Morbidity of adjuvant hepatic arterial infusion pump chemotherapy in the management of colorectal cancer metastatic to the liver

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1 The American Journal of Surgery 188 (2004) Scientific paper Morbidity of adjuvant hepatic arterial infusion pump chemotherapy in the management of colorectal cancer metastatic to the liver Robert C.G. Martin, M.D.*, Michael J. Edwards, M.D., Kelly M. McMasters, M.D., Ph.D. University of Louisville Department of Surgery, Division of Surgical Oncology, James Brown Cancer Center, 315 E. Broadway, Room 313, Louisville, KY 40202, USA Manuscript received July 20, 2004; revised manuscript August 7, 2004 Presented at the 56th Annual Meeting of the Southwestern Surgical Congress, Monterey, California, April 18 21, 2004 Abstract Background: Surgical resection remains the treatment of choice for patients with colorectal cancer metastatic to the liver. Hepatic arterial infusion pump (HAIP) chemotherapy in combination with surgical resection has been demonstrated in a recent study to improve disease-free and overall survival for patients with colorectal cancer metastatic to the liver. Other reports, however, have indicated significant toxicity related to HAIP chemotherapy in the form of biliary sclerosis. Thus, the value of adjuvant HAIP chemotherapy following hepatic resection or ablation remains controversial. The aim of this study was to examine the survival and toxicity in a single institutional experience with adjuvant HAIP chemotherapy. Methods: Review of a prospective hepatobiliary database was performed. HAIP were placed in the standard technique following resection and/or radiofrequency ablation (RFA) of all liver metastases. Patients received floxuridine (FUDR) via the HAIP at standard doses. Complications were graded according to a standard 5-point grading scale. Statistical analysis was performed by 2 test. Results: Thirty-four of 86 patients underwent placement of HAIP at the time of hepatic resection or ablation between January 1999 and November The HAIP group demonstrated a significantly greater (P 0.05) number (median 5 vs. 2) and size (median 5 cm vs. 3 cm) of hepatic lesions compared to the group without HAIP. The HAIP group experienced a greater frequency of complications (53% vs. 33%), with 6 (18%) patients in the HAIP group demonstrating biliary sclerosis. There were no deaths within 30 days of surgery. Median survival was similar in both groups (HAIP 20 months, no HAIP 24 months). Conclusions: Patients in the HAIP group had significantly worse overall predictors of outcome in metastatic colorectal cancer, yet the median overall survival in both groups was similar. However, adjuvant HAIP chemotherapy was associated with significantly greater morbidity. Given the availability of newer active systemic agents and regimens, the value of adjuvant HAIP chemotherapy remains controversial Excerpta Medica Inc. All rights reserved. Keywords: Hepatic artery infusion chemotherapy; Hepatic artery pump; Metastatic colorectal cancer, complications * Corresponding author. Tel.: ; fax: address: Robert.martin@louisville.edu Hepatic artery infusion pump (HAIP) chemotherapy has been administered for more than 40 years, since the initial report by Sullivan et al in 1964 [1]. HAIP chemotherapy in combination with surgical resection has been demonstrated in a recent study to improve disease-free and overall survival in metastatic colorectal cancer [2]. Other reports have failed to demonstrate improved survival and have demonstrated significant toxicity in the form of biliary sclerosis [3]. Thus, the value of adjuvant HAIP chemotherapy following hepatic resection or ablation remains controversial. The aim of this study was to examine the morbidity of adjuvant HAIP chemotherapy at a single institution. Methods Review of a prospective hepatobiliary database of consecutive hepatic resections performed by all 3 authors was performed from June 1997 to April A standard evaluation of patients with metastatic colorectal cancer patients included preoperative computed tomography (CT) scans of the abdomen and pelvis, chest roentgenogram, and, since the year 2000, positron emission tomography (PET) scan /04/$ see front matter 2004 Excerpta Medica Inc. All rights reserved. doi: /j.amjsurg

2 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) Table 1 Complication criteria Complication Criteria Maximum complication grade Maximum complication Grade Pump (n 23) No pump (n 23) 0 No complications 1 Oral antibiotics, bowel rest, basic monitoring, supportive care IV antibiotics, TPN, drainage not required, prolonged tube 12 (52%) 12 (52%) feedings, transfusions Perioperative (6) Perioperative (9) Delayed (6) Delayed (3) 3 Interventional radiology drainage, operative drainage, 10 (43%) 10 (43%) Perioperative (2) Perioperative (7) Delayed (8) Delayed (3) 4 Chronic disability, organ resection, enteral diversion Death due to complication 0 0 IV intravenous; TPN total parenteral nutrition. Liver resections were classified as in described by Couinaud [4]. Among patients undergoing hepatic resections, anatomic liver resections were performed in almost all cases, with atypical hepatic resection reserved for situations where the adequacy of the liver remnant was questionable or because of a contralateral hepatic disease identified at the time of operation. For patients with disease that was felt to be unresectable because of the size, number, distribution, and location of the tumors, or because of patient comorbid factors, radiofrequency ablation (RFA) was performed. RFA was performed using intraoperative ultrasound guidance to insure that at least a 1-cm ablation margin was achieved around the tumors. An HAIP was placed in a majority of patients who were unresectable because of the number, distribution, and location of lesions, as well as in patients who had failed multidrug chemotherapy. HAIP were placed in a standard fashion through the gastroduodenal artery after ligation of accessory vessels in a majority of patients. Preoperative planning for patients who were undergoing HAIP placement included a transcutaneous arteriogram or CT angiogram preoperatively. The standard regimen for HAIP chemotherapy was as follows: patients received the first cycle of floxuridine (FUDR) at a dose of 0.1 mg/kg/d along with 20 mg of dexamethasone. If this first dose was well tolerated, subsequent cycles were increased to a dosage of 0.16 mg/kg/d. Hepatic enzyme levels were monitored closely and dosages were either decreased or cycles terminated for significantly increased values according to previously published guidelines [2]. Almost all patients had received preoperative 5-fluorouracil (5-FU) based chemotherapy, and 50% of patients received a concomitant systemic therapy in conjunction with HAIP chemotherapy. All postoperative complications and the length of hospital stay were prospectively entered into the database. Complications were graded according to a standard 5-point grading scale (Table 1), which has been used prospectively since June 2002 [5,6]. All prior cases were retrospectively reviewed and reclassified by this scale. All in-hospital and 30-day postoperative complications were evaluated with the highest severity level recorded. Perioperative complications were defined as complications occurring within 30 days of surgery with delayed complications defined as after 30 days. Abdominal fluid collections were defined as large contained fluid collection with clinical signs and symptoms of systemic inflammation requiring drainage or a large collection seen on radiologic imaging. An abdominal abscess was defined as fluid from which bacteria or fungi were cultured. A biliary leak was defined as bilious drainage 50 ml/d beyond postoperative day 5, or requiring treatment. Liver dysfunction was defined as liver function tests (aspartate aminotransferase and alanine aminotransferase) 2.5 times the preoperative values 5 days after resection. Biliary sclerosis was defined in this study as with other studies to be clinically persistent elevated bilirubin or alkaline phosphatase after the cessation of HAIP FUDR therapy for a minimum of 4 weeks, or radiograpically by cholangiography [3]. Ascites was defined as significant abdominal fluid that required drainage or diuretics therapy because of pulmonary or bowel dysfunction. Either clinical signs or symptoms of pneumonia with positive sputum cultures defined pneumonia. Cardiac ischemia was defined as angina that was either new or increased in severity following the operation. Myocardial infarction was defined by the presence of at least 2 of the following: increased serum markers (troponin I or creatine kinase-mb), characteristic chest pain, and/or electrocardiogram changes. Cardiac arrhythmia was defined as multifocal ( 6/min) premature ventricular contractions, ventricular tachycardia, or any dysrhythmia requiring treatment or monitoring. Hemorrhage was defined as intraoperative blood loss requiring transfusion for hemoglobin 8, a drop in Hgb of 3 g/dl, or associated with shock. Infectious complications were defined by a positive (sputum, wound, urine, etc.) culture, with some combination of a systemic inflammatory response (i.e., tachycardia, fever, hypoxia).

3 716 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) Table 2 Patient characteristics Table 3 Perioperative characteristics Factor Pump (n 34) No pump (n 52) P Pump (n 34) No pump (n 52) P Age, median (range), y 54 (36 78) 62 (39 88) 0.03 Gender 12 F, 22 M 15 F, 37 M NS Node-positive colon cancer 23 (68%) 32 (62%) NS Synchronous colon 26 (76%) 30 (58%) NS metastases Extrahepatic disease 0 (0%) 9 (17%) Median no. of lesions 5 (1 15) 2 (1 9) (range) Median lesion size (cm) 5 (1 10) 3 (1 6) 0.04 Preoperative CEA level NS (mean) Preoperative chemotherapy FU and leucovorin FU and CPT FOLFOX 1 0 Comorbidities NS Smoking Diabetes 2 5 Cardiac 4 7 Preoperative albumin (mean), g/dl NS NS not significant; CEA carcinoembryonic antigen; 5-FU 5-fluorouracil; CPT-11 irinotecan; FOLFOX 5-fluorouracil, leucovorin, and oxaliplatin. Chi-square test, Student t test, and Mann-Whitney U test for nominal, continuous, and ordinal variables were used to evaluate the association of independent variables to surgical complications. Proportional hazards analysis was performed on all variables found significant by bivariate analysis. Relative risk (RR) with 95% confidence intervals was calculated as a measure of association. Differences of P 0.05 were considered significant. Statistical analysis was performed using JMP software (SAS Institute., Cary, NC). Results Thirty-four of 86 patients underwent placement of HAIP at the time of hepatic resection or ablation. Patients undergoing HAIP placement were younger, with a similar gender distribution (Table 2). There was a similar distribution of patients with node-positive colon cancers (68% HAIP vs. 62%) and a nonsignificant trend toward an increased number of patients with synchronous liver metastases in the HAIP group (76% HAIP vs. 58%). The HAIP group demonstrated a significantly greater number of hepatic lesions (median HAIP 5 vs. 2) and size of hepatic lesions (median HAIP 5 cm vs. 3 cm) (Table 2). The use of systemic chemotherapy for stage IV disease was more common in the HAIP group predominantly because of the number with synchronous disease. Preoperative carcinoembyronic antigen, albumin, and other comorbidities were similar in both groups. Surgical therapy RFA alone 9 17 RFA w/resection Resection Pump 12 NA Type of resections Lobectomy 0 3 Segmentectomy 4 10 Wedge resection 9 22 Blood loss (median) 200 (0 700) 325 (0 600) NS OR time (h, median) 3.5 (2 5) 3.0 (2 6) NS % Blood transfusion 15% 16% NS Length of stay (d, median) 6 (3 53) 7 (2 22) NS RFA radiofrequency ablation; NA not applicable; NS not significant; OR operating room. In an evaluation of perioperative factors, only the type of surgical technique was different in the HAIP group (Table 3). The HAIP group had significantly fewer resections than the non-haip group, with a similar distribution of RFA. Blood loss, operating time, and blood transfusions were similar. The gastroduodenal artery was the most common artery used for HAIP placement, but the right hepatic was used in 11 patients. Administration of perioperative antibiotics in the HAIP group varied from a median duration of 4 days (range 1 to 7) with a majority receiving either cefazolin or ampicillin/sulbactam. Perioperative toxicity There were a significant greater number of overall complications in the HAIP group, with 18 (53%) patients having 23 complications compared to 17 (33%) patients in the non-haip group having 23 complications (P 0.03). There were no deaths within 30 days of surgery. There were a significantly greater number of perioperative complications in the non-haip group (70%, P 0.04) predominantly related to the greater extent of surgical resection that was performed (Table 4). The severity of complications was similar among both groups (Table 1). The majority of perioperative complications for the HAIP were minor (grade 2) (Table 1), except for 1 patient who developed a small bowel fistula requiring a prolonged hospital stay. Delayed toxicity There were a significantly greater number of delayed complications in the HAIP group (65% vs. 30%; P 0.04; Table 4), with a greater severity of these complications (Table 1). The majority of these complications were related to pump infections, chemotherapy-induced hepatitis, and

4 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) Table 4 Perioperative complications Pump (n 34) No pump (n 52) Total complications Timing of complication Perioperative 8 (35%) 16 (70%) Delayed 15 (65%) 7 (30%) Wound infection 2 Abdominal fluid collection 1 Cardiac 1 2 Pulmonary Pneumonia 1 Pulmonary embolism 1 Effusion 1 Biliary sclerosis/stricture 5 (15%) Pump infection/dislodged 3 (9%) Intensive care unit stay 2 1 Hepatitis/hepatic failure 1 1 Deep venous thrombosis 2 Pump pain 1 Pancreatitis 1 Venous catheter infection 1 Portal vein thrombosis 1 Acute renal failure 1 Small bowel obstruction 1 Hernia 1 3 Tumor rupture bled 1 Other 4 7 biliary sclerosis (Table 4). Biliary sclerosis developed in 6 (18%) patients. Biliary sclerosis developed usually after the second or third dose of FUDR. All patients with biliary sclerosis discontinued HAIP chemotherapy. Two patients with biliary sclerosis had bilirubin levels of 3.3 and 2.9 mg/dl, respectively, that demonstrated diffuse sclerosis on cholangiogram not amenable to biliary stenting. Four other patients with biliary sclerosis underwent biliary stenting. In 3 of these 4 patients, the bilirubin levels normalized; the other patient had a bilirubin level that declined to a minimum of 2.9 mg/dl. A total of 16 (47%) patients received all 6 cycles of FUDR, with 6 requiring some form of dose reduction during this period. Median overall survival was similar in both groups: HAIP 20 months; no HAIP 24 months. Comments Since the initial report of HAIP chemotherapy in 1964 [1] there have been 19 reports evaluating HAIP in metastatic colorectal cancer to the liver (Tables 5 and 6) [2,3,7 24]. The majority of these reports concerned the management of unresectable metastatic colorectal cancer to the liver (Table 6). Few demonstrated any significant overall survival benefit for HAIP chemotherapy when compared to systemic chemotherapy alone. Thus, the value of HAIP chemotherapy alone without liver resection or ablation is of questionable benefit to the majority of patients. Similarly the use of HAIP chemotherapy in the adjuvant setting is quite controversial. In 1 single-institution randomized study, there was improvement in short-term diseasefree and overall survival associated with adjuvant HAIP chemotherapy plus systemic 5-FU compared to 5-FU alone [2]. In a smaller multi-institutional study, HAIP chemotherapy in combination with systemic 5-FU was beneficial in prolonging time to recurrence and preventing hepatic recurrence after hepatic resection of colorectal cancer. However, this study did not detect (nor was it powered to detect) an overall survival benefit [24]. An ongoing concern for HAIP chemotherapy has been the morbidity and relatively high incidence of long-term biliary sclerosis. Significant advances have been achieved in the management of HAIP, with significantly fewer postoperative complications related to catheter thrombosis, catheter dislodgment, arterial damage, and management of variant arterial anatomy. In general, greater experience has led to fewer pump- and catheter-related complications as the optimal techniques for arterial catheter placement has been defined. Reports by Curley et al and Allen et al have outlined the optimal technique of pump placement using the gastrodudodenal artery, with ligation of variant anatomy for better long-term catheter patency [14,25]. Catheter placement in either the remnant hepatic artery in the adjuvant Table 5 Biliary Sclerosis rate in resectable disease Author Year No. of patients Type of patients Response rate Rate of biliary sclerosis (%) Wagman [7] Unresectable 55 NR 15 Resected NA NR Lorenz [8] Resected NA 0.5 Kemeny, N [2] Resected NA 5.4 Kemeny, M [24] Resected NA 6.7 Onaitis [3] Resected NA 35 Kesmodel [23] Resected/Ablate NA NR Scaife [22] Resected/Ablate NA NR Present study Resected/Ablate NA 18 NA not available; NR not recorded.

5 718 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) Table 6 Response rates and biliary sclerosis rate in unresectable disease Author Year No. of patients Type of patients Response rate (%) Rate of biliary sclerosis (%) Balch [9] Unresectable 88 NR Daly [10] Unresectable Niederhuber [11] Unresectable 83 NR Chang [12] Unresectable Kemeny [13] Unresectable 50 8 Hohn [15] Unresectable Martin [16] Unresectable Rougier [17] Unresectable Curley [14] Unresectable NR 0 Allen-Mersh [18] Unresectable NR 0 Kemeny, N [19] Unresectable Lorenz [20] Unresectable 44 9 Kerr [21] Unresectable 54 0 NR not recorded. setting or the cystic artery, or dual catheters in the unresectable setting, have been demonstrated to lead to greater perioperative pump complications. Pump infections have also been reduced in recent studies, possibly related to the use of perioperative antibiotics. The optimal type and duration of perioperative antibiotics has not been defined or reported. However, most surgeons have used extrapolated data from the orthopedic literature [26,27] for permanent implants and thus administer some form of broad-spectrum antibiotic (cefazolin or ampicillin/ sulbactam) for at least 5 days postoperatively. The primary delayed toxicity and most significant devastating consequences of HAIP remains biliary toxicity (Tables 5 and 6). Many reports on the use of HAIP in a palliative setting failed to mention the rate of biliary sclerosis (Table 6); however, those that have meticulously documented the rate of biliary sclerosis have demonstrated an incidence to range from 8% to 26%. Several reports have suggested methods of reducing the rate of biliary toxicity. Hohn et al reported a dose reduction from 0.3 mg/kg/d to 0.2 mg/kg/d [28], which markedly decreased the percentage of patients requiring biliary instrumentation. However, this dose of 0.2 mg/kg/d remains a high initial dose, especially in the adjuvant setting, and a lesser dose of 0.1 mg/kg/d should be recommended for most patients. Others have successfully added dexamethasone to the intra-arterial treatment regimen, which led to a reduction in the need for dose reduction and trend for a lower overall serum bilirubin levels [19,21]. However, even in 3 large randomized studies of adjuvant HAIP [2,30,31], there was a significant increase in overall complications in the HAIP arm when compared to the systemic or observation arms. In terms of the perioperative complications, the German cooperative study demonstrated a 7.5% perioperative mortality rate in their 107 patients who received HAIP chemotherapy. Similarly, the large prospective randomized trial by the Memorial Sloan-Kettering group reported a perioperative mortality rate of 2.7% in 74 patients. Similarly, the Intergroup study demonstrated 2 plural effusions, 1 bile leak, 2 bile fistulas, 1 wound infection, 1 hemorrhage, and a perioperative mortality rate of 2.8% in the 35 patients enrolled [24]. This overall perioperative complication rate is similar to that in the majority of recent studies, as well as the present study. These data demonstrate that hepatic resection with adjuvant HAIP is reasonably safe with a moderate incidence of overall complications. The primary morbidity in patients receiving HAIP chemotherapy is ultimately reflected in the late complications that occur during FUDR therapy. An evaluation of the German cooperative study demonstrated only 1 case of biliary toxicity; however, they did not use interarterial FUDR [32]. The Memorial Sloan-Kettering study demonstrated a biliary sclerosis rate of 6%, but only 26% of the patients received more than 50% of the planned dose of FUDR due to hepatic enzyme elevation [2]. The Intergroup study, also using FUDR therapy, demonstrated only a biliary sclerosis rate of 6.7% [33]. Finally, a recent retrospective study by Onaitis et al demonstrated a significantly higher rate of biliary sclerosis at 35% [3]. Our study demonstrated a biliary sclerosis rate of 15%, which appears to be more comparable to the larger prospective randomized control trials; however, this still represents a high overall incidence. Finally, whether the benefit and toxicity of adjuvant HAIP chemotherapy is similar for patients who undergo RFA, as opposed to resection, remains to be completely determined in larger studies. These late complications remain the most powerful disadvantage of adjuvant HAIP chemotherapy in metastatic colorectal patients. The persistent hyperbilirubinemia or persistent elevation of alkaline phosphatase continues to be exceedingly common in many patients receiving adjuvant intra-arterial FUDR therapy following resection. These elevations continue to occur even with low- to moderate-dose FUDR regimens that have recently been reported [3]. Thus,

6 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) the overall learning curve or the optimal management of adjuvant HAIP FUDR therapy has yet to be established. Further work is required to optimize both the initial dose and improve the protective effects of dexamethasone or other agents that have been evaluated in animal studies. A recent report in a canine model demonstrated the protective effect of celecoxib to FUDR [34]. This effect was not as significant as with dexamethasone, but these results provide a possibility that in addition to pump dexamethasone, systemic celecoxib may offer additive protection to biliary toxicity. The limitations related to delayed toxicity remain the primary reason why any patient who is being considered for HAIP therapy should be considered in the context of some form of prospective trial to further optimize the learning curve and thus decrease the overall incidence of biliary toxicity. At present, the optimal management of patients with HAIP FUDR therapy has yet to be widely established in multi-institutional practice. This limited success with HAIP therapy continues to echo the exhaustive education that participating medical oncologists need to have to adequately, safely, and efficaciously dose and manage patients on this therapy. Emphasis on this education will continue to be required in any and all patients receiving HAIP chemotherapy. This initial report as well as the initiation of the American College of Surgeons Oncology Group Z05032 trial has raised further interest in the use of HAIP in the adjuvant setting. This important trial will help to evaluate the ability of all oncologists to use HAIP therapy to maximize efficacy and minimize toxicity. Conclusions Optimizing the true value of HAIP therapy has been limited by the persistently high rate of delayed complications, primarily in the form of biliary toxicity. The overall applicability of HAIP therapy for both the palliative and the adjuvant setting has been limited by this toxicity. The true role of HAIP therapy remains to be decided, especially in light of the plethora of new systemic agents that may induce similar response rates with less overall toxicity. References [1] Sullivan RD, Norcross JW, Watkins E. Chemotherapy of metastatic liver cancer by prolonged hepatic-artery infusion. N Engl J Med 1964;270: [2] Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341: [3] Onaitis M, Morse M, Hurwitz H, et al. Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases. Ann Surg 2003;237: [4] Couinaud C. Le Foie: Etudes Anatomiques et Chirurgicales. Paris, France: Masson & Cie; [5] Martin RC, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg 2002;235: [6] Martin RC, Jarnagin WR, Fong Y, et al. The use of fresh frozen plasma after major hepatic resection for colorectal metastasis: is there a standard for transfusion? J Am Coll Surg 2003;196: [7] Wagman LD, Kemeny MM, Leong L, et al. A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990;8: [8] Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998;228: [9] Balch CM, Urist MM, Soong SJ, et al. A prospective phase II clinical trial of continuous FUDR regional chemotherapy for colorectal metastases to the liver using a totally implantable drug infusion pump. Ann Surg 1983;198: [10] Daly JM, Kemeny N, Oderman P, et al. Long-term hepatic arterial infusion chemotherapy. Anatomic considerations, operative technique, and treatment morbidity. Arch Surg 1984;119: [11] Niederhuber JE, Ensminger W, Gyves J, et al. Regional chemotherapy of colorectal cancer metastatic to the liver. Cancer 1984; 53: [12] Chang AE, Schneider PD, Sugarbaker PH, et al. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987;206: [13] Kemeny N, Daly J, Reichman B, et al. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 1987;107: [14] Curley SA, Chase JL, Roh MS, et al. Technical considerations and complications associated with the placement of 180 implantable hepatic arterial infusion devices. Surgery 1993;114: [15] Hohn DC, Stagg RJ, Friedman MA, et al. A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial. J Clin Oncol 1989;7: [16] Martin JK Jr, O Connell MJ, Wieand HS, et al. Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 1990;125: [17] Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992;10: [18] Allen-Mersh TG, Earlam S, Fordy C, et al. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet 1994;344: [19] Kemeny N, Conti JA, Cohen A, et al. Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 1994;12: [20] Lorenz M, Muller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 2000;18: [21] Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003;361: [22] Scaife CL, Curley SA, Izzo F, et al. Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer. Ann Surg Oncol 2003;10:

7 720 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) [23] Kesmodel SB, Canter RJ, Raz DJ, et al. Survival following regional treatment for metastatic colorectal cancer to the liver using radiofrequency ablation and hepatic infusion pump placement. The Society of Surgical Oncology, 55th Annual Cancer Symposium, Denver, CO, [24] Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy an intergroup study. J Clin Oncol 2002;20: [25] Allen PJ, Stojadinovic A, Ben Porat L, et al. The management of variant arterial anatomy during hepatic arterial infusion pump placement. Ann Surg Oncol 2002;9: [26] Holtom PD, Patzakis MJ. Newer methods of antimicrobial delivery for bone and joint infections. Instr Course Lect 2003;52: [27] Tunney MM, Ramage G, Patrick S, et al. Antimicrobial susceptibility of bacteria isolated from orthopedic implants following revision hip surgery. Antimicrob Agents Chemother 1998;42: [28] Hohn DC, Stagg RJ, Friedman MA, et al. A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial. J Clin Oncol 1989;7: [29] Kemeny N, Seiter K, Niedzwiecki D, et al. A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer 1992;69: [30] Lorenz M, Muller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998;228: [31] Wagman LD, Kemeny MM, Leong L, et al. A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990;8: [32] Lorenz M, Muller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 2000;18: [33] Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy an Intergroup study. J Clin Oncol 2002;20: [34] Ensminger W, Knol J, DeRemer S, et al. Effects of dexamethasone or celecoxib on biliary toxicity after hepatic arterial infusion of 5-fluorodeoxyuridine in a canine model. Cancer Res 2004;64: Discussion Courtney Scaife, M.D. (Salt Lake City, UT): Hepatic artery chemotherapy is an invasive, morbid, and expensive intervention with little benefit to the patients. Several large prospective trials have shown that there is a delay in hepatic recurrence of 4 to 6 months, but no improvement in survival. The weakness of a retrospective small study is that it is difficult to compare the populations. There is also significant variation within the population groups which you are attempting the study. In that vein, could you comment on the inclusion of your study of 9 patients who had extrahepatic disease? In addition, you emphasize, in your manuscript that the significant increase in early perioperative complications in the nonpump group were secondary to the more extensive resections in that group. Yet within that group, you have 17 patients who had radiofrequency ablation only. Could you comment on this? Additionally, you noted that in previously reported studies, specifically the Margaret Kemeny study, less than 20% of patients received the planned dose of chemotherapy through hepatic artery infusion, and less than 50% of patients received 50% of the planned chemotherapy. Compliance with hepatic artery infusion chemotherapy is one of the weaknesses of this treatment and could you comment on compliance in your patients? Finally, one of the weaknesses in my opinion of hepatic artery infusion chemotherapy is that it is a very costly intervention. Have you done a cost analysis? Answer Robert C.G. Martin, M.D. (Louisville, KY): I could not agree more. Retrospective studies by definition have some form of selection bias. A majority of these patients were operated on by 1 of our 3 surgical oncologist and thus the selection bias pushing one or the other is obviously going to be a limitation of this study. In regards to the extra, extrahepatic disease, this represents a small subset of patients that we are evaluating in regards to a more aggressive forms of surgical resection and RFA. In collaboration with a medical-oncologist we are evaluating the ability to push metastatic colorectal cancer more towards an ovarian cancer type of treatment, meaning if we optimally debulk and surgically treat patients who then are given less toxic, but hopefully more responsive chemotherapeutic agents, could we possibly improve their quality of life? Unfortunately, I am not saying that from our 9 patients we are achieving that, but I am saying that in certain patients, most likely young, usually 40s and 50s, that we are beginning to push the envelope more such that patients with isolated extrahepatic disease, a single common hepatic artery lymph node, or a single falciform ligament metastases would not stop us from doing an operation that if we can do with minimal morbidity, it may improve a patient s quality of life years. In regards to the perioperative complications in the nonpump group, did these actually occur in the patients undergoing a more extensive resection and not in the RFA group? In regards to the planned dosing of FUDR, only 47% of the patients received all six cycles of FUDR and only 23% received all of their planned dosage of FUDR. In regards to a cost analysis, we have not done that type of review. Question Barbara Pockaj, M.D. (Scottsdale, AZ): The NSABP and NCCTG are going to embark on a phase III randomized

8 R.C.G. Martin et al. / The American Journal of Surgery 188 (2004) trial that will look at the use of oxaliplatin and capecitabine with or without hepatic artery infusion of FUDR for isolated colorectal metastases to the liver. The phase II feasibility study is near completion by the NCCTG. I think this will finally answer the question of what is the benefit of hepatic artery infusion for colorectal metastases to the liver; especially in the face of these new chemotherapy agents that are superior to the agents we had in the past to treat colorectal cancer. Answer Robert C.G. Martin, M.D. (Louisville, KY): I could not agree more. That is Larry Wagman s study and I applaud him for trying to answer this difficult question. The problem we have had in even selling that type of study has been the lack of medical-oncology support. I am hopeful he is successful but I think it will be difficult in getting that national trial completed.