ORIGINAL ARTICLE. A Second Liver Resection Due to Recurrent Colorectal Liver Metastases. accepted as the only curative

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1 ORIGINAL ARTICLE A Second Liver Resection Due to Recurrent Colorectal Liver Metastases Antonio Sa Cunha, MD; Christophe Laurent, MD; Alexandre Rault, MD; Philippe Couderc, MD; Eric Rullier, MD; Jean Saric, MD Background: Repeat liver resection because of recurrent colorectal liver metastases can provide survival benefit with a low rate of complications. Design: Retrospective study. Participants: Forty patients who underwent a second hepatectomy because of liver metastases from colorectal cancer. Main Outcome Measures: Short- and long-term results of a second hepatectomy and determination of prognostic factors. Results: The postoperative mortality rate was 2.5%. The postoperative morbidity rate was not significantly different after a second hepatectomy compared with single hepatectomy (42.5% and 27.5%, respectively; P=.10). Transfusion requirement and hospital stay were comparable for both a single and a second hepatectomy. Threeand 5-year overall survival rates were 55% and 31%, respectively. Disease-free survival rates at 3 and 5 years were, respectively, 49% and 27%. The interval between first and second hepatectomies and the presence of extrahepatic disease were independently related to survival (multivariate analysis). Conclusions: A second liver resection because of recurrent liver metastases from colorectal cancer is safe and provides a survival benefit similar to that with single hepatectomy. Our analysis suggests that the benefit of treatment is limited in patients who undergo a second hepatectomy within 1 year of the first operation and in those with extrahepatic disease. Arch Surg. 2007;142(12): Author Affiliations: Department of Digestive Surgery, University Hospital of Bordeaux, Bordeaux, France. HEPATIC RESECTION IS WELL accepted as the only curative treatment for colorectal liver metastases, offering 5-year survival of 25% to 58%. 1-6 However, two-thirds of patients experience recurrence. Of these, only onethird will have recurrent metastases limited to the liver. 2,4 As improvements in surgical techniques and perioperative See Invited Critique at end of article management have enabled the reduction in mortality and morbidity associated with liver surgery, the rate of a repeat hepatectomy has increased in the last years The development of percutaneous radiofrequency ablation and the increased efficacy of systemic chemotherapy regimens should lead us to evaluate the results and the role of a repeat hepatectomy. We performed a retrospective analysis of a 15-year experience with hepatic resection of colorectal metastases to assess the feasibility, morbidity, and survival benefits in patients undergoing a second hepatectomy and to determine prognostic factors. METHODS We report the single-center experience of a second liver resection because of recurrent liver metastases at Saint André Hospital, Bordeaux, France. Patients were identified by a computer-based indexing system, and hospital medical records were retrospectively reviewed. Data analyzed included demographic information, pathologic features of primary and metastatic disease, surgical and adjuvant treatment of primary and metastatic disease, and predictors of outcome and survival. All patients who underwent a second resection of hepatic metastases were enrolled in the study. SELECTION OF PATIENTS Our criteria for a second hepatectomy were similar to those for first hepatectomy. Repeat hepatectomy was considered, in the absence of any medical contraindication to liver surgery, 1144

2 when the recurrent metastasis was technically resectable, preserving at least 30% of the liver parenchyma. Patients with extrahepatic disease (local recurrence, lung metastases, or both) that was resectable (R0 resection) were included. The preoperative evaluation included carcinoembryonic antigen; abdominal ultrasonography; computed tomography of the abdomen, pelvis, and thorax; and colonoscopy. OPERATIVE PROCEDURE The operative technique of liver resection in our unit has been described previously. 23 At laparotomy, patients underwent surgical exploration via intraoperative ultrasonography and manual palpation to confirm the extent of the hepatic and extrahepatic disease. According to the anatomical classification of the liver by Couinaud, 24 hepatectomy was considered major if 3 segments or more were removed. FOLLOW-UP Systematic postoperative follow-up included clinical examination, serum carcinoembryonic antigen assay, and abdominal ultrasonography every 3 months and chest radiographic examination and computed tomography every 6 months. Colonoscopy was performed at 1 and 3 years to exclude local recurrence of the primary tumor. STATISTICAL ANALYSIS A retrospective study of factors predictive of survival was performed including patient age and sex; site and stage of the colorectal tumor; disease-free interval between primitive tumor and the first hepatectomy; resection margin at the first hepatectomy; disease-free interval between first and second hepatectomies; presence of extrahepatic disease; number, size, and distribution of metastases; preoperative level of carcinoembryonic antigen; resection margin at the second hepatectomy; postoperative morbidity; and adjuvant chemotherapy. The overall survival was evaluated using the Kaplan-Meier method and included operative mortality. Univariate analysis was performed using the log-rank test. All variables associated with survival with P.20 at univariate analysis were considered for multivariate analysis using a Cox proportional hazards regression model. P.05 was considered significant. RESULTS Table 1. Tumor Data in Patients With Colorectal Liver Metastases Who Underwent a Single and a Second Hepatic Resection Variable Patients Who Underwent a Single Hepatectomy (n=311) Patients Who Underwent a Second Hepatectomy (n=40) P Value Tumor size.80 Mean, mm cm cm No. of tumors Lobar involvement Unilobar Bilobar Hepatectomy procedure Major Minor Operative blood transfusion No Yes Residual tumor R R Operative mortality Operative morbidity, No. (%) 93 (30) 17 (42.5).15 Duration of hospital stay, 14 (8) 17 (8).70 mean (SD), d Adjuvant chemotherapy.50 No Yes From January 1, 1985, to December 31, 2000, among 311 patients who underwent liver resection because of colorectal metastases, 140 (45%) developed liver metastases with or without extrahepatic recurrence. Fifty-six patients developed liver metastases with nonresectable extrahepatic recurrence, 38 patients had liver metastases not amenable to resection, and 6 patients had general contraindications to surgery. Thus, 40 patients (12.9%; 27 men and 13 women; mean age, 63 years [age range, years]) were eligible for a second hepatectomy. The primary carcinoma was located in the colon in 30 patients (75%) and in the rectum in 10 patients (25%). Cancer stage was T2 in 6 patients (15%), T3 in 34 patients (85%), N0 in 9 patients (22.5%), and N in 31 patients (77.5%). Liver metastases were synchronous in 18 patients (45%). The median interval between the colectomy and the first hepatectomy was 10 months (range, 0-34 months), and 70% of patients underwent hepatectomy within 1 year. At the time of the first hepatectomy, no patients had extrahepatic disease. The median interval between the first and the second hepatectomies was 15 months (range, 4-63 months) and was less than 1 year in 37.5% of patients. Adjuvant chemotherapy (intravenous fluorouracil with folinic acid, 5 days a month for 6 months) was given to 138 of 311 patients (44%) after resection of liver metastases. In the 40 patients who underwent a second hepatectomy, 27 (67.5%) received adjuvant chemotherapy after the first hepatectomy and 15 (37.5%) received adjuvant chemotherapy (intravenous fluorouracil with folinic acid, 5 days a month for 6 months) after the second hepatectomy (including 3 patients who also received chemotherapy before surgery). Five patients (12.5%) had resectable extrahepatic disease: 3 locoregional recurrences that were resected during the same laparotomy and 2 pulmonary metastases that were resected after the second hepatectomy. All 5 patients underwent R0 resection of extrahepatic disease. Characteristics of tumors in patients who underwent a single and those who underwent a second hepatectomy are given in Table 1. Solitary metastasis was present in 122 patients (40%) who underwent a single hepatectomy and in 21 patients (52.5%) at the second hepatectomy. The mean diameter of metastases was larger in the single hepatectomy group (44±26 mm) than in the second hepatectomy group (36±16 mm). One hun- 1145

3 Table 2. Postoperative Morbidity a Variable Single Hepatectomy b (n=311) Second Hepatectomy c (n=40) Pleural effusion 17 (5.5) 7 (17.5) Biliary fistula 19 (6) 6 (15) Liver failure 17 (5.5) 1 (2.5) Liver cut hemorrhage 4 (1.2) 1 (2.5) Subphrenic abscess 19 (6) 6 (15) Intestinal obstruction 2 (0.6) 1 (2.5) Peritonitis 0 1 (2.5) Abdominal wound abscess 6 (2) 3 (7.5) a Values are given as number of patients (percentage). For pleural effusion, P=.03; all other P values were not significant. b There were 113 complications in 93 patients; 20 patients had 2 complications after a single hepatectomy. c There were 26 complications in 17 patients; 9 patients had 2 complications after a second hepatectomy. Overall Survival, % Second surgery Only surgery Follow-up, mo Figure 1. Kaplan-Meier curves comparing survival after liver resection in patients who underwent a single liver resection and those who underwent a second hepatectomy. dred ninety-four patients (62%) underwent major hepatectomy in the single hepatectomy group and 11 patients (27.5%) in the second hepatectomy group (P.001). The percentage of R0 resections was not significantly different between the 2 groups: 98% in the single hepatectomy group and 87.5% in the second hepatectomy group. OPERATIVE MORTALITY AND MORBIDITY One patient (2.5%) died of peritonitis after the second hepatectomy. Transfusion of red blood cells was necessary in 49 patients (15%) in the single hepatectomy group and 6 patients (15%) in the second hepatectomy group (P =.91). Two patients underwent additional operations, 1 because of intestinal occlusion and 1 because of peritonitis that was the result of an intestinal perforation. The mean complication rate was higher but not significantly different after the second hepatectomy compared with the first hepatectomy (42.5% vs 30%) (Table 2). The mean (SD) hospital stay was not significantly different between the 2 groups (14 [10] vs 17 [8] days). OVERALL AND DISEASE-FREE SURVIVAL The 3- and 5-year overall survival rates after the second hepatectomy were 55% and 31%, respectively, with a median of 31.8 months. In comparison, overall survival in the 271 patients who underwent only 1 hepatectomy was 49% at 3 years and 34% at 5 years (Figure 1). After a median follow-up of 31 months (range, months) after the second hepatectomy, 17 patients (42.5%) are alive, of whom 13 patients (32.5%) are disease free. Twenty-three patients (57.5%) died of disease recurrence. Ten patients are alive at 5 years, and 8 of these patients have had no disease recurrence. The 3- and 5-year disease-free survival rates were 49% and 27%, respectively. Twenty-seven patients developed recurrent disease: isolated liver metastases in 12 patients, hepatic and extrahepatic recurrence in 9 patients, isolated lung metastases in 3 patients, and other extrahepatic disease in 3 patients. PROGNOSTIC FACTORS AFTER REPEAT HEPATECTOMY The results of univariate analysis of overall survival after the second hepatectomy are given in Table 3. Survival was significantly better in patients without extrahepatic disease, with an interval of more than 1 year between the first and second hepatectomies, and with R0 resection. Multivariate analysis revealed that only an interval of less than 1 year between the first and second hepatectomies (mean hazard ratio, 7.3 [95% confidence interval, ]; P=.003, Cox proportional hazards regression model) and presence of extrahepatic disease (mean hazard ratio, 3.3 [95% confidence interval, ]; P=.04, Cox proportional hazards regression model) were independent prognostic factors of poor survival (Figure 2 and Figure 3). COMMENT To our knowledge, our study is one of the largest singlecenter studies of repeat liver resection because of recurrent liver metastases (Table 4). Results of the present study show that a second hepatectomy can be performed safely and provides a 5-year survival rate of 31%. Factors associated with poor prognosis are an interval of less than 1 year between the first and second hepatectomies and the presence of extrahepatic disease. Owing to recent advances in hepatic surgery and survival benefits observed after liver resection because of colorectal metastases, the repeat hepatectomy rate has dramatically increased. In our study, 13% of patients who underwent liver resection because of colorectal metastases underwent a second operation, according to the results from specialized institutes. 8,9,13,21 Repeat liver resection is associated with increased technical difficulties related to adhesions on the raw surface of the previous hepatectomy and consistency of the liver induced by regeneration. Therefore, some authors report increased morbidity and increased risk of bleeding. 25,

4 Table 3. Univariate Analysis of Prognostic Factors for Survival After a Second Liver Resection of Colorectal Liver Metastases Mean Survival, % Variable No. of Patients No. of Deaths Survival, y 1 Year 3 Years 5 Years Overall Age, y Sex Male Female Site of primary tumor Colon Rectum Parietal extension T NR NR T Lymphatic spread N N Metastases Synchronous Metachronous Interval from resection of primary tumor, mo Type of first resection Minor Major Residual tumor R R NR Extrahepatic disease Absent Present NR NR Disease-free interval, mo Type of repeat resection Minor Major Tumor size, cm No. of tumors Preoperative ACE level, UI/mL NR Clearance of surgical margin, mm Residual tumor R R NR NR Morbidity Yes No Chemotherapy Yes No P Value a Abbreviations: ACE, angiotensin-converting enzyme; NR, data not reported. a Log-rank test. 1147

5 100 No extrahepatic disease Extrahepatic disease y <12 y Survival Rate, % Survival Rate, % Survival, y Survival, y Figure 2. Kaplan-Meier curves comparing survival after liver resection in patients with and without extrahepatic disease. Figure 3. Kaplan-Meier curves comparing survival after liver resection according to interval between the first and second hepatectomies. Table 4. Summary of Large Series of Repeat Hepatectomy in Patients With Recurrent Liver Metastases Source No. of Patients Major Hepatectomy, % Mortality Rate, % Morbidity Rate, % Median Survival, mo Survival Rate After a Repeat Hepatectomy, % 5-Year 3y 5y Survivors, No. (%) Fernandez-Trigo et al, a 168 NR NR Nordlinger et al, a 130 NR NR Adam et al, NR (14) Tuttle et al, NR (13) Yamamoto et al, (12) Muratore et al, NR NR Suzuki et al, (15) Petrowsky et al, a (15) Takahashi et al, NR NR Present series, (25) Abbreviation: NR, not reported. a Multiple-center series. Despite a high incidence of major repeat hepatectomies in our study, morbidity was similar to that reported in the literature* and not significantly different than after the first hepatectomy. In addition, the transfusion rate and hospital stay were not significantly different than those observed after the first hepatectomy. We conclude that a second hepatectomy, even major resection, can be performed safely. Our policy is to always discuss the possibility of a second hepatectomy in patients with recurrence of liver cancer, using the same selection criteria as for a first hepatectomy. Repeat hepatectomy is associated with a 5-year survival rate (31%) similar to that observed after the first hepatectomy. In addition, 8 of our patients (20%) are alive without recurrence at 5 years. The resectability rate of recurrent liver metastases is similar to that reported for the first liver metastases. This rate could be increased by associated radiofrequency ablation. 27 Radiofrequency ablation was not used in the present study. *References 7-10, 12, 13, 16, 18, 19, 21, 22. References 7-10, 12, 13, 16, 18, 19, 21, 22. In our study, 2 variables were independently associated with overall survival after the second hepatectomy because of recurrent liver metastases: an interval of less than 1 year between the first and second hepatectomies and the presence of extrahepatic disease. As in the 3 other studies that identified independent prognostic factors by multivariate analysis, 8,13,21 no tumor factor related to the primary tumor and the first hepatectomy was found in our study to be an independent prognostic factor related to the second hepatectomy. Adjuvant chemotherapy after hepatic resection of colorectal metastasis has been advocated because of the substantial risk of tumor recurrence. In our study, survival in patients who underwent a second hepatectomy was not influenced by using adjuvant chemotherapy; nevertheless, fluorouracil with folinic acid was administered. The use of new drugs (irinotecan, oxiliplatin, and targeted therapies) and the response to preoperative chemotherapy, as shown by Adam et al, 28 should improve results and aid in selection of patients who can benefit from a second hepatectomy. In our study, only 5 patients (12.5%) underwent R1 liver resection; this rate is lower than those usually reported 1148

6 (17%-25%). This small number of R1 liver resections explains why we failed to show that residual tumor is an independent prognostic factor, as reported by others. 8,13 In the present study, 3-year survival was dramatically decreased in the presence of extrahepatic disease and, therefore, is an independent prognostic factor, as after the first liver resection. 29 The few patients with extrahepatic disease (2 patients with local recurrence and 3 patients with lung metastases) does not allow us to stratify free and overall survival by site of extrahepatic disease. Resection of liver and extrahepatic disease can lead to a 5-year survival of 20%. 29 Therefore, we cannot conclude that the presence of extrahepatic disease must be considered a contraindication to a second hepatectomy. As also shown by Adam et al, 8 the present study demonstrates that 5-year survival is significantly better if there is an interval of more than 1 year between the 2 hepatectomies compared with an interval of less than 1 year. These results may suggest that chemotherapy be given before surgery to enable observation of the evolution of the recurrent disease and to aid in the selection of patients who can benefit from a second hepatectomy. In conclusion, a second hepatectomy is feasible, safe, and effective in selected patients with hepatic cancer recurrence after a first hepatectomy. In patients without extrahepatic disease and with an interval of more than 1 year between hepatectomies, 5-year survival is similar to that obtained after the first hepatectomy. Repeat hepatectomy can offer prolonged survival and is the only treatment with potential for cure. Accepted for Publication: May 26, Correspondence: Antonio Sa Cunha, MD, Department of Digestive Surgery, University Hospital of Bordeaux, Ave de Magellan, Pessac 33604, Bordeaux, France. Author Contributions: Study concept and design: Sa Cunha, Laurent, Rullier, and Saric. Acquisition of data: Sa Cunha and Couderc. Analysis and interpretation of data: Sa Cunha and Saric. Drafting of the manuscript: Sa Cunha and Couderc. Critical revision of the manuscript for important intellectual content: Sa Cunha, Laurent, Rullier, and Saric. Statistical analysis: Sa Cunha. Study supervision: Sa Cunha and Saric. Financial Disclosure: None reported. REFERENCES 1. Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery. 1986;100(2): Nordlinger B, Guiguet M, Vaillant JC, et al; Association Francaise de Chirurgie. 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