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10.1245/ASO.2005.11.018
Annals of Surgical Oncology 12:778-785 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Changes in Indication and Results After Resection of Hepatic Metastases From Noncolorectal Primary Tumors: A Single-Institutional Review

Süleyman Yedibela, MD, Jonas Gohl, MD, Valentina Graz, MD, Mona Kathrin Pfaffenberger, MD, Susanne Merkel, MD, Werner Hohenberger, MD and Thomas Meyer, PhD

Department of Surgery, University of Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany

Correspondence: Address correspondence and reprint requests to: Süleyman Yedibela, MD; E-mail: suleyman.yedibela{at}chir.med.uni-erlangen.de.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The isolated occurrence of noncolorectal liver metastases is rare. The available data are inconsistent in terms of indication for surgery, treatment, and outcome, so a generally applicable therapeutic algorithm is currently lacking.

Methods: A total of 162 patients underwent resection for noncolorectal liver metastases between 1978 and 2001. The patients were divided into two groups from different time periods (group 1, 1978–1989; group 2, 1990–2001) that were similar in terms of number of patients, operating surgeons, and surgical techniques used. The groups were compared, and the data were retrospectively analyzed with regard to indication, survival, and factors predictive for survival.

Results: Resection was performed to remove liver metastases from noncolorectal gastrointestinal carcinoma (n = 50), neuroendocrine tumors (n = 12), genitourinary primary tumors (n = 11), breast carcinoma (n = 24), leiomyosarcoma (n = 15), and metastases from other primary cancers (n = 50). Extrahepatic tumor involvement was seen in 38 (23%) of the 162 cases. Sixty-two (38%) major hepatectomies and 100 (62%) minor resections were performed. In 100 (62%) of 162 patients, a curative resection (R0) could be achieved. Overall 2-and 5-year survival rates of 49% and 26%, respectively, were observed, and the median survival was 23 months. Survival was significantly longer in patients who underwent an R0 resection.

Conclusions: In selected patients, resection of noncolorectal liver metastases is associated with a 5-year survival rate of up to 50%. Resection of liver metastases from gastrointestinal adenocarcinomas correlates with a poor prognosis. Extrahepatic metastases may be considered a relative contraindication for liver resection.

Key Words: Noncolorectal liver metastases • Resection • Prognosis • Indication


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In contrast to colorectal liver metastases, the isolated occurrence of noncolorectal liver metastases is rare. Most reports are limited to the experience of single institutions, usually with only a few cases.1–8 The interpretation of data from these retrospective studies leaves much room for discussion, and a direct comparison is not readily possible. To date, no prospective studies have been forthcoming. It is, therefore, not surprising that there are no clear guidelines for the indication of surgical treatment in noncolorectal liver metastases. To gain a certain degree of standardization of the indications and operative treatment, it is important that high-volume centers that have the necessary technical facilities and deal with large numbers of patients should report on their experience and, within the framework of multicenter studies, should continue to investigate major aspects of this nonuniform group of patients.

In this study, we report on the results after resection of noncolorectal liver metastases over two decades. To investigate the possible changes in the indication for surgical resection, survival, and prognostic factors, we compared two groups containing similar numbers of patients seen and treated over different periods of time. These periods were selected such that both surgeons and technical expertise could be considered to have remained constant in both groups.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
According to data from the clinical tumor registry of the Department of Surgery, University of Erlangen, 1143 hepatic resections were performed for malignant liver tumors between 1978 and 2001. During this period, 203 hepatic resections were performed for noncolorectal liver metastases in 185 patients. Patients with recurrent liver metastases (n = 23) were excluded, so 162 patients were eligible for this study. The median age of the patients was 60 years (range, 20–84 years). The patient cohort comprised 86 (53%) women and 76 (47%) men. The sites of the primary tumors are listed in Table 1Go.


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  		TABLE 1. Primary tumors of noncolorectal liver metastases
 
The medical records were evaluated retrospectively with the aid of a questionnaire specially designed for liver metastases. The patients were followed up to January 1, 2002, or to the time of their death. Postoperative deaths were not excluded from the survival analyses. Two groups of patients of approximately identical size were compared that covered different time periods according to the overall number of patients (group 1, 1978–1989, n = 75; group 2, 1990–2001, n = 87).

Liver metastases diagnosed together with the primary tumor were defined as synchronous metastatic lesions and were confirmed by histological examination. The time frame to define a liver metastasis as metachronous was at least 2 months after completion of the treatment of the primary tumor.

A curative resection (R0) was defined as a complete removal of any clinically evident tumor lesion(s) in the patient—i.e., complete removal of liver metastases and the primary tumor, as well as extrahepatic lesion(s), if present. An infiltration of the resection margin with tumor cells in the histological specimen was defined as an R1 resection. If macroscopic residual tumor was left in or outside the liver, an R2 resection was stated. RX indicates that the presence of residual tumor cannot be assessed.

Statistical analysis was performed with SPSS 12.0 (SPSS Inc., Chicago, IL). Survival rates were calculated according to the Kaplan-Meier method. Statistical differences were tested for significance with the log-rank test. Frequencies were compared with the {chi}2 test or, when appropriate, with Fisher’s exact test. A P value of .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In 40 (53%) and 31 (36%) patients of groups 1 and 2, respectively, synchronous metastases were present at the primary operation. In 32 (80%) and 24 (77%) patients, respectively, these were removed simultaneously with the primary tumor. Ninety-one patients (56%) developed metachronous metastases (P = .024; Table 2Go). The mean tumor-free interval was 15 months (median, 25 months; range, 2–309 months). The number, localization, and time of appearance of the liver metastases can be seen in Table 2Go.


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  		TABLE 2. Characteristics of noncolorectal liver metastases and surgical aspects
 
The maximum diameter of the liver metastases in group 1 ranged between 10 and 230 mm (mean, 50 mm; median, 45 mm) and was virtually identical in group 2 (range, 2–230 mm; mean, 50 mm; median, 45 mm). In 38 patients (23%), recurrent extrahepatic tumor manifestation was found during preoperative evaluation (group 1, n = 27 [71%]; group 2, n = 11 [29%]; P < .05). In 13 (39%) of 38 patients, a resection of extrahepatic metastases could be performed.

According to preoperative evaluation, complete resection of the tumor(s) seemed technically possible (curative intent) in 59 (79%) patients of group 1 and in 74 (85%) patients of group 2. Sixty-two (38%) major hepatectomies (resection of ≥ 4 segments) and 100 (62%) minor resections (resection of <4 segments) were performed in this series (Table 2Go). The mean duration of the surgical intervention was 266 minutes (median, 235 minutes) and 257 minutes (median, 247 minutes), respectively. The intraoperative blood loss (P = .001) and the number of units of packed red blood cells (PRBCs; P = .001) was significantly lower in group 2 (Table 2Go). In group 1, a mean of 3.9 PRBC units (median, 3 PRBC units) were administered, and in group 2, a mean of 1.6 PRBC units (median, 1 PRBC unit) were administered. The amount of PRBCs transfused significantly correlated with overall survival (Table 3Go).


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  		TABLE 3. Two- and five-year survival rates related to intraoperative blood transfusion
 
In 54 (72%) and 71 (81%) patients in groups 1 and 2, respectively, a complete resection of the metastases at the liver could be performed. In group 1, residual tumor was detected microscopically at the resection margin in 9 (12%) patients, and a macroscopic residual tumor was left behind in 12 (16%) patients. In group 2, the corresponding figures were 4 (5%) and 10 (11%) patients, respectively.

With regard to R classification, a curative resection (R0) was achieved in 37 (49%) group 1 patients and in 63 (72%) group 2 patients. The overall observed survival rates were 49% after 2 years and 26% after 5 years, with a median survival of 23 months. The survival probability after 2 and 5 years was significantly higher in group 2 than in group 1. A breakdown by R classification revealed a significantly better survival after an R0 resection in group 2 patients and for all patients (Table 4Go; Figs. 1Go and 2Go). The observed survival after curative resection in patients with metachronous metastases tended to be more favorable in group 2. In contrast, the number of liver metastases had no effect on survival (Table 5Go).


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  		TABLE 4. Two- and five-year survival related to R classification
 


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  		FIG. 1. Survival after resection of noncolorectal liver metastases in relation to time period.

 


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  		FIG. 2. Survival after resection of noncolorectal liver metastases in relation to R classification. R0, complete removal of metastatic lesion; R1, residual tumor infiltrates resection margin (histologically); R2, residual tumor left in or outside the liver (macroscopically); RX, residual tumor cannot be assessed.

 

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  		TABLE 5. Two- and five-year survival related to time of appearance and number of metastases after curative liver resection (R0)
 
Survival did, however, differ considerably in relation to the primary tumor entity (Table 6Go). Within the different entities, also, the effect of curative resection on survival (5-year survival rate) was mostly significant (Table 6Go).


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  		TABLE 6. Survival in relation to primary tumor, time period, and curative versus noncurative resection of noncolorectal liver metastases
 
Postoperative complications occurred in 24 (32%) patients in group 1 and in 23 (26%) patients in group 2. Complications also included those associated with the primary tumor resection. The overall morbidity rate was 29%, and a revision operation was needed in 19 (25%) and 4 (5%) patients, respectively. Six (8%) patients and one (1%) patient died after surgery. Hepatic failure as the cause of death occurred in two (1%) patients and one (1%) patient, respectively. In four (2%) patients, nonsurgical complications led to death.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Radical hepatic resection is the only potentially curative approach to colorectal liver metastases9,10 and achieves 5-year survival rates of 20% to 45%.9,11,12 After palliative and symptomatic treatment, median survival does not exceed 15 months.13 This is no different from the natural course of colorectal liver metastases, as we have shown previously.13

In contrast to the well-defined guidelines for surgery in liver metastases from colorectal carcinoma, surgical policy for noncolorectal liver metastases is mainly based on institution-related criteria1–8,14–17; evidence is lacking because of a small number of available retrospective studies with limited numbers of patients. Thus, the clinical benefits of surgical resection of hepatic metastases from noncolorectal primary tumors are still not widely accepted. However, nonsurgical therapies do not achieve satisfactory results. Depending on the primary tumor, survival amounts to only a few months.18–20

Numerous prognostic determinants have been reported for metastatic colorectal cancer after hepatic resection.9–12 With regard to noncolorectal liver metastases, the data are contradictory. Common to all reports, however, is the excellent role of curative resection (R0).14–16 In our study patients, too, curative resection was the major prognostic factor. Comparing both groups of different time periods analyzed, it becomes clear that the rate of curative resections increased from 49% to 72%.

The reasons for this favorable development are numerous. As a result of patient selection, from the 1990s onwards, patients with extrahepatic tumor manifestations underwent resection of the liver only in exceptional cases. Both Harrison et al.15 and Lang et al.16 reported that extrahepatic metastases have no significant effect on survival. In our patients, however, the curative resection rate increased by roughly the same percentage as the proportion of patients with extrahepatic metastases decreased; therefore, today, we consider extrahepatic metastases to be a contraindication for liver resection.

Apart from the use of modern techniques for reducing bleeding during parenchymal dissection and managing the resected surfaces, the technical developments and advances in diagnostics are decisive factors for the overall progress in liver surgery. Improved resolution of computed tomography and magnetic resonance imaging equipment enables relatively exact preoperative planning. In patients with metachronous metastases, in particular, this has resulted in an appreciable increase in the percentage of curative resections (25 [71%] of 35 vs. 48 [86%] of 56 patients in groups 1 and 2, respectively). A further major factor for the lower morbidity and mortality and the higher percentage of curative resections in group 2 is the surgical procedure itself. An improved understanding of the segment-oriented resection techniques contributed, among other things, to an appreciable decrease of blood loss and reduced transfusion needs. This has also proved statistically significant in patients with colorectal metastases.9

In light of the fact that a curative resection of synchronous liver metastases together with the primary tumor was achieved in only 10% (4 of 40) and 26% (8 of 31) of cases in groups 1 and 2, respectively, a two-stage approach to surgery after a comprehensive diagnostic work-up is advocated. The observed potential survival advantage of patients with metachronous liver metastases is presumably an effect of selection, because these patients have a "test of time" of their disease. The literature uniformly reports a better survival for metachronous metastases, but in most cases without reaching the level of significance.1,5,8,14 This was also the case in our group 2 patients.

With regard to the number (single vs. multiple), localization (one lobe vs. two lobes), and size of the metastases, no significant differences are reported in the literature.5,8,14 We were also unable to establish any survival advantage for any of the previously described parameters in the individual groups or for all patients.

Several working groups have identified the tumor-free interval as a significant prognostic factor.1,15 This, of course, correlates with the number of metachronous metastases, which reveals a tendency toward longer survival. In our patients, the median tumor-free interval was approximately equal in both groups (23 and 27 months in groups 1 and 2, respectively; Table 4Go) and, thus, showed no correlation with prolonged survival.

The primary tumor itself is of major importance for the outcome. Because, however, patient numbers have been too small, no valid conclusions can be drawn from the results reported (Table 7Go).


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  		TABLE 7. Overview of the literature on surgery for noncolorectal liver metastases
 
It is generally accepted that liver metastases from noncolorectal neuroendocrine tumors (NCNE) are associated with the best long-term survival rates. Thus, this subgroup of patients should be separately analyzed in studies. At an overall percentage of 9%, patients with NCNE in our study represent a very small subgroup. A closer inspection of the sometimes surprisingly good overall 5-year survival rates reported by some working groups reveals a particularly high percentage of patients with NCNE.1,2,14 Individual authors have also reported a good outcome after resection of liver metastases from gastrointestinal adenocarcinomas.7,21,22 This is not confirmed by our own data, and in most studies, the overall prognosis for this group of patients is poor.14,17 In contrast, patients with mammary carcinoma metastases do seem to benefit from liver resection. The 2- and 5-year survival rates of 58% and 43%, respectively, with a mean survival of 33 months, largely correspond to the results after resection of colorectal liver metastases.

In summary, patients with noncolorectal liver metastases may benefit from resection, provided that a curative resection is achieved. If metastases from neuroendocrine tumors are excluded, 5-year survival rates could be as high as 50%, with a median survival of up to 62 months. Curative resection is particularly beneficial in liver metastases from mammary carcinoma, leiomyosarcoma, and renal carcinoma metastases, even over the long-term, whereas the indication for resection in hepatic metastases from gastrointestinal adenocarcinoma (other than colorectal carcinoma) should be applied more restrictively on account of the poor outcome.

In the presence of extrahepatic metastases, the decision for surgery should be based on the individual case. Wherever possible, synchronous liver metastases should be resected in a two-stage operation after a comprehensive diagnostic work-up. From a technical point of view, a segment-oriented anatomical resection minimizes bleeding and postoperative morbidity and mortality. Therefore, these patients should be treated in specialized referral centers.

For treatment of noncolorectal liver metastases, proper patient selection is essential. Thereby, exclusion of additional secondary tumors and locoregional recurrence is of particular importance. Data of the published literature and this study conclude that the shorter the interval to primary treatment, the more carefully the staging should be performed.

Because no single institution will be able to treat a sufficiently large number of patients with varying primary tumor entities, the data should be pooled and prospectively collected in a multicenter network, with the aim of obtaining valid results to establish a generally acceptable therapeutic algorithm.

Received for publication November 15, 2004. Accepted for publication May 4, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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