Hepatic Resection of Noncolorectal Nonneuroendocrine Metastases

Hepatic Resection of Noncolorectal Nonneuroendocrine Metastases Alan W. Hemming, * Tim D. Sielaff, Steven Gallinger, * Mark S. Cattral, * Bryce R. Taylor, * Paul D. Greig, * and Bernard Langer * Because hepatic resection is generally a safe procedure, the indications for resection of noncolorectal nonneuroendocrine (NCNNE) hepatic metastases have broadened. The prognostic features of NCNNE metastases treated surgically were reviewed to define better the value of resection. A retrospective review of patients undergoing liver resection for NCNNE metastases between 1978 and 1998 was undertaken. Thirty-seven patients were identified. Mean age was 56 years, with a median follow-up of 22 months. Primary tumor sites were grouped into gastrointestinal (GI) adenocarcinoma (small bowel, n 4; pancreas, n 2; esophagus, n 1) and other (renal cell, n 7; sarcoma, n 7; melanoma, n 5; adrenal, n 3; unknown adenocarcinoma, n 3; thyroid, n 2; testicular, n 1; ovarian, n 1; breast, n 1). All patients underwent surgery for cure. Metastases were synchronous in 14 patients. There was no surgical mortality. Overall 5-year survival rate was 45%. Five-year survival rates were better for patients with non GI-origin metastases (60% v 0%; P.01). Long-term survival was seen only in patients with non GI-origin metastases. The extent of resection, presence of synchronous metastases, or disease-free interval from time of original disease to presentation with liver metastases were not predictive of outcome. We conclude that patients with NCNNE hepatic metastases can undergo liver resection with an expectation of prolonged survival. However, patients with liver metastases from GI primary tumors other than the colorectum are unlikely to show extended survival. Copyright 2000 by the American Association for the Study of Liver Diseases L iver resection for metastatic colorectal cancer in selected patients has become the standard of care, with 5-year survival rates in the range of 25% to 40%. Improvements in surgical technique, patient selection, and perioperative care have increased the safety of liver resection such that even with extensive liver resections, surgical mortality in recent series is in the range of 0% to 5%. 1-3 Patients with neuroendocrine tumors metastatic to the liver have also been shown to benefit from resection, with improvements in both symptoms and survival. 4,5 The role of liver resection for noncolorectal nonneuroendocrine (NCNNE) tumors metastatic to the liver remains controversial. This report examines a single center s experience of resection of NCNNE tumors metastatic to the liver to assess whether results justify an aggressive surgical approach to this problem. Methods Thirty seven patients undergoing attempted curative hepatic resection for NCNNE metastases between 1978 and 1998 by the University of Toronto Hepatobiliary Surgery group were reviewed. Information was gathered from patient records, with patient follow-up by clinic visit or personal communication. Follow-up was complete in all patients. Curative resection was defined as a resection of all gross disease with negative pathological margins. Patients undergoing hepatic resection for direct tumor extension from the primary cancer were excluded. Records were reviewed for the following potential prognostic factors: (1) demographics, (2) primary tumor type, (3) synchronous versus metachronous presentation, (4) disease-free interval, (5) extent of hepatic resection, (6) curative versus noncurative resection, and (7) lobar versus bilobar involvement. Values are expressed as median and range. Parametric statistical analysis was performed using Student s t-test. Nonparametric statistical analysis was performed using chi-squared or Fischer s exact tests when appropriate. Survival was calculated using the Kaplan-Meier method, with comparison of groups using the log-rank test. Those variables found to be significant by univariate analysis were assessed by multivariate analysis using a Cox proportional hazard model, with significance specified as alpha equal to 0.05. Results Thirty-seven patients underwent hepatic resection for NCNNE tumors during the period examined. Patient demographics are listed in Table 1. As the experience with liver resection accumulated, the number of liver resections for NCNNE tumors increased as well (1978 to 1984, n 6; 1985 to 1992, n 9; 1993 to 1998, n 22). Median age was 56 years (range, 25 to 80 years), with a man-woman ratio of 1.3:1. Thirty-eight percent of the patients presented with synchronous From the *Department of Surgery, University of Toronto, Toronto, Canada; and the Department of Surgery, University of Minnesota, Minneapolis, MN. Address reprint requests to Alan W. Hemming, MD, University of Florida College of Medicine, Department of Surgery, PO Box 100286, Gainesville, FL 32610. Copyright 2000 by the American Association for the Study of Liver Diseases 1527-6465/00/0601-0003$3.00/0 Liver Transplantation, Vol 6, No 1 ( January), 2000: pp 97-101 97

98 Hemming et al Table 1. Characteristics of 37 Patients Undergoing Resection for NCNNE Metastases Total no. of patients 37 Men:women 21:16 Age (y) 56 (25-80) Presentation Synchronous 14 Metachronous 23 Symptoms Asymptomatic 19 Abdominal pain 7 Right upper quadrant fullness 2 Weight loss 2 Jaundice 2 Other 5 Site of disease Bilobar 9 Right lobe 21 Left lobe 7 Resection type Segmental 14 Lobectomy 17 Extended lobectomy 6 Table 2. Origin of Primary Tumor GI Origin Non-GI Origin Pancreas 2 Renal 7 Duodenum 2 Adrenal 3 Gastric 1 Testicular 1 Esophagus 1 Ovarian 1 Small bowel 1 Sarcoma 7 Melanoma 5 Unknown adenocarcinoma 3 Thyroid 2 Breast 1 lesions, whereas 62% had metachronous lesions. The median disease-free interval in all patients after primary treatment was 12 months (range, 0 to 21 years). The median disease-free interval in patients presenting with metachronous disease was 28 months (range, 2 months to 21 years). Fifty-one percent of the patients were asymptomatic at presentation. Metastatic lesions were in the right lobe in 57%, left lobe in 19%, and bilobar in 24%. The site of primary tumor is listed in Table 2. For purposes of analysis, tumors were classified into gastrointestinal (GI)-origin tumors or non GI-origin tumors. Adenocarcinomas of unknown origin were evaluated histologically using immunohistochemistry to attempt to rule out peripheral cholangiocarcinomas. GI tumors originated from the pancreas (n 2), duodenum (n 2), gastric area (n 1), esophagus (n 1), and small bowel (n 1). The two hepatic resections for pancreatic cancer were performed in patients with previous resections of papillary cystic carcinomas; 1 patient is alive and free of disease at 9 months, whereas the other died of recurrent disease at 26 months. Non GI-origin tumors included renal (n 7), sarcoma (n 7), melanoma (n 5), adrenal (n 3), unknown adenocarcinoma (n 3), thyroid (n 2), testicular (n 1), ovarian (n 1), and breast (n 1). Of the 7 patients with sarcoma, subtypes were leiomyosarcoma (n 2), uterine (n 2), cardiac (n 1), retroperitoneal (n 1), and abdominal wall (n 1). The 3 patients with unknown primary adenocarcinomas had undergone a histological review to attempt to rule out peripheral cholangiocarcinoma and had undergone upper and lower GI endoscopy, chest and abdominal computed tomographic scans, and mammography in the single woman. Two of 3 patients with unknown primary tumors were dead with widely metastatic disease within 10 months of resection; the third patient is alive and free of disease at 2 years. The 2 patients with testicular and ovarian tumors had undergone previous chemotherapy with failure to control hepatic disease. Surgical Results Of the 37 patients, 14 patients underwent segmental resection of one or more segments of Couinaud, 17 patients underwent formal right or left hepatic lobectomy, and 6 patients underwent right or left trisegmentectomy. Median surgical time was 4 hours (range, 1.5 to 6 hours). Median surgical blood requirement defined as transfusion during or within the first 24 hours of the procedure was0uofredcells (range, 0 to 12 U). Five patients had coexistent extrahepatic disease and underwent a simultaneous resection of another organ at the time of hepatic resection. Extrahepatic disease represented primary disease in 4 patients and metastatic disease in 1 patient. Four patients had positive microscopic margins and were therefore classified under noncurative procedures. Outcome There were no surgical deaths in this series. Median follow-up was 22 months, with no patients lost to follow-up. Actuarial survival at 1, 3, and 5 years was 85%, 55%, and 45%, respectively, with a median

Noncolorectal Nonneuroendocrine Metastases 99 Figure 1. Five-year overall actuarial survival in NCNNE patients undergoing hepatic resection for metastatic disease was 45%. survival of 46 months (95% confidence interval, 14 to 79 months; Fig. 1). There are 5 survivors at 5 years, to date. These include 2 patients with primary adrenocortical tumors, 2 patients with sarcoma, and 1 patient with metastatic renal cell carcinoma. By univariate analysis, only tumor origin (Fig. 2) and curative resection (Fig. 3) were predictive of outcome. These two factors remained significant on multivariate analysis (Table 3). Disease-free interval of 36 months or greater was not predictive of outcome (Fig. 4). Discussion Surgical resection is the only potentially curative treatment for most cancers metastatic to the liver. The Figure 3. Patients with positive microscopic margins did significantly worse than patients who received curative procedures (P.03). benefit of hepatic resection in the setting of hepatic metastases from colorectal primary tumors has been well documented, with a surgical mortality rate less than 5% and 5-year survival rates reported between 25% and 40%. 1-3 Hepatic resection for neuroendocrine metastases has also been shown to be of benefit for both symptomatic relief and prolonged survival. 4,5 It has been less well documented that resection of NCNNE hepatic metastases is of benefit. In our study, the overall 5-year survival rate was 45% for resection of NCNNE hepatic metastases, which compares favorably with results reported for colorectal metastases. Recent studies by Harrison et al 6 and Berney et al 7 have shown 5-year survival rates of 37% and 27%, respectively, in reports of hepatic resection for noncolorectal primary tumors. It is Table 3. Univariate and Multivariate Analysis Shows Only Tumor Origin and Curative Resection Are Significant Predictors of Outcome Figure 2. Patients who underwent resection with noncolorectal GI-origin tumors had a significantly worse prognosis than patients with non GI-origin tumors (P.02). Univariate P Multivariate P Type of liver resection NS Unilateral v bilateral NS Extrahepatic disease NS Symptoms NS Age NS Disease-free interval NS Origin of primary tumor.01.02 Curative resection.01.03 Abbreviation: NS, not significant.

100 Hemming et al Figure 4. There was no difference in outcome for patients with disease-free intervals (DFIs) greater or less than 36 months between the time of the original surgery and the time of the liver resection. therefore implied that selected patients with NCNNE metastases will potentially benefit from resection. The challenge is to accurately identify such patients and offer curative resection. Patients with noncolorectal GI-origin tumors metastatic to the liver clearly do poorly, with no 3-year survivors in either the present series or in the other largest single-center experience reported by Harrison et al. 6 Analyzing the present series along with 10 other series reported in the literature shows a 5-year survival rate of only 6% in patients with resected noncolorectal GI-origin hepatic metastases (2 of 33 patients). 6-15 There are reported long-term survivors after liver resection for metastatic gastric cancer; however, these are primarily anecdotal reports. 16 In patients with direct hepatic extension of gastric cancer, en bloc hepatic resection may achieve extended survival. 13,16-19 However, there is little support for resecting discontinuous gastric metastases. There are also anecdotal reports of hepatic resection for pancreatic adenocarcinoma 20 ; however, the mean overall reported survival is only 18 months. 21 It would seem clear that hepatic resection of noncolorectal GI-origin metastases offers minimal benefit. Not surprisingly, patients with resections performed with positive margins did not do well, showing a median survival of 12 months. Although all patients in this series underwent surgery with curative intent, the poor outcome of patients undergoing resection with eventual positive margins provides indirect evidence against undertaking resection for palliation. The few reports of palliative resection of NCNNE tumors reported in the literature confirm the futility of this approach, with no long-term survivors. 6,7 One would intuitively expect patients with longer disease-free intervals to have less aggressive tumor biological characteristics and subsequently have improved outcome after hepatic resection. Alternatively, late hepatic metastases may represent escape from either immune surveillance or other tumor regulatory factors that subsequently signal a change to a more aggressive tumor behavior, in which case one would not see a difference in survival based on disease-free interval. In this series, neither the presence of synchronous versus metachronous metastases nor the diseasefree interval in patients with metachronous lesions could be shown to affect outcome. In contrast, several other series 6,7 have shown improved outcomes in patients with longer disease-free intervals before hepatic resection. However, these series also could not show differences in outcome in patients with synchronous versus metachronous liver metastases. The relatively small sample size and patient heterogeneity in all studies may explain the discrepancy between the present and other series. Resection of colorectal cancer metastases to liver is accepted as standard treatment in selected patients. Results of hepatic resection for colorectal cancer metastases from our institution 22 show a 34% overall 5-year survival rate, similar to the 5-year survival rate of 45% obtained for resection of NCNNE metastases. The natural history of unresected colorectal cancer metastatic to the liver has been well documented, with few patients surviving 5 years, 23 whereas to date, the natural history of hepatic metastases from NCNNE tumors has been less well defined. Evaluation of the natural history of hepatic metastases from NCNNE tumors, the effect of chemotherapy on natural history, and a comparison to resection is required to confirm the role of hepatic resection for NCNNE metastases. However, our study indicates that selected patients with NCNNE hepatic metastases who undergo curative resection will achieve prolonged survival. Therefore, liver resection should be considered for patients with disease resectable with curative intent who have primary tumors that do not arise from the GI tract. References 1. Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997;15:938-946. 2. Scheele J, Stang R, Attendorf-Hofmann A, Martin P. Resection of colorectal liver metastases. World J Surg 1995;19:59-71. 3. Gayowski TJ, Iwatsuki S, Madariaga JR, Selby R, Todo S, Irish W, et al. Experience in hepatic resection for metastatic colorectal cancer. Analysis of clinical and pathological risk factors. Surgery 1994;116:703-711.

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