Hepatic Transcatheter Arterial Chemoembolization Alternating … · Hepatic Transcatheter Arterial Chemoembolization Alternating with Systemic Protracted Continuous Infusion 5-Fluorouracil

Hepatic Transcatheter Arterial Chemoembolization Alternating withSystemic Protracted Continuous Infusion 5-Fluorouracil forGastrointestinal Malignancies Metastatic to Liver:A Phase II Trial of the Puget Sound OncologyConsortium (PSOC 1104)1

Linda M. Bavisotto, Nilesh H. Patel,Sandra J. Althaus, Douglas M. Coldwell,Hanh V. Nghiem, Tove Thompson, Barry Storer,and Charles R. Thomas, Jr.2

Division of Oncology, Departments of Medicine [L. M. B.] andRadiology [N. H. P., S. J. A., D. M. C., H. V. N.], University ofWashington Medical Center, Seattle, Washington 98195; Puget SoundOncology Consortium, Seattle, Washington 98195 [L. M. B., T. T.,C. R. T.]; Clinical Statistics, Clinical Division, Fred HutchinsonCancer Research Center [B. S.], Seattle, Washington 98195; andDepartment of Radiation Oncology, Medical University of SouthCarolina/Hollings Cancer Center, Digestive Disease Center,Charleston, South Carolina 29425 [C. R. T.]

ABSTRACTWe assessed a regimen of alternating regional and sys-

temic therapy in patients with gastrointestinal malignancieswith liver-dominant metastases for feasibility, toxicity, re-sponse rate, response duration, patterns of progression, andprogression-free and overall survival. Regional therapy com-prised selective hepatic transcatheter arterial chemoemboliza-tion (TACE) using a suspension of cisplatin and particulatepolyvinyl alcohol. This procedure was delivered between cyclesof protracted continuous infusion 5-fluorouracil (PCI-5FU) assystemic chemotherapy. Patient eligibility criteria included: (a)having histologically documented adenocarcinoma arisingfrom a gastrointestinal primary site with unresectable livermetastases bidimensionally measurable on computerized to-mography scan; (b) age greater than 18 years; and (c) perform-ance status 0–2 (Zubrod). PCI-5FU (250 mg/m2/day) was ad-ministered i.v. for 28 days, followed by the first TACE (TACE1) delivered to the hepatic artery supplying the lobe with thegreatest tumor burden. Restaging was performed beforeTACE 2 and TACE 3, which followed at monthly intervals.

PCI-5FU for 21 days was sandwiched between each of theTACE treatments. After the final TACE, maintenance PCI-5FU was given for 28 days of each 35-day cycle until toxicity orprogression. Between December 23, 1991, and January 19,1995, 32 patients were registered in this trial, of whom 27 wereeligible; 20 completed one or more treatment cycles and wereevaluable for radiographic response. Patients with colorectalliver metastases predominated (74%). Twelve (44%) of 27patients had failed one or more prior treatment regimens.There were no treatment-related deaths, and hematologicaland hepatic toxicities were generally manageable and reversi-ble. Two patients, however, developed hepatic abscesses requir-ing drainage, and one patient developed an infarcted gallblad-der, which necessitated cholecystectomy. There were nopatients with complete responses; there were 8 (40%) withpartial responses, 4 (20%) with minor responses, 2 (10%) withstable disease, and 6 (30%) who progressed on the treatment.The median duration of response for partial responders was4.2 months (127 days; range, 56–245 days). The median reduc-tion in carcinoembryonic antigen for responders was 87.5%.Two patients underwent subsequent resection of residual me-tastases; one of them is still alive at 58.4 months follow-up. Thepredominant site of disease progression was the liver; 25% ofthe patients progressed in extrahepatic sites. The median over-all survival for the whole group is 14.3 months (95% confi-dence interval, 7.2–16.2). Actuarial overall survival for thewhole group at 1 year and 2 years is 57 and 19%, respectively.Alternating systemic PCI-5FU and regional TACE (cisplatin/polyvinyl alcohol) is an active and feasible regimen with man-ageable toxicities in patients with metastatic gastrointestinalmalignancies with liver-dominant disease and merits furtherinvestigation. The complications seen were in line with thosereported at other specialized centers.

INTRODUCTIONOver 200,000 GI3 malignancies are diagnosed annually in

the United States, and the liver is the predominant site ofReceived 7/9/98; revised 9/29/98; accepted 10/2/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisementin accordance with 18 U.S.C. Section 1734 solely toindicate this fact.1 Early data from this clinical trial were presented in abstract form byC. R. Thomas, Jr., at the American Radium Society meeting on May 3,1995, Paris, France.2 To whom requests for reprints should be addressed, at Departmentof Radiation Oncology/Hollings Cancer Center, Digestive DiseaseCenter, Medical University of South Carolina, 171 Ashley Avenue,Charleston, SC 29425. Phone (803) 792-3273; Fax: (803) 792-5498;E-mail: [email protected].

3 The abbreviations used are: GI, gastrointestinal; CDDP,cis-diammine-dichloro-platinum (cisplatin); CEA, carcinoembryonic antigen; CR, com-plete response; CT, computerized tomography; 5FU, 5-fluorouracil; FUdR,fluorodeoxyuridine (floxuridine); HAE, hepatic artery embolization; OS,overall survival; PCI-5FU, protracted continuous infusion 5FU; PFS, pro-gression-free survival; PR, partial response; PVA, polyvinyl alcohol; RR,response rate; SWOG, Southwest Oncology Group; TACE, transcatheterarterial chemoembolization; TTP, time to progression; HAI, hepatic arterialinfusion; MR, minor response; PCA, patient-controlled analgesia.

95Vol. 5, 95–109, January 1999 Clinical Cancer Research

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metastasis in most of them. Colorectal carcinoma is the thirdleading cause of cancer-related death in men and women inNorth America, with an incidence of 160,000 cases and approx-imately 60,000 deaths annually (1, 2). Liver metastases arepresent at the time of initial diagnosis of colorectal cancer in20% of patients and are the only site of metastatic disease inone-half of these (3). Approximately 60% of all patients who dieof colorectal cancer will develop liver metastases during thecourse of their disease (3, 4). For patients with colorectal cancermetastases confined to the liver, surgical resection where ame-nable is the only potentially curative treatment option, but onlya small fraction of patients will be candidates for surgery. Thesurvival rate for patients with colorectal cancer after liver me-tastasectomy with curative intent is 23–65% at 3 years and25–45% at 5 years (5, 6). For patients with GI malignancieswhose liver metastases are considered unresectable, there re-mains a compelling need to develop treatments with higherefficacy.

Little has been published on the results of hepatic-directedtherapy in the setting of liver metastases from GI adenocarci-nomas other than those of colorectal primary (7). The metasta-sectomy experience does not generalize easily to other GI ade-nocarcinomas (7), which have distinctive natural histories.Chemoresponsiveness is generally lower, and projected survivalfor advanced disease generally shorter, than for colorectal can-cer. Although promising options for second-line therapy in5FU-refractory disease have only recently begun to expand forcolorectal cancer (8–10), there are fewer options for otherprimary GI adenocarcinomas with liver-dominant metastases.For this reason, a treatment such as chemoembolization is ofinterest in that its effectiveness may rely more on the depend-ence of a given tumor on its vascular supply than strictly on itschemosensitivity. Moreover, it may be possible to overcomesteep dose-response curves for chemotherapy effect by attainingmore protracted and locally concentrated levels of chemother-apeutic agents near the tumor.

Liver metastases have been shown to depend heavily on thehepatic artery for most of their blood supply, whereas thenormal liver parenchyma derives the majority of its blood sup-ply from the portal vein (11). Exploitation of the differentialdependence on the hepatic artery between tumor and normalparenchyma has allowed the development of regional treatmentstrategies, including direct HAI of chemotherapy and variousmethods of reversible or irreversible vascular occlusion. Thehistorical development and optimization of these regional tech-niques have been recently reviewed (1, 7, 12–28).

Hepatic artery occlusion has been studied in depth and itsphysiological consequences explored (1, 29–31). Ligation of thehepatic artery results in rapid formation of collaterals. Smallerbranches can be embolized for more prolonged tumor ischemia.Chemoembolization increases the local concentration of region-ally delivered chemotherapeutic agents up to 20-fold and pro-longs local dwell time (1), which may increase the activity ofdrugs that are marginally active at concentrations achievablewith systemic delivery. In the case of drugs with significantfirst-pass hepatic extraction, hepatic arterial chemoembolizationcan minimize otherwise limiting systemic toxicities. The em-bolic particles travel preferentially to the highest flow areas,thereby shunting blood flow to previously less well-perfused

areas and increasing drug concentration in hypoxic tumor areas.Anoxia-induced increase in vascular permeability and reperfu-sion injury may augment local toxicity synergistically (32, 33).

Chemoembolization has utility in the treatment of unresect-able hepatocellular carcinomas (1, 20, 21, 23, 34–40) both forpalliation and for neoadjuvant treatment of borderline unresect-able tumors with the aim of downstaging for potentially curativeresection. HAE has a well-documented role in the palliation ofneuroendocrine tumors metastatic to liver (1, 22, 41), whichresults in improved performance status and reduction of symp-toms from vasoactive hormone release. Both of these hypervas-cular tumors types, as well as other hypervascular malignanciesthat tend to have isolated liver metastases such as ocular mel-anoma and GI sarcoma, have occasionally shown marked re-gression with chemoembolization (1, 17, 42). Less is knownabout the RRs of hypovascular tumors such as hepatic metas-tases from adenocarcinomas of various primary sites.

The relationship between RRs and survival in colorectalcancer appears to be complex in that the measures that havesignificantly enhanced RRs have often failed to translate intoclinically significant gains in median survival. Conventionalsystemic i.v. chemotherapy with single agent 5FU in advancedcolorectal cancer has produced RRs of only 7–20% with amedian survival of 25–55 weeks (43). Modulation with folinicacid (leucovorin) has boosted tumor RRs (16–45%) but hasproduced only marginal survival benefit (2, 43). PCI-5FU pro-duced a RR of 22%versus14% (P 5 0.0002) for bolus 5FUregimens in a recent meta-analysis of the Phase III randomizedtrials that compared these schedules (44) and produced a slightbut statistically significant increase in OS. Median survivalswere close for both arms, however, at 12.1 months for PCI-5FUversus11.3 months for bolus 5FU, with similar response dura-tions of 7.1versus6.7 months, respectively. To its advantage,PCI-5FU delivers a higher dose-intensity, has produced re-sponses in patients who had progressed on prior 5FU/leucovorinregimens, and is well-tolerated with less hematological toxicitythan seen with other delivery schedules (44, 45). In addition, asignificant prolongation of TTP of disease has also been re-ported with PCI-5FU compared with bolus 5FU regimens inadvanced colorectal cancer (46).

In terms of regional therapy, HAI of FUdR for liver-dominant metastatic colorectal cancer produces uniformly su-perior RRs of 40–60%, but in individual trials (47–51), iteluded proof of survival benefit. The Meta-Analysis in CancerGroup (52) found that the overall RR for HAI was 41%versus14% for systemic chemotherapy, with an OR of 0.25 (CI,0.16–0.40;P , 0.0000000001). Despite this highly significantresult, a survival benefit for HAI was achieved only when all ofthe trials including untreated controls were included in theanalysis (P 5 .0009) but not when trials comparing only HAIand systemic chemotherapy were analyzed (P 5 0.14; Ref. 52).Another meta-analysis using a different method (53) found thatHAI with FUdR produced a modest 10% (P 5 0.041) and 6%(P 5 0.124) survival advantage at 1 and 2 years, respectively,over systemic chemotherapy.

On the basis of prior experience at our institution with thesafety and efficacy of particulate PVA (Ivalon) as a nondegrad-able embolizing agent (15, 54), we elected to use this agent inconjunction with CDDP as the chemoembolizing mixture for

96 Chemoembolization of Hepatic Metastases



this study. Given systemically, CDDP has activity in combina-tion with 5FU in gastric and esophageal carcinomas. A numberof clinical trials have explored the utility of adding CDDP inlow, weekly doses or in standard doses to i.v. bolus or infusionalschedules of 5FU in advanced colorectal cancer, showing atrend toward increased RRs but without prolonging survival (46,55). The concentration of CDDP in the liver can be increased upto 20-fold by hepatic intra-arterial infusion, and the safety,toxicity, and pharmacokinetics of hepatic intra-arterial CDDPadministration have been well described (38, 56–58).

Although a minority of patients with advanced colorectalcancer may have isolated liver metastases without detectableextrahepatic disease for extended periods of time, it is notpossible to determinea priori which patients will fall into thiscategory. Given the systemic nature of the disease, it stands toreason that a significant proportion of patients treated withregional therapy alone will demonstrate predictable failure atextra-hepatic sites (59). Accordingly, we elected to alternateregional therapy for liver-dominant disease with ongoing sys-temic therapy using PCI-5FU to retard the development orprogression of failure in extrahepatic sites, hypothesizing thatthe addition of systemic chemotherapy might favorably impactsurvival and PFS relative to regional treatment alone.

PATIENTS AND METHODSThe design of this trial was approved by the Institutional

Review Board of the Fred Hutchinson Cancer Research Centerand the Human Subjects Committee of the University of Wash-ington Medical (both in Seattle). All patients gave written,informed consent before treatment.

Patient Selection. Eligible patients were required: (a) tohave histologically verified adenocarcinoma from a GI primarysite with unresectable liver metastases measurable on cross-sectional imaging (CT); (b) to have good performance status(SWOG 0–2); (c) to have a life expectancy.8 weeks; and (d)to be at least 18 years old. Patients may have received priorsystemic chemotherapy or immunotherapy but could not havereceived prior 5FU by continuous i.v. infusion, prior hepaticartery or portal vein chemotherapy infusion, or prior HAE orchemoembolization. Small volume (nondominant) extrahepaticmetastases were permitted provided the most immediately life-threatening disease was in the liver. Pretreatment laboratorystudies required: (a) a WBC.4000/ml; (b) platelets.100,000/ml; (c) serum creatinine,2.0; and (d) one of the following: (a)a prestudy CT scan showing,50% of the liver involved withmetastatic disease; or (b) total bilirubin,2.0 mg/dl, aspartateaminotransferase,100 mg/dl, and lactate dehydrogenase,450mg/dl. Patients with ascites, hepatic encephalopathy, prior he-patic irradiation, poor nutritional risk, active infections, activegastric ulcer, pyschiatric risk, or other illnesses that wouldpreclude the safe administration of chemotherapy or chemoem-bolization were excluded, as were pregnant or lactating women.

Treatment with Systemic PCI-5FU. Induction chemo-therapy consisting of 5FU 250 mg/m2/day as a protracted con-tinuous i.v. infusion (PCI-5FU) was administered by ambulatoryinfusion pump via an indwelling central venous access devicefor 28 days before the first chemoembolization (TACE 1).Pyridoxine (50 mg p.o. t.i.d.) was given while receiving 5FU.

Modifications were made in the event of toxicity developmentas follows:

(a) for Grade 2 toxicity from palmar-plantar erythrodyses-thesia (hand-foot syndrome), 5FU was withheld until the toxic-ity resolved and then resumed at full dose; and

(b) for Grade 3–4 toxicity from hand-foot syndrome, 5FUwas withheld until the toxicity resolved and then was restartedwith dose reduction to 150 mg/m2/day.There was no dose reduction for hematological toxicity, but ifgranulocytes dropped below 1,000/ml or platelets below 50,000/ml, 5FU was withheld until these counts recovered to thoselevels. Development of angina-like chest pain was a contrain-dication to further 5FU administration.

PCI-5FU at the same dosage was also administered be-tween TACE procedures, was resumed on hospital discharge,and continued for 21 days until the following TACE. After thefinal TACE, maintenance chemotherapy with PCI-5FU wasadministered for 28 days of each 35-day cycle (4 weeks on, 1week off) until there was evidence of progression.

Regional Selective Hepatic TACE Procedure. Chemo-embolization procedures on all patients were performed by onegroup of investigators (D. M. C., N. H. P., S. J. A.) in the Inter-ventional Radiology suite at the University of Washington Med-ical Center. Patients arrived early on the day of the procedure toreceive a liter of i.v. prehydration with 5% dextrose in normalsaline supplemented with potassium chloride. Antibiotic pro-phylaxis was not standardized by protocol but was given at thediscretion of the medical oncologist or the interventional radi-ologist performing the procedure. Patients received a celiacplexus block immediately before the procedure, which has beenshown to significantly reduce the pain incurred as part of thepostembolization syndrome (60, 61). The TACE procedure wasmodeled after the original HAE procedure of Chuanget al. (62)and modified from the procedure previously used at our insti-tution (15, 54). Via a transfemoral approach using the Seldingertechnique (63), celiac and superior mesenteric arteriogramswere performed using a selective catheter to ascertain anyvariant arterial visceral anatomy and to document portal veinpatency. Coaxially through the selective catheter, a microcath-eter was placed into the right or left hepatic artery trunk, whereanother arteriogram was performed to precisely delineate thedistribution of all of the vessels feeding the tumor and todetermine optimal placement of the microcatheter tip for embo-lization. In a few cases where applicable, the internal mammaryartery was also selected to determine whether its branchessupplied any anterior subcapsular tumor metastases in the liver(64). When the catheter was within the origin of the artery, 3–6ml of nonabsorbable PVA foam particles (Ivalon, Contour Em-boli, San Francisco, CA)—measuring 150–250mm in diameterand suspended in dilute nonionic contrast—were injectedthrough the microcatheter in aliquots of approximately 1–3 mluntil the slowing of the flow was fluoroscopically evident. ACDDP suspension for intra-arterial injection was used wherein10 ml of saline was used to suspend particles of a 50-mg vialand injected slowly in 1–3-ml aliquots. (The first three patientson the study received a total administered CDDP dose of 75mg/m2; in the absence of undue toxicity, the dose for subsequentpatients was escalated as planned to 90 mg/m2.) The CDDPinfusion was followed with further PVA particle embolization

97Clinical Cancer Research



until near-complete stasis of the selected hepatic artery, docu-mented by hand-injection of a contrast. All of the catheters werethen removed, and manual digital compression applied over thepuncture access site until hemostasis was achieved. Each patientwas admitted to the hospital after completion of the procedure,maintained at strict bedrest, and his/her femoral arterial puncturesite and distal pulses were monitored by the nursing staff for 6 hpostprocedure. After each TACE procedure, patients were mon-itored for the anticipated postembolization syndrome of fever,pain (abdomen, right upper quadrant, and right shoulder), tran-sient leukocytosis, and elevated transaminases, as well as anyother potential complication. Pain was managed with PCApumps using morphine sulfate or hydromorphone (61). Patientswere discharged when pain could be managed with oral anal-gesics, when able to take adequate oral fluids, and when serumtransaminases were beginning to decline (65), usually within2–3 days. Other supportive measures during hospitalizationincluded the regular administration of an H2-blocker (ranitidineor nizatidine) as well as the administration of dexamethasone,ondansetron, and lorazepam as antiemetics before and afterCDDP TACE.

Chemoembolization was repeated at monthly intervals fora maximum of two embolizations for unilobar involvement andthree embolizations for bilobar involvement. The initial chemo-embolization was delivered to the hepatic lobe containing thelargest tumor burden. The second chemoembolization was given1 month later to the same lobe for unilobar and opposite lobe forbilobar involvement; and for patients with bilobar involvement,a third chemoembolization that treated both lobes of the liverwas delivered 1 month thereafter. A reduced dose of CDDP (50mg/m2 was given if at the nadir of the previous cycle, granulo-cytes dropped,1,000/ml or platelets,70,000/ml, or if theserum creatinine, drawn before the planned TACE, was elevatedin the range of 1.6–2.0 mg/dl. If the serum creatinine exceeded2.0 mg/dl, TACE was delayed until the serum creatininedropped below this value.

Patient Monitoring. Serum liver transaminases, totalbilirubin, alkaline phosphatase, lactic dehydrogenase, CBC andplatelet count, protime, and activated partial thromboplastintime were monitored for each patient just before and 24 h aftereach TACE procedure. Liver transaminases and WBC werefollowed daily until hospital discharge. CEA was measured onstudy entry, before each TACE procedure, and then every 2months until the patient was off the study.

Restaging with abdominal CT scan, chest radiograph, andphysical examination was carried out just before TACE 2 andTACE 3 (weeks 10 and 14). The objective status was recordedat each evaluation. Patients were removed from the study forhepatic or extrahepatic disease progression, for toxicity unac-ceptable to either the patient or the physician, or if for anyreason the patient and/or physician decided it is was in thepatient’s best interest to withdraw from the study. All patientswere followed until death for PFS and OS.

Definition of Response Criteria and Survival EndPoints. Three of the authors (H. V. N., C. R. T., L. M. B.)together reviewed and coded responses for all of the CT scans.Radiographic (CT) responses were judged by standard criteriaas follows:

(a) CR indicated complete disappearance of all measurable

and evaluable disease, no new lesions, and normalization oftumor markers;

(b) PR indicated a greater than 50% reduction under base-line in the sum of the products of the longest perpendiculardiameters of all measurable lesions, no new lesions, and noprogression of evaluable disease; and

(c) MR indicated a decrease greater than 25% but less than50% under baseline in the sum of the products of the perpen-dicular diameters of all measurable lesions.Progression was coded for the following circumstances: (a)an increase of 50% or of 10 cm2 (which ever is smaller) in thesum of the products of the perpendicular diameters of themeasurable lesions over the smallest sum observed (overbaseline if no decrease); (b) the reappearance of any lesionswhich had disappeared; (c) a clear worsening of any evalu-able disease; (d) the appearance of any new lesion; and (e)the failure to return for evaluation due to deteriorating con-dition (unless clearly due to causes other than the cancer).Stable disease was coded for responses not qualifying for CR,PR, MR, or progression.

Duration of response was defined as the interval fromthe date that tumors first met the criteria for CR or PR to thedate that the disease progression was first detected. PFS andOS were measured from the date of study entry to progres-sion or death.

Statistical Analysis. The primary study end point wasthe objective radiographic (CT) RR; secondary end points werePFS status and OS. RRs were determined in two ways, with bothresults given. In the first determination, all of the eligiblepatients without exclusion, including those who received no orless than one complete cycle of the planned treatment or hadprotocol violations, were included in the denominator for RRaccording to intent-to-treat principles; patients not assessable forradiographic response or inevaluable due to protocol violationwere counted as treatment failures. A parallel analysis includingonly protocol-adherent patients who completed one or morecycles of planned treatment and were, therefore, evaluable forradiographic response is given for comparison.

Pre- and posttreatment CEA tumor marker levels wererecorded as another indicator of tumor response for each subject.Mean values of pre- and posttreatment CEA levels were com-pared using a two-sided Student’st test for paired data for bothradiographic responders and nonresponders.

PFS and OS were estimated using the product-limitsmethod of Kaplan and Meier (66).

RESULTSPatient and Tumor Characteristics. Between Decem-

ber 23, 1991, and January 19, 1995, the Puget Sound OncologyConsortium registered 32 patients from 13 participating institu-tions into this clinical trial coordinated through the University ofWashington Medical Center, with follow-up through December1997. Patient characteristics and primary disease sites are sum-marized in Tables 1 and 2. Median age was 57 years (range,38–77), and males outnumbered females 2:1. The majority—20(74%) of 27—had a primary adenocarcinoma of the colon orrectum; 2 patients each had gastric and pancreatic carcinoma, 1patient each had esophageal, intrahepatic bile duct, and gall-




bladder primary sites. Twelve (44%) of 27 had progressed onone or more prior treatment regimens. Six had unilobar hepaticinvolvement with metastases; and in 21, the involvement wasbilobar. Eleven (40.7%) of 27 patients had small-volume extra-hepatic metastases on entering the study. All but one patient hadperformance status 0–1. The number of chemoembolizationscompleted is also shown in Table 1, with 17 patients completingtwo or more TACEs.

Of 27 eligible patients in our trial, 7 were inevaluable forresponse, although all of them were included in an analysis ofRR using intent-to-treat principles. Two of the seven patientslacked appropriate CT documentation to assess response, andfive received less than one complete cycle of therapy. This rateof early withdrawal from our study was higher than we wouldhave liked but on further examination did not appear to be dueto excessive toxicity from the initial 28-day PCI-5FU systemicchemotherapy nor to rapid/early progression of disease on studyentry. Rather, several patients declined further participation onreceiving decisions of noncoverage from their insurers forTACE procedures and the associated hospital admissions; onepatient declined, stating concerns over anticipated toxicity fromthe TACE procedure after starting on PCI-5FU, and one patient

who was enrolled and started on PCI-5FU at a remote locationsubsequently refused the first TACE procedure.

Toxicity. Twenty-six patients with a total of 48 TACEprocedures were evaluable for toxicity. There were no treat-ment-related deaths. Of the 26 patients evaluable for toxicity, 21(81%) experienced at least one grade 3 event, and 8 (31%)experienced a grade 4 event. The incidence of grade 3 and grade4 toxic events is summarized in Table 3. Palmar-plantar eryth-rodysesthesia (hand-foot syndrome) was responsible for delaysand dosage reductions in a minority of patients while receivingPCI-5FU (one grade 3 and three grade 4 events). One patientdeveloped grade 4 diarrhea. After TACE procedures, nearly allof the patients experienced signs and symptoms compatible withpostembolization syndrome, namely fever, pain, transient leu-kocytosis, and elevated transaminases. This was especially pro-nounced after the first TACE procedure and often less promi-nent after subsequent chemoembolizations. Fatigue was afrequent accompaniment, particularly after the initial TACEprocedure. Nausea and vomiting, despite premedication andongoing prophylaxis with ondansetron and dexamethasone,were common. Hematological toxicities were infrequent. Twopatients developed grade 4 thrombocytopenia (lowest plateletcount5 22,000/ml 1 week after TACE 1), and two patients hadgrade 3 granulocytopenia without related complication. Neph-rotoxicity or peripheral neurotoxicity potentially related to sys-temic CDDP exposure were not seen; only one patient had ahighest serum creatinine greater than 1.4 mg/dl.

Pain ratings were lower in the first 24 h post-TACE inpatients who had successful celiac plexus blocks, but in all ofthe cases, pain was well managed with opioid PCA pumps. Painratings were frequently lower after subsequent TACE proce-dures than after the initial TACE.

Ten patients (38%) experienced one or more of the treat-ment-related complications listed in Table 4. One patient (4%)

Table 1 Patient characteristics

Number registered 32Number ineligible 5

.50% liver involvement and/orelevated LFTsa 3Ascites 1Prior hepatic arterychemoembolization 1

Number eligible 27Number of prestudy treatment

regimensNone 15One 8Two or more 4

Performance status0 171 92 1

Median age 57 (range, 38–77)Gender (M:F) 18:9 (2:1)Race (Caucasian:Asian) 26:1Number of chemoembolizations

completed0 51 52 83 9

Number evaluable for toxicity 26Eligible but no study therapygiven

1

Number inevaluable for response 6 (0b)Less than one cycle therapy 4No CT scans done 1CT scans lost 1

Number evaluable for response 20 (27b)a LFTs, liver function tests.b These numbers reflect the determination, using intent-to-treat

principles, in which all of the eligible patients without exclusion (in-cluding those with protocol violations or completing less than one cycleof planned treatment) are included in the analysis of treatment failures.

Table 2 Tumor characteristics

Primary Tumor SitesColon 18

Cecum 5Transverse 1Splenic flexure 1Descending 2Sigmoid 9

Rectum 2Stomach 2Esophagus 1Intrahepatic bile ducts 1Gallbladder 1Pancreas 2

Histology of primary tumorAdenocarcinoma, NOSa 23Mucinous adenocarcinoma 2Adenocarcinoma in a villous adenoma 1Cholangiocarcinoma 1

Number of liver lobes involved with metastasesOne 6More than one 21

Small-volume extrahepatic metastases on study entryAbsent 16Present 11a NOS, not otherwise specified.




with colon cancer developed an infarcted gallbladder afterTACE 2 and required a cholecystectomy. The patient recoveredfully. Two patients (8%) developed hepatic abscesses. One ofthese, a patient with colon cancer, developed a liver abscess thatwas culture-negative after percutaneous drainage but grewKleb-siella pneumoniaein blood cultures. This patient recovered fullywith antibiotic treatment. The second patient, who had pancre-atic cancer metastatic to the liver, developed a liver abscess thatgrew enterococcus andClostridium perfringensin cultures ob-tained by percutaneous drainage, and blood cultures grewK.pneumoniae.This patient suffered grade 4 hypotension andhyperglycemia in the setting of sepsis and mild baseline pan-creatic insufficiency but recovered fully with percutaneousdrainage and antibiotic treatment. Two patients developed deepvenous thrombosis related to central venous catheters and weretreated with anticoagulation. One patient with colon cancerreceived chest tube drainage for a unilateral pleural effusionafter TACE 2, symptomatic with dyspnea at rest. These symp-toms did not recur.

RR. Best responses on study and response durations areshown in Table 5.

When only those patients who completed one or more ofthe planned treatment cycles and were, therefore, evaluable forradiographic response were included in the determination of RR(n 5 20, see Table 5A), there were no complete responders, 8(40%) partial responders, 4 (20%) patients with MRs, 2 (10%)

with stable disease, and 6 (30%) who progressed on treatment.In a parallel determination of RR according to intent-to-treatprinciples, all eligible patients without exclusion were includedin the denominator for RR, and those with protocol violations orthose who received less than one cycle of planned treatment andwere, therefore, technically unassessable for radiographic re-sponse were counted as treatment failures (n 5 27; see Table5B). In this analysis, the PR and MR rates are slightly decreasedto 30 and 15%, respectively. The median response duration forthe partial responders was 4.2 months (range, 56–245 days).Representative CT scans from two of the partial responders areshown in Fig. 1.

The median on-study reduction in CEA levels in radio-graphic responders was 87.5%. Changes in CEA with eachtreatment cycle are shown graphically in Fig. 2 for radiographicresponders and nonresponders. Pre- and posttreatment meanCEA values were significantly different (P , 0.05 by two-tailedStudent’st test for paired data) for radiographic responders butnot for nonresponders.

In cases where CEA was informative as a tumor marker,the decline in CEA generally paralleled or slightly preceded the

Table 3 Incidence of grade 3–4 toxic events (n 5 26 patients; 48TACE procedures evaluable)

Event Grade 3 Grade 4

Hand-foot syndrome 1 3Abdominal pain 16Other pain 3Nausea 5Vomiting 3 2Constipation 1Diarrhea 1Stomatitis 1GI other 1Respiratory infection 1Other infection 1 1Fatigue 4Anxiety 1Insomnia 1Hypotension 2Dysrhythmia 1Dyspnea 2Embolism 2Transaminase elevationa 9Bilirubin elevationa 3 1Alkaline phosphatase elevationa 2Hyperglycemiaa 1Anemia 2Thrombocytopenia 2Granulocytopenia 2

Total events 56 16a SWOG toxicity criteria were used to determine grade. For lab

values: grade 3 transaminase or alkaline phosphatase signifies an ele-vation of 5.1–20-fold above normal, and grade 4 signifies a value morethan 20-fold above normal; for total bilirubin grade 3 is 1.5–3-foldabove normal, and grade 4 is more than 3-fold above normal. Grade 4thrombocytopenia connotes nadir platelet count less than 25,000/ml.

Table 4 Complications (n5 26 patients)Note that an individual patient may be listed for more than one

specific complication,e.g.,bacteremia and liver abscess occurring in thesame individual.

Event Number of patientsn (%)

Gallbladder infarction 1 (3.8)Liver abscess 2 (7.6)Bacteremia 2 (7.6)Deep venous thrombosis 2 (7.6)Pleural effusion, symptomatic 1 (3.8)Gastritis/ulcer

Symptoms only 3 (11.5)UGI-a or EGD-documented 0 (0.0)

Ischemic colitis 1 (3.8)a UGI, upper gastrointestinal barium series; EGD, esophagogas-

troduodenoscopy.

Table 5 Best response on-study and response durations

Response categoryNumber of patients

n (%)

Duration ofresponse (days)

Median Range

A. Patients completing less than one treatment cycle who wereexcluded from analysis (n 5 20 evaluable)

CR 0 (0%)PR 8 (40%) 127 56–245MR 4 (20%) 116 42–211Stable disease 2 (10%)Progressive disease 6 (30%)

B. Patients completing less than one treatment cycle who wereincluded in analysis as treatment failures (n 5 27 evaluable)

CR 0 (0%)PR 8 (30%) 127 56–245MR 4 (15%) 116 42–211Stable disease 2 (7%)Progressive disease 13 (48%)




radiographic reduction in lesion size for a given patient. Therewere interesting exceptions, however, as in the case of onepatient who had a significant drop with near-normalization ofCEA—a 93% reduction from 95.2 to 5.8 units/ml over thecourse of three TACE procedures–but who did not achievesufficient radiographic reduction in lesion size to qualify for aMR. Development of a tiny new abnormal but indeterminatearea in the liver led to the patient’s being taken off the study andcoded as progression (in fact, this may have been a smallparenchymal infarct, although new metastasis could not beexcluded; see “Discussion.”) Although the prestudy evaluationfor this patient had deemed her liver metastases unresectable,she went on to further radiolabeled monoclonal antibody treat-ment and subsequently underwent trisegmentectomy for resec-tion of residual metastases. She is alive and without evidence ofrecurrence at 58.4 months of follow-up.

A second patient also was recommended for metastasec-tomy of residual hepatic lesions after maximal response onstudy. This patient, whose metastatic lesions were confined tothe left hepatic lobe, was considered unresectable prestudybecause of the proximity of metastases to the middle hepaticvein. She experienced modest radiographic tumor shrinkageon-study, although insufficient to qualify by the criteria for aMR. On clinical reassessment after TACE 3 with CT arterio-

gram and chest radiograph, and with intraoperative ultrasoundfailing to show any new liver lesions, the possibility of achiev-ing a reasonable surgical margin was suggested, and she went onto have a left hepatic lobectomy. Unfortunately, the surgicalresection specimen revealed microscopic tumor abutting themiddle hepatic vein; therefore, a clear margin was not achieved.This patient died at 9.1 months of follow-up.

Sites of Progression. Table 6 summarizes the first site ofdisease progression—categorized as liver only, extrahepaticonly, or both—that was responsible for each patient being takenoff-study. The table is further categorized according to thepatient’s metastatic status on study entry (liver only, or liver andextrahepatic). The upper panel shows the sites of progression forall of the radiographically evaluable patients (n 5 20), and thebottom panel shows the sites of progression for patients onlywith radiographically-responsive disease in the study (respond-ers with either PR or MR,n 5 12).

Of the 16 patients without detectable extrahepatic metastasesprestudy, 3 were not evaluable radiographically for progression. Ofthe 11 patients who had small-volume extrahepatic disease pre-study, 4 were not evaluable for progression (1 progressed and wentoff the study before receiving a cycle of therapy, 3 refused therapyand/or had protocol violations). For all 20 radiographically evalu-able patients, the predominant site of disease progression was in the

Fig. 1 Representative CT scans from two partial responders before treatment (left panels) and after treatment (right panels). The patient whose scansare shown in the upper panels had 95% reduction in CEA; the patient whose scans are shown in the lower panels had 75% reduction in CEA.




liver. One-fourth of the patients (5 of 20) showed progression in anextrahepatic site: 3 progressed exclusively outside of the liver, and2 progressed simultaneously in the liver and an extrahepatic site.Regarding these five patients who demonstrated progression in anextrahepatic site, three had no detectable prestudy extrahepaticdisease. The remaining two patients who progressed in extrahepaticsites had pre-existing minimal extrahepatic disease on study entry.

TTP, PFS, and OS. All of the 27 eligible patients wereevaluable for survival. All but one of these patients have died.The median OS for the whole group is 14.3 months (95%confidence interval, 7.2–16.2), whereas the median PFS is 4.4months (95% confidence interval, 3.3–6.8; see Fig. 3. ActuarialOS is 57% at 1 year, and 19% at 2 years.

DISCUSSIONWe compare our results to those of other hepatic TACE

regimens described in the literature for patients with unresect-able hepatic metastases from colorectal cancer (13, 17, 21, 33,

67–79), as summarized in Table 7, none of which added con-current, sequential, or alternating systemic chemotherapy tochemoembolization as our trial did. Although it is difficult tomake meaningful interpretations because of the heterogeneouspatient selection criteria, small trial sizes, and varying tech-niques and agents for chemoembolization, some general impres-sions can be drawn from a review of these studies. Many trials(33, 69, 72–74) have required that enrolled patients have pro-gressed on prior front-line chemotherapy; exclusion of patientswith extrahepatic metastases was variable. Most studies showeda median survival of 10–13 months. CRs were occasionallyseen (68, 71). A study from the European Organization forResearch and Treatment of Cancer observed responses in hypo-vascular as well as hypervascular tumors (68) and reported animproved performance status in patients treated with chemoem-bolization. Early attempts at whole liver embolization resultedin hepatic insufficiency and extreme, often protracted, fatigue(69, 80) leading to a recommendation for staged, sequential

Fig. 2 Log-linear scatter plotsof change in CEA levels inunits/ml over time after thebaseline (prestudy) assessment.The X-axis indicates time inter-vals between TACE treatments,generally one month apart.Up-per panel, CEA values for all ofthe patients with these dataavailable at the time of each as-sessment. The mean CEA valuefor each assessment time is alsoshown. —-, connects mean val-ues for radiographic responders;- - -, connects mean values forradiographic nonresponder. Themedian reduction in CEA forradiographic responders was87.5%. Comparing the meanprestudy CEA value with themean CEA value obtained justbefore the final TACE using atwo-tailed Student’st test forpaired data, a significant differ-ence (P, .05) was shown forresponders but not for nonre-sponders.Lower panel, CEAvalues at the time of each as-sessment are compared longitu-dinally for individual patientsfor both radiographic respond-ers (left, —-) and nonresponders(right, - - -).




unilobar embolizations at intervals of 4–6 weeks (80) andlimiting the volume of the embolizing mixture. To determinewhich patients might derive the most benefit from chemoembo-lization, multivariate regression analysis identified several prog-nostic factors associated with improved survival, including agood performance status and the absence of extrahepatic metas-tases (74) and uniform radiographic distribution of the emboli-zing mixture throughout the metastatic lesions (71).

The complication of gallbladder infarction and, to a lesserdegree, the symptoms suggestive of gastritis seen in our studyare presumably related to inadvertent misperfusion or reflux ofembolic materials into the cystic artery or gastroduodenal artery,

respectively. Gallbladder infarction has been a noted complica-tion in other HAE or chemoembolization trials (20, 21, 81–83).Improvements in technique have reduced the morbidity associ-ated with chemoembolization since the earliest reported trials, asincreasing experience with the chemoembolization procedure atspecialized centers has decreased the rate of inadvertent mis-perfusions (15, 82, 83). Hepatic abscess with sepsis, seen in twopatients in our study, is also a previously described risk ofchemoembolization (81, 84, 85). In hind sight, optimal antibi-otic prophylaxis was not used in our trial, and it is likely that theseptic complications in our trial would have been reduced oreliminated if antibiotic prophylaxis had been standardized byprotocol. The adoption of extended and often broad-spectrumparenteral antibiotic prophylaxis (13, 20, 21, 27, 72, 80, 81, 84,85), routine blood culturing, and in some cases a bowel prepbefore the chemoembolization procedure (33) have decreasedthe complication rates of hepatic abscesses and sepsis reportedby a number of centers, particularly where microfibrillar bovinecollagen (Angiostat) was used as the embolizing agent.

When compared with the historical data from TACE trialsin colorectal cancer, none of which added systemic chemother-apy, our median survival of 14.3 months does compare favor-ably (is in the higher end of the published range of mediansurvivals given in Table 7), despite some patient selectionfeatures in our trial that could be expected to produce adversesurvival effects. Although the majority of patients in our trial(74%) had colorectal cancer, the inclusion of patients with otherprimary GI adenocarcinomas metastatic to liver may dilute theRR and lower the median OS somewhat when compared withtrials looking at colorectal cancer alone. In addition, severalpatients in our study had unresectable primary tumors (in eachcase, liver metastases dominated the clinical picture), whichmight be expected to adversely affect survival. It is not com-pletely clear whether the addition of systemic chemotherapy inour trial may have helped to offset the potential adverse survivaleffects from these patient selection factors in our trial. Otherfactors affecting the mix of patients among different trials (theproportion of patients who had progressed on prior therapy,bulky versusearly metastatic disease, and the presence or ab-sence of extrahepatic disease on study entry) can certainly beexpected to influence the variation in the range of mediansurvivals reported.

Despite reasonable RRs, reported response durations withchemoembolization remain short. Some reasons for this may bethe development of drug resistance, formation of collateralvessels, or acceleration of extrahepatic metastatic growth in the

Fig. 3. Upper panel, Kaplan-Meier curve showing cumulative OS forall of the 27 eligible patients (median survival, 14.3 months).Lowerpanel, TTP for the same group (median TTP, 4.4 months).

Table 6 Sites of progression

Liver only Extrahepatic only Both Total

Prestudy sites of progression in all evaluable patients (n 5 20)Liver metastases only 10 1 2 13Liver 1 extrahepatic metastases 5 2 0 7

Total 15 3 2 20Prestudy sites of progression in patients with responsive disease on study (n 5 12)

Liver mets only 6 1 1 8Liver 1 extrahepatic metastases 3 1 0 4

Total 9 2 1 12




Table 7 Results of selected reported chemoembolization trials in colorectal cancer metastatic to liver

Group Design Procedure/agents na RR Survival measures

Patt, Y. Z.et al. (73)M. D. AndersonCancer CenterHouston, TX1983

Prospectivenonrandomized

Gelfoam or metal coil;FUdR (100 mg/m2/d3 5 d) MMC (10 mg/m2 once q 5 wk)

22 10 of 22, PRs 12 of 22nonresponders

Median 14 morespondersMedian 20 moresponders with CEMedian 6 mononresponders

Hunt, T. M. et al. (70)University ofSouthamptonSouthampton, UnitedKingdom1990

Prospectiverandomized

A, HAE group:lyophilized duramater1 Gelfoam

22 of 61 CTs were not done;survival only endpoint

Median, 8.7 mo

B, CE group: 5FU (500mg) 1 degradablestarch microspheres

19 of 61 Median, 13.0 mo

C, Untreated group 20 of 61 Median, 9.6 mo

Lang, E. K., and Brown,C. L. (71)Louisiana StateUniversityNew Orleans, LA1993


Doxorubicin1 iodizedoil

46 8 CRs32 PRs

71% (OS, 1 yr)51% (DFS, 1 yr)40% (OS, 2 yr)29% (DFS, 2 yr)

Daniels, J. R.et al. (69)University ofSouthern CaliforniaLos Angeles, CA1992

Prospectivenonrandomized[whole liverembolization]

CDDP (10 mg/ml)doxorubicin (3 mg/ml)MMC (3 mg/ml)collagen (10 mg/ml)

52 78% had.50% CEAreduction; 34% RR byCT

Projected median, 335days (11 mo)

Tellez, C.et al. (17, 33,67)NorthwesternUniversityChicago, IL1998


CDDP (10 mg/ml)doxorubicin (3 mg/ml)MMC (3 mg/ml)collagen (10 mg/ml)

30 95% had.25% CEAreduction; 63% RR byCT

Median, 8.6 mo

Fiorentini, G.et al. (79)City HospitalRavenna, Italy1996


CDDP (10 mg/m2)epirubicin (30 mg/m2)MMC (10 mg/m2)Gelfoam, Lipiodol q3–5 wk

45 66% by CT76% by CEA80% by both

Median, 9.0 mo TTP,6.5 mo

Civalleri, D. et al. (68)EORTCGastrointestinal Group1994


5FU (500 mg)1degradable starchmicrospheres

39 5 CRs5 PRs6 stable7 early prog

Median TTP, 6 moMedian survival, 16mo

Martinelli, D. J.et al.(72)Montefiore MedicalCenter New York, NY1994


A, HAE group: PVA1contrast

11 of 24 No difference betweengroups, RR 25% (6 of24)

Median, 9.3 mo overallfor both groups

B, CE group: 5FU 750mg/m2 1 IFN-a 2a9MU 1 PVA

13 of 24

Hafstrom, L.et al. (78)Sahlgrenska HospitalGoteborg, Sweden1994


Plastic slings aroundproper hepatic andcommon hepatic aa;5FU (1000 mg/m2/d3 5 d) allopurinol(300 mg/d po3 10 d)

32 of 60, treated28 of 60, untreated

PRs, 25% Median, 17 mo, treatedgroupMedian, 8 mo,untreated groupMedian responders, 22mo

Berger, D. H.et al. (81)M. D. AndersonCancer CenterHouston, TX1995

Retrospective(1988–1990)

Gelfoam1 FUdR (350mg) 1 MMC (10 mg)

121 (11 had colon CAwith 26 CEprocedures)

Not given Median, 294 days forcolon CA (9.8 mo)

Sanz-Altamira, P.et al.(74, 75)Beth Israel/DeaconessMedical CenterUniversity of ChicagoBoston and Chicago1997


Gelfoam1 5FU (1000mg) 1 MMC (10 mg)1 ethiodol (10 ml)

40 63% had “morphologic”response; 18 of 29had.50% CEAreduction

67% (OS, 1 yr)Median TTP, 7 moMedian survival, 10mo

Soulen, M. C.et al. (21)University ofPennsylvaniaPhiladelphia, PA1997


CDDP 1 doxorubicin1MMC 1 iodized oil1 PVA

40 PRs, 40%MRs, 30%CEA response, 89%

94% (OS, 1 yr)65% (OS, 2 yr)22% (OS, 3 yr)

a n, number of patients; DFS, disease-free survival; MMC, mitomycin C; IFN-a, interferon-a; CE, chemoembolization; aa, amino acid; CA,carcinoma; d, day; q, every; EORTC, European Organization for Research and Treatment of Cancer.




absence of concomitant systemic chemotherapy. Huntet al.(70)observed in a group of patients carefully selected to excludeextrahepatic metastases at presentation that 36% developed ex-trahepatic disease sites while on the study, which did not includesystemic chemotherapy. In an early study by the University ofMichigan group, 73% of patients whose metastatic disease wasclinically confined to the liver on study entry and who receivedonly regional treatment via hepatic artery infusion of FUdR diedof uncontrolled extrahepatic malignant disease (86). More re-cently, the University of Michigan group (87) reported results ofa trial combining three exclusively regional modalities for 47patients with diffuse hepatic involvement with either primaryhepatobiliary tumors, or metastases from other cancers, mostlycolorectal. Concurrent HAI (FUdR plus leucovorin) was admin-istered for radiosensitization along with whole liver radiother-apy, followed by hepatic arterial chemoembolization usingmitomycin C and PVA. Hepatocellular carcinomas, neuroendo-crine tumors, and metastases of unknown primary tumorsshowed higher RRs than metastatic colorectal cancers or cholan-giocarcinoma. During this trial, 54% of the colorectal cancerpatients progressed in an extrahepatic site after delivery of thismultimodal regional regimen, which included no systemicchemotherapy.

During our study of alternating systemic and regional treat-ment, in contrast to the foregoing, only 5 (25%) of 20 patientsshowed progression in extrahepatic sites, and 2 of these 5patients had prestudy baseline extrahepatic metastases. Thismay suggest a benefit from the addition of systemic chemother-apy to our TACE regional regimen in terms of reduction in theproportion of patients failing in extrahepatic sites when com-pared with the foregoing studies, but given the patient selection(and other) differences between these separate trials, confirma-tion with larger numbers of patients in a prospective compara-tive trial would be required to ascertain a benefit from theaddition of systemic chemotherapy. In our study, there does notappear to be a major improvement in TTP or OS compared withpublished hepatic chemoembolization studies in colorectal can-cer that did not employ systemic chemotherapy.

Whether the addition of systemic treatment to chemoem-bolization reduces the incidence of extrahepatic metastases, andindeed the converse, whether the “addition” of TACE to sys-temic therapy reduces the intrahepatic progression of disease,are compelling questions that, given the limitations of any PhaseII trial, our study, as designed, cannot completely answer. In thisregard, it will be of interest to learn the results of a pilot PhaseII trial recently conducted by the SWOG (SWOG 9051) andcoordinated through the University of Southern California-Nor-ris. This trial administered multi-agent whole liver chemoem-bolization and sequential systemic chemotherapy to patientswith advanced colorectal cancer. The study has completed ac-crual, with results yet to be reported. Recently, Waneboet al.(59) reported a superior median survival of 18 months usingsystemic chemotherapy (continuous infusion 5FU plus leucov-orin) in alternation with regional therapy (HAI with FUdR plusdexamethasone) with low toxicity in patients with colorectalcancer and dominant liver metastases.

The evaluation of radiographic response by standard crite-ria may not be adequate for hepatic chemoembolization studies(23, 33). The strict criterion defining partial (major) response in

our study ($50% reduction in lesion size) may have excludedsome patients with clinically meaningful responses. The previ-ously noted patient in our study who is still alive at 58.4 monthsfollow-up after poststudy resection of residual liver metastasesby trisegmentectomy illustrates this consideration. Although itcannot be definitively claimed that a resectable status wasachieved as a result of therapy from this study (as she went onto have additional treatment before resection), her significanton-study decrease in CEA, despite the relatively minor associ-ated radiographic changes, suggests a biological response thatmay have contributed significantly to her ability to undergosubsequent resection. Venooket al. (23) found liquefactionnecrosis both radiographically and pathologically after hepaticchemoembolization for hepatocellular carcinoma, and observedthat radiographic response may underestimate true response,because of the constraints on tumor shrinkage of a backgroundof edema and necrosis.

In this regard, at least two groups (33, 79) have used adifferent set of criteria to define radiographic response in theirrespective hepatic chemoembolization studies. Responses weredefined by either a decrease in density on CT scan in at least75% of a metastatic lesion or a cystic pattern, (both consistentwith necrosis) or a$25% (instead of$50%) decrease in thesize of the lesion without development of concomitant lesions.We did not specifically compare CT attenuation of metastaticlesions in our study, but if we were to apply the more liberal sizereduction criterion for response to our study, both the partial andminor responders (12 of 20; 60%) would qualify for majorresponse. Our experience suggests that radiographic responseshould not be viewed in isolation from other markers of tumorresponse. To document true response would require biopsy or,less invasively, metabolic imaging by positron emission tomog-raphy, as in the small series by Vitolaet al. (30) in patients withliver metastases treated with chemoembolization.

Meakemet al. (88) have described the evolution over aperiod of time in CT appearance of metastatic liver lesions inseven patients after chemoembolization with Angiostat (cross-linked bovine collagen), CDDP, mitomycin C, and doxorubicin,using volumetric rather than cross-sectional area measures. At 1month after chemoembolization, despite declining CEA levelsthat suggested response, three patients developed low attenua-tion regions in areas in which there had been no previous lesion,but in the distribution of the arterial tree. Although the signifi-cance of these areas was uncertain, the decreasing CEA levelsand subsequent evolution in appearance of these sites on CTwith sharper demargination and diminishing size suggested thatthey were regions of hepatic ischemia/infarction as opposed toheretofore unidentifiable metastases now “unmasked.” Fol-low-up CT scans at 2–3 months after a single chemoemboliza-tion revealed maximal effect on tumor volume in their study.

Several unsettled questions include whether multi-drugchemoembolization is superior to single-drug chemoemboliza-tion in activity and in delaying the development of drug resist-ance, and which drug(s) is most effective when administered inconjunction with a hepatic arterial embolizing agent. A prom-ising agent to consider in this regard is the new third-generationplatinum analogue oxaliplatin, a member of the 1,2-diaminocy-clohexane family of platinum compounds. Whereas conven-tional systemic chemotherapy trials combining CDDP with var-




ious schedules of 5FU proved generally disappointing (46),oxaliplatin has been recently found to possess distinct first- andsecond-line activity as a single agent in treating advanced colo-rectal cancer (9, 10) and, when given in combination with 5FUand leucovorin, has been shown to increase the objective RRmore than 2-fold, while increasing TTP with a gain of 3 months(89). Hence, it may be advantageous to use oxaliplatin ratherthan CDDP, alone or in combination, in future chemoemboli-zation studies along with the embolizing agent. Another widelyused agent, mitomycin C, has alternative advantages of anenterohepatic recirculation and conversion to more active me-tabolites in a hypoxic milieu (1, 20, 21, 90, 91).

The RR in our trial, even employing the intent-to-treatanalysis in which patients who receive less than one cycle oftreatment are counted as treatment failures instead of inevalu-able for response (30% PR, 15% MR; see Table 5B), wouldordinarily be indicative of an active regimen meriting furtherexploration, particularly in previously treated patients, in theabsence of undue toxicity. Several factors, however, make thestraightforward introduction of this regimen into Phase III test-ing somewhat problematic. Drawbacks of this approach are thetechnical difficulty, expense, and need for hospitalization afterchemoembolization. Given the higher-than expected early with-drawal rate, the risk of procedure-related complications, and theinterim development of promising new systemic treatment op-tions, it may be that our study, as designed and analyzed, doesnot merit further testing currently in the Phase III setting.Prospective randomized clinical trials to further study hepaticchemoembolization may be challenging to perform given theintrinsic clinical heterogeneity of patients with hepatic tumors(7) and the diversity of strategies in the reported Phase IIstudies. Future trials must continue to be carried out in centerswith expertise in the required technical skills to minimize pro-cedure-associated morbidities. Patient accrual may be slowerbecause of the availability of several promising new therapeuticoptions for 5FU-refractory advanced colorectal cancer since theclosure of this trial. Active second-line agents in current clinicaltrials such as irinotecan, oxaliplatin, and several thymidylatesynthase inhibitors will likely compete for patients who, whentherapeutic options were more limited, would have been reason-able candidates for chemoembolization. More importantly, thesenew agents, the availability of which could not have beenanticipated at the outset of our trial, are generally less techni-cally complex to administer, do not require hospitalization orPCA for procedure-related pain, and may, therefore, representless toxic, less expensive, and more convenient treatment alter-natives. It would be both ethical and prudent to await earlyresults and toxicity profiles from the major trials underway withthese agents, as new treatment algorithms for their usage areevolving, before deciding whether and how to appropriatelyfurther test TACE with or without systemic chemotherapy;perhaps this would be in a subset of patients failing to respondto these systemic therapies, where the risk of potential treat-ment-related complications from the TACE procedure might bejustified. In addition to RR and survival measures to assessefficacy, such trials should include quality of life and cost asadditional outcome measures.

ACKNOWLEDGMENTSWe thank Fran Chard and Deborah Bassuk at Puget Sound Oncology

Consortium for expert assistance with data management and Karen Cappsfor preparation of the manuscript. We acknowledge Robert Livingston andPatrick Freeny and thank the participating member-investigators of PugetSound Oncology Consortium and other regional physicians who enrolledpatients from the following institutions into this clinical trial: Bishop Clark-ston Hospital (Omaha, NE); Everett Clinic (Everett, WA); Evergreen Can-cer Center (Kirkland, WA); Internal Medicine Associates (Anchorage,AK); Madrona Medical (Bellingham, WA); Memorial Clinic (Olympia,WA); Oncology Hematology Specialists (Lewiston, ID); Overlake InternalMedicine (Bellevue, WA); St. Mary Regional Cancer Center (Walla Walla,WA); Tacoma General Hospital (Tacoma, WA); University of WashingtonMedical Center (Seattle, WA); Valley General Medical Center (Auburn,WA); and Western Montana Clinic (Missoula, MT).

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1999;5:95-109. Clin Cancer Res Linda M. Bavisotto, Nilesh H. Patel, Sandra J. Althaus, et al. Trial of the Puget Sound Oncology Consortium (PSOC 1104)for Gastrointestinal Malignancies Metastatic to Liver: A Phase IIwith Systemic Protracted Continuous Infusion 5-Fluorouracil Hepatic Transcatheter Arterial Chemoembolization Alternating

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