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10.1245/s10434-006-9105-x
Annals of Surgical Oncology 13:1493-1499 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Hepatic Resection for Colorectal Metastasis: Impact of Tumour Size

Zaed Z. R. Hamady, MRCS, Hassan Z. Malik, MD, FRCS, Robert Finch, FRACS, Robert Adair, MBChB, Ahmad Al-Mukhtar, FRCS, K. Rajendra Prasad, FRCS, Giles J. Toogood, DM, FRCS and J. Peter A. Lodge, MD, FRCS

HPB and Transplant Unit, St. James’s University Hospital, Leeds, LS9 7TF, UK

Correspondence: Address correspondence and reprint requests to: J. Peter A. Lodge, MD, FRCS; E-mail: Peter.Lodge{at}leedsth.nhs.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Many colorectal liver metastasis patients are denied surgical resection on the basis of tumour size. The aim of this study was to explore the impact of metastasis size on modern liver resection.

Methods: Using a prospectively collected database, this was a retrospective analysis of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into two groups: smaller metastases (<8 cm) and larger metastases (≥ 8 cm). Those with larger metastases were then further stratified into big metastases (8–12 cm) and giant metastases (>12 cm). Demographic, pathological, surgical technique and outcome data were compared between the groups.

Results: There were 88 (18%) patients with metastases measuring 8 cm or larger. There was an association between higher carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels and larger metastases. The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for smaller metastases (not statistically significant). Patients with giant metastases had poorer overall and disease-free survival (both nonsignificant) compared with those with big metastases: 29% and 28% at 5 years, respectively.

Conclusion: Patients with colorectal liver metastasis greater than 8 cm and up to 12 cm in size should not be treated differently from those with smaller lesions.

Key Words: Colorcetal liver metastases • Liver neoplasm • Liver resection • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer remains the second most common cause of cancer death in the Western world: liver metastases occur in about 50% of colorectal cancer patients. Synchronous lesions are detected in 15–25%, and the remaining metastases are detected within 3 years of potentially curative colorectal resection.1,2 Following diagnosis, the median survival for patients with colorectal liver metastases (CRLM) is less than 9 months in most series for untreated patients and only 12–18 months for patients treated with chemotherapy alone.3–5 Liver resection remains the gold-standard curative treatment for CRLM, with a reported median survival time of 35–69 months.1

Selection of patients for surgery in most centres is based around an established set of criteria, some aspects of which have changed little from the contraindications to surgery laid down by Ekberg et al. in the mid-1980s.6 Many series report that patients with more than four metastases, metastasis diameter ≥ 5 cm and bilobar metastases have a higher incidence of recurrence and lower survival.7–10 This data seems compelling, and the "5-cm maximum metastases diameter" has become accepted in many centres as a necessary factor in potentially curative hepatic resection for metastatic disease. Yet, some data is emerging that smaller metastasis size is not essential for curative hepatic resection as long as margin clearance is achieved.11–13 The aim of the current study was to explore in depth the impact of large metastasis size on surgical techniques as well as outcome following resection for CRLM.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This report details a retrospective longitudinal study of 484 consecutive patients who underwent hepatectomy for metastatic colorectal carcinoma between January 1993 and December 2003. Data was obtained from a prospectively collected database and confirmed by medical records and patient reviews. Criteria for acceptance for surgery included fitness for major surgery and lack of disseminated or unresectable extrahepatic disease identified by computed tomography (CT) and magnetic resonance imaging (MRI). Patients deemed initially unresectable were offered neoadjuvant chemotherapy, with 5-fluorouracil and folinic acid (5-FU/FA) and, more recently, oxaliplatin, and then restaged at 3-monthly intervals to assess resectability. All patients, according to our unit protocol, were offered postoperative adjuvant chemotherapy with 5-FU/FA unless they had undergone chemotherapy adjuvant to bowel resection within the previous 12 months. Resection was performed using the Cavi-Pulse Ultrasonic Surgical Aspirator (CUSA, Model 200T, Valley Lab., CO, USA). If necessary, an intermittent Pringle manoeuvre was used with 15 min of ischaemia, followed by 5-min of reperfusion.

An intensive policy of postoperative surveillance exists within this unit. Patients had 3-monthly chest and abdominal CT performed during the first postoperative year, then 6 monthly during year 2. From years 3–5, a CT scan is performed yearly and then at years 7 and 10 of follow-up. Tumour markers [carcinoembryonic antigen (CEA) and cancer antigen (CA) 19–9] and liver function tests were performed during each clinic visit. Patients with localised liver recurrence, without unresectable extrahepatic disease (as defined by CT and MRI) and fit for further surgery were considered for repeat hepatectomy. In all recurrence cases, chemotherapy was offered as well.

Data examined included patient demographics, liver resection histology, prehepatectomy CEA and CA19-9 tumour marker studies, postoperative morbidity/mortality and recurrence and survival rates. Patients with larger metastases defined as ≥ 8 cm were analysed separately. Those with larger metastases were then further stratified into those with big (8–12 cm) and giant (> 12 cm) metastases. Survival and recurrence patterns were compared between the groups. These cut-off values were based on observational data.

Statistics
An SPSS (version 9) statistical programme was used to analyse the data. The chi-squared test with continuity correction was used to compare between proportions. Where variables did not follow a standard distribution, the Mann–Whitney U test was applied to compare between continuous data. Results were considered significant when two-tailed P value was < .05. Cumulative survival rates were calculated with the Kaplan–Meier method. The log rank test was used for comparison of survival between groups. A Cox regression analysis was then performed in a step-wise manner in order to perform a multivariate analysis of clinicopathological factors that impact both overall and disease-free survival. The following factors were input into the regression model: CEA level, CA 19-9, timing of liver metastases, primary tumour lymph node involvement, size of liver lesions, number of liver lesions and liver resection margin involvement.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics and Tumour Characteristics
Mean age at time of surgery was 62 (range 23–84) years. There were 303 (62%) men. A total of 225 (46%) patients had synchronous disease. The size of individual largest metastatic deposits ranged from .3 cm to 20 cm [median 4, interquartile range (IQR) 2.5–6.5 cm]. There were 88 (18%) patients with metastases measuring 8 cm in diameter or more. Differences in clinicopathological features between patients with larger (≥ 8 cm) and smaller (< 8 cm) metastases are presented in Table 1Go. Of note was the association between higher CEA and CA 19-9 levels and large metastases (P = .001). Resection margin involvement (R1 resection) was seen more frequently in the larger metastases group, but the difference was not significant; P = .077.


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  		TABLE 1. Clinicopathological differences among patients with small and large liver metastases from colorectal cancer
 
Surgical Technique, Morbidity and Mortality
A variety of surgical procedures were employed to deal with the 88 patients with larger metastatic deposits (Table 2Go). A total of 76 (86%) patients underwent a "major" liver resection performed (three or more Couinaud segments resected). The most frequent procedure performed was a right trisectionectomy (resection of hepatic segments 4, 5, 6, 7, 8 ± 1): half of the patients with large metastases compared with only 20% of patients with smaller metastases. There was an increased use of the intermittent Pringle manoeuvre among patients undergoing resection for larger metastases: 56% versus 46%. However, this difference was not statistically significant; P = .125. The median duration of total time for the Pringle manoeuvre in small metastases was 20 min (IQR 14–32) compared with 37 min (IQR 20–50) with large metastases: this difference was statistically significant: P = .001. Total vascular exclusion was used more frequently in patients with larger metastases: 15% compared with 2% of those with smaller metastases; P < .001. This difference was almost limited to patients with giant metastases (> 12 cm), as total vascular exclusion was used more frequently in patients in this group than in those with big (8–12 cm) metastases (31% vs 2%; P < .001). Concomitant inferior vena cava (IVC) resection was performed in four patients (one with large metastases and three with giant metastases), and two of them needed ex vivo resection technique. Those patients have been previously reported.14


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  		TABLE 2. Types of liver resections performed for large and small liver metastases from colorectal cancer
 
Among patients with large metastases, the median postoperative hospital stay was 11 (range 3–62) days compared with a median of 8 days for patients with small metastases group (P = .372). There were no inhospital postoperative deaths compared with 3% for patients with smaller metastases. Postoperative morbidity rate was 33% compared with 25% for patients with smaller metastases (P = .139). A list of postoperative complications is illustrated in Table 3Go. The rate of transient hepatic failure, postoperative haemorrhage and bile leak was not increased by resecting large metastases.


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  		TABLE 3. Post operative complications encountered after liver resection for large and small colorectal liver metastases (CRLM)
 
Outcome
The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for patients with smaller metastases (Fig. 1Go). This difference was not statistically significant (log rank = 2.06; P = .303). Furthermore, there was no association between larger metastases and poorer disease-free survival (30% vs 34% at 5 year) (log-rank test .2; P = .655) (Fig. 2Go). After adjustment for other parameters by stepwise entry method, metastases size did not influence overall or disease-free survival [hazard ratio (HR) = 1.1, 95% confidence interval (CI) .7–1.7, P = .565; HR = .9, 95% CI .6–1.4, P = .949, respectively). When comparing big (8–12 cm) to giant (> 12 cm) metastases, we found a trend towards poorer overall survival with giant metastases: 29% at 5 years compared with 46%, respectively; however, this did not reach significance (log rank = 3.08; P = .079) (Fig. 3Go). Similarly, 5-year disease-free survival was poorer for the giant compared with the big metastases group: 28% vs 31%, respectively (log rank = .54, P = .461).


Figure 1
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  		FIG. 1. Overall survival comparing large (≥ 8 cm) and smaller (< 8 cm) metastases. Thin line: small metastases, median survival 45 months. Bold line: large metastases, median survival 35 months. Log rank 2.06; P = .303.

 

Figure 2
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  		FIG. 2. Recurrence rate comparing large (≥ 8 cm) and smaller (< 8 cm) metastases. Thin line: small metastases, median disease-free survival 22 months. Bold line: large metastases, median disease-free survival 21 months. Log rank .2; P = .655

 

Figure 3
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  		FIG. 3. Overall survival comparing big (8- to 12-cm) and giant (≥ 12-cm) metastases Thin line: large metastases, median survival 54 months. Bold line: giant metastases, median survival 27 months. Log rank 3.08; P = .079

 
In order to analyse the impact of clinicopathological factors on outcome among patients with large metastases (≥ 8 cm), a Cox regression multivariate analysis was undertaken. Primary colorectal tumour lymph node metastasis was the only predictor for poorer overall survival; P = .004 (HR 2.7; 95% CI 1.4–5.4). The presence of a hepatic positive resection margin was a predictor for poorer disease-free survival; P = .035 (HR 1.8; 95% CI 1.04–3.13).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We assessed the outcome following resection of CRLM in a consecutive series of 484 patients, with special reference to patients with larger metastases (≥ 8 cm). Of note was the association between higher CEA and CA 19-9 levels and larger metastases. Resection margin involvement was seen more frequently in larger metastases; however, this difference was not significant. The survival rate in our study was comparable with the most recent reports,10,15 despite the late stage of disease within our cohort. This may reflect the aggressive surgical approach used in our unit: reresection is employed routinely whenever possible for recurrent metastases (Fig. 4Go). Major hepatic resection was performed in 86% of the cohort with no operative mortality.


Figure 4
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  		FIG. 4. Magnetic resonance imaging (MRI) scan of a 57-year-old male patient who presented with metachronous colorectal liver metastasis (18 cm in diameter). A Coronal oblique section: note the impingement of the metastasis on portal triad structures. B Cross-section: note obliteration of the right and middle hepatic veins and involvement of the left hepatic vein and inferior vena cava (IVC). He had an extended right hepatic trisectionectomy (resection of segments 3, 4, 5, 6, 7, 8, with parts of 2 and 3) with clear margins (R0) and subsequently had repeated resection for multiple (x3) hepatic recurrences at 1 year postresection. He is still alive 6 years following his initial surgery. Patients with giant tumours such as this should be offered the benefit of curative surgical therapy.

 
In this study we examined for the first time the impact on outcome of CRLM larger than 8 cm. Larger metastasis size was found not to be a predictor of overall or disease-free survival using univariate and multivariate analysis. Giant metastases (> 12 cm), however, were found to have a trend towards poorer outcome. This trend may become significant if a larger cohort of giant metastases is analysed.

Our aim was to critically appraise the real impact of liver metastasis size and define its relevance to modern CRLM surgery. Further analysis was performed on patients with larger metastases (≥ 8 cm). The only independent predictor of survival was metastatic disease within the lymph nodes at the time of primary colorectal tumour resection. Our study also revealed that in patients with larger metastases (≥ 8 cm), liver resection margin involvement was an independent predictor of poorer disease-free survival. This confirms the findings of many previous studies that have indicated that a positive hepatic resection margin is a poor prognostic indicator after resection of CRLM.16–18

Metastasis size has been considered an adverse factor in prognosis after surgery. Some reports have advocated surgical resection only for metastases less than 5 cm in size. This was due to the potential for breach of the 1-cm resection margin rule proposed previously.9,19 In a recent study, metastasis size was an independent predictor of overall and disease-free survival after curative (R0) resection.15 Fong et al. suggested that lesions larger than 5 cm have a worse outcome and included metastases size as one point in their clinical risk score.10 Other authors have considered a 4-cm maximum metastasis diameter as the cut-off for their patient selection.20 Contradictory reports give less importance to metastases size compared with multiplicity of metastases and suggest that size dose not greatly influence survival.18,21,22 In our previous experience, patients with lesions greater than 5 cm in diameter had life expectancy and recurrence rates similar to those with lesions less than 5 cm.23

In this study, a higher proportion of patients with larger metastases required total vascular exclusion to enable resection in a bloodless field. However, complication rate and in-hospital mortality was not increased as a result of this surgical approach. Apart from four patients who required ex vivo resection, all patients with larger metastases were amenable to resection using standard resection techniques.

In summary, although large colorectal metastases pose a surgical challenge, in our experience, they can usually be resected using conventional techniques utilised for smaller lesions. Furthermore, larger metastases are not associated with poorer overall survival, and metastasis size in and of itself should no longer be considered a major contraindication to surgical resection.

Received for publication May 31, 2006. Accepted for publication May 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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