Extent of hepatic resection does not correlate with toxicity following adjuvant chemotherapy

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<ul><li><p>Journal of Surgical Oncology 2004;87:8590</p><p>Extent of Hepatic Resection Does Not Correlate WithToxicity Following Adjuvant Chemotherapy</p><p>WALDEMAR F. CARLO,1 AMANDA J. HUMMER,2 LAWRENCE SCHWARTZ,1,4 DEIDRE SULLIVAN,1</p><p>MITHAT GONEN,2 WILLIAM JARNAGIN,3 YUMAN FONG,3 AND NANCY KEMENY1*1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York</p><p>2Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York3Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York</p><p>4Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York</p><p>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 (P 0.47),leukopenia (P 0.37), neutropenia (P 0.31), high bilirubin (P 0.27), or alkalinephosphatase (P 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;87:8590. 2004 Wiley-Liss, Inc.</p><p>KEY WORDS: hepatic arterial infusion; liver resection; toxicity; liver volumes</p><p>INTRODUCTION</p><p>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].</p><p>Both hepatic and systemic toxicities occur with thistherapy. In studies using HAI of floxuridine (FUDR) andsystemic 5-fluorouracil (5-FU) following resection,</p><p>*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</p><p>Accepted 26 April 2004</p><p>DOI 10.1002/jso.20074</p><p>Published online in Wiley InterScience (www.interscience.wiley.com).</p><p> 2004 Wiley-Liss, Inc.</p></li><li><p>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</p><p>may be expected to be detrimental to the patient. Indeed,large resections are more likely to produce patientmorbidity than minor resections [24]. 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</p><p>(CT) scan has proven to be an accurate method forestimating pre- and post-operative liver volumes andtumor volumes [68]. 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.</p><p>PATIENTS AND METHODS</p><p>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-FU 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-FU/LV or CPT-11), thus all the information was pooled for analysis.Systemic and hepatic toxicities were defined according</p><p>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</p><p>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</p><p>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</p><p>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</p><p>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</p><p>(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.</p><p>RESULTS</p><p>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 tumor38 patients, 221, 312, 47, &gt;49). 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: 41,377 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:2561 days). The median percentage decrease in total</p><p>86 Carlo et al.</p></li><li><p>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 was</p><p>not 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 (P0.47), leukopenia (P 0.37), or neutropenia (P 0.31).Similarly, the percentage decrease in healthy liver</p><p>volume 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</p><p>variable, no significant association was revealed betweenpercentage of healthy liver volume resected and highbilirubin (P 0.27) or alkaline phosphatase (P 0.79).Some patients had increased liver function tests</p><p>2 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&lt; 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 was</p><p>unaffected 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 CT</p><p>scans 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(P 0.90) or systemic toxicities (P 0.77).</p><p>DISCUSSION</p><p>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</p><p>TABLE I. Effect of Percentage Change in Healthy Liver Volume on Systemic Toxicity</p><p>Systemic toxicity</p><p>Diarrhea Leukopenia Neutropenia</p><p>% toxic (no.) P value* % toxic (no.) P value* % toxic (no.) P value*</p><p>Percentage change in healthy liver volume</p><p>30% loss 18.2 (4/22) 0.47 13.6 (3/22) 0.37 27.3 (6/22) 0.31</p><p>2030% loss 31.8 (7/22) 27.3 (6/22) 18.2 (4/22)</p><p>020% loss 13.6 (3/22) 0 (0/21)a 13.6 (3/22)</p><p>No loss/increase 13.6 (3/22) 9.1 (2/22) 18.2 (4/22)</p><p>*P values obtained from logistic regression using percentage change in healthy liver volume as a continuous.aPatient missing toxicity information.</p><p>Fig. 1. Percent change in healthy liver volume does not correlatewith gastrointestinal or hematologic toxicity.</p><p>Extent of Hepatic Resection Does Not Correlate With Chemotherapy Toxicity 87</p></li><li><p>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</p><p>that patients with positive surgical margins have higherrecurrence rates [9,10]. Positive surgical margins arepresent in 216% 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.</p><p>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</p><p>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 a...</p></li></ul>