Tumor recurrence after resection of liver metastases

Recurrence occurs in 48 to 78% of patients, the common sites being liver (30–70%), lungs (20%), peritoneal cavity (10–20%), and brain (<10%). Liver-only recurrence is detected in 20–31% (7). Factors predicting early recurrence after liver resection include advanced stage of the primary tumor and bilobar involvement. Genuinely R0-resected metastases recur only rarely. Local recurrence is seen more often if the disease-free resection margin is less than 1 cm. In this case we are dealing with a local, persistent tumor. Most often, recurrence represents a re-manifestation of the systemically spreading disease. It may be due to the presence of micrometastases which have not been identified. Metastases of a locally-recurrent tumor after surgery of the primary colorectal carcinoma are another possible source of new liver localy infiltration.

Interval between the resection of the primary tumor and liver metastases surgery

Isolated, distant metastases are found in 11–30% of patients after resection of the primary tumor. The interval between primary tumor surgery in the large intestine and diagnosis of liver metastases in patients in whom liver resection is feasible is about 12–18 months. However, 69% of liver metastases are diagnosed either during or shortly after surgery of the primary tumor (2–4 months). Predictors of early recurrence after liver resection include advanced stage of the primary tumor, bilobar involvement of the liver, and positive resection margins.

Interval between liver resection and recurrent liver metastases

Resected liver metastases recur in 60–80% of patients, depending on the subsequent observation period. In our patients the recurrence rate was 42% after one year, 64% after two years and 83% after five years (Kaplan-Meier analysis). The median recurrence-free interval after the first hepatic resection was between nine and 21 months. In our own series the recurrence-free time was 14 months. More sensitive ultrasound, CT or MRI and better aftercare may shorten this time. The impact of the disease-free interval after the operation of the primary tumor on the disease-free interval after liver resection remains controversial. The interval between first and second hepatic resection varies between 0 and 88 months. The mean interval can vary between 9 and 33 months.

Tumor spread at the time of liver metastases recurrence

Whereas a potentially curative re-resection is possible in up to 25% of patients with liver metastases from colorectal carcinoma, this percentage is reduced if there are too many recurrences, local infiltration, and/or extrahepatic manifestations. In our group of 198 patients with colorectal carcinoma who had had primary curative resection of liver metastases, a second liver resection could be successfully performed in 12%.

Factors influencing the rate of recurrence

Prognostic criteria for early recurrence are: more than four metastases, bilateral involvement, and metastatic spread over more than 50% of the liver. As yet, there is no connection made between the pattern of disease (localization, number and size of metastases) of the first and second recurrence (8).

Perioperative effects on recurrence rates

According to one study adjuvant chemotherapy significantly delayed metastatic recurrence, but did not significantly improve the overall survival rates. We await the results of ongoing studies on adjuvant chemo- and immunotherapy. Early results of liver resection after neoadjuvant chemotherapy for otherwise not resectable liver metastases are promising (9).

Recurrence after repeat hepatic resection

Recurrence rate after repeat hepatic resection was shown to be up to 60%. Of these 47% had recurrence in the liver, 20% in the lung, 10% local, 5% in lymph nodes and bone, and 8% were located elsewhere. The re-resectability rate after the second hepatic resection is not known. The interval between second and third liver resection is reported to vary between three and 32 months, with the respective median values of 13 to 15 months. The surgical procedures ranged from minor wedge resection to major anatomic resection. Although morbidity and mortality are acceptable, definite cure does not seem likely. In these patients twoyear survival appears to reach only 16%. Still larger numbers of patients are needed.

Hepatic recurrence in patients with non-colorectal primary tumors

Patients with untreated metastases of neuroendocrine malignancies have a relatively good prognosis. In cases of untreated liver metastases the five-year survival reaches 30–40%, with median survival of 3–4 years. Therapy is aimed at relieving the symptoms of hormonal activity which can be achieved in 90% of patients receiving a liver resection.

Reports on repeated resection of liver metastases from non-colorectal, non-endocrine primary tumors are anecdotal. In most of these patients outcome is poor. As long as there are no more data available these patients should only be treated in specialized centers (10).

Surgical technique

Preoperative localization and intraoperative palpation as well as intraoperative ultrasound examination determine the surgical technique. A margin of at least 1 cm is mandatory for achieving a R0-resection. Typically, anatomical resections are preferred in the second liver operation (in our patient group 55% vs. 40% at first resection). The proportion of patients who had smaller resections at first operation is higher at second resection. Thus resectability of recurrent liver metastases seems to be better when the primary resection was limited. Second liver resection involves hemihepatectomy in 40–50% of patients (16).

Morbidity and mortality

The morbidity varies between 19 and 52% (in our patient group 37%). Serious complications occur only rarely. With regard to the functional liver reserve, the general guidelines for liver resection apply. In most cases, more than 50% of residual liver tissue will suffice. Here, the second resection depends on the extent of primary liver resection. Temporary clinical manifestations of hepatic insufficiency are seen in 0–7% of patients. The similarity of the risk profile in the patient groups is demonstrated by the almost identical morbidity after primary or second resection. The morbidity is between 0 and 3% (no deaths in our patient group).

Long-term survival after repeat resection of liver metastases

The recurrence-free interval after primary and secondary hepatic resection is surprisingly similar, with a median of 12–14 months. Even those patients who do not fulfil the criteria for repeat resection show almost the same median recurrence-free period. The better survival suggested in the selected group is confirmed by the actual survival times. After the last liver resection the median survival is 25–32 months median in both groups (figure 1). The five-year survival rates are 20–25% (in our patient group median 32 months and 24% five-year survival). This rate is much higher than that seen in a spontaneous course of disease, with a five-year survival below 1%. Even after systemic or locoregional chemotherapy survival times of maximum 14 months median and twoyear survival rates of 1–32% are seen. A review of the literature on the outcome of repeat hepatic resection of liver metastases is given in table I.

Figure 1

Typical disease course after liver resection from the time of the primary tumor operation to, death is shown on a time scale. The time of liver resection (LR) is marked. Arrows demonstrate the median survival times. A) Patients who only had one liver (more...)

Table I

Literature review on repeat hepatic resection for colorectal cancer.

Prognostic criteria after first and second liver metastases resection

The prognostic criteria for the first resection of liver metastases have been analyzed extensively, though not necessarily without contradiction. R0-resection with an adequate safety margin represents the most important prognostic factor. The pattern of spread or size and number of metastases, the primary tumor stage, extrahepatic metastases, and lymph node involvement in the mesenterium, increased CEA levels, and patient age have been named as prognostic factors for the first resection. This suggests that in selected cases survival rates of 60% after five years are possible. Patients with lymph node involvement and extrahepatic metastases have the worst prognosis (80% after one year, 12% after three years and 0 after five years) (26). To date the size of the patient group with repeat resection does not permit such analysis. The similar biological behavior after both first and repeat resection indicates that the prognostic factors are the same. To date R0 liver resection and absence of involvement of contiguous structures of the primary tumor are prognostic factors for survival.

Conclusion

Repeat resection of liver metastases from colorectal carcinoma can be performed with acceptable morbidity and low mortality if typical indication criteria are followed. The survival data show an improved survival, in comparison to the historical course and patient groups receiving systemic or local chemotherapy,.

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