Annals of Oncology Advance Access originally published online on April 13, 2007
Annals of Oncology 2007 18(7):1190-1195; doi:10.1093/annonc/mdm106
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© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections
1 Department of Surgery, Hospital de Girona "Josep Trueta", Girona
2 Department of Surgery, Bellvitge Hospital, Barcelona
3 Assessoria Metodològica en Investigació Biomèdica, Institut Municipal Investigacions Mediques, Barcelona, Spain
* Correspondence to: Dr J. Figueras, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Hospital de Girona "Dr Josep Trueta", Crta de França s/n 17007 Girona, Spain. Tel: +34 972940256; Fax: +34 972940270; E-mail: info{at}jfigueras.net
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Abstract |
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Objective: To elucidate if a nonpositive <1-cm resection margin has any effect on hepatic recurrence in patients undergoing liver resection for colorectal liver metastases.
Patients and methods: Six hundred and nine patients underwent 663 liver resections. Patients with positive margin were excluded from the analysis. Two groups were studied: group A, <1-cm resection margin and group B, 
1-cm resection margin.
Results: A total of 545 liver resections in 523 patients were carried out with nonpositive resection margins. With a median follow-up of 25 months, the 5-year cumulative hepatic recurrence reached 54% in group A (n = 206) and 41% in group B (n = 339). Factors associated with hepatic recurrence were synchronic metastases (P = 0.0015), bilobar (P < 0.001), two or more metastases (P < 0.001), margin <1 cm (P = 0.0123) and extrahepatic disease (P = 0.0037). A strong correlation between resection margin and number of metastases was confirmed (P < 0.001). At multivariate analysis only two factors were independent predictors of hepatic recurrence: multinodular disease in the liver specimen [4 metastases hazard ratio (HR) = 3.45; 95% confidence interval (CI): 2.2–5.38; P < 0.001] and extrahepatic disease at hepatectomy (HR = 1.58; 95% CI: 1.58–3.32).
Conclusion: Subcentimeter nonpositive resection margins do not directly influence hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases.
Key words: colorectal cancer, hepatectomy, liver metastases, liver neoplasms, liver surgery, resection margin
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introduction |
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In patients with colorectal cancer (CRC), up to 25% of patients have synchronous hepatic metastasis at the time of laparotomy, and 50% will develop metachronous metastases [1]. Prospective studies have demonstrated that the use of chemotherapy in patients with metastatic disease prolongs survival and enhances quality of life in comparison to palliative care alone [2]. Liver resection has been accepted as the standard treatment of colorectal liver metastases (LM). Several large series have reported a 25%–40% long-term survival rate after curative resection of LM, whereas the survival without therapy is <2% [1, 3]. However, after resections with curative intention, recurrences in the remaining liver are observed in up to 50% of patients and are among the most important determinants of survival [4, 5]. Most authors have reported that resection margin involvement by tumor disease (i.e. positive margin) is a significant, if not the most important factor influencing liver recurrence and survival [5–27]. Traditionally, 1-cm margin has been usually considered necessary to avoid liver recurrence and to optimize long-term survival [5, 6, 9, 10, 12–17, 24]. The reason why "a positive margin was usually considered to be a margin <1 cm" is arbitrary. However, Ambiru et al. [4] described micrometastasis located at a median of 3 mm from the metastatic tumor edge in 31% of their patients. Most of these studies that had advocated ‘the 1-cm rule’ did not exclude patients with involved resection margins from their analysis. In other words, a positive margin was usually considered to be a margin <1 cm, hence they might have biased their results [25, 27]. Furthermore, minimal margins are frequently linked with extensive disease and greater tumor burden. Therefore, multivariate analyses are clearly needed to disclose actual influences of resection margin on liver recurrence and survival [18, 25, 28].
In any case, the required or desired minimal margin of clearance is currently the most important factor that is under the surgeon's control with a significant impact on outcome [12, 17]. Therefore, while technical improvements in recent years have permitted more extensive resections with expanded indications, there is an ongoing need for scrutiny of long-term data to justify such aggressive therapy [20, 29]. In this scenario, evaluation of the more discriminator values of resection margin width with regard to liver recurrence and survival remains a relevant issue in clinical practice and is the major aim of this paper. More specifically, we aimed to elucidate if a nonpositive <1-cm resection margin by itself has any effect on liver recurrence.
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material and methods |
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From January 1990 to May 2006, 609 patients underwent a total of 663 liver resections for LM at the Department of Surgery, Bellvitge Hospital, University of Barcelona (1990–2004), and the Department of Surgery, Hospital "Josep Trueta", University of Girona (2005–2006). The first author (JF) participated in all these operations. The study design and analysis was retrospective. However, the patient information, primary CRC tumor-related factors, metastasis specifically related factors, perioperative evolution and history of chemotherapy were entered prospectively into a computer database. The primary end point of the study was to analyze if a subcentrimetric nonpositive margin was an independent factor associated with higher hepatic recurrence rate. The study was approved by the hospital's ethics committee. All patients had histological confirmed colorectal adenocarcinoma with resectable LM. However, neo-adjuvant chemotherapy was administered when the disease was initially unresectable and continued until the LM became resectable, or showed maximal toxicity or when response ended. But, when a patient had two or more unfavorable criteria (synchronous presentation, bilateral or multinodular LM, increased size, or extrahepatic disease), a short course of preoperative chemotherapy was also administered in some patients. The response evaluated by tumor marker levels and computed tomography (CT) scan was carried out every six cycles (3 months). Selection criteria for liver resection were as follows: (i) medical fitness for major surgery, (ii) no signs of disseminated disease on preoperative imaging and (iii) adequate and enough liver parenchyma could be preserved. Therefore, there were no predefined criteria for resectability with regard to either the number or the size of the tumors, bilobarity, locoregional invasion or to the presence of extrahepatic disease, except that resection had potentially to be complete and macroscopically curative. The routine imaging studies carried out before liver resections were chest X-rays and abdominal dual phase (portal and equilibrium) helical CT. Details of the technique and the results have been reported elsewhere [30]. Colonoscopy was repeated in the absence of a normal examination. Positron emission tomography/CT scan was carried out during the last 4 years whether extrahepatic disease was suspected. The histopathological report of the primary tumor was carefully reviewed in order to confirm that the first resection was complete. The biochemical profile included carcinoembryogenic antigen (CEA) and CA 19.9 tumor markers. Radiographic examinations were reviewed at a twice-weekly multidisciplinary meeting and surgical resection was scheduled. All patients signed appropriate informed consent for surgical operation and to their inclusion in the study.
Patients with synchronous LM were considered for partial colectomy and hepatic resection at the same time. Should pulmonary metastases were encountered before hepatic resection they were removed after LM and subsequent chemotherapy treatment.
Intraoperative examination included in every patient: (i) regional exploration of primary tumor resection, (ii) bimanual palpation of the liver with assessment of number, size and localization of the nodules and (iii) intraoperative ecography to assess number, size, density and localization with special attention to closest intrahepatic vascular structures. All these intraoperative findings were correlated with both preoperative imaging and histopathological data with an appropriate collection sheet.
All the patients undergoing hepatic resections were advised to start postoperative adjuvant chemotherapy. After hepatic resection, all patients were followed up every 6 months by personal contact with liver function tests, toracoabdominal helical CT, CEA and CA 19.9 levels. Colonoscopy was carried out every 2 years. Repeated hepatectomy was carried out provided that further liver recurrence was technically resectable and if helical CT scan of the chest, abdomen and pelvis revealed no unresectable extrahepatic recurrence. During the last 5 years, radiofrequency ablation of LM was used either alone or in combination with surgery for otherwise unresectable patients.
definitions
- Positive margin: Following Fong et al. [20] criteria, it was defined as the presence of any exposed tumor along the line of transection or the presence of tumor cells at the line of transection detected by histological examination.
- Resection margin: According to Pawlik et al. [25], it was defined as the minimum distance from the edge of the nearest metastases to the transection line measured in millimeters.
- Number of metastases: Number of metastases assessed by appropriate histopathological study in the liver specimen.
statistics
Patient's demographics, primary and liver tumor characteristics, surgical therapy, histopathological analysis, history of chemotherapy and follow-up information were entered prospectively into a computer database. According to the aim of this paper, patients with positive margin in any hepatectomy were excluded from the analysis. The rest of the patients were distributed in two groups: group A (<1-cm resection margin) and group B (1-cm resection margin). The chi-square test was used to compare frequencies whereas mean values of the variables were compared using the Student t-test between both groups. Hepatic recurrence was calculated with the Kaplan–Meier method. The log-rank test was used to compare cumulative hepatic recurrence between both groups. Factors found to be significant predictors on univariate analysis were subjected to multivariate analysis using Cox proportional hazards model (backward stepwise regression analysis). Results were expressed as hazard ratio (HR) with 95% confidence interval (CI). Differences in variables were considered to be significant at a threshold of P < 0.05. Statistical analyses were carried out with statistical software (version 12.0; SPSS, Chicago, Ill).
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results |
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patient's and liver resection characteristics
In the 16-year period of the study, from 663 liver resections carried out in 609 patients, the resection margin was considered positive in 86 (13%) liver resections after macroscopic and microscopic evaluation of the liver specimens. Therefore, 545 liver resections in 523 patients were carried out with nonpositive resection margins. From them, 356 liver resections were carried out in men and 189 in women and the median age was 63 (range 32–84); 133 were carried out in patients aged 70 or older. Distribution of these liver resections as related to resection margin groups is shown in Table 1. Primary tumors were in the colon in 358 cases and in the rectum in 187. Preoperative CEA level was unknown in 20 cases; it was considered normal (0–5 ng/ml) in 192 (35%) and abnormal in the remaining 333 (61%). Dukes' staging of the primary tumor was unknown in one case, ‘A’ in nine cases (2%), ‘B’ in 194 (36%) and ‘C’ in 341 (63%). Liver tumor disease was diagnosed synchronously with the primary in 248 cases. Extrahepatic deposits of the disease were known at liver surgery in 82 cases (16%) including 29 cases with resectable pulmonary metastases. The neo-adjuvant chemotherapy was administered for unresectable LMs in 38 cases (36%) and due to other unfavorable factors in 67 patients. The regimen of chemotherapy administered was unknown in 23 patients, it consisted of a combination of 5-Fluorouracil (5-FU) and folinic acid alone in 13 patients, associated either to oxaliplatin (n = 38), irinotecan (n = 28) or both (n = 3). Bevacizumab was also used in different combinations in 12 patients, and cetuximab in two cases. After resection of the LM, adjuvant chemotherapy was given to 285 patients (52%). The remaining 260 did not receive postoperative chemotherapy. Most treatments were based on 5-FU, 119 patients (42%) received 5-FU and folinic acid, 66 (23%) in combination with irinotecan, 38 (13%) in combination with oxaliplatin, other regimens in 13 patients (5%), and it was unknown in 49 patients.
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Liver resections consisted of right or left hepatectomies in 184 cases, extended right or left hepatectomies in 119, segmental or bisegmental resection in 161, other anatomical resections in 11 and wedge or atypical resections in 70 cases. The median number of liver tumors was two (range 1–21). The median size of the biggest metastases in the liver specimen was 3.2 cm (range 0.3–18 cm). Chemotherapy was administered before or after liver surgery according to the above guidelines in 115 (21%) and 301 (55%) cases, respectively. Median follow-up of patients was 25 months (range 1–182 months). The majority of the recurrences occur in other sites of the liver, and only a minority on the cut surface.
univariate analysis of prognostic factors for liver recurrence
Excluding patients with positive resection margins the 1-, 3- and 5-year cumulative hepatic recurrence was 22%, 42% and 46%, respectively. At univariate analysis, five factors were associated with higher risk of hepatic recurrence (Table 2): synchronic presentation of primary and liver tumor disease (P = 0.0015), liver tumor disease in both lobes of the liver (e.g. bilobar presentation) (P < 0.001), two or more metastases in liver specimen (P < 0.001), resection margin <1 cm (P = 0.0123) (see also Figure 1) and extrahepatic disease at hepatectomy (P = 0.0037). Neo-adjuvant chemotherapy was used only in 105 patients. However, the impact of neo-adjuvant chemotherapy on hepatic recurrence rate was not significant on univariate analysis (P = 1). Adjuvant chemotherapy was used only to 285 patients (52%). However, the impact of adjuvant chemotherapy on hepatic recurrence rate was not significant on univariate analysis (P = 0.337).
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relationship between resection margin and number of metastases
When focusing in nonpositive resection margin of <1 cm as a predictor factor of liver recurrence, a relationship with greater number of metastases was observed (Table 1). Thus, whereas 54% of patients in group B (
1-cm resection margin) had only one metastases only 35% of group A (<1-cm resection margin) had a solitary metastases. Conversely, proportion of cases with >4 metastases was more than two-fold greater in patients of group A compared with group B (see Table 3). The correlation between both variables was also shown by Pearson chi-square test (value: 21, P < 0.001). Bilobar tumoral deposits in the liver were also more frequent in patients with <1 cm margin (52%) than in patients with >1 cm margin (28%), P < 0.001 (Table 1).
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multivariate analysis of prognostic factors for liver recurrence
At multivariate analysis only two factors were independent predictors of hepatic recurrence (Table 4): two or more metastases in liver specimen (<5 metastases with HR = 2.0; 95% CI: 1.47–2.86 and >4 metastases with HR = 3.45; 95% CI: 2.2–5.38) and extrahepatic disease at hepatectomy (HR = 1.58; 95% CI: 1.58–3.32). The impact of neo-adjuvant and adjuvant chemotherapy on hepatic recurrence rate was not evaluated on the multivariate analysis because there were not significant in the univariate analysis. In this analysis, nonpositive margin resection of <1 cm did not show any significant influence and therefore it was not an independent factor for liver recurrence.
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discussion |
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Resection margin involvement by the tumor in patients undergoing hepatectomy for liver colorectal metastases is one of the leading predictors for hepatic recurrence and it is a well-known determinant of survival [5–27]. If one bears also in mind that it is usually the most important factor to influence outcome that is directly under the surgeon's control [12, 17] it is conceivable why is one of the most frequently studied factors in clinical series of resectable colorectal LM. However, when the optimum resection margin to avoid liver recurrence is studied, contradictory data in the literature are often encountered [18, 27]. Even though 1-cm resection margin was traditionally considered necessary to minimize hepatic recurrence and overall survival [5, 6, 9, 10, 12–17, 24], more recent publications have advocated that a subcentimeter resection margin should not preclude resection of liver secondaries provided that a nonpositive resection margin can be obtained [18, 25, 27]. Several reasons may explain these conflicting data: (i) most of the studies advocating the the 1-cm rule did not exclude patients with positive resection margin [25, 27] and (ii) a strong relationship between less resection margin with greater tumor burden is usually observed which may account for a poorer liver disease outcome in patients with lower resection margin [18, 25, 28]. Notwithstanding, Wray et al. [24] have recently supported the concept that a subcentimeter resection margin is linked to a greater liver recurrence even though it should not preclude resection. This concept might match properly with the single finding of Ambiru et al. [4] who described micrometastasis located at a median of 3 mm from the metastatic tumor edge in 31% of their patients.
In order to clarify these contradictory data from the literature, we aimed to specifically focus on the effect of nonpositive subcentimeter (<1 cm) resection margin on liver recurrence in a 16-year period clinical series, consisting of 545 liver resections in 523 patients. Stratification of nonpositive margin resection widths <1 cm was not considered in our study because of lack of enough consistent sample size within these values. Nevertheless, stratification of nonpositive margins of 1–4 mm, 5–9 mm and >10 mm did not show any significant influence on hepatic recurrence in other studies [25, 31]. In univariate analysis, five factors were associated with poorer liver disease outcome (Table 2): synchronic presentation of primary and liver tumor disease, liver tumor disease in both lobes of the liver, two or more metastases in liver specimen; extrahepatic disease at hepatectomy, and finally, resection margin <1 cm (P = 0.0123). Regarding resection margin (see Table 2 and Figure 1), the 5-year cumulative hepatic recurrence was 54% for patients who underwent a subcentimeter resection margin whereas when the rule of 1-cm margin was respected, the 5-year cumulative hepatic recurrence was only 41%. However, a strong relationship between resection margin, number of metastases and bilobar tumoral deposit were observed in the baseline characteristics of patients (Table 1). The Pearson chi-square test confirmed this correlation (P < 0.001) when resection margin was appropriately stratified by number of metastases. When all significant variables influencing liver recurrence on univariate analysis were studied through the multivariate analysis, only two factors remained as independent predictors of hepatic recurrence (Table 4): two or more metastases (P < 0.001) in liver specimen and extrahepatic disease at hepatectomy (P = 0.018). Therefore, subcentimeter nonpositive resection margin failed to show any influence as an independent factor on liver recurrence. Thus, according to the results of our study we should state that subcentimeter resection not only should preclude resection but also directly influence outcome provided that resection margin is not directly involved by the liver tumor itself.
Several limitations of this study should also be addressed: Accurate assessment of the resection margin in hepatic surgery can be difficult. Current techniques of gross evaluation after formalin fixation may bias actual measurement of surgical margin. Thus, friability of the liver itself can cause the liver to crack, making assessment of the true margin difficult. Furthermore, current usage of either ultrasonic dissector or irrigating floating ball device while or after transection of the liver may overestimate the true-positive margin rate [25, 32]. In fact, irrigating floating ball devices have been shown to improve resection margin during transection of the liver [33]. Only global rates of hepatic recurrence were taken into account in our study. It is conceivable that there may be several patterns of recurrence as other studies [5, 25] have described that might influence outcome in a specific group of patients.
In conclusion, our study provides evidence supporting the concept that subcentimeter nonpositive resection margins do not directly influence hepatic recurrence in patients undergoing hepatectomy for LM.
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Footnotes |
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Present address: Department of Surgery, Hospital del Mar, Barcelona, Spain. 
Received for publication December 17, 2006. Revision received February 16, 2007. Accepted for publication February 19, 2007.
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