Although the prognosis of metastatic colorectal cancer is poor with few patients surviving for 5 years or more (Stangl et al, 1994
) long-term survival has been reported following surgical resection of isolated hepatic metastases (Fong and Salo, 1999
; Geoghegan and Scheele, 1999
). The nature of the published studies of surgical resection for colorectal liver metastases did not allow for a quantitative analysis to be performed and we have thus undertaken a qualitative systematic review to summarize the available evidence for the effectiveness of this intervention.
Surgical resection of hepatic metastases from colorectal cancer can be undertaken safely in the majority of patients. The median postoperative (30 day) mortality reported by 24 studies was only 2.8% (0–6.6%). There was patchy reporting of the causes of postoperative death, with the most frequent causes being hepatic failure, postoperative haemorrhage, and sepsis. It is likely that current surgical and anaesthetic practice is associated with perioperative mortalities nearer to 1% as demonstrated in a recent multicentre trial (Nordlinger et al, 2005
). Operative morbidity was more difficult to quantify as many studies reported only fatal morbidity or a very limited range of postoperative complications. It was therefore difficult to determine the proportion of patients experiencing operative morbidity and thus its overall impact on patients in the majority of studies. Some studies presented information on outcomes that may be surrogate markers for operative morbidity. Two studies reported information on the duration of stay in intensive care following surgery, the median time in one study was 1 day, while the mean from the two studies was 3 days. These limited results suggest that most patients require only a short period of intensive care following hepatic resection for colorectal metastases. The median or mean length of hospital stay reported by 17 studies ranged from 7–21 days indicating that while most patients made a rapid recovery following surgery, some experienced a more prolonged hospital stay possibly as a result of complications from their surgery. None of the studies included in this review presented information on recovery of patients' functional status or quality of life following discharge from hospital.
Two studies presented outcome data for all patients with isolated colorectal hepatic metastases who underwent surgery, resection and laparotomy only, with 15 and 31% of patients surviving 5 years, respectively (Fuhrman et al, 1995
; Harms et al, 1999
). Studies including only patients who underwent resection reported a survival of around 30% at 5 years for patients undergoing potentially ‘curative' resection of isolated hepatic metastases and the majority are disease free at this time. The survival of patients undergoing R0 resections were substantially better (32% at 5 years) than for patients undergoing R1 resections (7.2% at 5 years) and those who did not undergo resection (0% at 5 years).
Patients undergoing surgery may have a better prognosis than other patients with metastatic colorectal cancer as their disease is both confined to the liver and circumscribed within it. The patients are also more likely to be of good performance status and have little or no comorbidity. Identifying a comparable control group in the absence of randomised trials is difficult. Goldberg et al (1998
) identified 548 patients with recurrent colorectal cancer in a longitudinal study, of whom 222 (41%) were thought to be suitable for ‘curative intent' surgery. Potentially curative surgery was performed in 109 (20%) and of these 28 (5%) were performed for isolated liver metastases. The estimated recurrence-free survival of patients following liver resection was 32% at 5 years, similar to survival after lung resection and complete resection of local recurrence. The 5-year survival after curative surgery at other sites and multiple sites appeared worse (16 and 0%, respectively). Although not stated, the survival of the patients not treated surgically or who had palliative surgery was by implication poor, but two out of 19 patients with circumscribed disease liver or lung disease treated nonsurgically were alive at final follow-up. A small number of retrospective studies have attempted to determine the natural history of patients with isolated liver metastases. In a review of 484 untreated patients with liver metastases from colorectal cancer, those with the best prognosis (
25% liver involvement, primary tumour grade 1/2, no extra hepatic tumour and no mesenteric nodal involvement), had a median survival of 21.3 months, compared with 30 months in patients undergoing hepatic resection in the same institution (Stangl et al, 1994
). In a group of 125 patients with liver-only metastases, most of whom had had no therapy, the median survival was 12.5 months. All patients died within 5 years. Survival correlated with the extent of liver disease. The presence of three or fewer liver metastases was associated with a median survival of 24 months (Goslin et al, 1982
). Lahr et al (1983)
studied 175 untreated patients with liver metastases from colorectal cancer. The median survival of these patients was 6.1 months and the longest survivor lived for 67 months. Patients with 1–4 liver metastases lived longer than those with five or more metastases (median survival 11.8 vs
4 months) (Lahr et al, 1983
). A study of 113 patients with hepatic metastases from colon cancer, reported a mean survival of 3 months in patients with widespread liver disease (Wood et al, 1976
). Patients with metastases localised to a segment or lobe had a mean survival of 17 months, compared with 25 months for patients with a solitary liver metastases. The overall 1-year survival rates were 6, 27, and 60%, respectively. Another study attempted to distinguish potentially resectable from unresectable disease (Wagner et al, 1984
). Three groups of untreated patients were studied. Patients with solitary (n
=39), multiple unilateral (n
=31) and widespread (n
=182) had 3-year survivals of 21, 6 and 4%, respectively. However by 5 years virtually all were dead (3, 0 and 2% survival, respectively). Some small studies have examined the outcome of patients with unresected synchronous hepatic metastases (Bengtsson et al, 1981
; Boey et al, 1981
; Finan et al, 1985
; Gorog et al, 1997
). The median survival of patients in these series ranged from 4.5 to 10.3 months. These studies suggest that there is a small select group of patients with isolated liver metastases from colorectal cancer who may live a long time without surgical intervention. However, their prognosis remains poor because of the inexorable hepatic progression and extrahepatic spread.
Disease recurrence is common after resection of colorectal hepatic metastases indicating that in the majority of cases the extent of the metastatic disease is underestimated by pre and intraoperative staging investigations. Around one-third of patients experienced disease recurrence in the liver alone and may be candidates for repeat resection. The remainder experienced recurrence concurrently in the liver and extrahepatic sites or in extrahepatic sites only. It may be that biological features in the tumour itself may be important as optimal imaging and this requires further study.
Identification of prognostic factors that predict the outcome following surgical resection of colorectal hepatic metastases would assist in the identification of those patients most likely to benefit from this intervention, or more importantly assist in the identification of patients who were unlikely to benefit. Comparison of the different studies included in this review was hampered by differing definitions of the prognostic factors considered for univariate or multivariate analyses. However, some potential prognostic factors were found to be significant in more than half of the studies. We are currently attempting to evaluate these potential prognostic factors using a large prospectively collected data set contributed by multiple centres. This will be published in due course.
This review was performed deliberately on series published up to the millennium as in recent years major changes have occurred in the management of colorectal liver metastases. These factors will almost certainly impact increasingly on the reported outcomes after 2000 (Poston et al, 2005
). Firstly modern chemotherapy using cytotoxic agents alone offers extension of median survival to 2 years in patients with nonresectable disease (Cals et al, 2004
; Goldberg et al, 2004
; Grothey et al, 2004
; Tournigand et al, 2004
). When monoclonal biological agents are added to cytotoxic chemotherapy, the prospect of median survival now extends beyond 2 years, and 20% of patients will still be alive 4 years after detection of unresectable liver disease (Cunningham et al, 2004
; Hurwitz et al, 2004
; Saltz et al, 2004
). It is therefore inevitable that the combination of surgical resection and chemotherapy, which is becoming commonplace, will impact on the survival in the surgical series. The EORTC EPOC trial which is the first to randomise liver resection patients to receive additional, modern, chemotherapy is due for reporting in 2007 (Nordlinger et al, 2005
). Secondly, novel surgical strategies such as preoperative portal vein embolisation to increase residual acceptably safe volume, or two-stage hepatectomy to allow compensatory hepatic hyperplasia before completion of R0 resection (Abdalla et al, 2002
; Pawlik et al, 2005
; Poston et al, 2005
), have also widened the number of resectable patients including those with extensive liver-only disease. These changes in the definition of resectability means that >20% of patients with liver metastases can now be considered for surgery with curative intent at the outset. It is unclear what the long-term outcome of these strategies will be but the results appear encouraging (Abdalla et al, 2002
; Pawlik et al, 2005
; Poston et al, 2005
). This present review should both set the standard for the reporting of subsequent surgical series and provide baseline results to which they may be compared.
In summary there is a substantial body of evidence from prospective and retrospective case series summarised in this review demonstrating that resection of colorectal hepatic metastases can be performed safely with a low mortality rate and around one-third of patients will survive for 5 years or more. These outcomes in highly selected patients exceed those normally associated with metastatic colorectal cancer. Randomised trials comparing surgical resection with nonsurgical treatment are not now possible. Further information must come from well-documented prospective studies examining consecutive series of patients with colorectal cancer and randomised trials comparing liver resection alone with liver resection plus additional chemotherapy.