In 2013, 142,000 new patients with colorectal cancer were diagnosed in the United States (1). Although, the incidence and mortality of colorectal cancer have been declining over the recent years, about 10–25% of these patients present with synchronous liver metastasis; while another 20–50% will develop metachronous liver metastases during the course of their disease (2-6). Liver resection is the only potentially curative treatment in these patients, resulting in 5-year survival rates of 32% to 58% (2,3,6-11). However, hepatic recurrence occurs in 50% of patients during follow-up, with 2.8% to 13.9% presenting with surgical margin recurrence (SMR) (6,11-15). SMR is not reported consistently in the hepatectomy literature. Furthermore, there are very few studies focusing on the incidence and predictors of SMR (12,14,15).
The aim of this study is to define the incidence and identify predictors of SMR after hepatectomy in patients with colorectal liver metastasis (CLM).
Materials and methods
Patients who underwent liver resection for CLM between April 2000 and April 2012 were identified from a prospectively maintained, institutional review board (IRB)-approved database. The details of the surgical technique were described previously (16). An intraoperative ultrasound was performed in all procedures, whereas frozen section was not performed routinely to assess margins. An R0 resection was defined as no malignant cells seen at surgical margin on final pathology.
A major hepatic resection was defined as three or more liver lobe resection according to Brisbane International Hepato-Pancreato-Biliary Association (IHPBA) classification (17). The patients were followed up with abdominopelvic and chest CTs quarterly for the first 2 years and then biannually. The scans were reviewed by independent radiologists. An SMR was defined as a recurrence seen along the resection line on follow-up imaging. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans were not obtained routinely in follow-up.
Demographic, clinical, and survival data were assessed with the univariate Kaplan–Meier analysis. Those parameters with a significance of P<0.1 on Kaplan–Meier univariate analyses were entered into a multivariate Cox proportional hazards model. Continuous data are presented as mean ± SEM. A P value of <0.05 was accepted for statistical significance.
There were a total of 206 patients with a mean age of 62.1±11.2. Eighty-five patients were female and 121 male. The average tumor size was 3.8 cm and number of tumors 1.7. Thirty-five percent (n=73) of the procedures were major and 65% (n=133) minor hepatectomies. An R0 resection was performed in 157 patients (76%) and R1 resection in 49 (24%). The patients were followed up for a median of 29 months (range, 3–121 months). An SMR was detected in 32 patients (15.5%), with an incidence of 32.6% (n=16) after an R1, and 10% (n=16) after an R0 resection (P<0.0001). Surgical margin width was <5 mm in 60 patients, 5–10 mm in 48, >10 mm in 43 and unknown in 6. In these subgroups, SMR was detected in 11%, 9%, 10%, and 0%, respectively. Demographic, clinical, intraoperative and oncologic parameters are summarized in Tables 1,2.
On univariate analysis, factors affecting SMR were tumor size (P<0.0001), preoperative carcinoembryonic antigen (CEA) level (P<0.0001), and margin status (P<0.0001). On multivariate analysis, a positive surgical margin was the only independent predictor of SMR. A positive surgical margin was associated with a 3.6 fold-increased risk of SMR in follow-up (P=0.0007, 95% CI: 1.7–7.4). There were 166 (80%) patients who received neoadjuvant chemotherapy. Surgical margin clearance was similar in patients who received and did not receive neoadjuvant chemotherapy (23% vs. 24%). The receipt of adjuvant chemotherapy did not affect SMR, either.
Figure 1 shows the development of SMR for both the R0 and R1 resections in a Kaplan Meier format. After an R0 and R1 resection, 5-year disease-free survival (DFS) was 19% and 11%, respectively (P=0.318) and 5-year overall survival (OS) 54% and 51% (P=0.363), respectively. SMR was an independent predictor of worsened DFS (P<0.0001) and OS (P=0.009) (Tables 3,4).
This study documents the incidence of SMR after liver resection in patients with CLM and analyzes the possible predictive factors. The incidence of R0 resection in our series (76%) is similar to that reported in the literature (4,11,13-15,18). This reflects our aggressive utilization of resection in the treatment of CLM. In this cohort of patients who had intense follow-up after hepatectomy with regular office visits and imaging studies, the incidence of SMR was 15.5%. A positive surgical margin was the only independent predictor of SMR. Furthermore, SMR was found to adversely affect both DFS and OS. The current study is one of the few reports in the literature critically analyzing SMR after hepatectomy and documenting an associated worse DFS and OS (11,12,19).
Hepatic resection is the only curative treatment for CLM, but recurrence develops in 50% of patients during follow-up, with up to 13.9% of recurrences occurring at the surgical margin (6,11-15). There is no consensus about the impact of positive surgical margin on SMR. Some authors have reported that an increased incidence of SMR after an R1 resection, whereas others have not shown a difference between R1 and R0 resection (12,14,15,18,20). Among these studies, only one multicenter study, by Pawlik et al., analyzed parameters that may affect SMR (12). In this report, a positive surgical margin was the only factor that affected SMR. The results of the current study are similar, with tumor size, CEA and margin status being associated with SMR in univariate analysis and margin status being the only independently predictor on multivariate analysis.
Although, the goal of a hepatic resection for CLM is to obtain negative margins, this is not possible in 7.6% to 27% of the patients (3,4,8,10,12,15,18). Larger tumor size, bilobar involvement, intraoperative blood transfusion, higher CEA levels and the presence of >3 tumors were reported to be risk factors for an R1 resection (11,18,21). In the current series, the incidence of a positive surgical margin was 24%. The effect of a positive surgical margin on survival is controversial. Some authors have reported worse DFS or OS with a positive surgical margin; whereas others have not (3,4,9,11-13,15,18,19,22). Recently Sadot et al. has reported a study of 2,368 patients who underwent liver resection for CLM from The Memorial Sloan Kettering Cancer Center. In this study it was shown that a larger surgical margin width was associated with better OS. Patients with surgical margin clearance of 1 mm or more had a better OS compared patients with submillimeter surgical margin. Patients with submillimeter surgical margin also had a better OS than patients with positive surgical margin (23). In the current study, the width of the negative surgical margin didn’t affect DFS or OS but, SMR was found to negatively affect both DFS and OS. To the best of our knowledge, this association has not been analyzed or reported in the literature. Although some studies have suggested that R1 resections are still associated with long-term survival (6,13,15,18), our results show that every effort should be made for an R0 resection during liver resection.
The effect of chemotherapy on the development of SMR after an R0 or R1 resection is controversial. In one study, the receipt of adjuvant chemotherapy did not affect the SMR rate after an R0 or R1 resection (20). Eveno et al. has reported on 86 patients who underwent hepatectomy for CLM. An R0 resection was achieved in 73% and R1 resection 27%. Although the 5-year OS and DFS were not different between the two groups, intrahepatic recurrences and SMR were more frequent in the R1 group (52% vs. 27%, respectively) (15). In the present study, neo-adjuvant or adjuvant chemotherapy did not affect the incidence of SMR.
The limitations of the current study are the retrospective nature of data collection and the fact that multiple surgeons were involved in the procedures. Nevertheless, it critically analyzes an important issue in liver resection for CLM, SMR, for which there are scant data in the literature.
An R1 resection is a risk factor for SMR, which adversely affects DFS and OS. Therefore, every effort should be made to achieve a negative margin during liver resection for CLM.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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