mice, it prevented liver regeneration [69].There are small studies suggesting that it does not increase

Table 5. Comparison of chemotherapy-naïve patients with patients treated with preoperative 5-FU/LV or5-FU/LV/Oxaliplatin: Complications and pathologic changes

ComplicationNone(n � 17)

5-FU/LV(n � 23)

5-FU/LV/Oxaliplatin(n � 52)

Mean intraoperative transfusions, unitsa 0.5 1.5 2.0

Local complications 6% 26% 17%

Mean hospital stay, days 12.0 12.4 12.5

Operative mortality �6 months 0% 0% 4%

Moderate steatosis 12% 22% 8%

Portal fibrosis 35% 74% 42%

Sinusoidal alterations 12% 30% 19%

Peliosis 6% 30% 31%

Hemorrhagic centrilobular necrosis 6% 4% 35%aPacked red blood cells.Abbreviations: 5-FU, 5-fluorouracil; LV, leucovorin.From Aloia T, Sebagh M, Plasse M et al. Liver histology and surgical outcomes after preoperative chemotherapy withfluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006;24:4983–4990.

Figure 4. Steatohepatitis. Black arrows indicate hepatocyteinjury in the form of ballooning degeneration and yellow ar-rows indicate Mallory body formation (meaning degeneratedand condensed cytoskeleton filaments). Red arrows point to in-flammatory cells. The liver also has pericellular fibrosis,which is best seen using trichrome stain.

Source: Courtesy of Dr. Jinru Shia, Memorial Sloan-Ket-tering Cancer Center, New York.

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toxicity. In an article by Scappaticci et al. [70], data werepooled from two studies in which patients were randomizedto receive either bevacizumab and chemotherapy or chemo-therapy alone. One of the problems with the study is thatthey eliminated all patients with significant atheroscleroticvascular disease, as well as those on cyclo-oxygenase-2 in-hibitors, aspirin, and low-dose warfarin. When bevaci-zumab was given after liver resection, the complicationrates for chemotherapy with or without bevacizumab were1.5% and 0.5%, respectively. In the second study, in whichbevacizumab was given before resection, the complicationrates were 3.4% with no bevacizumab and 13% for thosewho received bevacizumab. The total number of surgicalprocedures was higher in the bevacizumab-treated patients,75/616 (12%) versus 29/516 (5.6%) in the group not receiv-ing bevacizumab [70].

In a review from MSKCC [71], 32 patients underwenthepatic resection receiving perioperative bevacizumab,eight before, eight before and after, and 16 after surgery. Ofthe 16 patients who received preoperative bevacizumab,seven (43%) had complications, including pulmonary em-bolus, deep vein thrombosis, subphrenic abscess, threewound infections, and one urinary tract infection. In the 24patients who received postoperative bevacizumab, therewas one ventricular arrhythmia, three wound infections,one groin abscess, and one superficial thrombophlebitis.Thus, there were four (12.5%) cardiovascular events inthese 32 patients. In the 32 matched controls, there were nocardiovascular events, although the matched controlsseemed to have undergone more extensive surgery, withmore extrahepatic disease resected. In another retrospectivedatabase of 1,186 patients who underwent liver resection,two subgroups were identified: those who had preoperativechemotherapy and bevacizumab (group 1) and those whohad preoperative chemotherapy without bevacizumab(group 2). Forty-five patients from group 1 were comparedwith 82 patients from group 2. For patients who had con-comitant surgical procedures, wound complications weremore frequent in group 1 (p � .05) as were greater bloodloss and hepatobiliary complications. Overall complica-

tions were not greater with the use of bevacizumab periop-eratively [72].

To evaluate whether preoperative bevacizumab affectspatients going for liver resection, the Bevacizumab Ex-panded Access Trial (BEAT) study was designed, in whichbevacizumab (5 mg/kg) is given every 2 weeks with sys-temic chemotherapy (FOLFIRI or FOLFOX). Of the 43 pa-tients who have undergone resection thus far, the mediantime from first bevacizumab treatment to surgery was 183days, and the median time to resection after stopping bev-acizumab was 67 days. Twenty-eight percent of patientshave had complications, including operative site infection,gastric perforation, right pleural effusion, thrombosis of theportal vein, and myocardial infarct, as well as other toxici-ties, but the conclusion was that metastasectomy was feasi-ble after bevacizumab treatment [73]. The results of largerstudies are needed to ascertain whether bevacizumab is safebefore resection. Ellis et al. [74] suggested that surgery 6–8weeks after the last bevacizumab treatment is safe. How-ever, waiting two half-lives or 6 weeks would still leaveabout 1.25 mg/kg of bevacizumab in the circulation.

Secondary SplenomegalyAs some patients develop liver toxicity, they get secondaryhypertrophy of the spleen and may develop a clinical syn-drome similar to portal hypertension [52] with varices andthrombocytopenia (Fig. 5). Hepatotoxicity increases withthe duration of treatment [75]. However, even short coursesof chemotherapy can cause hepatotoxicity. Figure 6 illus-trates that these problems can occur early in treatment, al-though a longer time on chemotherapy generally producesmore toxicity [75].

Risk for ProgressionDuring preoperative therapy, there can be progression inexisting sites, development in new sites, and/or spread toextrahepatic sites if the tumor fails to respond to preopera-tive chemotherapy. Certainly, surgeons have seen hepaticlymph node involvement at the time of liver resection, sug-gesting that liver metastases may spread to these lymph

Table 6. Liver injury stratified by type of chemotherapy

Sinusoidal dilatation Steatosis >30% Steatohepatitis

No chemotherapy 1.9% 8.9% 4.4%

5-fluorouracil 0% 16.6% 4.8%

Irinotecan 4.3% 10.6% 20.2%

Oxaliplatin 18.9% 3.8% 6.3%

From Vauthey JN, Pawlik TM, Ribero D et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-daymortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–2072.

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nodes. In one study of 29 resectable patients, Bathe demon-strated that five of the patients (17%) became unresectableafter preoperative chemotherapy, three because of the de-velopment of extrahepatic disease, one as a result of clinicaldeterioration, and one refusal [76].

The EORTC has completed a study (EORTC 40983) toevaluate 3 months of preoperative FOLFOX and 3 monthsof postoperative FOLFOX versus immediate surgery alone.The eligibility criteria included no previous oxaliplatin che-motherapy and no extrahepatic disease. Of the 365 patientsrandomized to date, 94% have one to three metastases, and42% have stage II disease. Of the 182 patients randomizedto preoperative chemotherapy, 21 (11.5%) could not un-dergo surgery: seven because of disease progression, sevenbecause of refusal or toxicity, and another seven for un-stated reasons. Of the 182 patients without preoperativechemotherapy, nine (4.9%) were not operated on: five be-cause of progression and four for unstated reasons [77]. It istoo early to examine disease-free survival or overall sur-vival. The pathology has been reviewed for 59 patients. Si-nusoidal changes occurred in 48% of the treated group and11% of the control group, while severe sinusoidal changeswere seen in 41% and 0%, respectively (p � .0032). There

has been no difference between groups in surgical compli-cations thus far [78].

Management of Hepatic Metastases After a CompleteResponse to ChemotherapyWhen patients undergo preoperative chemotherapy, theaim is to decrease the size of the tumor, but what happenswhen there is a complete response and the tumor is nolonger visible? If the tumor is not visible by scan or intra-operatively, but is present microscopically, there can laterbe a recurrence at that site. Benoist et al. [79] prospectivelyfollowed 586 patients treated for liver metastases fromcolorectal cancer, and 38 patients (6%) obtained a completeresponse of at least one lesion; 66 sites disappeared on im-aging. Surgery was done 4 weeks after the imaging. Of the66 disappearing sites, 20 had macroscopic disease presentat surgery, and in 46 sites, no lesion was found at surgery.Fifteen of the 46 disappearing lesions were resected, and 12(80%) still had viable tumor. Thirty-one sites where previ-ous tumor had been seen were left in place and followed,and in situ recurrence was seen in 23 (74%). Therefore, 55of 66 sites (83%) were not cured (Fig. 7). The authors con-cluded that medical oncologists should refer patients prior

Figure 5. Enlarged spleen after systemic oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) chemotherapy. (A): Computed to-mography (CT) scan prior to chemotherapy. (B): CT scan after 1 year of FOLFOX showing enlarged spleen.

Figure 6. Hepatic toxicity after 6 weeks of chemotherapy. (A): 62-year-old male patient with colorectal cancer metastatic to the liver,received three treatments of oxaliplatin/5-fluorouracil/leucovorin (6 weeks of therapy) as neoadjuvant treatment prior to resection. (B):After 6 weeks of treatment, the liver appeared fatty, and there was new ascites. The patient’s bilirubin level increased from 0.8 to 2.0mg/dl, and his alkaline phosphatase increased from 101 to 261 u/l. Ascites indicated by arrow.

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to getting a complete response in order not to miss “dormant”metastases. In the Adam et al. [23] trial of 1,104 patients, ofwhom 138 (12.6%) became resectable, 80% had tumor recur-rence, and 71% of these recurrences were in the liver.

At MSKCC, 435 patients seen by the hepatobiliary sur-geons and treated with neoadjuvant chemotherapy wereevaluated. One hundred seventeen lesions disappeared in39 patients. Sixteen of these lesions were never evaluated inthe operating room because the patients did not undergosurgery. Of the 95 surgically evaluated lesions, 52 lesionswere not resected and 30 never recurred, with a median fol-low-up of 40 months. Forty-nine lesions were resected, and43 had pathological complete response. There may be somedifferences in these results compared with those of theFrench study because some of these patients had HAI priorto having resection. In the patients receiving HAI, thepathological complete response rate was about 68%, whilein the systemic alone group it was 29%. In patients who re-ceived preoperative HAI therapy alone, 14% of the lesionsrecurred, compared with a 42% recurrence rate with preop-erative systemic chemotherapy (p � .001). They also foundthat lesions were significantly more likely to be found atsurgery in patients whose surrounding liver demonstratedsteatosis (p � .001) and in patients with a high BMI (�30kg/m2; p � .002) [80].

Elias et al. [81] also demonstrated less recurrence after pre-operative HAI therapy. They examined 104 patients who un-derwent liver resection for colorectal cancer over a 4-yearperiod and found that 15 patients had a dramatic response tochemotherapy and a complete disappearance of at least one le-sion by imaging. In four patients (27%), the lesions were foundat laparotomy and removed, while in 11 patients the tumorscould not be found and were not removed (“missing lesions”).Eight of these 11 patients did not have a recurrence, with a me-dian follow-up of 31 months. There is no description of thetype of chemotherapy given preoperatively to the wholegroup, but the authors do describe the therapy for those withmissing lesions. Six of the 11 patients with missing lesions hadreceived hepatic arterial therapy, either before (four patients)or afterward (two patients). Four of the eight patients who hadreceived HAI never had a recurrence of the missing lesions[82].

CONCLUSION

For many years, the diagnosis of liver metastases from co-lon cancer portended a dismal outcome. The developmentof therapeutic agents that produce response rates in the 50%range has led to longer survival times, even in patients withunresectable disease. One of the advantages of these newagents is that they allow initially unresectable patients to

Figure 7. Complete response after chemotherapy: Does it mean cure?From 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.

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become resectable, thus providing a chance of cure orlonger survival. A challenge over the next few years will beto decide when these different modalities are best used. Ifchemotherapy can decrease the tumor size to a point wherelesions cannot be seen but are not completely eradicated,then preoperative chemotherapy may be a disservice to ini-tially resectable patients. Additionally, if preoperative che-motherapy produces more liver toxicity and therebyincreases the risk for surgery, then preoperative chemotherapymay not prove to be advantageous for resectable patients.

In patients who are clearly unresectable, there is noquestion that chemotherapy is the appropriate treatment.However, for those who are clearly resectable, there may beharm in giving preoperative chemotherapy. Until studies

demonstrate that preoperative chemotherapy is useful in theresectable patient, those patients should be offered resec-tion first and then be treated with postoperative chemother-apy (systemic therapy or HAI plus systemic therapy) [82–86]. A multidisciplinary approach is essential to develop aneffective treatment plan for patients with liver metastasesfrom colorectal carcinoma.

ACKNOWLEDGMENTS

Thank you to Deirdre B. Casey for manuscript preparation.

DISCLOSURE OF POTENTIAL CONFLICTS

OF INTEREST

The author indicates no potential conflicts of interest.

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