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10.1245/ASO.2005.06.032
Annals of Surgical Oncology 12:422-428 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Treatment of Liver Metastases From Uveal Melanoma

Michel Rivoire, MD, PhD1,2, Laurent Kodjikian, MD, PhD3, Stefano Baldo, MD1, Pierre Kaemmerlen, MD4, Sylvie Négrier, MD, PhD5 and Jean-Dominique Grange, MD3

1 Department of Surgery, Centre Léon Bérard, 28 Rue Laennec, 69373 Lyon, Cedex 08, France
2 Institut de Recherches Chirurgicales, Unitéde Formation et de Recherche Lyon-Nord, 8 Avenue Rockefeller, 69373 Lyon, Cedex 08 France
3 Department of Ophthalmology, Hôpital de la Croix Rousse, 103 Grande Rue de la Croix - Rousse, 69317 Lyon, Cedex 04 France
4 Department of Radiology, Centre Léon Bérard, 28 Rue Laennec, 69373 Lyon, Cedex 08, France
5 Department of Medicine, Centre Léon Bérard, 28 Rue Laennec, 69373 Lyon, Cedex 08, France

Correspondence: Address correspondence and reprint requests to: Michel Rivoire, MD, PhD; E-mail: rivoire{at}lyon.fnclcc.fr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Uveal melanoma patients with liver metastases have a poor prognosis. The effect of screening and multimodality treatment (including surgery) should be evaluated.

Methods:: A total of 602 patients treated for uveal melanoma during a 14-year period had abdominal ultrasonography screening every 6 months. Sixty-three developed liver metastases as the first extraocular metastatic site. When possible, liver surgery and intra-arterial catheter implantation were performed. The influence on survival of demographics, uveal tumor characteristics, liver metastasis presentation, and treatment was studied.

Results: The median time to liver metastasis was 29 months. Twenty-eight patients (44%) were operated on: 14 (22%) had R0 liver surgery, and 14 with diffuse liver involvement had R2 liver surgery (there were no significant surgical complications). Thirty-five patients with diffuse liver involvement received systemic chemotherapy or best supportive care only. The median overall survival was 15 months (range, 3–110 months): 25 months for the 14 patients with R0 surgery, 16 months for the 14 with R2 surgery, and 11 months for the 35 with chemotherapy or supportive care. By univariate analysis, age (≤70 years), number of metastases (≤10), and quality of operation (R0) were predictive of a better prognosis.

Conclusions: In the case of liver metastases from uveal melanoma, aggressive treatment permitting tumor eradication seems to offer a chance of long-term survival to selected patients. Nevertheless, neither ultrasound screening nor quality of operation had an effect on the outcome of most patients (78%). Better screening tests and more effective multimodality treatments are required to improve survival in uveal melanoma patients with hepatic metastases.

Key Words: Uveal melanoma • Liver metastases • Liver surgery • Hepatic resection • Chemotherapy • Prognosis factors


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Melanomas are the most common primary intra-ocular malignancy in the Caucasian population. Most studies show a median age at diagnosis of approximately 55 years, and rates decrease after 70 years.1,2 Hematogenous dissemination to the liver is the most frequent form of metastatic spread. The overall 5-year survival of patients with localized uveal melanoma is approximately 70% after treatment. Once metastases occur, the liver is the only organ site involved in 70% to 80% of cases3,4 and is usually responsible for death. Although survival is longer when liver metastases are diagnosed by screening (5 vs. 3 months) and treated (5 vs. 2 months), patient prognosis is poor, and differences in terms of individual patient benefit are negligible.5 The best survival rates in patients with liver metastases were obtained by maximal tumor reduction—ideally, complete resection of the metastases followed by intra-arterial chemotherapy.6–8 In this study, we reviewed 14 years of treatment of uveal melanomas metastatic to the liver and evaluated the influence of early detection and multimodality treatment, including liver surgery, on survival.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between June 1, 1983, and December 31, 1996, 602 uveal melanoma patients were registered in the database of the University Eye Clinic of Croix-Rousse Hospital in Lyon, France. All patients were followed up every 6 months with clinical examination, chest x-ray, and ocular and abdominal ultrasonography (US). Liver function tests were not performed systematically because liver function is known to be modified mainly when the tumor burden is high. When liver metastases were suspected, a computed tomography (CT) scan analysis was performed to confirm the diagnosis. Final diagnosis of liver metastases was confirmed with fine-needle cytology or biopsy. Sixty-three patients developed histologically proven metastases to the liver as the first extraocular metastatic site. Before treatment, they underwent total-body CT scanning with precise evaluation of the number of visible liver metastases. They were consecutively treated in Léon Bérard Cancer Center (Lyon, France). All patients but one had normal liver function tests. Clinical charts were systematically discussed on a multidisciplinary basis to assess the possibility of surgical removal of liver metastases. Selection criteria for liver resection were as follows: (1) medical fitness, (2) no signs of disseminated disease, and (3) tumor anatomically confined to the liver with 30% to 40% of normal parenchyma that could be preserved after complete tumor resection. The operation consisted of abdominal and hepatic investigation, including intraoperative US. If preoperative data were confirmed or if only minor changes occurred in the description of metastases, we performed liver resection with intra-arterial catheter implantation. Postoperative intra-arterial chemotherapy was performed with fotemustine (100 mg/m2 infused over 4 hours every week or every 2 weeks in case of platelet decrease, over 2 to 4 months) or cisplatin (80 mg/m2 infused over 4 hours every week or every 2 weeks in case of platelet decrease, over 2 to 4 months). When laparotomy disclosed multiple diffuse metastases presenting as numerous millimeter-sized black spots, major liver resection was contraindicated. Then we performed resection of the largest metastases to clear as much tumor as possible and performed intra-arterial catheter implantation. The type of resection was classified as complete R0 or incomplete R2 surgery. R0 resections were defined as the removal of all gross metastatic disease at operation; conversely, R2 resections implied gross residual disease remaining after surgery. When preoperative work-up showed disseminated metastatic disease contraindicating liver resection or precluding safe liver resection, patients received intravenous chemotherapy or best supportive care only.

Medical records were reviewed to determine significant prognostic factors for survival after the diagnosis of metastatic tumor in the liver. The following information was collected: sex, age at diagnosis of uveal melanoma, age at diagnosis of metastases, thickness, largest tumor diameter, histology (when available) of the primary uveal melanoma, type of treatment of the primary tumor, time interval from initial tumor treatment to diagnosis of metastasis, preoperative number of metastases, metastasis treatment, morbidity and mortality related to treatment, and overall survival after treatment of metastases.

Patient survival was calculated from the date of metastasis treatment to the date of death. The database was last updated on January 1, 2003. Observations of patients alive at this date were censored. Survival and time-to-event rates, with standard error, were calculated by the Kaplan-Meier method and compared by using the log-rank test.9 Statistical tests with P values <5% were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics and Follow-Up Evaluation
Sixty-three patients presented with liver metastases during the study period. There were 30 men and 33 women. The median age of the patients at initial eye treatment was 57 years (range, 28–81 years). The median age at diagnosis of liver metastases was 61 years (range, 31–85 years). Fifty-three patients had died at the date of analysis, with a median time from liver metastasis to death of 13 months (range, 2.5–110 months). Thirty-eight patients survived more than 1 year, 17 more than 2 years, and 9 more than 3 years. Ten patients were alive: three without any evidence of recurrence and seven with evolutive disease (two isolated liver metastases, four multiple metastatic sites including the liver, and one isolated lung metastasis). The median follow-up in survivors was 29 months (range, 16–110 months). Eight of the survivors were in the R0 resection group.

Liver Metastases
The 63 patients with liver metastases represented 10.5% of the 602 uveal melanoma patients treated during the 14-year study period and followed up with semiannual abdominal US screening. All patients but one were asymptomatic at the time of diagnosis of liver metastases. Fifty-four patients (85%) had isolated liver metastases, and nine had metastases in the liver plus other sites, including lungs in five patients, bones in three, and skin, pancreas, and lymph nodes in 1.

The time interval between ocular treatment and diagnosis of metastasis ranged from 0 months (four patients) to 145 months (median, 29 months). Thirty-nine patients developed liver metastases within 3 years, whereas the time to liver metastases was >5 years in 12 patients and >10 years in 2 patients.

The diameter of the largest metastasis was <30 mm (median, 12 mm; range, 5–75 mm) in all patients but one. Liver metastases involved both liver lobes in 59 patients. Seventeen patients (3% of the screened population; 27% of the metastatic population) presented ≤10 metastases (median, 3; range, 1–10) at the time of preoperative work-up. Most (n = 11) had ≤4 liver metastases. The 6 other patients had 5 and 8 liver metastases (1 patient each), and 6 and 10 liver metastases (2 patients each).

Treatment Procedures
Twenty-eight patients (44%) were operated on (Table 1Go). At direct examination and intraoperative US, 14 patients were found to have diffuse liver involvement presenting as numerous millimeter-sized black spots. This miliary liver disease was missed by preoperative imaging. They underwent R2 resection and received intra-arterial postoperative chemotherapy with fotemustine (10 patients) or cisplatin (4 patients; median, 8 cycles; range, 4–14 cycles). Three patients (21%) receiving fotemustine achieved a partial response. The durations of response were 9, 12, and 22 months; patients survived, respectively, 16, 23, and 40 months. Fourteen patients had R0 resection of liver metastases, and 11 received postoperative intra-arterial chemotherapy with fotemustine (9 patients) or cisplatin (5 patients; median, 7 cycles; range, 2–12 cycles). Three patients did not receive postoperative intra-arterial chemotherapy. Two of them, who were treated by left hepatectomy (one metastasis and eight metastases), had a remaining right hepatic artery originating from the superior mesenteric artery. They had no intra-arterial catheter placement. The third patient treated by right hepatectomy (one liver metastasis) refused intra-arterial chemotherapy. No significant surgical complications were experienced. Thirty-five patients with major liver involvement or diffuse metastases after initial work-up were not operated on and received only systemic chemotherapy (26 patients) or best supportive care (9 patients). Systemic treatments consisted of an association of cisplatin, vinblastine, and dacarbazine (CVD) in 8 patients, dacarbazine alone in 14 patients, and interferon with or without inter-leukin 2 in 4 patients. One patient (4%) receiving CVD achieved a partial response that lasted for 11 months. This patient died of liver and lung metastases at 24 months.


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  		TABLE 1. Type of liver operation (28 patients)
 
Survival After Treatment of Liver Metastases
The median survival of the 63 patients with liver metastases calculated from the time of primary uveal tumor diagnosis was 47 months (range, 3–190 months). It was 15 months (range, 3–110 months) when calculated from the time of liver metastasis treatment. The overall survival rate was 59% (SE, 6%) at 1 year, 29% (SE, 6%) at 2 years, and 13% (SE, 5%) at 4 years (Fig. 1Go). The median overall survival after treatment of liver metastases reached 25 months (range, 11–110 months) in the 14 patients who underwent R0 resection, 16 months (range, 3–35 months) in the 14 patients who underwent R2 resection, and 11 months (range, 3–52 months) in the 35 patients treated by systemic chemotherapy or best supportive care only (Fig. 2Go).


Figure 1
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  		FIG. 1. Overall survival (n = 63) after treatment of uveal melanoma metastatic to the liver—Kaplan-Meier estimator.

 

Figure 2
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  		FIG. 2. Overall survival according to the treatment of liver metastases. R0 liver operation significantly influenced patients’ outcome (P = .0002). There was no survival difference between the R2 surgery group and the systemic chemotherapy or best supportive care group (P = .32).

 
Predictors of Survival (Univariate Analysis)
Patient Demographics
The sex of the patient was not predictive of outcome (Table 2Go). Survival was significantly influenced by age (P = .048). Patients ≤70 years of age had a median overall survival of 16.3 months (range, 3–110 months) compared with 11.5 months (range, 3–35 months) for patients >70 years.


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  		TABLE 2. Predictors of survival (univariate analysis; Kaplan-Meier method with log-rank test)
 
Characteristics of the Uveal Tumor
Thickness and largest tumor diameter, as well as the initial treatment of the primary uveal melanoma, were not predictive of outcome.

Presentation and Treatment of Liver Metastases
Presentation with a disease-free interval of <24 or 60 months after primary tumor treatment was not predictive of outcome. Nevertheless, the outcome of the four patients with synchronous liver metastases was poor. One patient with symptomatic liver metastases received supportive care only and died 3 months later. Two patients presented with numerous bilobar liver metastases, and one also had lung metastases. Both received systemic chemotherapy (CVD and dacarbazine) and died 8 months later. The last patient was in the R2 group. She received intra-arterial postoperative fotemustine and died 11 months later. Conversely, the two patients whose disease recurred after 10 years were operated on. One was in the R0 group, and he was alive with evolutive liver disease 34 months after treatment. The other one was in the R2 group, and he died of liver metastases 11 months later. In the four patients with the longest survivals (52, 96, 103, and 108 months), liver metastases were diagnosed, respectively, 39, 72, 36, and 20 months after eye treatment.

Treatment of liver metastases significantly influenced patient outcome. The 2-year overall survival was 59.5% (SE, 15%) in patients receiving R0 liver surgery, 14.3% (SE, 9%) in patients receiving R2 liver surgery, and 16.1% (SE, 6%) in patients treated with systemic chemotherapy or best supportive care (Fig. 2Go). There was no survival difference between the R2 group and the nonoperative group (P = .32).

Pathologic Features of Liver Metastases
The preoperative number of liver metastases (≤10) was a strong indicator of outcome (Fig. 3Go). All 5-year survivors in this study had ≤10 liver metastases. Ten (59%) of the 17 patients with ≤10 liver metastases belonged to the R0 liver surgery group, versus only 4 (9%) of the 46 patients with >10 liver metastases.


Figure 3
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  		FIG. 3. Overall survival according to the number of liver metastases (P = .0002).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study was retrospective and relatively small. Its main advantages are that it was population-based and that all patients were treated by the same group with constant follow-up organization, thus reducing bias. This study made it possible to assess the effect of semiannual screening with abdominal US, with complementary total-body CT scan in case of anomaly, on treatment organization and patient outcome. Ten percent of the screened patients (63 of 602) were found to have liver metastases, and all but 1 were asymptomatic at the time of diagnosis. Twenty-eight (4% of the screened population and 44% of the metastatic population) were selected for liver surgery and postoperative intra-arterial chemotherapy. Finally, only 14 of these patients (2% of the screened population and 22% of the metastatic population) were able to undergo an R0 resection. This subgroup achieved a median survival of 25 months. These results are somewhat disappointing, but this screening program is considered nowadays as the most efficient and cost-effective.

This positive selection obviously started with semiannual US screening after initial treatment of melanoma, which permitted early detection of liver metastases. Most centers currently monitor patients with clinical examination, liver function tests, and chest x-rays.10,11 Liver US is recommended as an additional measure12 but is not performed routinely. This simple method has been shown to be effective in detecting up to 98% metastases while patients were still asymptomatic.13 In our series, this screening program permitted detection of liver metastases that were small and asymptomatic in all but one patient. All but one of these patients had normal liver function tests. Furthermore, it permitted selection of a subgroup of 17 patients (3% of the screened population; 27% of the metastatic population) with ≤10 liver metastases.

Many groups consider that screening programs for the early detection of liver metastases are of no benefit given the limited effect of treatment. The therapeutic options for liver metastases from uveal melanoma are systemic or intra-arterial chemotherapy, hepatic artery embolization, and liver resection. Traditionally, chemotherapy is a treatment option, although it provides only 9% partial responses and no survival benefit.14,15 Hepatic artery infusion of fotemustine or carboplatin has been reported to result in a 22% to 40% response rate and a median survival of 12 to 14 months.16–18 Chemoembolization can be effective because liver metastases are usually hyper-vascular19; it achieves a 36% response rate but offers no survival advantage over systemic chemotherapy.6

Partial hepatectomy should be considered as a treatment option for metastatic uveal melanoma, because disease is limited to the liver in >85% of the patients5,20,21 and because no alternative therapy has been shown to provide highly effective results. Over the past two decades, liver surgery has become increasingly safe, thereby increasing its indications for the treatment of liver metastases.22,23 Thus far, the evidence for a survival benefit from the resection of uveal melanoma liver metastases has been largely anecdotal. Aoyama et al.24 reported complete surgical removal of metastases in 12 highly selected patients (9 of whom had liver metastases), with an overall 5-year survival of 53%. Fournier et al.25 and Gunduz et al.26 described three patients who had major liver resection for metastatic uveal melanoma. One died of recurrence 32 months after liver surgery; the other two were alive at 24 and 84 months. Rajpal et al.3 reported a median survival of 24 months in eight patients who underwent resection of all gross metastatic disease, but none of them had liver metastases. More recently, Hsueh et al.27 reported a series of 24 patients who underwent resection of metastatic lesions (most were extrahepatic) with a median survival of 38 months and a 5-year survival rate of 39%. The largest series reported to date included 69 patients.7 This study had no screening program and no criteria for patient selection. All patients with a diagnosis of liver metastases from uveal melanoma were operated on if they were <75 years old and had a performance status and liver function compatible with liver operation, regardless of the size and number of liver metastases and the presence of extrahepatic metastases. No patient in this series survived >4 years. R0 liver operation followed with intra-arterial chemotherapy was possible in 19 patients, with a median survival of 22 months. Most of the patients did not benefit from liver surgery and had biopsy (23%) or R2 resection (50%) only. Their median survival was 9 months, identical to that of historical untreated patients. Eleven patients died within 4 months after surgery. These poor results demonstrate the need for selecting candidates for liver surgery.

In our series, patients who underwent hepatectomy were selected from 63 patients with liver metastases screened by semiannual US from a cohort of 602 uveal melanoma patients. Our objective was to make careful preoperative selection, to perform as many R0 liver resections as possible, and to avoid R2 liver operations. Variables such as primary tumor diameter and thickness, treatment, patient sex, status of the primary tumor at the date of diagnosis of liver metastases, and disease-free interval did not show any prognostic significance. Age and number of liver metastases (≤10) on CT scan were the only preoperative prognostic factors for better outcome. In these highly selected patients, quality of surgery (R0 vs. R2) was also a strong indicator of better outcome. Despite rigorous selection, 50% of our patients underwent R2 resection associated with postoperative chemotherapy. Although no major postoperative complication was noted, these patients did not experience a prolonged survival compared with those who received systemic chemotherapy or best supportive care only. The main cause of R2 surgery was the intraoperative discovery of miliary metastatic disease to the liver. These metastases were too small to be picked up by conventional imaging or even by positron emission tomography scanning. More intensive work-up with systematic use of staging laparoscopy may be of value to improve liver assessment and patient selection and to avoid unnecessary laparotomy.

Our results compare favorably to other treatment alternatives reported so far in the literature. Median survival ranges from 5 to 9 months.3,5,6,13,21,28 The best results (14 months) were obtained with intra-arterial chemotherapy in a small group of selected patients.16 However, the results of R0 liver resection cannot be fully compared with these data because patients suitable for surgery usually represent a positively selected subgroup and are often in better physical condition.

In conclusion, our results, together with the scarce data reported in the literature, support the notion that hepatic resection for metastases from uveal melanoma may offer a chance of long-term survival to a subgroup of carefully selected patients with isolated liver metastases. The only patients who benefit from this treatment are those with <10 lesions and those who can undergo an R0 resection. It is far more likely that tumor biology and patient selection, rather than US screening, govern final outcome. In this study, >90% of hepatic metastases detected by screening US had already metastasized in both lobes, and more than 70% of patients had >10 lesions to the liver. Semiannual US screening clearly was ineffective for the early detection of hepatic metastases in most patients with uveal melanoma. Furthermore, 50% of the patients who were operated on after complete preoperative work-up had only ineffective R2 surgery because of the presence of miliary liver disease missed by imaging. In this setting, further staging modalities should include the systematic use of laparoscopy, because miliary disease is too small to be picked up by conventional imaging methods or even by positron emission tomography imaging. Better screening tests and more effective multimodality treatments are required to improve survival in uveal melanoma patients with hepatic metastases.


   ACKNOWLEDGMENTS
 
Supported by a grant from the Léa and Napoléon Bullukian Foundation.


   FOOTNOTES
 
Presented at the 27th Congress of the Societa Italiana di Chirurgia Oncologica, Cagliari, Italy, May 29–31, 2003, and published as an abstract.

Received for publication June 22, 2004. Accepted for publication January 19, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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