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The Significance and Clinical Factors Associated With a Subcentimeter Resection of Colorectal Liver Metastases

¹ Department of Surgery, Division of Surgical Oncology, University of Cincinnati Medical Center, 234 Goodman Street, ML 0772, Cincinnati, Ohio 45219
² Department of Radiology, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio 45267
³ Department of Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, 7th Floor, Boston, Massachusetts 02215

Correspondence: Address correspondence and reprint requests to: S.A. Ahmad, MD; E-mail: ahmadsy{at}uc.edu.

	ABSTRACT

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Background: Prognosis after resection of colorectal liver metastases is influenced by various factors. A positive margin of resection (MOR) has been shown to adversely influence prognosis. Although a 1-cm MOR has been accepted as adequate, the data to support this guideline are sparse.

Methods: Our hepatobiliary database was queried for patients who underwent liver resection for colorectal metastases between January 1992 and July 2003. All patients were divided into three groups: MOR <.5 cm (group A), .5 to 1 cm (group B), and >1 cm (group C). Operative reports from each hepatic resection were analyzed to determine local factors that may have contributed to a subcentimeter MOR.

Results: A total of 112 patients (67 men and 45 women) underwent liver resection for colorectal metastases with negative margins. Fifty-three patients were in group A, 26 patients were in group B, and 33 patients were in group C. Group C demonstrated decreased local recurrence (LR; P = .003), distant recurrence (DR; P = .008), and disease-free recurrence (P = .002). A significant difference in the overall time to LR (P = .003), time to DR (P = .003), and disease-free survival (P = .002) was also demonstrated. Factors associated with a subcentimeter MOR included nonanatomical resection (P = .043), proximity to a major vessel (P = .003), and central location (P = .002).

Conclusions: A <1-cm resection for colorectal liver metastases is associated with increased LR and DR, as well as decreased disease-free survival. When a nonanatomical resection is performed, a MOR >1 cm should be attempted, because an adequate margin is often underestimated. Considerations should be made for extended resections when tumors are centrally located or near major vessels.

Key Words: Colon cancer • Hepatic metastases • Resection margin • Liver surgery

	INTRODUCTION

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Liver metastases complicate up to 30% of cases of colorectal cancer (CRC), and hepatic metastases are the primary cause of death in this subset of patients.^1,2 In the patient with metastatic disease limited to the liver, resection offers the greatest likelihood of cure. Although there are no prospective, randomized trials comparing surgery with medical therapy, many case-controlled and retrospective studies have shown a distinct survival advantage with surgical resection.^3,4 In the last 10 years, single-institution series often exceeding several hundred patients have reported 5-year survival rates ranging from 25% to 49% after liver resection.^5–8

Over the last several decades, the use of hepatic resection for CRC metastases with curative intent has increased dramatically.^9–11 Factors associated with improved overall survival (OS) after surgery include the following: absence of extrahepatic disease, number of metastases, small tumor size (<4.0 cm), presence of metachronous lesions, tumor grade, and negative margin of resection (MOR).^12,13 The current standard of care during hepatectomy for CRC metastases is to obtain at least a 1-cm MOR. Although this is a widely held belief among surgeons, few reports have addressed the extent of MOR and survival data.^14–17 Because major hepatic resection remains a technically challenging procedure, several intraoperative factors may contribute to a subcentimeter resection. These factors include tumor size, proximity to a large blood vessel, number of metastases, and central location within the liver. In this article, we review our institutional experience with hepatic resection for colorectal liver metastases to determine the relationship between MOR and patterns of recurrence. In addition, we reviewed all operative reports to determine which, if any, intraoperative factors or variables may have led to a subcentimeter MOR.

	MATERIALS AND METHODS

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Patients
Institutional review board approval was obtained for this study. A retrospective review of all cases of hepatic resection for colorectal metastases at the University of Cincinnati Medical Center between December 1992 and July 2003 was performed by using an institutional hepatobiliary database. Charts were reviewed to identify patients with known CRC who subsequently underwent hepatic resection for colorectal metastases. Patients receiving preoperative chemotherapy or adjuvant hepatic arterial infusion chemotherapy were excluded from this study. None of the patients received adjuvant systemic chemotherapy. Radiofrequency ablation or cryoablation was not used in any of the patients included in this study group. Nonanatomical resections were performed according to surgeon preference. In general, patients with peripheral-based lesions or those with poor hepatic reserve underwent nonanatomical resections.

Perioperative evaluations included selected imaging studies (computed tomography [CT] and magnetic resonance imaging), routine blood work (complete blood count, coagulation profile, electrolytes, and liver functions tests), and serum tumor markers (carcinoembryonic antigen [CEA]). Hospital records were reviewed for primary tumor characteristics; number, size, and location of liver metastases; need for blood transfusions; and hospital course. Estimated blood loss was determined by the surgeon of record in accordance with the records of the operating room staM. Patient charts were further evaluated for long-term follow-up. Specifically, liver recurrence (LR), distant recurrence (DR), and OS were analyzed. Outpatient clinical assessment consisted of a physical examination and laboratory test every 3 months for 2 years and then every 6 months for 3 years. Chest radiographs and CT scans were performed every 6 months for 2 years and then each year for another 3 years. Abdominal CT scan, magnetic resonance imaging, positron emission tomography scan, laboratory values, and clinical assessment were the primary modalities used to determine recurrence. The use of chest CT and/or positron emission tomography scan as a mode of surveillance was physician dependent and did not follow an established protocol.

Surgical Margins
According to protocol by the University of Cincinnati Department of Pathology, all surgical specimens had the margins inked. The specimen was then bivalved, and standard hematoxylin and eosin examination was performed; additional step sections were then taken at 2- to 3-mm intervals for additional hematoxylin and eosin microscopic examinations. Each pathology report was analyzed for all surgical margins. The closest surgical margin to the metastatic tumor was recorded as the final MOR.

Resection Factors
All operative reports for each hepatic resection were carefully analyzed to determine whether local factors or variables might have contributed to a subcentimeter MOR. Specifically, each report was screened for five main variables that may have influenced the MOR. These variables were (1) anatomical or nonanatomical resection, (2) central location within the liver, (3) proximity to a large blood vessel < 1.0 cm, (4) tumor size > 4.0 cm, and (5) multiple metastases with more than four lesions.

Recurrence
In the University of Cincinnati hepatobiliary database, local recurrence (LR) is defined as the presence of new lesions in the hepatic parenchyma after operative resection. Recurrence was recorded as ipsilateral, contralateral, or bilateral with regard to the lobe of primary resection. The finding of new lesions in the lungs, brain, or bone was defined as DR. In our patient series, there was no case of isolated nodal recurrence.

Statistics
Summary and descriptive statistics were obtained by using established methods. Chi-square analysis was used to determine significance among MOR groups for the following variables: sex, tumor presentation, tumor location, American Joint Committee on Cancer stage, tumor differentiation, CEA level, number of metastases, distribution of metastases, tumor size, presence of capsular invasion, type of surgical resection, MOR, blood transfusion requirement, LR, DR, and OS. Kaplan-Meier survival analysis was used to determine significance between MOR and time to LR, time to DR, and OS. Statistical differences between variables that may have contributed to a subcentimeter resection (nonanatomical resection, proximity to a major blood vessel, central location, tumor size, and number of metastases) and actual MOR were analyzed by ² analysis and the Kruskal-Wallis test. The University Hospital Hepatobiliary Database was analyzed by using SAS statistical software (SAS version 8.1; SAS Institute Inc., Cary, NC).

	RESULTS

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Patients
From January 1992 to July 2003, 114 patients (67 men and 45 women; mean age, 64 years) underwent hepatic resection for colorectal metastasis. Two patients had positive surgical margins and were excluded from analysis. The remaining 112 patients were divided into 3 groups: MOR <.5 cm (group A), MOR .5 to 1.0 cm (group B), and MOR >1.0 cm (group C). Ten patients had multiple bilobar (nonanatomical) resections; the closest surgical margin was used as the final MOR. The overall mean length of follow-up for these patients was 33.1 months (range, 1–130 months). The median follow-up was 25 months, and 5% of patients were lost to follow-up.

Surgical Margins
There were no significant differences among the three groups with respect to age, sex, tumor presentation, tumor location, American Joint Committee on Cancer stage, tumor differentiation, pre–hepatic resection CEA level, number of metastases, distribution of metastases, tumor size, presence of capsular invasion, type of surgical resection, or blood transfusion requirements, as demonstrated by ² analysis (Table 1).

View larger version (18K): [in this window] [in a new window]   FIG. 1. (A) Bar graph demonstrating statistical differences in local recurrence (LR) among the three margin of resection (MOR) groups. Patients with a MOR >1.0 cm demonstrated a statistically significantly decreased rate of LR by 2 analysis (*P < .05). (B) Bar graph demonstrating statistical differences in distant recurrence (DR) among the three MOR groups. Patients with a MOR >1.0 cm demonstrated a statistically significantly decreased rate of DR by 2 analysis (*P < .05).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Kaplan-Meier analysis of local recurrence among the three margin of resection (MOR) groups. Patients with a MOR >1.0 cm demonstrated a statistically significantly decreased rate of local recurrence by log-rank test (P = .003).

View larger version (18K): [in this window] [in a new window]   FIG. 3. Kaplan-Meier analysis of distant recurrence among the three margin of resection (MOR) groups. Patients with a MOR >1.0 cm demonstrated a statistically significantly decreased rate of distant recurrence by log-rank test (P = .003).

View larger version (16K): [in this window] [in a new window]   FIG. 4. Kaplan-Meier analysis of disease-free survival (DFS) among the three margin of resection (MOR) groups. Patients with a MOR >1.0 cm demonstrated a statistically significantly decreased DFS by log-rank test (P = .0015).

View larger version (17K): [in this window] [in a new window]   FIG. 5. Kaplan-Meier analysis of overall survival among the three margin of resection (MOR) groups. There was no statistical difference among MOR groups by log-rank test (P = .32).

	DISCUSSION

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Many factors can influence the patterns of recurrence or survival in patients with CRC metastases to the liver. Scheele et al.¹⁴ reviewed 1700 patients over a 30-year period and found that increased tumor grade, synchronous metastases, the presence of satellitosis, a maximum diameter of lesions of 5 cm, and margin of clearance were all significantly related to a worse overall prognosis. Other large series have demonstrated similar results.¹⁸ The one factor that seems to be most consistently related to prognosis after curative surgery is the final margin status of resection.¹⁹ The purpose of this study was 2-fold: first, to define how the primary surgical MOR affects locoregional recurrence and DR, and second, to determine what factors may have led to a subcentimeter resection.

Numerous authors have investigated the significance of margin status for resection of colorectal liver metastases. Although the existence of positive margins seems to universally affect survival, the extent of the negative margin that is required has not been fully studied.^12,20 To our knowledge, only one previous study has analyzed the extent of resection.¹⁴ In this study, patients were divided into those undergoing resection with a >1-cm margin and those undergoing resection with a <1-cm margin. Patients with a resection margin >1 cm had improved 5- and 10-year survival (43% and 28%) relative to >1 cm (37% and 21%). More recently, DeMatteo et al.²¹ have demonstrated that nonanatomical resections are associated with a higher incidence of positive margins (17% vs. 2%). Similar to Scheele’s study, we have analyzed the significance of margin status >1 and <1 cm; in addition, we have looked at margin status >.5 and <.5 cm. Our findings are similar to Scheele’s, with the best overall results in the subset of patients with MOR >1 cm. Similar to DeMatteo’s study, a greater percentage of patients with MOR >1 cm had undergone an anatomical resection (67% vs. 33%).

Our results demonstrate that the MOR significantly influences both local and systemic recurrences. In our series, approximately 45% of patients with a MOR <1.0 cm (groups A and B) developed LR. In contrast, patients with a MOR >1.0 cm had decreased LR and DR and improved disease-free survival when compared with patients with subcentimeter resections. These clinical observations are supported by pathologic studies performed by Yamamoto et al.,²² who performed microscopic examinations of the margins surrounding resected colorectal metastases in 40 patients with 89 liver tumors. Nine patients were found to have gross extension to Glisson’s sheath, eight had bile duct invasion, and one had neural invasion. The distance from the edge of the tumor to the tip of the extension ranged from 4 to 23 mm. These results suggest that tumors can spread along Glisson’s sheath and that a wide surgical margin is necessary to obtain a true R0 resection status.

Some authors also have proposed that a formal anatomical resection may confer an oncological benefit compared with limited wedge resections.²³ Our current results support this hypothesis. A significant proportion of patients who underwent nonanatomical resections had a subcentimeter resection. In our cohort, 64% of patients in group A, 75% in group B, and 42% in group C underwent a nonanatomical resection. Scheele et al. compared the results of patients undergoing anatomical versus nonanatomical resections.¹² An improved 5-year survival rate was noted for patients undergoing anatomical resections (42% vs. 27%; P < .05); this suggests that anatomical resections provide a greater clearance of tumor. In addition, it is thought that when multiple wedge resections are performed, the incidence of close or positive margins is higher. This concept is supported by the findings of DeMatteo et al.,²¹ who demonstrated by univariate analysis that segmentectomy resulted in longer survival compared with wedge resection (53 vs. 38 months). However, DeMatteo’s survival difference is probably a factor of positive margin status in the group (38 months) with poor survival.

An additional purpose of this study was to identify intraoperative factors that may have contributed to a subcentimeter resection. We found that patients with subcentimeter resections were more likely to have a central lesion and to have tumors in close proximity to large blood vessels. In addition, as in DeMatteo’s study, we also found that nonanatomical resections were associated with subcentimeter MOR. To the best of our knowledge, this is the first report to demonstrate central lesions and proximity to blood vessels as factors contributing to a subcentimeter resection for CRC metastases. Large tumor size (>5 cm) was not statistically significant; however, the P value (.096) approached significance. It is our belief that these factors contribute to a more technically challenging hepatectomy and may predispose the patient to a suboptimal MOR.

Two factors have been proposed to contribute to suboptimal tumor clearance after nonanatomical wedge resection.²¹ First, traction on the specimen during dissection of the hepatic parenchyma often produces a fracture at the interface of the fragile, soft liver tissue and the dense colorectal metastases. Second, because of restricted exposure and a lack of vascular control, significant bleeding regularly occurs at the base of the wedge resection. This hemorrhage may obscure the plane of the intended parenchymal transection and accordingly compromise the final margin. Currently, there have been no randomized, prospective clinical trials comparing formal anatomical resection with nonanatomical limited wedge resection for CRC metastases. It is our opinion that the type of resection is probably not as important as the actual MOR (a margin as long as 1 cm can be obtained).

At this point, there is a great deal of clinical interest surrounding novel chemotherapeutic agents and their role in various human cancers.²⁴ There are numerous preclinical and clinical trials involving specific monoclonal antibodies, tyrosine kinase inhibitors, next-generation platins, and new oral formulations of chemotherapeutic medications. A recent report from Hurwitz et al.²⁵ details the findings of a promising new phase III trial involving bevacizumab (anti–vascular endothelial growth factor antibody) plus irinotecan, 5-fluorouracil, and leucovorin in the treatment of advanced CRC. In this report, patients treated with the antiangiogenic compound and irinotecan, 5-fluorouracil, and leucovorin demonstrated an improved overall response and survival. Previously, trials using adjuvant therapy after curative liver resection have not demonstrated an advantage over surgery alone.²⁶ In the era of new chemotherapeutic drugs and biologic agents, the role of adjuvant chemotherapy after curative liver resection needs to be defined. It is possible that the MOR will become less important in the future, when more powerful biologic and chemotherapeutic agents can be used synergistically with surgical resection.

For now, however, we believe that the surgical MOR is a powerful factor that affects prognosis after hepatic resection for CRC metastases. A subcentimeter MOR seems to increase the incidence of LR, which may ultimately lead to systemic failure and DR. The surgical margin is one of the only factors that can be directly influenced by the physician, unlike most prognostic factors, which relate principally to underlying tumor anatomy and biology. A subcentimeter MOR has previously been considered a technical problem—as a suboptimal surgical resection. However, it may be a predictor or surrogate marker for a tumor with a more aggressive tumor biology and may be completely unrelated to the surgeon or the resection.

We recommend that extensive preoperative imaging, tumor localization, and operative planning occur before resection in an attempt to provide the best opportunity for a >1.0-cm MOR. We believe that a nonanatomical wedge resection is a viable surgical option for peripherally or superficially located metastases. When a nonanatomical resection is being performed, a MOR >1 cm should be attempted, because an adequate margin is often underestimated. Intraoperative factors, such as central location and proximity to major blood vessels, may contribute to a more technically difficult resection and may ultimately lead to a subcentimeter resection. Therefore, if the lesion is centrally located or near major vessels, considerations should be made for an extended anatomical resection.

Received for publication July 1, 2004. Accepted for publication December 19, 2004.

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