© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60095-8

 

 

Contributors: LAJ proposed the study. YXY and LAJ performed research and wrote the first draft. YXY collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LAJ is the guarantor.

Funding: This study is supported by a grant from the Chinese Key Project for Infectious Diseases (2008ZX10002-025).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

 

 

 

 

(Hepatobiliary Pancreat Dis Int 2013;12:602-606)

 

KEY WORDS: liver metastasis; uveal melanoma; therapy

Uveal melanoma is the most common primary intraocular malignancy in Caucasians. About 70%-80% of tumors will eventually metastasize to the liver.^{[1, 2]} Once liver metastasis occurs, the prognosis is extremely poor and the median survival is only about 4.4 months.^[3] Any treatment that controls a metastatic hepatic lesion potentially prolongs the survival. Treatment options include surgery, local ablative therapy, chemotherapy, immuno-chemotherapy, isolated hepatic perfusion therapy, transarterial chemotherapy (TAC) and transarterial chemoembolization (TACE). Unlike the Western world, uveal melanoma with liver metastasis is an extremely rare event in the Chinese population. Reports from the Western hemisphere revealed that hepatectomy may prolong the survival of patients with liver metastases,^{[4, 5]} but to our knowledge there was no similar documentation in China. The current study reported our single institutional experience in the management of metastatic uveal melanoma to the liver.

 

 

From January 1996 to September 2008, ten patients with liver melanoma were admitted to our hospital. In these patients, 3 were diagnosed by fine-needle aspiration biopsy and 7 were diagnosed pathologically during the operation. The tumor was of unknown origin at the time of presentation in 2 patients, but liver metastasis with diagnosed uveal melanoma in the remaining 8 patients. The protocol of treatment was decided together by the patient and the treatment team including surgeons, hepatologists and oncologists after discussion. Partial hepatectomy was performed for the patients with resectable lesions. Tumor resection (R0: negative microscopic margins, R1: positive microscopic margin, or R2: gross residual disease) was documented. For the number or location of the tumor, these patients underwent other therapies (TACE, RFA, PEI). Demographics, treatment procedures, postoperative course, and disease progression were collected retrospectively from our liver surgery database and analyzed. Primary outcome measures included the overall survival of the patients. Secondary outcome measures included procedure-related complications and hospital mortality. The patients were followed up by means of abdominal ultrasonography or contrast-enhanced CT of the abdomen, liver function test every 2 months for the first 3 years, and then the follow-up interval was gradually increased.

 

For the patients who didn't receive partial hepatec-tomy, the criteria for response evaluation criteria in solid tumors (RECIST) were used to determine tumor response on contrast-enhanced CT every 1-2 months during TACE: complete response or disappearance of all target lesions; partial response or more than 30% decrease in the sum of the longest diameter of target lesions; stable disease or small changes that did not meet the above criteria; progressive disease or 20% increase or more in the sum of the longest diameter of target lesions.^[6]

 

Patient survival was calculated from the day of initial treatment to the date of last follow-up or death. Disease-free survival was calculated from the time of hepatectomy to the day of relapse. Overall survival was calculated from the time of diagnosis of liver metastases until the last follow-up or death. Overall survival with standard error was calculated by the Kaplan-Meier method and compared using the log-rank test. A P value <0.05 was considered statistically significant.

 

 

In the 8 patients, 3 were male and 5 female; their median age was 44 years (range 31-60). Five of the 8 patients underwent partial hepatectomy, 3 were subjected to non-surgical treatment. Six patients were dead at the date of analysis. Their median survival time from liver metastasis to death was 9 months (range 3.5-31). The largest diameter of the metastatic lesion was 8.1 cm (median 5.45 cm, range 3.3-8.1). One patient had 6 hepatic metastatic lesions, another one had 4, but the remaining 6 had 1 or 2 or 3 lesions. The median number of metastatic lesions was 2.5 (range 1-6). Primary tumor was found in the right eye in 4 patients and in the left eye in 4. Six patients showed metastatic lesions when primary tumors were diagnosed. The interval from diagnosis of uveal melanoma to liver metastasis in the remaining two patients was 9.5 and 32.5 months, respectively.

 

In 5 patients who underwent surgical resection, 2 were subjected to postoperative intra-arterial chemo-therapy with lipiodol, cisplatin and 5-fluorocuracil. One patient also received adjuvant immunotherapy. In the 5 patients, 2 who had had R0 resection underwent left lateral sectionectomy and right posterior sectionectomy, respectively; 2 who had had R2 resection underwent left hemihepatectomy and right posterior sectionectomy; and 1 who had received left hemihepatectomy underwent R1 hepatectomy. These patients were confirmed patholo-gically during the operation (Tables 1 and 2).

 

The remaining 3 patients did not receive any surgical exploration. One of these patients received one course of intra-arterial chemotherapy with lipiodol, cisplatin and adriamycin, followed by radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI). The other two patients only received 1 or 2 courses of intra-arterial chemotherapy with lipiodol, cisplatin and 5-fluorocuracil. All of the 3 patients had a stable disease response according to RECIST (Table 3).

 

There was no procedure-related mortality in this small cohort. One patient in the hepatectomy group developed pleural effusion and 1 in the non-surgical group developed prolonged hyperbilirubinemia. The treatment details and outcomes of patients are shown in Tables 2 and 3. The median disease-free survival in the hepatectomy group was 5.5 months (range 4.5-14), with a median overall survival of 11.5±2.2 months (range 8.5-31; 95% CI: 7.2-15.8) (Table 2). The median overall survival from the diagnosis of liver metastasis to death was 7.5±1.6 months (range 5.5-11; 95% CI: 4.3-10.7) (Table 3). There was a trend towards better survival in those patients who received hepatectomy. However, no statistical difference was found in comparison to other therapeutic methods (P=0.257, Fig.).

 

 

Malignant melanoma accounts for 1%-3% of all malignant tumors in Western countries and nearly one-third of malignant melanoma cases are associated with liver metastasis.^[7-9] The pathogenesis of melanoma is complicated and not well understood, and the tumor is thought to be related to environmental factors, accumulation of sequential genetic alterations, activation of oncogenes, inactivation of tumor suppressor genes, vasculogenic mimicry, and impaired DNA repair.^[10-12]

 

We treated 8 patients with liver metastasis of uveal melanoma at our institution during a 13-year period. Metastatic liver disease is the leading cause of death in patients with uveal melanoma. Therapeutic options for this tumor include systemic or intra-arterial chemotherapy and hepatectomy. But systemic and intra-arterial chemotherapy produces no better survival benefit.^[13-15] Cytotoxic agents such as dacarbazine, treosulfan, temozolamide, fotemustine, cisplatin and vincristine have been used alone or in combination, and the median survival of such patients is about 6-12 months.^[16-19] A recent study^[20] reported that ipilimumab plus dacarbazine improved the overall survival in patients with untreated metastatic melanoma. It is only the hepatectomy that probably prolongs the survival.^[21-24] The largest series (104 cases) of hepatectomy for melanoma metastases was reported by Adam et al.^[23] They reported a 5-year survival rate of 21% in patients who underwent hepatectomy. Pawlik et al^[24] reported 16 patients with choroid melanoma and liver metastasis. The 5-year survival of these patients was 20.5% after surgery. These data suggest that hepatectomy is possible in a small proportion of patients, and aggressive treatment may result in prolonged survival. In the majority of patients, hepatectomy is impossible because of the number or location of metastatic melanoma. Liver metastasis has proven to be resistant to most systematic chemotherapy and immunotherapy regimens.^[25] A retrospective analysis showed that TACE with a cisplatin-based regimen was the only regimen for the improvement of survival when compared with other therapies, including systemic chemotherapy and chemotherapy through a surgically implanted arterial port.^[26] Sharma et al^[27] reported the results of 20 patients who had been treated with 46 sessions of TACE including a mixture of cisplatin, doxorubicin, and mitomycin C. The treatment was well tolerated and the median survival of the patients was 271 days. Sosman et al^[28] reported that vemurafenib can induce clinical response in more than half of the patients with treated BRAF V600-mutant metastatic melanoma and that the median overall survival was approximately 16 months.

 

Probably, statistical comparison in our series is not adequate because of the small sample size. In the series, the median disease-free survival of the 5 patients who underwent hepatectomy with or without other therapies was 5.5 months, with a median overall survival of 11.5 months. On the other hand, the median overall survival for the 3 patient who did not undergo operation was 7.5 months. Although there was a trend towards better survival in the patients who received resection of the tumor, it's hard to analyze the data and make such a conclusion because of the small number of patients.

 

In conclusion, our limited single institutional experience shows that partial hepatectomy or other non-operative therapies are safe and feasible in the treatment of isolated liver metastases from uveal melanoma. Aggressive treatment with comprehensive modalities may result in prolonged survival of such patients.

 

 

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