Journal of Surgical Oncology 2004;87:85–90

Extent of Hepatic Resection Does Not Correlate WithToxicity Following Adjuvant Chemotherapy

WALDEMAR F. CARLO,1 AMANDA J. HUMMER,2 LAWRENCE SCHWARTZ,1,4 DEIDRE SULLIVAN,1

MITHAT GONEN,2 WILLIAM JARNAGIN,3 YUMAN FONG,3 AND NANCY KEMENY1*1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

2Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York3Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York

4Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York

Background: In patients with liver metastases from colorectal cancer, survival can beincreased by hepatic resection. Treatment with hepatic arterial infusion (HAI) andsystemic chemotherapy following resection may further increase survival anddecrease recurrence, but may also result in hepatic and systemic toxicity. This articlewill address the question of whether large hepatic resections resulting in a greater lossof healthy liver predisposes patients to developing toxicity from the subsequentchemotherapeutic regimens.Design: Retrospective analysis of 88 patients who underwent liver resection ofcolorectal metastases followed by adjuvant HAI and systemic chemotherapy andwhose computerized tomography (CT) scans were done at Memorial Sloan-KetteringCancer Center (MSKCC). Liver volumes were calculated from CT scans and used todetermine the percentage change in healthy liver volume between the pre- and post-operative CT scans. Hepatic and systemic toxicities were defined according to theCommon Toxicity Criteria of the National Cancer Institute.Results: Patients experienced a mean percentage decrease in healthy liver tissue of17% (range: 57% decrease to 32% increase) at an estimated 1 month after resectionand at the initiation of chemotherapy. In a logistic regression model using percentagechange in the healthy liver volume as a continuous variable, no significant associationwas revealed between percentage of healthy liver resected and diarrhea (P¼ 0.47),leukopenia (P¼ 0.37), neutropenia (P¼ 0.31), high bilirubin (P¼ 0.27), or alkalinephosphatase (P¼ 0.79).Conclusions: A greater loss of healthy liver following resection of hepatic metastasesfrom colorectal cancer does not seem to predispose to the development of toxicityfrom adjuvant HAI and systemic chemotherapy.J. Surg. Oncol. 2004;87:85–90. � 2004 Wiley-Liss, Inc.

KEY WORDS: hepatic arterial infusion; liver resection; toxicity; liver volumes

INTRODUCTION

Approximately 80,000 Americans are diagnosedannually with colorectal metastases to the liver, andabout 14,300 of these patients are able to undergo hepaticresection of these metastases. Hepatic arterial infusion(HAI) and systemic chemotherapy following hepaticresection has proven to be an effective treatment modalityfor improving local and systemic disease control in twostudies [1,2].

Both hepatic and systemic toxicities occur with thistherapy. In studies using HAI of floxuridine (FUDR) andsystemic 5-fluorouracil (5-FU) following resection,

*Correspondence to: Dr. Nancy Kemeny, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, New York, NY 10021. Fax: 212.794.7186.E-mail: kemenyn@mskcc.org

Accepted 26 April 2004

DOI 10.1002/jso.20074

Published online in Wiley InterScience (www.interscience.wiley.com).

� 2004 Wiley-Liss, Inc.

toxicities included neutropenia (in 18% of patients),diarrhea (29%), stomatitis (11%), and elevated bilirubinlevel above 3 mg/dl (18%) [1].Resections resulting in greater loss of healthy liver

may be expected to be detrimental to the patient. Indeed,large resections are more likely to produce patientmorbidity than minor resections [2–4]. In terms ofchemotherapy, a smaller remaining volume of healthyliver might result in hepatic insufficiency, reducing themetabolism of chemotherapeutic agents, and potentiallyincreasing their toxicities [5]. However, there have beenno studies addressing the potential increase in che-motherapy-induced toxicities in patients with extensiveliver resections.Volumetric analysis using computerized tomography

(CT) scan has proven to be an accurate method forestimating pre- and post-operative liver volumes andtumor volumes [6–8]. We examined whether hepaticresections resulting in a greater loss of healthy liver, asmeasured by CT scans, predispose patients to developingmore systemic or hepatic toxicities when given adjuvantHAI and systemic chemotherapy. In addition, we in-vestigated whether these toxicities were influenced by thetype of resection, number of tumors, prior to chemother-apy, presence of hepatic steatosis on pathology speci-mens, and hepatic enzyme elevation post-resection.

PATIENTS AND METHODS

Eighty-eight patients with colorectal metastases to theliver who received HAI and systemic chemotherapyfollowing resection of hepatic metastases and had con-trast CT scans performed at Memorial Sloan-KetteringCancer Center (MSKCC) were analyzed. Thirty-three ofthese patients were treated with our next protocol of HAIplus systemic 5-FUþ or � leucovorin (LV) and 53 weretreated with HAI plus irinotecan (CPT-11). All patientsreceived HAI FUDR and dexamethasone. Data frompatients were examined to determine systemic andhepatic toxicities as part of their respective trial. Therewere no significant differences in toxicities betweenchemotherapy groups (systemic 5-FUþ/�LV or CPT-11), thus all the information was pooled for analysis.Systemic and hepatic toxicities were defined according

to the Common Toxicity Criteria of the National CancerInstitute. Hepatic toxicity was defined as bilirubin levelsgreater than 3.0 ng/dl or alkaline phosphatase levelsgreater than twice the baseline levels.Pre- and post-operative liver volumes and tumor

volumes were measured from axial slices from pre- andpost-operative CT scans. Axial CT sections were ob-tained using standard techniques. Volumetric calculationswere carried out using a General Electric AdvantageWindows Workstation Version 4.0A (GE Medical

Systems, Milwaukee, WI). A semi-automated edgedetection algorithm was employed along with manualediting for each section based on anatomy and inherentcontrast. Volumetric calculations were generated fromthese contours for each region of interest.Healthy liver volume before surgery was calculated by

subtracting the tumor volume from pre-operative livervolume. Percentage change in healthy liver volume wascalculated as the difference between pre-operativehealthy liver volume and post-operative liver volume,expressed as percentage of pre-operative healthy livervolume. Negative values reflect a decrease in healthyliver volume. Percentage change in total liver volumewasalso calculated as the difference between the pre-operative liver volume (including both healthy liver andtumor volumes) and post-operative liver volume,expressed as a percentage of pre-operative liver volume.Finally, the above analysis was repeated including only

the 63 (72%) patients who specifically had post-resectionCT scans at MSKCC within 2 months after surgery. Fortythree (49%) had their post-resection CT scans within1 month after surgery. The excluded patients had earlypost-resection CT scans performed at outside institutions,which could not be volumetrically analyzed by ourcomputer program. For these patients, the initial analysisutilized scans from beyond the 2 month window.Statistical analysis was carried out using SAS software

(SAS institute, Cary, NC). Logistic regression was usedto analyze the association between the percentagedecrease in healthy liver volume as a continuous variableand toxicity. The data on percentage decrease in healthyliver volume were divided into quartiles solely for use inthe figures. Chi-square tests were used to analyze theassociation between the extent of resection (number ofsegments, procedure type, and number of tumors), priorto chemotherapy, hepatic steatosis from pathology speci-mens, hepatic enzyme elevations post-resection, andhepatic and systemic toxicity after chemotherapy.

RESULTS

The 88 patients included in the study averaged 56 yearsof age. They were 53% male and 47% female. Mediannumber of tumors was two (distribution: 1 tumor—38 patients, 2—21, 3—12, 4—7, >4—9). Twenty fivepercentage underwent a trisegmentectomy and 19% werenoted to have hepatic steatosis. Prior to chemotherapywas reported by 61% of patients. The median intervalbetween resection and the analyzed post-resection CTscan was 33 days (range: 4–1,377 days) and 63 patients(72%) had their early scans within the 2 month windowdone at MSKCC. The median interval between resectionand the initiation of chemotherapy was 32 days (range:25–61 days). The median percentage decrease in total

86 Carlo et al.

liver volume among all patients was 22% (range: 61%decrease to 29% increase). The median percentagedecrease in healthy liver volume among all patients was17%, (range: 57% decrease to 32% increase).

The percentage decrease in healthy liver volume wasnot associated with increased rates of systemic toxicities(Fig. 1 and Table I). Overall, subgroups of systemictoxicities including diarrhea, leukopenia, and neutropeniaoccurred in 19.3, 12.6, and 19.3% of patients, respec-tively. In a logistic regression model using percentagechange in healthy liver volume as a continuous variable,no significant association was revealed between percen-tage of healthy liver volume resected and diarrhea (P¼0.47), leukopenia (P¼ 0.37), or neutropenia (P¼ 0.31).

Similarly, the percentage decrease in healthy livervolume was not associated with increased rates of hepatictoxicities (Fig. 2 and Table II). Overall, 13.7 and 35.2%of patients demonstrated hepatic toxicity, defined asincreases in bilirubin or alkaline phosphatase levels,respectively. In a logistic regression model using per-centage change in healthy liver volume as a continuous

variable, no significant association was revealed betweenpercentage of healthy liver volume resected and highbilirubin (P¼ 0.27) or alkaline phosphatase (P¼ 0.79).

Some patients had increased liver function tests2 weeks after surgery but prior to initiation of chemo-therapy. Percentage decrease in healthy liver volume wasassociated with higher 2-week bilirubin levels post-surgically. Patients with bilirubin levels greater than orequal to 1.5 within 2 weeks post-resection had signifi-cantly higher liver loss (24� 18%) than those who hadbilirubin levels lower than 1.5 (11� 20%) (P< 0.01).However, patients with higher bilirubin levels within2 weeks post-resection did not manifest higher rates ofhepatic or systemic toxicity while on adjuvant HAI andsystemic chemotherapy. Bilirubin levels in all patientsnormalized by the time chemotherapy was initiated.

Development of hepatic and systemic toxicities wasunaffected by any of the following: number of segmentsremoved, type of resection, number of tumors, whether ornot the patient had prior to chemotherapy, presence ofhepatic steatosis, and hepatic enzyme elevations post-resection (Tables III and IV).

Finally, when including only those patients who had CTscans performed atMSKCCwithin 2months post-resection,65 patients (72%) were included in the analysis. Themedianpercentage decrease in healthy liver volume among thesepatients was 21%, (range: 57% decrease to 31% increase).No significant association was revealed between thepercentage of healthy liver resected and, either hepatic(P¼ 0.90) or systemic toxicities (P¼ 0.77).

DISCUSSION

The purpose of this study was to determine whether thedevelopment of systemic and hepatic toxicities due toHAI and systemic chemotherapy was related to theamount of healthy liver removed during resection ofhepatic metastases from colorectal carcinoma. To ourknowledge, this study represents the first attempt to

TABLE I. Effect of Percentage Change in Healthy Liver Volume on Systemic Toxicity

Systemic toxicity

Diarrhea Leukopenia Neutropenia

% toxic (no.) P value* % toxic (no.) P value* % toxic (no.) P value*

Percentage change in healthy liver volume

30% loss 18.2 (4/22) 0.47 13.6 (3/22) 0.37 27.3 (6/22) 0.31

20–30% loss 31.8 (7/22) 27.3 (6/22) 18.2 (4/22)

0–20% loss 13.6 (3/22) 0 (0/21)a 13.6 (3/22)

No loss/increase 13.6 (3/22) 9.1 (2/22) 18.2 (4/22)

*P values obtained from logistic regression using percentage change in healthy liver volume as a continuous.aPatient missing toxicity information.

Fig. 1. Percent change in healthy liver volume does not correlatewith gastrointestinal or hematologic toxicity.

Extent of Hepatic Resection Does Not Correlate With Chemotherapy Toxicity 87

correlate loss of healthy liver with toxicity from adjuvantchemotherapy. Volumetric analysis of pre- and post-operative CT scans demonstrated no significant differ-ences in the amount of healthy liver removed betweenthose patients who developed toxicities and those whodid not. Following resection, there appeared to be anincreased hepatic enzyme elevation with larger resec-tions; however, this transient increase did not translateinto differences in toxicity upon treatment with theadjuvant chemotherapy.The findings in this study are important considering

that patients with positive surgical margins have higherrecurrence rates [9,10]. Positive surgical margins arepresent in 2–16% of cases at experienced centers [11]. Ifremoving greater amounts of healthy liver is not detri-mental to the patient undergoing adjuvant chemotherapy,then surgeons may be able to focus their attention onattaining negative margins at the expense of some extrahealthy liver.

There are several reasons why removing greateramounts of healthy liver may not be detrimental to thepatient undergoing resection of hepatic metastases. First,loss in healthy liver volume, equal in magnitude to thoseof this study, may not be significant enough to impairliver function. Another reason may be that tumor growthforces healthy liver tissue aside but does not actuallyreduce the amount of healthy tissue [12]. Finally, sur-geons may avoid extensive resections on weaker patientsthus avoiding possible subsequent toxicities in thesepatients and introducing a selection bias into the analysis.This study may have limitations. First, a mean loss of

17% of healthy liver may be insufficient to impair liverfunction to a degree that would increase toxicities fromadjuvant chemotherapy. Though the mean percentageloss of liver does not seem high, the average actualamount of liver removed was greater before adjusting forthe tumor-involved liver and accounting for the fact thatthese CT scans were usually taken about 1 month post-resection, by which time some hepatic regeneration hasoccurred. Regardless, one previous study noted that ratesof hepatic toxicity in trials of HAI with FUDR in patientswho did not undergo resection were similar to rates inthose who were first resected [13]. This may imply thatthe amount of healthy liver tissue remaining after thetypical resection of hepatic metastases may be enough topreserve normal hepatic function. In fact, it has beensuggested that at least 35% of the functional liver shouldremain after hepatic resection to ensure good recovery[14].A second possible limitation deals with volumetric

analysis using CT scans. Even though previous studiesconfirm the accuracy of this technique [6–8], differencesin the program used or in volume operator skill couldpotentially reduce the accuracy of this method. Such alimitation would most likely be a systematic error andthus not significantly change the conclusions.

TABLE II. Effect of Percentage Change in Healthy Liver Volume on Hepatic Toxicity

Hepatic toxicity

Bilirubin> 3 2� alkaline phosphatase

% toxic (no.) P value* % toxic (no.) P value*

Percentage change in healthy liver volume

>30% loss 9.1 (2/22) 0.27 36.4 (8/22) 0.79

21–30% loss 4.6 (1/22) 31.8 (7/22)

0–20% loss 27.3 (6/22) 36.4 (8/22)

No loss/increase 13.6 (3/22) 36.4 (8/22)

*P values obtained from logistic regression using percentage change in healthy liver volume as a

continuous variable.

Fig. 2. Percent change in healthy liver volume does not correlatewith liver toxicity.

88 Carlo et al.

Another possible limitation of the study is the failure toaccount for liver regeneration after hepatic resection.Most liver regeneration in normal livers is completedwithin 1 month after surgery, although cirrhotic and otherdiseased livers as well as livers experiencing largeresection volumes take longer [15]. Even though CTscans obtained immediately post-resection would betterassess the actual amount of liver removed, they would notrepresent the actual percentage change in healthy liver

volume that is present at the initiation of chemotherapy,which is the more clinically significant data since this isthe volume of liver encountered at the time of initiation ofchemotherapy. Interestingly, return of liver function mayfollow the timeline of liver regeneration causing a patientundergoing extensive resection for hepatic metastases toencounter a delay in return of liver function [15]. Thisstudy refutes any significant delay with regards tometabolism of chemotherapeutic agents.

TABLE IV. Factors Affecting Hepatic Toxicity Secondary to Adjuvant HAI andSystemic Chemotherapy

Hepatic toxicity

Bilirubin> 3 2� alkaline phosphatase

% toxic (no.) P value % toxic (no.) P value

Number of segments

�3 15.2 (5/33) 0.76 39.4 (13/33) 0.65

>3 13.0 (7/54) 33.3 (18/54)

Procedure type

Trisegmentectomy 18.2 (4/22) 0.49 31.8 (7/22) 0.80

Other 12.3 (8/65) 36.9 (24/65)

Number of tumors

1 10.5 (4/38) 0.64 31.6 (12/38) 0.59

2–3 18.2 (6/33) 42.4 (14/33)

�4 12.5 (2/16) 31.3 (5/16)

Prior to chemotherapy

No 20.6 (7/34) 0.20 32.4 (11/34) 0.82

Yes 9.3 (5/54) 37.0 (20/54)

Steatosis

No 16.2 (11/68) 0.44 38.2 (26/68) 0.40

Yes 5.9 (1/17) 23.5 (4/17)

TABLE III. Factors Affecting Systemic Toxicity Secondary to Adjuvant HAI and Systemic Chemotherapy

Systemic toxicity

Diarrhea Leukopeniaa Neutropenia

% toxic (no.) P value % toxic (no.) P value % toxic (no.) P value

Number of segments

�3 21.2 (7/33) 0.79 12.1 (4/33) 1.00 18.2 (6/33) 1.00

>3 18.5 (10/54) 13.2 (7/53) 18.5 (10/54)

Procedure type

Trisegmentectomy 9.1 (2/22) 0.22 9.1 (2/22) 0.72 13.6 (3/22) 0.75

Other 23.1 (15/65) 14.1 (9/64) 20.0 (13/65)

Number of tumors

1 23.7 (9/38) 0.66 8.1 (3/37) 0.50 13.2 (5/38) 0.29

2–3 15.2 (5/33) 15.2 (5/33) 18.2 (6/33)

�4 18.8 (3/16) 18.8 (3/16) 31.3 (5/16)

Prior to chemotherapy

No 17.7 (6/34) 1.00 20.6 (7/34) 0.10 20.6 (7/34) 1.00

Yes 20.4 (11/54) 7.6 (4/53) 18.5 (10/54)

Steatosis

No 14.7 (10/68) 0.08 10.5 (7/67) 0.22 17.7 (12/68) 0.73

Yes 35.3 (6/17) 23.5 (4/11) 23.5 (4/16)

aPatient missing information.

Extent of Hepatic Resection Does Not Correlate With Chemotherapy Toxicity 89

Finally, while the sample size of this study is largewhen compared with most studies reporting on HAI, itmay still be inadequate to detect small, yet importantdifferences in toxicities among patients. We will continueto monitor patients receiving HAI after liver resection forexcessive toxicity and update our results.

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