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10.1245/ASO.2006.05.039
Annals of Surgical Oncology 13:668-676 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience

Alice C. Wei, MD, MSc, FRCSC, Paul D. Greig, MD, FRCSC, David Grant, MD, FRCSC, Bryce Taylor, MD, FRCSC, Bernard Langer, MD, FRCSC and Steven Gallinger, MD, MSc, FRCSC

Hepatobiliary & Pancreatic Surgical Group, Divisions of General Surgery, University Health Network and Mount Sinai Hospital, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4

Correspondence: Address correspondence and reprint requests to: Steven Gallinger, MD, MSc, FRCSC, Suite 1225, Mount Sinai Hospital, 600 University Ave., Toronto, ON, Canada M5G 1X5; E-mail: sgallinger{at}mtsinai.on.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Metastatic colorectal cancer is a major cause of cancer death in North America. Hepatic resection offers the potential for cure in selected patients. We report the long-term outcomes of patients who underwent hepatic resection for colorectal metastases over a 10-year period at a single hepatobiliary surgical oncology center.

Methods: All patients who underwent liver resection for metastatic colorectal cancer between 1992 and 2002 were identified. Data were retrospectively obtained through chart review. Major outcome variables were disease-free survival and overall survival. Risk factors for disease recurrence and mortality were identified by multivariate analysis by using the Cox proportional hazard method.

Results: A total of 423 hepatectomies were performed for metastatic colorectal cancer. Most operations (n = 276; 65%) were major (four or more segments) hepatectomies. Perioperative morbidity occurred in 74 (17%) patients. There were seven (1.6%) perioperative deaths. The disease-free survival at 1, 5, and 10 years was 64%, 27%, and 22%, respectively. The overall survival at 1, 5, and 10 years was 93%, 47%, and 28%, respectively. Multivariate analysis identified four negative predictive factors for overall survival (hazard ratio; 95% confidence interval): a positive surgical margin (2.9; 1.5–5.3), large metastases (>5 cm; 1.5; 1.1–2.0), multiple metastases (1.4; 1.1–1.9), and age >60 years (1.4; 1.1–1.9).

Conclusions: Hepatic resection for metastatic colorectal cancer is safe and provides good long-term overall survival rates of 47% at 5 years and 28% at 10 years. An aggressive approach is justified by the low operative mortality rate and good long-term survival, even in individuals with multiple bilobar metastases.

Key Words: Liver neoplasm • Colorectal neoplasm • Hepatectomy • Survival • Prognosis • Mortality


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer is the fourth most common cancer in North America.1 One third of patients with colorectal cancer will develop metastatic disease. The natural history of untreated metastatic colorectal cancer is uniformly poor, with a median survival of 10 months. Despite substantial improvements in systemic therapy, including the widespread use of 5-fluorouracil, oxaliplatin, and irinotecan, metastatic colorectal cancer remains a formidable problem, and these treatments remain palliative.2,3

The liver is the only site of disease in 5% to 15% patients who present with metastatic colorectal disease. For these patients, metastasectomy by hepatic resection can offer the potential for cure. In a previous report covering the period 1977 to 1993, our group demonstrated a 5 year overall survival of 34% after hepatic resection for colorectal metastasis.4,5 This finding is in keeping with results published by several other groups, which reported 5 year survival rates of 25% to 50% after hepatic metastasectomy.6–8

Over the past decade, liver surgery has become increasingly refined. Improvements in surgical technique, anesthesia, and perioperative care have reduced perioperative morbidity and mortality rates. This has led to an increasingly aggressive surgical approach for this disease. Larger, more complex procedures are undertaken in patients with tumors that were previously considered unresectable. Combination treatment with staged surgical resection, surgery plus ablation, locoregional chemotherapy, and neoadjuvant chemotherapy have all been used to increase resectability.9–13

Our institution has a long experience with liver resection for colorectal metastases.5,14 The goal of this study was to report our experience with hepatic resection for colorectal metastases over the past decade. Disease-free survival (DFS) and overall survival (OS) were determined, and predictors of survival were examined by multivariate analysis.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients who underwent liver resection for metastatic colorectal cancer over a 10 year period (between April 1, 1992, and March 31, 2002) were identified at two university-affiliated hospitals. A total of 423 hepatectomies were performed on 395 patients. Thirty-eight procedures were repeat hepatectomies. Patient demographics, perioperative details, and follow-up data were extracted by retrospective chart review. This study was approved by the Research Ethics Boards of the Mount Sinai Hospital and the University Health Network.

Assessment of Resectability
All patients underwent routine preoperative investigations, including cross-sectional imaging of the thorax and abdomen (usually computed tomography [CT]), recent colonoscopy (within 12 months), and liver function tests. Most patients had carcinoembryonic antigen levels measured. Most patients underwent sequential resection of their colorectal primary tumor, followed by resection of hepatic metastases. The occasional patient (n = 10) who presented with synchronous colorectal liver metastases was a candidate for simultaneous resection of colorectal primary and hepatic metastases. Simultaneous resection was performed only if the resection criteria for both operations were met and if the surgeon believed that each resection could be completed safely. The criteria for resection were the ability to resect all metastatic disease with grossly negative margins, a predicted liver remnant size adequate to sustain life on the basis of clinical experience (volumetric analysis was not routinely performed), no significant medical conditions that precluded surgery, and the absence of extrahepatic disease (except for resectable pulmonary metastases). For selected patients with limited nonresectable disease within the liver, resection was undertaken if residual disease could be ablated (cryotherapy or radiofrequency ablation [RFA]) with adequate margins.

Surgical Technique
Intraoperative ultrasonography was performed before resection. An anatomical resection was performed when possible with occasional inflow and outflow occlusion. Parenchymal transection was usually performed with the Cavitron ultrasonic dissector (Valleylab, Boulder, CO) under low central venous pressure conditions. In addition to resection, 40 patients underwent concomitant ablation of non-resectable hepatic lesions. Seventeen patients had RFA, 22 had cryotherapy, and 1 patient had intra-operative ethanol injection.

Statistical Analysis
The primary outcome for this study was OS. The secondary outcomes were DFS, perioperative morbidity, and mortality. OS was defined from the date of hepatic resection until the date of last follow-up or death. DFS was defined from the date of hepatic surgery until the date of disease recurrence identified by serial imaging or biopsy. Perioperative deaths (see the definition below) were excluded from survival analysis.

Morbidity was defined as any perioperative morbidity, including bleeding, that necessitated reoperation; liver failure; biliary complications; sepsis of any etiology; and pulmonary, cardiac, and other complications that prolonged hospital stay. Perioperative mortality was defined as in-hospital mortality or 30-day mortality in cases where patients were discharged from the hospital. Survival outcome was analyzed by using the Kaplan-Meier method.15 Univariate analyses were performed with the log-rank test. Multivariate analysis was performed by using a Cox proportional hazard model. Statistical significance was defined as P < .05 (two tailed). All statistical analyses were performed by using the statistical software package SPSS 11.0 (SPSS Inc., Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
A total of 423 hepatectomies were performed on 395 patients over the 10 year period. Thirty-eight hepatectomies were re-resections performed for recurrent metastatic disease. The baseline demographics at the time of hepatectomy are listed in Table 1Go. The median patient age was 62.7 years (range, 23–88 years). There were 249 men and 174 women. Patients most commonly presented with stage III colorectal cancer (40%). One hundred thirty-seven (32.4%) patients had synchronous metastatic disease (i.e., stage IV colorectal cancer). One hundred ninety patients (45%) received chemotherapy with or without radiotherapy before hepatectomy at the discretion of their referring physician. Most treatment was administered as adjuvant therapy after resection of the colorectal primary tumor. The occasional patient received "palliative" chemotherapy and was referred for liver resection because of the response to chemotherapy. No patient received planned neoadjuvant chemotherapy before liver resection, because this was not the policy of our institution during this period. After hepatectomy, 135 (32%) patients received 5-fluorouracil–based chemotherapy, administered in a pseudoadjuvant manner.


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  		TABLE 1. Patient demographics (n = 423)a
 
The median length of follow-up was 31 months. At the time of last follow-up (May 2004), 128 patients had no evidence of disease, 72 patients were alive with disease, 171 patients were dead of disease, and 24 had died of other causes.

Operative Details
Anatomical resections were performed according to Couinaud’s classification when possible. Most patients underwent major hepatectomy (four or more segments). The procedures performed are listed in Table 2Go. In addition to the primary procedure, 99 (23%) patients underwent an additional surgical procedure during the same operation; 66 (16%) patients underwent a concomitant nonanatomical liver resection, 16 (4%) patients had en-bloc excision of the diaphragm, and 16 (4%) patients had nonliver procedures performed. Ten patients underwent simultaneous resections of the colorectal primary tumor and the hepatic metastases, including four right hemicolectomies, four anterior resections, and two abdominoperineal resections. The median operative time was 278 minutes (range, 60–1100 minutes); the median estimated blood loss was 1 L (range, .10–25 L). The median transfusion amount was 1 unit (range, 0–28 units). The Pringle maneuver was used selectively in 46 (11%) patients.


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  		TABLE 2. Procedures performed (n = 423)
 
Pathology
From the resected specimen, the mean number of tumors was 1.76 (range, 0–11) with a mean size of 4.6 cm (range, 0–17 cm) and a mean margin of 1.49 cm (range, 0–7 cm). There was a microscopically positive surgical margin in 16 (4%) patients.

Perioperative Morbidity and Mortality
The overall morbidity rate was 19.6%. Sixty (14%) patients had a single complication, and 23 (5.4%) patients had more than one complication. The most common complications were intra-abdominal sepsis and bile leak in 21 (5.0%) and 21 (5.0 %) patients, respectively. Liver failure was uncommon in this patient population, occurring only in six (1.4%) patients. Seven (1.7%) patients died in the hospital or during the first 30 days after surgery. Perioperative morbidity and mortality details are listed in Table 3Go.


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  		TABLE 3. Perioperative morbidity and mortality (n = 423)
 
Disease-Free Survival
The mean and median DFS were 45 months (95% confidence interval [CI], 38–50 months), and 19 months (95% CI, 17–22 months), respectively. The 1, 5, and 10 year DFS rates was 64%, 27%, and 22%, respectively. The Kaplan-Meier analysis is shown in Fig. 1Go. Univariate analysis was performed with the log-rank test. The variables analyzed and the results of the univariate analysis of DFS are listed in Table 4Go. Risk factors for disease recurrence were a node-positive colorectal primary tumor, multiple metastases, and the year of operation (before 1996 or 1996 or later). Multivariate analysis was performed with the Cox proportional hazard model. Variables examined by multivariate analysis for DFS were sex, age, number of metastases, and size and node status of the primary colorectal cancer. Independent risk factors for disease recurrence were multiple metastases, large tumors (>5 cm), and a node-positive colorectal primary tumor. The results of multivariate analysis for DFS are listed in Table 5Go.


Figure 1
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  		FIG. 1. Kaplan-Meier curve: disease-free survival after hepatic resection for colorectal cancer.

 

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  		TABLE 4. Univariate analysis: risk factors for DFS and OS
 

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  		TABLE 5. Multivariate analysis: risk factors for disease recurrence
 
Overall Survival
The mean and median OS were 68 months (95% CI, 63–74 months) and 53 months (95% CI, 44–62 months), respectively. The 1, 5, and 10 year OS were 93%, 47%, and 28%, respectively. The Kaplan-Meier analysis is shown in Fig. 2Go. Univariate analyses of the risk factors for decreased OS are listed in Table 4Go. Univariate analysis by log-rank test showed that older age (>60 years), multiple metastases, larger metastases (>5 cm), and a positive surgical margin were risk factors for worse OS.


Figure 2
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  		FIG. 2. Kaplan-Meier curve: overall survival after hepatic resection for colorectal cancer.

 
Multivariate analysis using the Cox-proportional hazard model was performed for OS. Variables examined by multivariate analysis for DFS were sex, age, number of metastases, tumor size, and margin status. Multivariate analysis demonstrated that all the variables significant by univariate analysis—age >60 years, multiple metastases, larger metastases (>5 cm), and a positive surgical margin—were independent risk factors for worse OS. Patient sex was not an independent predictor of OS. The results of multivariate analysis for OS are listed in Table 6Go. The strongest association for overall mortality was a positive surgical margin, with a hazard ratio (HR) of 2.9 (95% CI, 1.5–5.1).


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  		TABLE 6. Multivariate analysis: risk factors for worse OS
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this study demonstrate that liver resection provides good long-term survival for patients with liver metastases from colorectal cancer, with a 5 and 10 year DFS of 27% and 22%, respectively. The 5 year OS was 47%, and the 10 year OS was 28%. The perioperative morbidity was acceptable, at 19.6%, and the perioperative morality was low, at 1.7%. These results confirm that liver resection is the treatment of choice for patients with metastatic colorectal disease limited to the liver. The risk factors for decreased OS identified by multivariate analysis are a positive surgical margin (HR, 2.9; 95% CI, 1.5–5.3), large metastases (>5 cm; HR, 1.5; 95% CI, 1.1–2.0), multiple metastases (HR, 1.4; 95% CI, 1.1–1.9), and age >60 years (HR, 1.4; 95% CI, 1.1–1.9). Our findings are in agreement with other recently published large series that demonstrate OS survival rates of 35% to 50% at 5 years.6,7,16–18

This article represents an ongoing series from our institution extending back to the 1970s.5,14 In our previously published series, the 5 year OS was 34%, compared with the present results of 47%. This study also demonstrates that disease that recurs usually does so within the first 5 years after metastasectomy, because the 5- and 10- year DFS were similar: 27 and 22%, respectively. Thus, patients without evidence of disease at 5 years are likely to remain disease free. The apparent improvement in OS is likely due to a combination of factors, including an aggressive surgical approach to recurrent colorectal metastases, improved preoperative imaging and patient selection, improved perioperative care, and the use of multimodality treatment, including ablation and perioperative chemotherapy.

Aggressive surgical strategies including repeat resection for recurrent disease seem to increase OS with acceptable morbidity and mortality. Many groups now advocate sequential hepatic resection for disease that in a previous era would have been considered "unresectable." Repeat hepatectomy for recurrent colorectal metastases and excision of oligometastatic disease located in extrahepatic locations are also used.9,19–29 In our series, 36 (9%) patients underwent 38 repeat hepatectomies, and 39 (10%) patients underwent 54 pulmonary resections for recurrent colorectal metastases. The 5 year OS from initial metastasectomy for patients who underwent aggressive surgical re-resection for recurrent liver or lung colorectal metastases was 52% and 74%, respectively.30 This compares favorably to a 5 year OS of 42% for patients who underwent a single metastasectomy.

Improvements in preoperative imaging, including the widespread use of helical CT scans and the addition of magnetic resonance imaging, have allowed earlier detection of metastatic deposits and better preoperative assessment.31–33 Increased sensitivity and specificity in cross-sectional imaging allow better preoperative patient selection by avoiding surgery in patients with extrahepatic disease. Furthermore, postoperative surveillance is enhanced with earlier detection of recurrent or residual disease after hepatectomy. Improved detection of recurrent disease may identify patients who are candidates for re-resection.

More recently, positron emission tomography (PET) and PET/CT have been used in several centers to improve the preoperative staging of patients.33–37 In this study, our patients did not undergo preoperative PET scans. It is possible that this modality will further improve long-term survival rates by improving patient selection. We are currently undertaking a study to examine the preoperative role of PET/CT in selecting patients for metastasectomy.

Furthermore, ablation, either cryotherapy or RFA, is increasingly used and is a useful adjunct to surgery. Ablative techniques can facilitate surgery in some patients who would otherwise have technically unresectable disease. However, the role of ablation as a potentially curative treatment remains to be defined. In our study, 40 (9%) patients underwent ablation at the time of hepatic resection. In the group of patients who underwent intraoperative ablation, the DFS was significantly worse than that in patients who did not require intraoperative ablation, with a DFS of 14.6 vs. 47.3 months (P < .01), respectively. This finding is in keeping with the findings of Abdalla et al.,38 who reported that DFS and OS rates of patients who underwent resection and RFA were significantly worse than those in patients who underwent resection alone. However, other groups have had a more favorable experience with RFA as an adjunct to resection, reporting a 3 year OS of 47% and minimal added morbidity.24 Thus, the role of ablation in conjunction with hepatic resection remains unclear. The approach at our institution is to offer resection with ablation for patients who would otherwise have technically unresectable disease, with the understanding that RFA may be palliative rather than curative in this context.

Newer chemotherapeutic agents such as oxaliplatin and irinotecan have increased treatment options for patients with metastatic colorectal cancer.2,39,40 The utility of chemotherapy for patients with surgically resectable stage IV colorectal disease remains ill defined. Various groups have used chemotherapy in a neoadjuvant (i.e., before metastasectomy) and/or pseudoadjuvant manner (i.e., after potentially curative metastasectomy), with some success in small, highly selected case series.12,24 However, convincing evidence from larger randomized trials is absent. Previous studies that have examined the role of pseudoadjuvant chemotherapy have been underpowered to detect a significant difference between patients who do or do not receive pseudoadjuvant chemotherapy.12

However, the biological rationale for pseudoadjuvant chemotherapy is compelling, particularly for patients who are chemotherapy naive. Therefore, our group currently recommends pseudoadjuvant chemotherapy (oxaliplatin based) for all patients who are chemotherapy naive after hepatectomy of colorectal cancer hepatic metastases and on a case-by-base basis for all other patients. We do not routinely recommend neoadjuvant chemotherapy. However, in some patients with nonresectable disease at presentation, we will consider surgical resection if there is a demonstrated response to palliative systemic chemotherapy.

The good long-term survival data obtained in this study are accompanied by acceptable perioperative morbidity and mortality rates. The overall morbidity rate was 19.6%, and the mortality rate was 1.7%. These results are in keeping with outcomes from other high-volume hepatobiliary surgery specialty institutions.6,7,16 The most common complications observed were intra-abdominal sepsis and bile leak. These two complications often presented together. This is not surprising because most cases of intra-abdominal sepsis after liver resection are related to an unrecognized bile leak from the cut surface of the liver. In our cohort, the only significant risk factor by univariate analysis for intra-abdominal sepsis was the extent of hepatic resection. Patients who underwent resections of less than one anatomical liver lobe were more likely to develop intra-abdominal sepsis than patients who underwent hepatic resections of greater than one liver lobe (P < .05; data not shown). This may be due to divided bile ducts along the raw edge of the liver associated with nonanatomical wedge resections of one or two liver segments. No other risk factor, including age, sex, previous chemotherapy, or intraoperative ablative therapy, was significantly associated with postoperative intra-abdominal sepsis.

It should also be noted that the rate of perioperative liver failure was low in this study, at 1.4%. This reflects an adequate liver remnant size in most patients. During the time frame of this study, the amount of remnant liver required to sustain life was based on clinical judgment for each individual patient. Formal volumetric analysis was not used. As our surgical approach for this disease has become more aggressive, we now consider patients for hepatic resection who previously would have been considered at high risk for liver failure. For these patients, we may elect to perform more formal tests of liver reserve, including volumetric studies of the predicted liver remnant size, and functional tests, such as indocyanine green clearance, before recommending surgical resection.41–44 These measures may decrease the rate of perioperative liver failure, a serious and potentially fatal complication.

We identified four negative prognostic factors of OS by multivariate analysis: positive surgical margin, large metastases (>5 cm), multiple metastases, and age >60 years. These factors are similar to those previously reported by others. A positive surgical margin was the strongest negative predictor of OS, with an HR of 2.9 (95% CI, 1.5–5.3). The principle of complete tumor removal has been identified in almost all published series to date.5,16,17,45–47 The effects of the number and size of metastatic lesions have been variably identified to be negative prognostic factors in different series.6,7,16 This is likely related to differences in the definition of cutoff values for analysis. These characteristics likely act as surrogates for the extent of metastatic tumor burden. In future studies, techniques for examining tumor burden, such as preoperative analysis of total tumor volume by using cross-sectional CT volumetric analysis, may be used to assess the effect of this factor on DFS and OS. In previously published reports, the distribution of metastatic disease, in particular unilobar versus bilobar distribution, is believed to be a negative prognostic factor. In our series, bilobar distribution was not a risk factor for disease recurrence or a decreased OS (data not shown). In our study, age >60 years was identified as a negative prognostic factor for OS. The effect of age on short- and long-term survival after hepatectomy for colorectal metastases has not been consistently demonstrated in studies to date. Some investigators, such as Nordlinger et al.,16 have found an association with decreased survival in older patients. Other large series have not found an association with age and long-term survival. Furthermore, the perioperative risks for elderly patients seem acceptable.48,49 In our series, the influence of age is probably multifactorial. It may reflect a subtle difference in treatment strategies for older patients. Although there was no statistically significant difference in the number of patients who underwent major hepatectomy, perioperative chemotherapy, or repeat resection for recurrent metastatic disease, it is possible that these patients were treated less aggressively than younger patients. We did note a slightly increased number of nonanatomical resections performed in the older age group (n = 64; 25%) compared with the younger age group (n = 29; 31%), and this may be a manifestation of a slightly more cautious approach in older patients. As our experience continues to grow with an aggressive approach for this disease for all fit patients, we expect that the prognostic significance of age will decrease.

The limitations of our study include some loss of follow-up at longer time periods, because the median follow-up time of this study was 31 months. At 5 years, there were 263 patients with sufficient follow-up. This loss to follow-up is reflected by the difference between the actuarial estimate and the actual 5 year OS rates, which were 47% and 33%, respectively. Most of the loss to follow-up was the result of routine discharge of the patient from surgical care. Thus, the actual 5 year OS survival rate is likely an underestimate of the true 5 year OS. Because the Kaplan-Meier actuarial estimate is the statistic most commonly reported for survival data, we believe that the actuarial 5 year OS is the statistic that should be compared with other studies. This modest limitation does not detract significantly from the study findings, which rest on the strengths of this study. The most significant strengths of this study are the large cohort size, the contemporary study period, and the uniform surgical management in a high-volume hepatobiliary specialty center.

In conclusion, our large series of 423 hepatectomies for colorectal metastases shows that an aggressive surgical approach should be used whenever possible for patients with metastatic colorectal cancer. Excellent long-term survival is possible, with a 5 year OS of 47% and a 10 year OS of 28%. These long-term survival rates are superior to results reported in previous decades and represent a trend toward better control of metastatic colorectal cancer. This is likely due to a combination of surgical and nonsurgical factors, including an aggressive multimodality treatment strategy. From a surgical perspective, we favor an anatomical approach (i.e., lobectomy) over nonanatomical or wedge resections. This approach is associated with a lower morbidity rate, a lower positive-margin rate, a decreased intrahepatic recurrence rate, and increased survival in several reports.19,50,51 Our results support this conclusion, because we had a low positive-margin rate of 4% and a high 5 year survival rate of 47%. Furthermore, surgical resection should be combined with multimodality strategies such as RFA, chemotherapy, and repeat surgical resection when possible.

Received for publication July 15, 2005. Accepted for publication November 9, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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