multidisciplinary management of metastatic colorectal cancer

Surgical Oncology 7 (1998) 197}207

Multidisciplinary management of metastatic colorectal cancer

Sam S. Yoon, Kenneth K. Tanabe*Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Cox 626, 100 Blossom Street, Boston, MA 02114, USA

Abstract

When colorectal cancer metastasizes to distant organs, usually multiple sites are involved and treatment consists primarily ofsystemic chemotherapy and supportive care. Chemotherapeutic agents e!ective against metastatic colorectal cancer include5-#uorouracil, often used in combination with leucovorin or methotrexate, and irinotecan (CPT-11). Median survival with optimalchemotherapy regimens ranges from 10 to 15 months. Less frequently, colorectal cancer metastasizes only to the liver or lung. Ina minority of these cases, surgical resection can be performed and results in a median survival of 28}46 months for hepatic resectionsand 24}25 months for pulmonary resections. Five-year survival rates range from 24 to 38% and 21 to 44% for hepatic and pulmonaryresections, respectively. For isolated liver metastases that are not surgically resectable, other regional therapies that can be consideredare hepatic cryosurgery, radiofrequency ablation, and hepatic arterial infusion chemotherapy. Median survival following cryosurgeryis between 26 and 30 months, while median survival following radiofrequency ablation has not been established in large series.Hepatic arterial infusion chemotherapy, especially with newer combination drug regimens, may increase survival in patients withisolated liver metastases compared to systemic chemotherapy, but this must be con"rmed in randomized, prospective trials.Colorectal cancer metastases to the brain can be treated with radiation therapy or surgical resection, but median survival withtreatment is less than one year. ( 1999 Elsevier Science Ltd. All rights reserved.

Keywords: Colorectal cancer; Metastasis; Chemotherapy; Hepatectomy; Cryosurgery; Radiofrequency ablation; Intra-arterial infusion; Pulmonaryresection

1. Introduction

With an estimated 131,600 new cases and 56,500deaths in 1998, colorectal cancer (CRC) is the fourthmost commonly diagnosed cancer and the second lead-ing cause of cancer death [1]. The overall "ve-year sur-vival rate for CRC is about 50% [2]. At the time of initialdiagnosis, 70% of patients with CRC will have limiteddisease that is resectable with curative intent and 30%will have advanced disease (i.e. unresectable local diseaseor distant metastases) [3]. Of patients with resectableCRC, about 35% will subsequently develop recurrentdisease either in the form of local recurrence or distantmetastases [3].

CRC can spread di!usely to several sites or can spreadto one or two isolated organs. The majority of patientswith initially advanced CRC or recurrent CRC havemultiple sites of disease [3] and are commonly treatedwith systemic chemotherapy or supportive care. WhenCRC metastases are limited to one or at most two sites,

*Corresponding author. Tel.: #1-617-726-8555; fax: #1-617-724-3895.

regional therapies such as surgical resection can be con-sidered. The liver is the most common site of distantmetastasis from CRC, with liver metastases occurring inalmost one-half of all patients with CRC. The next mostcommon site of CRC metastasis is the lung. In oneautopsy series of 1541 patients who died of CRC, 44% ofautopsies revealed liver metastases and 21% revealedlung metastases [4]. Other sites of metastases includedadrenal glands (7%), bone marrow (6%), spleen (3.4%),pleura (2.8%), and brain (2.5%). The treatment of pri-mary CRC and local recurrences is discussed elsewhere inthis edition. This article will discuss the management ofdisseminated CRC metastases with systemic chemother-apy, management of isolated metastases to the liver andlung with surgical resection and other regional therapies,and management of brain metastases with surgical resec-tion and radiation therapy.

2. Surveillance

The majority of CRC recurrences occur within the "rst2.5 years of surgical resection, and the remainder of

0960-7404/99/$ - see front matter ( 1999 Elsevier Science Ltd. All rights reserved.PII: S 0 9 6 0 - 7 4 0 4 ( 9 9 ) 0 0 0 2 2 - 5

recurrences occur within the next 2.5 years [2]. Thegoal of surveillance of patients with a history of CRCis to discover recurrences as early as possible tooptimize the results of further therapy. A reasonablesurveillance schedule for patients who have undergonesurgical resection of CRC with curative intent includesregular history and physical examination, digitalrectal examination, and fecal occult blood testing.Carcinoembryonic antigen (CEA) levels may bemonitored every three months for 3 years for patientswho are candidates for aggressive evaluation and therapyshould the levels rise. For patients with rectal cancer,a pelvic computed tomography (CT scan) may beobtained three or four months after operation to estab-lish a baseline and then annually for three years.Colonoscopy should be performed after one year andrepeated every three years as long as no abnormalitiesare found. A chest X-ray may be obtained every year for"ve years.

Surveillance will diagnose recurrent disease earlier butthere is no de"nitive evidence that intense surveillancewill improve survival. One meta-analysis of seven non-randomized studies reported that patients receiving in-tensive follow-up including CEA monitoring had a 9%better "ve-year survival than patients receiving minimalor no follow-up [5]. Subsequent randomized, prospectivestudies have failed to con"rm this bene"t. In onestudy, 597 patients were randomized to frequent orinfrequent follow-up and prospectively followed, butneither group had CEA monitoring [6]. The frequentfollow-up group had their recurrences diagnosed earlierand underwent more operations, but there was nodi!erence in survival between the frequent and infrequentfollow-up groups. An ongoing prospective, randomizedtrial in the United Kingdom is monitoring CEA levelsmonthly after resection of CRC [7]. If the CEA levelrises above 10 ng/ml, patients are randomized toeither physician and patient noti"cation or no noti"ca-tion. Thus far, there has been no di!erence in survivalbetween the 2 groups. Thus, the intensity of follow-upand CEA monitoring should be determined on an indi-vidual basis.

3. Systemic chemotherapy

For the majority of patients with initially advancedCRC or recurrent CRC, disease will have advanced to thepoint where systemic chemotherapy and supportive careare the only therapeutic options. 5-#uorouracil (5-FU) isthe most commonly used agent against CRC [8]. Clinicaltoxicity from 5-FU includes anorexia, nausea, stomatitis,diarrhea, myelosuppression, hair loss, and skin changes[9]. Although objective response rates for 5-FU widelyvary, an objective response rate of about 20% is generallyattainable [10]. The administration of 5-FU is associated

with a median survival of 6}8 months in all patients and12}18 months in patients with an objective response [7].Continuous infusion of 5-FU as opposed to bolus admin-istration has been demonstrated to improve responserates and provide a small survival advantage in onemeta-analysis [11].

Biochemical modulation strategies have been used toincrease the e$cacy of 5-FU against CRC. The mostsuccessful strategy thus far has been the addition ofleucovorin. A meta-analysis of nine randomized studiesfound 5-FU combined with leucovorin resulted inbetter response rates than 5-FU alone, but no survivaladvantage was observed [12]. Objective tumor responserates with this combination have been about 20}25%,and median survival has been about 10}12 monthsin all patients [8]. In addition, biochemical modulationwith methotrexate at least 24 h prior to 5-FU administra-tion has been shown in a meta-analysis of randomizedtrials to have a small survival advantage over 5-FUalone [13]. The addition of interferon or N-(phos-phonacetyl)-L-aspartate (PALA) has not been shownto be more e!ective than 5-FU alone in randomized trials[14].

Combination chemotherapy with 5-FU and severalother chemotherapeutic agents has been used againstCRC with mixed results. Combinations of 5-FU,methyl-CCNU, mitomycin, vincristine, and streptozocinhave not demonstrated a survival advantage in random-ized trials [7]. While the combination of 5-FU withcisplatin was initially encouraging, several randomizedtrials have failed to demonstrate a better response rate orincreased survival compared to 5-FU alone [7].

One promising agent for metastatic CRC is irinotecan(CPT-11), a topoisomerase I inhibitor. In a prospective,randomized trial of 279 patients with metastaticCRC who failed 5-FU therapy, irinotecan treatmentled to a one-year survival of 36% compared to 14%after treatment with best supportive care [15]. Theirinotecan-treated group also experienced improvedquality of life. Another prospective, randomized trialcompared irinotecan to infusional 5-FU in 267 patientswith metastatic CRC who had failed conventional 5-FUtherapy [16]. One-year survival was 45% for theirinotecan group compared to 32% for the infusional5-FU group, and the irinotecan group had a longerperiod until quality of life deteriorated. Toxicity fromirinotecan includes severe diarrhea and neutro-penia [8].

Thus, for patients with advanced or widely metastaticCRC, initial systemic chemotherapy should include 5-FUpossibly combined with a biochemical modulator such asleucovorin or methotrexate. If there is no response to5-FU-based therapy, irinotecan is currently the bestsecond-line agent. Patients who do not respond toirinotecan can be considered for participation in clinicaltrials of investigational agents.

198 S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197}207

4. Surgical resection of isolated liver metastases

Almost one-half of patients with CRC will developliver metastases at some point in their course. About15}25% of patients will have liver metastases at the timeof primary CRC diagnosis and another 20% will developmetachronous liver metastases [17]. Unfortunately, onlya small minority of patients with liver metastases arecandidates for surgical resection, which o!ers a reason-able chance for long-term survival. Of all patients withCRC liver metastases, about 25% will have no other sitesof metastases [18], and only 10}20% of these patientswill have metastases that are surgically resectable [19].Thus, of the more than 131,000 patients who developedCRC in 1998, an estimated 2000 patients will at somepoint have surgically resectable liver metastases.

Careful preoperative assessment should be performedwhen considering surgical resection of CRC liver meta-stases to (1) exclude extrahepatic disease as reliably aspossible; (2) determine the location of all metastases inrelation to the liver's anatomic segments and vital struc-tures; and (3) determine the ability of the patient totolerate hepatic resection. Thus, the preoperative assess-ment should include a history and physical examination,hematology and chemistry panels, coagulation pro"les,liver function tests, CEA level, electrocardiogram, chestX-ray, and abdominal and pelvic CT scans. We routinelyobtain chest CT scans to rule out pulmonary metastases.In a recent study of patients with apparently isolatedCRC liver metastases and normal chest X-rays, chest CTscans had a positive yield of 4% and a positive predictivevalue of 36% for lung metastases [20]. Colonoscopyshould be performed if not done within the past 12months. Cardiology or pulmonology consultationsshould be obtained when necessary to better assesscomorbid conditions.

Further preoperative radiological evaluation is basedupon surgeon preference. The sensitivity of helical CTscans with intravenous contrast for CRC liver metastasesis about 80% [21,22]. The sensitivity of CT arteriopor-tography (CTAP), in which intravenous contrast is injec-ted into the superior mesenteric or splenic artery and CTimages are obtained during the portal venous phase, isover 90% [23]. The speci"city of CTAP is reduced due tofrequent perfusion abnormalities and pseudolesions [24].Magnetic resonance imaging with liver-speci"c contrastagents is increasingly being used in the evaluation of livermetastases. MRI performed with contrast agents suchas manganese-pyridoxyl diphosphate (Mn-DPDP) orsuperparamagnetic iron oxide particles (SPIO) can be assensitive as CTAP for liver metastases and even morespeci"c [25]. At the Massachusetts General Hospital,MRI with Mn-DPDP is currently the study of choice forthe preoperative evaluation of CRC liver metastases.

Radioimmunodetection (RAID), otherwise known asimmunoscintigraphy (IS), is another modality used to

detect primary CRC and metastases. This test utilizesradiolabeled antibodies directed against tumor-asso-ciated antigens such as CEA or TAG-72. Following in-travenous injection, the radiolabeled antibody binds totumor foci, which can then be visualized on either planarscintigraphy or single-photon emission computed to-mography (SPECT). RAID is less sensitive than CT scanin identifying liver metastases but more sensitive in iden-tifying extrahepatic disease [26]. Thus, RAID has beenadvocated for use in patients considered for curativeresection of CRC liver metastases to exclude extrahepaticdisease [27}29]. However, Stocchi and Nelson havenoted that almost 20% of patients with RAID would beincorrectly considered to have extrahepatic disease anddenied potentially curative surgery because the speci"cityof RAID for extrahepatic disease is only about 60% [26].For this reason, we do not routinely perform RAID onpatients with CRC liver metastases as part of the pre-operative workup.

Despite extensive preoperative evaluation, a smallbut signi"cant percentage of patients who undergolaparotomy for resection of CRC liver metastases haveunresectable disease. Diagnostic tests are being investi-gated to more accurately identify those with unresectabledisease. Laparoscopy combined with laparoscopicultrasound may be the most sensitive technique for iden-ti"cation of intra-abdominal disease. In one study,laparoscopy and laparoscopic ultrasound detectedunresectable disease in 25% of patients with liver tumorsjudged to be resectable by conventional imaging studies[30]. Further studies are needed to determine if routineuse of laparoscopy and laparoscopic ultrasound arebene"cial in all candidates for resection of their CRCliver metastases. Another modality that may help inidentifying additional foci of CRC is radioimmunoguidedsurgery (RIGS). RIGS is performed by intravenouslyinjecting a radiolabeled monoclonal antibody which isspeci"c for a tumor-associated antigen. After a couple ofweeks, during which time the background radioactivitydeclines, the patient undergoes an exploratorylaparotomy, and a hand-held gamma detection probe isused to identify areas of increased radioactivity whichcan be biopsied or resected. In a series of patients oper-ated on for CRC liver metastases, extrahepatic diseasewas identi"ed in 65% of patients operated on with RIGSwhile extrahepatic disease was identi"ed in only 28% ofpatients without RIGS [31]. The true sensitivity andspeci"city of RIGS for identi"cation of extrahepatic dis-ease and the impact of RIGS on survival in patientsexplored for apparently resectable CRC liver metastasesis unknown. The utility of resecting all RIGS-positivetissue in these patients is also unknown. In the future,techniques such as laparoscopic ultrasound and RIGSmay allow surgeons to more con"dently select patientswho stand to bene"t from hepatic resection and helpidentify more metastases that can be resected.

S.S. Yoon, K.K. Tanabe / Surgical Oncology 7 (1998) 197}207 199

Table 1Results of resection of CRC liver metastases

Study (year) Number ofpatients

Operativemortality (%)

Operativemorbidity (%)

Median survival(months)

5-year survival (%)

Schlag [39] (1990) 122 4 34 28 *

Doci [40] (1991) 100 5 39 * 30Rosen [41] (1992) 280 4 * 33.6 25Gajowski [42] (1994) 204 0 * 33 32Scheele [43] (1995) 434 4.4 22 * 33Wanebo [44] (1996) 74 7 38 35 24Fong [45] (1997) 456 2.8 24 46 38

Patients may be considered candidates for surgicalresection of their liver metastases if they have no ex-trahepatic disease, all their liver metastases can be resec-ted with a tumor-free margin (preferably of at least 1 cm),and adequate liver parenchyma can be spared. In theabsence of underlying liver disease, about 75% of theliver can be removed without subsequent hepatic failure[32]. The operative procedure is carried out usuallythrough a right subcostal incision frequently extendedacross the midline to the left. The abdominal cavity isthoroughly explored for extrahepatic disease and suspi-cious areas are biopsied. The liver is then fully mobilizedby dissection of its supporting ligaments. Following vis-ual inspection and palpation of the liver, intraoperativeultrasound is used to identify all liver lesions and delin-eate vascular anatomy. Liver resections are performedbased on the liver's segmental anatomy as described byCouinaud [33]. One or more segmental resections areoften performed as opposed to a major contiguous resec-tion to spare more normal liver or to allow resection ofdistantly spaced metastases. A variety of techniques areused to divide liver tissue including "nger fracture, clampfracture, electrocautery, morselization and aspirationwith a small suction tip, and ultrasonic dissection andaspiration. Ideally, 1 cm surgical margins are obtainedaround all metastases.

Surgical resection of CRC liver metastases o!ers thebest chance of long-term survival. Median survival ofpatients with isolated CRC liver metastases after systemicchemotherapy is 10}16 months and 5-year survival israre [34]. Retrospective analysis of patients with poten-tially resectable CRC liver metastases that went unresec-ted have found mean survival to be about 20 months and"ve-year survival to be near 0% [35}38]. In contrast,surgical series have consistently reported median survivalfollowing resection of CRC liver metastases to be be-tween 28 and 46 months and "ve-year survival between22 and 45% (see Table 1) [39}45]. Major causes ofoperative mortality included bleeding, liver failure, andsepsis. Additional major causes of morbidity includedbiliary leak or "stula, intra-abdominal abscess, woundinfection, pneumonia, and pleural e!usions. Operativemorbidity rates ranged from 22 to 39%.

There are no absolute contraindications to surgicalresection except when those criteria listed previously asprerequisites for operation are not met. However, numer-ous retrospective analyses have identi"ed factors thathave been associated with decreased survival followingsurgical resection of CRC liver metastases. Table 2 liststhe negative prognostic factors that have been reportedto be statistically signi"cant in at least two studies fromthe past decade [40}46]. The majority of these factorssuggest more aggressive tumor biology or larger tumorburden. The only factor under the surgeon's control is thesize of the tumor margin, and Cady et al. have empha-sized the importance of having at least 1 cm tumor-freemargins [47]. Some groups have considered 4 or moreliver metastases to be an absolute contraindication toresection. In the largest surgical series this decade fromMemorial Sloan-Kettering Cancer Center, patients with4 or more metastases had a 5-year survival of 24% [45].While 4 or more metastases is certainly a negative prog-nostic factor, we do not de"nitively exclude such patientsfrom surgical resection.

About 65}80% of patients who undergo resection oftheir CRC liver metastases will develop a recurrence, anda signi"cant proportion of these patients will again haveisolated metastases to the liver that are amenable torepeat liver resection. The criteria for repeat hepaticresection are the same as those for initial hepatic resec-tion. There have been numerous small series and threeseries each with over 60 patients who underwent repeathepatic resection for CRC liver metastases [48}50]. The"ve-year survival rates in the three largest series were 16,32 and 41%. The majority of patients in the last studyreceived adjuvant chemotherapy [50]. The mortality andmorbidity rates were comparable to those after initialhepatic resection. Negative prognostic factors includedincomplete resection, short interval between hepatec-tomies, three or more metastases, elevated CEA level,and extrahepatic disease.

Some centers have performed hepatic resections onpatients with unresectable liver metastases following re-gression from systemic chemotherapy or hepatic arterialinfusion chemotherapy [51}53]. One study of 53 patientswho underwent systemic chemotherapy followed by


Table 2Negative prognostic factors after surgical resection of CRC liver meta-stases [40}46]

Primarycolorectal tumorcharacteristics

Metastases characteristics Surgical resectioncharacteristics

Advanced stageHigh grade

Lymph node involvementExtrahepatic metastases

Less than 1 cmtumor-free marginExtensive resectionLarge size

Increased numberSatellitosisBilobar distributionShort disease-free intervalSynchronous metastasesElevated CEA level

surgical resection of initially unresectable CRC livermetastases reported a "ve-year survival of 40% [53].Such aggressive treatment should be left for experiencedcenters as part of a clinical trial.

5. Hepatic cryosurgery

In situ liver tumor ablation allows treatment of a widerrange of metastatic liver disease and avoids some of thedangers of surgical resection. Hepatic cryosurgery de-stroys liver tumors in situ by freezing them. Presently, itis used to treat patients with isolated CRC liver meta-stases who have: (1) lesions that are not surgicallyresectable; (2) residual lesions not encompassed by aperformed surgical resection; (3) an involved or closesurgical margin; or (4) comorbidity that precludes amajor liver resection [54].

Hepatic cryosurgery is performed during an operativeprocedure by placing a cryoprobe into the center ofa liver tumor either under direct vision or with ultra-sound guidance. Liquid nitrogen is circulated throughthe cryoprobe and an `iceballa is created which is ob-served with ultrasound. The liquid nitrogen is circulateduntil the iceball extends at least 1 cm beyond the tumormargin. Two freeze}thaw cycles appear to enhancetumor destruction. Some surgeons use hepatic in#owocclusion to increase the size of the iceball or the speedwith which it forms. However, this maneuver theoret-ically places vessel walls and bile ducts at greater risk forinjury. Postoperative mortality from this procedureranges from 0.9 to 3.7% in the largest series [55,56].Complications are not uncommon and include crackingof the frozen liver with subsequent bleeding, right-sided pleural e!usion, intra-abdominal abscess, bilecollection or "stula, thrombocytopenia, myoglobinuria,acute renal failure, and cryoshock phenomenon (dis-

seminated intravascular coagulation and multisystemorgan failure) [54]. The risk for many of these complica-tions appears to be proportional to the volume of normalliver parenchyma that is treated.

The results with hepatic cyrosurgery have been en-couraging in patients with unresectable CRC livermetastases who normally have a median survival withsystemic or hepatic artery infusion chemotherapybetween 12 and 17 months [34]. Median survival in thetwo largest series of patients with CRC liver metastasestreated with cryotherapy was 26}30 months and "ve-yearsurvival for one study was 13.4% [55,56]. Thus, forpatients with unresectable but isolated CRC liver meta-stases, hepatic cryosurgery is a reasonable option.

6. Radiofrequency ablation

Radiofrequency (RF) ablation uses RF energy ratherthan freezing to destroy tumors. The indications forits use are similar to those for hepatic cryosurgery.RF ablation is performed percutaneously, laparoscopi-cally, or intraoperatively by insertion of a RF electrodeinto the center of a liver tumor under ultrasound orCT guidance [57]. RF energy is run through thelow-resistance electrode and absorbed by the high-resistance liver tumor, leading to tissue heating anddestruction. Recent advances such as internal coolingof the tip of the RF electrode and multi-probearrays have allowed the RF energy to be dispersed overlarger areas and enabled treatment of larger tumors[58,59].

Mortality from RF ablation has not been reported,and morbidity is uncommon. In "ve published studies,two reported no complications and the three other stud-ies reported a total of three minor complications (twocases of self-remitting bleeding and one case of transientascites) [59}63]. At the Massachusetts General Hospital,over 100 tumors have been treated with only two minorcomplications.

The e!ectiveness of RF ablation compared to cryosur-gery in destroying liver metastases is unclear. Thepublished studies using RF ablation to treat CRC livermetastases have been small, lacked long-term follow-up,and used equipment and techniques that have since beenimproved. Solbiati et al. treated 29 patients with 44 livermetastases, mostly from CRC, and found at 18 monthsan overall survival of 89% and a disease-free survivalof 33% [59]. Of lesions treated with RF ablation,34% progressed during follow-up. Another study of 14patients with 24 liver metastases found that 52%of tumors had complete necrosis six months after treat-ment [60].

RF ablation of CRC liver metastases is currently underinvestigation. Technological advances are needed to in-crease the ability of RF energy to destroy tumors of


Table 3Prospective randomized clinical trials of HAI chemotherpy versus systemic chemotherapy!

Study (year) Study size HAI treatment(sample size)

Systemic treatment(sample size)

Median survivalHAI vs. systemic (months)

p value

Kemeny [69] (1987) 99 FUDR [48] FUDR [51] 17 vs. 12 NSChang [70] (1987) 64 FUDR [32] FUDR [32] 17 vs. 12 NSHohn [71] (1989) 143 FUDR [67] FUDR [76] 15.5 vs. 15.8 NSMartin [72] (1990) 69 FUDR [33] 5-FU [36] 12.6 vs. 10.5 NSWagman [73] (1990) 41 FUDR [31] 5-FU [10] 13.8 vs. 11.6 NS

!Cancer Vol. 78, No. 8, 1996, 1639}45. Copyright ( (1996) American Cancer Society. Adapted by permission of Wiley-Liss, Inc., a Subsidary of JohnWiley Sons, Inc.

larger diameter and to ensure all tumor tissue is de-stroyed. Presently, numerous overlapping ablation zonesare required to treat tumors greater than 3.5 cm in dia-meter. This strategy requires a precision that may not beattainable. Given the low incidence of complications andthe ability to perform this technique percutaneously orlaparoscopically, RF ablation holds signi"cant promiseas a future therapy for CRC liver metastases.

7. Hepatic arterial infusion chemotherapy

For patients with isolated CRC liver metastases thatare not surgically resectable, regional chemotherapythrough the hepatic artery has been extensively investi-gated. Hepatic arterial infusion (HAI) chemotherapy hastheoretical advantages over systemic chemotherapy inthat (1) liver metastases larger than a few millimeters aresupplied primarily by the hepatic artery while normalliver is supplied primarily by the portal vein [64]; and (2)"rst-pass clearance of certain chemotherapeutic agentsby the liver limits systemic toxicity [65]. HAI of the mostcommonly used agent, #oxuridine (FUDR), allows a levelof liver exposure 100}400 times greater than with intra-venous administration [66].

HAI chemotherapy requires laparotomy for placementof an HAI pump and cannula. Patients initially undergoa preoperative angiogram to de"ne the arterial anatomybecause over one-third of patients have variant arterialanatomy [67]. During laparotomy, a careful search isperformed for extrahepatic metastases. If metastases out-side the liver are identi"ed, HAI pump and cannulaplacement is generally contraindicated since therapydoes not generally help patients with extrahepatic dis-ease. The gallbladder is removed to prevent subsequentchemotherapy-induced cholecystitis. Meticulous dissec-tion is performed to identify the artery to be cannulated(usually the gastroduodenal artery) and to prevent mis-perfusion of the stomach, duodenum, or pancreas [68].The HAI pump is placed in a subcutaneous pocket in theanterior abdominal wall, and the cannula is connected tothe pump, tunneled into the abdomen, and inserted intothe appropriate artery. The procedure is completed by

injecting #uorescein into the pump sideport and observ-ing abdominal organs under a Wood's lamp to con"rmfull hepatic perfusion and no extrahepatic perfusion.A radiolabeled, macroaggregated albumin scan is ob-tained about 3 days postoperatively to again verify fullhepatic perfusion and exclude misperfusion. Followingrecovery from the operation, HAI chemotherapy can beinitiated. A typical regimen at the Massachusetts GeneralHospital involves a 14-day continuous infusion of0.15 mg/kg/day of FUDR, 4 mg/m2/day of leucovorin,and 20 mg/14 days of dexamethasone, followed by a 14-day continuous infusion of heparinized saline. The cycleis then repeated. Liver function tests are followed closelyto guide dose adjustments, and follow-up abdominal CTscans are obtained to monitor response. Complica-tions include chemical hepatitis, biliary sclerosis,misperfusion leading to gastritis, duodenitis, or pancre-atitis, catheter or arterial thrombosis, and pump pocketcollections [68].

Five prospective, randomized trials have comparedHAI of FUDR with intravenous administration ofFUDR or 5-FU (see Table 3) [69}73]. Two Europeantrials compared HAI chemotherapy to best supportivecare, which in a majority of cases did not include systemicchemotherapy [74,75]. Response rates for HAI of FUDRin these studies has ranged from 42 to 62% compared to10 to 21% for systemic chemotherapy. Median survivalfor patients treated with HAI of FUDR ranged from 12.6to 17 months compared to 10.5 to 15.8 months for pa-tients who received systemic chemotherapy. The onlystudies demonstrating a di!erence in overall survivalwere those in which many patients in the control groupreceived supportive care only [74,75]. New studies haveinvestigated HAI of a combination of agents (FUDRwith leucovorin and dexamethasone) and HAI infusionof FUDR combined with intravenous administration ofFUDR, 5-FU, or CPT-11 [76]. Additional studies haveexamined HAI chemotherapy in the adjuvant settingfollowing surgical resection of CRC liver metastases [76].Many of these studies have demonstrated improved re-sponse rates and overall survival compared to historicalcontrols, but randomized prospective trials are needed tocon"rm their bene"ts.


Table 4Results of resection of CRC lung metastases

Study (year) Number ofpatients

Operativemortality

Operativemorbidity

5-yearsurvival

10-yearsurvival

Negativeprognosticfactors(%) (%) (%) (%)

Goya [79] (1989) 62 * 4.8 42 22 Tumor'3 cm

Mori [80] (1991) 35 * * 38 * Tumor'3 cm'1 metastasis

McAfee [81]!(1992)

139 1.4 12.2 30.5 19.1 '1 metastasisCEA'5 ng/ml

McCormack [82](1992)

144 0 2.1 44 26 None

Regnard [83](1995)

101 * * 21" * Synchronousdisease

van Halteren [84]!(1995)

38 * * 43 * Disease-freeinterval(24months

Girard [85] (1996) 86 1.2 * 24 20 IncompleteresectionCEA'5 ng/ml

!Series included only curative resections."Survival rate only for those with curative resections.

8. Surgical resection of lung metastases

The second most common site of metastases fromCRC is the lung [4]. For the small percentage of patientswith CRC metastases to the lung and no other organs,surgical resection may be considered. The preoperativeassessment of these patients is similar to that for patientswith isolated liver metastases. Pulmonary function testsmay be helpful in some patients. Chest MRI is as sensi-tive as chest CT scan in identi"cation of lung metastases[77], but is more expensive and usually adds little in-formation to chest CT scan. Upon completion of pre-operative testing, criteria for resection are the following:(1) there is no extrapulmonary disease; (2) all pulmonarymetastases can be removed with clear surgical margins;and (3) the patient has adequate pulmonary reserveand overall health to allow a pulmonary resection[78].

Isolated pulmonary metastases may be resected usingvideo-assisted thoracoscopic surgery (VATS). Alterna-tively, a posterior lateral thoracotomy may be performedfor unilateral metastases and staged bilateral tho-racotomies or a median sternotomy for bilateral meta-stases. Open thoracotomies allow manual palpation ofthe lung to identify possible additional lesions [78]. Pa-tients with a history of CRC and two or more newpulmonary nodules can be considered to have metastaticdisease. In patients with a solitary pulmonary nodule,one cannot exclude the possibility of a new primary lung

cancer. In these patients, a more aggressive pulmonaryresection and mediastinal lymph node dissection is gen-erally indicated in case the "nal diagnosis turns out to beprimary lung cancer.

The reported survival of patients undergoing resectionof isolated lung metastases for CRC in surgical seriesof 35 or more patients over the past decade hasbeen 24}44% at "ve years and 19}26% at ten years (seeTable 4) [79}85]. Median survival was reported in only2 of these studies and was 24}25 months [79,85]. Opera-tive mortality and morbidity in these series ranged from0}4.8% to 2}15%, respectively. Negative prognostic fac-tors included greater than 1}2 metastases, CEA levelgreater than 5 ng/ml prior to resection, and incompleteresection.

In patients with CRC metastases to both the lung andliver and no other sites of metastases, some groups haveresected metastases at both sites [79,85}91]. Thesestudies included a total of only 77 patients, andmedian survival ranged from 16 to 27 months. This isrelatively low given the highly select nature of thisstudy group. Five-year survival reported in one retro-spective study was 9% for resected patients and 0%for unresected patients [91]. Given the small numberof patients and modest results in these studies, thebene"t of surgical resection in patients with CRCmetastases to both the liver and lung is unclear. Theseresections should be performed on an individualizedbasis.


9. Brain metastases

As noted previously, the brain is an infrequent site ofmetastasis from CRC and the vast majority of brainmetastases are in conjunction with metastases to othersites. When CRC has spread to the brain and otherorgans, treatment is directed toward slowing the progres-sion of systemic disease and palliation of symptoms.Treatments directed speci"cally at CRC brain metastasesinclude steroids, whole brain radiation therapy, and sur-gical resection. Farnell et al. retrospectively reviewed 150patients with CRC brain metastases and observed a me-dian survival of 2 months with supportive care (usuallywith steroids), 3.7 months with radiation therapy, 10.4months with surgery, and 9.7 months with surgery andradiation therapy [92]. Another retrospective study of100 similar patients measured a median survival of1 month with steroids, 3 months with radiation therapy,and 9 months with surgery [93]. A surgical series of 73patients with CRC brain metastases found median sur-vival after craniotomy to be 8.3 months [94]. The mortal-ity rate in this last study was 4.1% within 30 days ofcraniotomy. Signi"cant negative prognostic factors fol-lowing surgical resection of CRC brain metastases in-cluded systemic disease, memory loss, early onset of brainmetastases, and infratentorial location [92}94].

10. Conclusion

Colorectal cancers represent a heterogeneous group oftumors with varying tumor biology. When a colorectaltumor has progressed to the point where it can metasta-size to distant organs, most often the tumor biology isfairly aggressive leading to disseminated disease. Theseaggressive tumors are best treated with systemic chemo-therapy to incrementally prolong survival. However, curefor patients with such tumors is rare, and newer therapiesare needed. Patients with brain metastases from CRCcancer usually have disseminated disease but, given theirvery short life-expectancy without treatment, may bene"tfrom whole brain radiation therapy or surgical resection.

A minority of colorectal tumors have a tumor biologythat is not overly aggressive, and these tumors metasta-size preferentially to only the liver and/or lung. Most ofthese tumors are still too aggressive to allow cure withcomplete surgical resection, but a signi"cant minority ofthem can be cured with surgical resection. Numerousprognostic factors have been elucidated to help in decid-ing which liver or lung metastases are most likely to becured with surgical resection, and most of these factorsare indicators of favorable or unfavorable tumor biology.In most instances, however, isolated and resectable CRCliver or lung metastases should be surgically removed inmedically "t individuals to obtain the best chance oflong-term survival.

Often, surgical resection of isolated CRC liver meta-stases is not possible and other regional treatments canbe employed. Hepatic cryosurgery has been tested inseveral large series and appears to be an e!ective supple-mental ablative technique when surgical resection is notpossible or is incomplete. RF ablation holds promise asa less invasive and morbid option to cryosurgery, buttechnological advances and more studies are needed.With fewer technical complications and newer combina-tion drug regimens, HAI chemotherapy can be an e!ec-tive option against di!use but isolated CRC livermetastases.

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