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10.1245/s10434-006-9068-y
Annals of Surgical Oncology 14:1151-1160 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Outcome After Hepatectomy for Multiple (Four or More) Colorectal Metastases in the Era of Effective Chemotherapy

Peter Kornprat, MD1, William R. Jarnagin, MD, FACS1, Mithat Gonen, PhD2, Ronald P. DeMatteo, MD, FACS1, Yuman Fong, MD, FACS1, Leslie H. Blumgart, MD, FACS, FRCS1 and Michael D’Angelica, MD, FACS1

1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
2 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA

Correspondence: Address correspondence and reprint requests to: Michael D’Angelica, MD, FACS; E-mail: dangelim{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hepatic resection is generally accepted as the only potential for long-term survival in patients with colorectal metastases confined to the liver. Despite an unknown benefit, hepatic resection is playing an increasing role in patients with extensive disease.

Methods: A retrospective review of a prospectively maintained hepatobiliary surgical database was carried out. Outcome after hepatectomy for four or more colorectal hepatic metastases was reviewed.

Results: Between 1998 and 2002, out of a total of 584 patients, 98 (17%) with four or more colorectal hepatic metastases were resected. Actuarial 5-year survival was 33% for the entire group, with seven actual 5-year survivors. There were no perioperative deaths, and the perioperative morbidity was 28%. Positive margins and extrahepatic disease resection were independently associated with poor outcome. The median disease-free survival was 12 months, with no actuarial disease-free survivors at 5 years. Recurrence pattern, response to neoadjuvant chemotherapy, time to recurrence, and resection of recurrent disease were also associated with outcome.

Conclusions: Long-term survival can be achieved after resection of multiple colorectal metastases; however, because most patients will experience recurrence of disease, effective adjuvant therapy and close follow-up is necessary.

Key Words: Liver metastases • Colorectal • Multiple • Hepatectomy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer is the third most common cancer in the United States, and its incidence is increasing, with over 145,000 new cases estimated in 2005.1 Approximately 25% of patients present with synchronous liver metastases, and an additional 35% to 45% of patients will develop hepatic metastases during the course of their disease.2 Patients with untreated liver metastases have a median survival of less than 1 year, but this is increased to 20 months with modern systemic chemotherapy.3,4 Hepatic resection remains the only chance of long-term survival, which occurs in up to 41% of patients after 5 years and 22% after 10 years.5–7

When partial hepatectomy was first proposed for the treatment of colorectal liver metastases, resection was generally limited to small and solitary lesions because these had a favorable prognosis and limited chemotherapy options were available at the time. Furthermore, complex liver resections were associated with marked morbidity and mortality. With advances in surgical techniques, anesthetic management, and perioperative care, mortality rates for partial hepatectomy of less than 5% are now reported in high-volume centers.5,7 Improvements in systemic chemotherapy for colorectal cancer have also been made in recent years, leading to response rates exceeding 50% with combinations including oxaliplatin and irinotecan and targeted agents such as bevacizumab.3,8–10

Among the prognostic factors associated with outcome after hepatectomy, the number of tumors has been one of the most consistently reported.5,6,11–13 Furthermore, multiple tumors and, specifically, the presence of four or more tumors has commonly been cited as a reason to exclude patients from resection.14–16 The extensive use of new and more effective chemotherapeutic agents combined with safer surgery has encouraged surgeons and oncologists to extend the indications for hepatectomy to patients with more tumors. However, the benefits are still not well documented in this particular group of patients.

In a previous series17 from MSKCC reporting data from 155 patients with four or more tumors resected between 1985 and 1998, the actuarial 5-year survival rate was 23%. However, effective adjuvant chemotherapeutic agents were not available at the time. Since then, more effective chemotherapy agents have been developed, greatly changing the management strategy of patients with extensive hepatic metastases. The purposes of this study were to review our experience with partial hepatectomy for multiple tumors in the era of modern chemotherapy and to analyze factors associated with survival and recurrence.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From January 1998 to December 2002, a total of 584 patients with colorectal hepatic metastases were resected at Memorial Sloan-Kettering Cancer Center. Of these, 98 patients (17%) with four or more tumors underwent hepatic resection and constituted the study group. A retrospective review of the medical record including operative, pathology, and follow-up reports was conducted. Institutional Review Board approval was obtained to conduct this study, and data collection adhered to HIPAA principles.

Criteria for resection included the following: the primary disease was controlled; preoperative imaging revealed no extrahepatic disease (selected patients with resectable extrahepatic disease were included); hepatic resection would remove all tumors completely with negative surgical margins; and an acceptable amount of liver parenchyma could be preserved. All patients underwent preoperative abdominal and pelvic computed tomographic (CT) scans, either chest roentgenograms or chest CT, and colonoscopy. Other imaging studies such as ultrasonography, magnetic resonance imaging, or positron emission tomography scans, were obtained at the discretion of the treating surgeon.

A standardized approach to hepatic resection was used and has been previously published.18 In brief, this includes low central venous blood pressure anesthesia and vascular control before parenchymal transection, which was performed by a clamp-crushing technique. An intermittent Pringle maneuver was generally used throughout the parenchymal transection phase. Intraoperative ultrasound was carried out in all patients. The number of tumors was determined with serial sectioning by a pathologist. A negative surgical margin was thought to have been secured when the tumor was not exposed at the cut surface of the liver either macroscopically or microscopically.

Definitions
Resections were defined on the basis of the Couinaud description of hepatic anatomy.19 Resection of segments 4, 5, 6, 7, and 8 was defined as an extended right hepatectomy; resection of segments 2, 3, 4, 5, and 8 as an extended left hepatectomy; resection of segments 5, 6, 7, and 8 as a right hepatectomy; and resection of segments 2, 3, and 4 as a left hepatectomy. Resections less than hemihepatectomies were defined as wedge resections or by the segments resected. The largest resection was labeled as the primary procedure and additional smaller resections as secondary procedures. Bilobar tumor involvement was defined as "tumor involving any segments of the left and right hemi liver."

Complications were graded on a 1-to-5 scale according to a previously published grading system.20 Grade 1 complications were those requiring no major medical interventions, grade 2 involved moderate interventions such as intravenous medications or prolonged tube feeding, grade 3 involved complications requiring surgical or radiologic intervention, grade 4 were those complications producing chronic disability, and grade 5 complications resulted in death. Grade 1 and 2 were grouped as minor and grades 3 to 5 as major complications.

Response to chemotherapy was evaluated from serial imaging studies (abdominopelvic and chest CT scan) and assessments of oncologists, and was based on tumor diameter changes within the lesions using the Response Evaluation Criteria in Solid Tumors.21 Changes in metastatic tumors were categorized as responding, stable, or progressing while the patient was receiving chemotherapy and were determined when a direct comparison of radiologic studies was possible.

Statistical Analysis
SPSS software, version 12 (SPSS, Inc., Chicago, IL), was used for data analysis. Univariate analysis was performed by the {chi}2 test (for categorical variables) or t-test (for continuous variables). The Kaplan-Meier method and the log-rank test were used to evaluate patient survival for various prognostic factors. The Cox proportional hazard regression model was used to assess the independent prognostic influence of various factors on patient survival. All variables that were significantly associated with survival on the univariate level were included. Significance levels were set at P < .05. All complications and deaths within 30 days of surgery were considered postoperative morbidity and mortality. Synchronous disease was defined as tumor occurrence within 1 year of presentation of the primary colorectal carcinoma. Survival time was measured from the time of diagnosis of colorectal hepatic metastases, except where specified. Patients alive were censored at the time of their last follow-up.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics and Tumor Characteristics
Ninety-eight patients with four or more hepatic colorectal metastases underwent hepatectomy during the study period; 57 (58%) were male. The median age at time of hepatectomy was 55 years (range, 25–89 years), and 13 patients (13%) were 70 or older. Primary lesions were in the colon in 60 patients (61%), and the primary tumor was associated with regional lymph node metastases in 61 patients (62%). Vascular and/or perineural invasion was present in 38 (41%) of the primary tumors. Median preoperative carcinoembryogenic antigen level (CEA) was 26.4 ng/ mL (range, 1–6855 ng/mL), and 78% of the patients had a CEA of <200 ng/mL.

Liver metastases were detected within 12 months of the presentation of the primary colorectal tumor in 68 patients (69%). The median number of tumors was five (range, 4–15). Fifty-five patients (56%) had 4 or 5 tumors, and 43 (44%) had between 6 and 20 tumors. The median size of the largest tumor was 4.3 cm (range, 1–27 cm), and 39 patients (40%) had tumors larger than 5 cm. Bilobar distribution of tumors was present in 63 patients (64%).

Surgical Procedures and Perioperative Outcome
A total of 44 extended hepatectomies (45%), 31 hemihepatectomies (32%), and 23 segmental and/or wedge resections (23%) were performed as the primary procedure. No patient in this series had ablative therapy performed as a primary procedure, but four patients (4%) underwent radiofrequency ablation, and five (5%) underwent cryoablation as a secondary procedure to ablate tumors outside of the primary resection. Overall, 47 patients (46%) required additional hepatic resections or ablations in addition to the primary resection (Table 1Go). Hepatic arterial infusion pumps were placed in 51 patients (52%).


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  		TABLE 1. Summary of surgical procedures
 
Extrahepatic resections were performed in 18 patients (18%). Twelve (67%) were due to local extension, and of these, five (42%) were histologically involved (Table 2Go). Eight (8%) patients underwent simultaneous resection of the primary colorectal tumor and hepatic metastases. Portal vein embolization was performed preoperatively in nine patients (9%) believed to have an inadequate future liver remnant. Surgical margins were histologically involved in 22 patients (22%).


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  		TABLE 2. Sites of extrahepatic disease resection
 
The median operative time was 275 minutes (range, 120–690 minutes), and the median time for the Pringle maneuver was 40 minutes (range, 0–95 minutes). The median intraoperative estimated blood loss was 600 mL (range, 150–3000 mL). A median number of zero (range, 0–4) packed red blood cells and zero (range, 0–20) units fresh frozen plasma were transfused per patient. Overall, 38 patients (39%) received a postoperative blood transfusion. The median postoperative hospital stay was 8 days (range, 6–32 days).

There was no postoperative mortality. Perioperative complications occurred in 29 patients (28%). The distribution is shown in Table 3Go. Five patients (17%) experienced major complications. A radiologic-guided drain was necessary in three patients with peri-hepatic abscess, and two patients underwent postoperative surgical adhesiolysis for small bowel obstruction.


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  		TABLE 3. Summary of perioperative morbidity
 
Survival Analysis
Median follow-up was 33 months for all patients and 41 months for survivors. At the time of last follow-up, 50 patients (51%) were dead of disease, 29 (30%) were alive with disease, and 19 patients (19%) had no evidence of disease. Actuarial 5-year survival was 33%, with a median survival of 41 months for the entire group measured from time of diagnosis (Fig. 1Go). Actuarial 5-year survival and median overall survival as measured from time of resection were 31% and 34 months, respectively.


Figure 1
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  		FIG. 1. Kaplan-Meier survival plot of disease-specific survival.

 
On univariate analysis, involved margins, vascular and/or perineural invasion of the primary tumor, extrahepatic resection, number of tumors six or more, and size of largest tumor 5 cm or more were associated with a worse prognosis (Table 4Go). As the number of tumors increased, the actuarial 5-year survival decreased from 39% in patients with four or five tumors to 19% in those with six or more tumors. The number of tumors had no marked impact on survival above six tumors (Fig. 2Go). Compared with patients with four or five tumors, patients with six or more tumors had significantly (P = .003) more positive margins and a trend toward more tumors 5 cm or more in size (P = .06). Multivariate analysis revealed that extrahepatic resection and positive margins were the two independent prognostic factors.


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  		TABLE 4. Analysis of predictors of prognosis
 

Figure 2
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  		FIG. 2. Bar chart of median survival rates corresponding to number of hepatic metastases.

 
Neoadjuvant and Adjuvant Chemotherapy and Survival
Neoadjuvant chemotherapy was administered in 54 patients (55%) for a median time of 7 months (range, 1–16 months). All of them received a combination of 5-fluouracil and leucovorin. In 26 patients (48.1%), irinotecan was added, and in seven patients (12.9%), oxaliplatin was added. Of the 54 patients who received neoadjuvant chemotherapy, 15 (28%) had progression of disease, 20 (37%) had stable disease, and 19 (35%) had a response. Adjuvant chemotherapy after hepatic resection was provided to 91 patients (92%). Fifty-one patients (52%) received postoperative hepatic arterial infusion chemotherapy with floxuridine combined with systemic chemotherapy.

Patients who received neoadjuvant chemotherapy had a worse but not statistically significantly different survival (as measured from time of diagnosis) compared with patients with no neoadjuvant chemotherapy (Fig. 3Go). The worst survival was seen in patients whose disease progressed while receiving neoadjuvant chemotherapy (P = .005). Patients who received neoadjuvant chemotherapy had a significantly higher proportion of bilobar (P = .006) and synchronous (P = .001) disease.


Figure 3
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  		FIG. 3. Chart illustrating impact of neoadjuvant chemotherapy on disease-specific survival.

 
Recurrence Pattern and Disease-free Survival
The median disease-free survival, as measured from the time of resection, was 12 months (range, 10–15 months), with an actuarial disease-free survival of 50% at 1 year, 12.2% at 3 years, and 0% at 5 years (Fig. 4Go). Recurrence of disease occurred in 81 patients (83%). Of these, 46 patients (57%) had their initial recurrence within the first year, 26 (32%) in the second year, and nine (11%) after the second year. Seventeen patients (17%) have not experienced recurrence at a median follow-up of 27 months (range, 1–53 months).


Figure 4
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  		FIG. 4. Kaplan-Meier survival plot of disease-free survival.

 
The most frequent site of initial recurrence was the lung in 31 patients (32%), the liver in 27 (28%), other single sites in 6 (6%) (kidney, pancreas, bone, and spine), and multiple recurrence sites in 17 (17%). The most common combination was simultaneous liver and lung metastasis in 7 (41%) of these 17 patients. Thirty-three patients (34%) underwent resection of their first recurrence. Of these, 20 (61%) underwent lung and 13 (39%) underwent liver resection. The median number of resected recurrent tumors was two (range, 2–9) in the liver and two (range, 1–11) in the lung. No patient underwent simultaneous liver and lung resection for recurrence. One patient underwent lung resection and subsequent resection of a liver recurrence. One patient (8%) underwent three liver resections, three (15%) underwent two lung resections, and one (5%) underwent three lung resections.

The impact of time to recurrence and pattern of recurrence as measured from time of hepatic resection and from time of recurrence is summarized in Table 5Go. Time interval to recurrence was associated with survival. Patients who experienced recurrence of disease within the first year had a worse median survival compared with patients who recurred after the first year. Furthermore, the recurrence pattern was associated with outcome. Patients with a lung-only or liver-only initial recurrence had a better survival than the other patterns of recurrence. Patients with resected recurrence had a better median survival compared with patients with unresected recurrent disease. Resection of recurrent disease was associated with a longer disease-free interval (P = .001) from the time of initial hepatic resection and with a lower number of recurrent tumors (P < .001). These survival advantages were evident as measured from the time of hepatic resection and from the time of recurrence.


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  		TABLE 5. Pattern of initial recurrence and its influence on survival measured from time of hepatic resection and from time of recurrence
 
Of the 19 patients who had no evidence of disease at last follow-up, 17 had no recurrence, 1 patient underwent three separate lung resections, and 1 patient had a liver and subsequent adrenal resection performed. There were seven actual 5-year survivors. All of these patients had clear margins, and their first recurrence was resected in six of them. At the time of last follow-up, all 5-year survivors had recurrent disease.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Historically, at many institutions, patients with four or more hepatic metastases were excluded from hepatic resection for metastatic colorectal cancer because of an associated poor prognosis.14,15 However, with safer surgery and better chemotherapy, hepatic resection is playing an increasing role in patients with multiple tumors. Despite an unclear benefit, the safety of hepatic resection, more effective adjuvant chemotherapy, and the lack of other potentially curative options support the concept of an aggressive surgical approach for patients with multiple colo-rectal metastases.

In recent years, an increasing but still small number of patients who have undergone resection for multiple hepatic metastases has been reported.11–13,22–26 The prognostic importance of tumor number and other clinicopathologic factors (such as the size of largest tumor, positive margins, extrahepatic disease, node-positive primary tumor, and preoperative CEA) have been demonstrated in several studies.5–7,11–13,17,22–29 Survival rates in these series demonstrate that long-term survival is possible in patients with multiple tumors. However, most studies report on multiple tumors in the context of an entire cohort of patients undergoing hepatectomy.5–7,11–13,24,26,28 Furthermore, the number of patients with multiple tumors is often small,7,22,23 and few series have specifically addressed long-term outcome and recurrence rates in patients with four or more tumors.17,29 We have previously reported out-comes in patients who have undergone resection of four or more metastases, but this report reflected an era of relatively ineffective chemotherapy. The purpose of this subsequent review was to specifically analyze patients who underwent resection in the era of effective modern chemotherapy.

In the present series, 17% of the total number of patients resected in this 5-year period had four or more tumors, which is similar to our previous report reflecting the fact that our general approach to patients with multiple tumors has not appreciably changed over time.17 In some centers, patients with multiple tumors account for a larger percentage of cases. A recent French study reported that patients with four or more tumors accounted for 32% of all patients undergoing hepatic resection for colorectal metastases.29 Although this may be a reflection of an aggressive approach, it may also be the result of selection bias in a particular referral center.

The low morbidity rate in the present series and the lack of perioperative death further emphasize that safe surgery is possible in patients with extensive disease. The actuarial 5-year survival rate of 33% in this study reinforces the fact that long-term survival is possible in this high-risk group. As demonstrated in other studies, the outcome of these patients becomes less favorable as the number of tumors increases.5,6,11–13,17,22,23,28 This is reflected in our series by the decrease in actuarial survival from 39% in patients with four or five tumors to 19% in those with six or more tumors. Conversely, as the tumor number increased beyond six, there was no significant difference in survival. One other large study by Scheele et al.7 found no difference in outcome as the number of tumors increased; however, this study was limited by a very small number of patients with four or more metastases (32 out of 434 patients).

One important finding of this study was that an involved margin was an independent predictor of poor outcome. The relevance of the margin status on patient outcome has been shown in other series (including our previous series)5–7,17,25,27 and is reconfirmed in the present series. Margin status and extrahepatic resection were the only two factors independently associated with outcome. Involved margins were found in 22% of patients, and this relatively high rate probably reflects the high proportion of patients with between 6 and 20 tumors as well as bilobar disease requiring secondary hepatic procedures and limited wedge resections.30 Of note, all actual 5-year survivors had a clear margin. Whether margin status is a reflection of tumor biology or is truly related to the effect of the operative result is impossible to discern from these data. Nonetheless, it is reasonable to make all attempts to avoid positive margins.

Eighteen patients underwent extrahepatic resection in this series, and most had local invasion into adjacent structures. The importance of extrahepatic resection is emphasized by the fact that it was an independent predictor of outcome. Although outcome was worse in this group, these patients had a median survival of 32 months. Extrahepatic disease should not necessarily be viewed as an absolute contraindication to resection, but rather as potentially reasonable in the setting of limited disease involving one site. A recent publication demonstrated a 5-year survival rate of 28% in patients who underwent partial hepatectomy, with concomitant resection of extrahepatic disease supporting this concept.31 Local invasion of adjacent structures is not a contraindication because it is often not associated with histologic involvement, as was seen in this series.5,17,24

Despite long-term survival in an encouraging percentage of patients, this series clearly demonstrated a very high risk of recurrence after surgery. There were seven actual 5-year survivors, but all of them had recurrent disease. Seventeen patients (17%) have not experienced recurrence, and of these, nearly half have had a follow-up time of less than 2 years. Recurrence occurred relatively shortly after resection, with 89% having their initial recurrence within 2 years of surgery. Longer time interval to recurrence, isolated lung or liver recurrence, and resected recurrence were associated with improved outcome. These findings have implications for both the practitioner and patient in terms of interpreting prognosis at the time of recurrence. Furthermore, an active follow-up regimen is justified because most patients will recur and should undergo resection when feasible.

Although this study did not intend to compare survival rates between eras, 5-year survival has increased when we compare this series (33%) to the prior study (23%) from our institution. The difference in survival statistics is small and should be interpreted with caution because this study did not formally compare the two groups. The major difference over these two time periods has been the development of effective chemotherapy. Although it is impossible to prove in a retrospective setting, improved chemotherapy may play a role in this minor increase in survival. This is also supported by the fact that a similar high rate of recurrence was found. Several trials have shown that novel chemotherapeutic combinations have improved response rates and median survival in patients with advanced disease.8–10 Adjuvant chemotherapy was administered in nearly all of our patients, and 55% received neoadjuvant treatment. Neoadjuvant chemotherapy was associated with a higher percentage of patients with bilobar tumors and synchronous disease, reflecting the tendency to use this modality in patients with poor biologic parameters. Twenty-eight percent of patients who received neoadjuvant chemotherapy progressed, and these patients had significantly worse survival compared with all other groups. A report of 131 patients with multiple tumors who received neoadjuvant chemotherapy showed that 26% progressed while receiving therapy, and that these patients also had markedly worse survival.29 Resection in patients whose disease progresses while they are receiving chemotherapy has appropriately been questioned in this situation.29,32 Progression of disease while receiving chemotherapy is a predictor of a poor outcome after resection and may therefore be useful as a criterion to help select patients for resection. This may be especially applicable to the group of patients with multiple tumors, given their overall worse prognosis and high recurrence rates.

In summary, because of the absence of other alternative therapies associated with long-term survival, the presence of multiple tumors should not be a contraindication to surgery. It is critical that this surgery is practiced with low morbidity and mortality rates. Long-term survival is possible in patients with multiple metastases; however, it is important for the surgeon and patient to understand that the disease of most patients will ultimately recur. These patients will likely receive chemotherapy as an adjuvant and for recurrent disease, and they may be subjected to further resections and/or more chemotherapy. It is therefore important for patients to be counseled regarding the likelihood of multiple treatment regimens and their potential chronicity. Recurrence pattern, time interval to recurrence, and resected recurrence are associated with outcome, and it is important to follow these patients regularly and more frequently in the first 2 years when most recurrences occur. Neoadjuvant chemotherapy may be one way to select patients for resection in this high-risk group because those whose disease progresses have a very poor outcome after resection. Ultimately, only novel combinations of surgery and active chemotherapy regimens will provide the potential for true cure in these patients.

Received for publication June 28, 2006. Accepted for publication June 29, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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B. Nordlinger, E. Van Cutsem, T. Gruenberger, B. Glimelius, G. Poston, P. Rougier, A. Sobrero, M. Ychou, and on behalf of the European Colorectal Metastases Tr
Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel
Ann. Onc., June 1, 2009; 20(6): 985 - 992.
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A. W. Hemming
Heading in the Right Direction: Improved Outcome of Surgery for Advanced Colorectal Liver Metastases
Ann. Surg. Oncol., January 1, 2008; 15(1): 7 - 8.
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