Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.     

Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients

Uveal melanoma metastases occur most commonly in the liver. Given the 50% mortality rate in patients at high risk of developing liver metastases, we tested an adjuvant intra-arterial hepatic (i.a.h.) chemotherapy with fotemustine after proton beam irradiation of the primary tumour. We treated 22 high-risk patients with adjuvant i.a.h. fotemustine. Planned treatment duration was 6 months, starting with four weekly doses of 100 mg/m(2), and after a 5-week rest, repeated every 3 weeks. The survival of this patient group was compared with that of a 3 : 1 matched control group randomly selected from our institutional database. Half of the patients experienced > or =grade 3 hepatotoxicity (one patient developing cholangitis 8 years later). Catheter-related complications occurred in 18%. With a median follow-up of 4.6 years for the fotemustine group and 8.5 years for the control group, median overall survival was 9 years [95% confidence interval (CI) 2.2-12.7] and 7.4 years (95% CI 5.4-12.7; P=0.5), respectively, with 5-year survival rates of 75 and 56%. Treatment with adjuvant i.a.h. fotemustine is feasible. However, toxicities are important. Although our data suggest a survival benefit, it was not statistically significant. Confirming such a benefit would require a large, internationally coordinated, prospective randomized trial.     

Isolated hepatic perfusion with high-dose melphalan for the treatment of uveal melanoma metastases confined to the liver

Uveal melanoma is the most common primary intraocular tumour in adults. After treatment of the primary tumour, up to 50% of patients will ultimately develop metastases. Treatment options for metastases are limited. When uveal melanoma metastases are confined to the liver, isolated hepatic perfusion (IHP) could be a treatment option. Herein, we report the results of a small group of patients with uveal melanoma metastases of the liver treated with IHP. Eight patients with uveal melanoma metastases confined to the liver underwent IHP with high-dose melphalan (200 mg) for 1 h. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria and tumour response was assessed according to World Health Organization criteria. The tumour response rate (complete or partial remission) was 50%. The median time to progression was 6.7 months (range, 1.7-16.9 months). The overall median survival was 9.9 months (range, 4.7-34.6 months), with a 1 year survival of 50% and a 2 year survival of 37.5%. Three patients experienced grade 3-4 hepatotoxicity which was transient within 3 months. Although only a small group of patients has been treated and evaluated so far, IHP is a treatment option for uveal melanoma metastases confined to the liver which can result in tumour responses and may lead to survival benefits in a selective group of patients.     

Pilot study of hepatic intraarterial fotemustine chemotherapy for liver metastases from uveal melanoma: a single-center experience with seven patients

Background. Uveal melanoma is characterized by a high frequency of hepatic metastases. For patients with liver metastases, who have a median survival of 5 to 7 months, surgery and systemic conventional chemotherapy have little to offer. Methods. Between February 1995 and July 1999, seven patients with isolated hepatic metastases from uveal melanoma were enrolled into a pilot trial of intraarterial fotemustine therapy. An implantable Port-A-Cath catheter was inserted into the hepatic artery for regional chemotherapy via the gastroduodenal artery. Fotemustine 100 mg/m² was administered intraarterially over a 4-h period. The induction phase consisted of one administration per week for 4 weeks, followed by a 5-week rest period. Maintenance therapy with administration of fotemustine every 3 weeks continued until progression or toxicity. Results. Ten patients were evaluated for the trial. One patient was not eligible because of impaired liver function, and in two patients implantation of the port system was not possible for anatomic reasons. Seven patients received a median of 16 treatment cycles (range, 4–28) and all were evaluable for response. Two patients achieved a partial response (PR), three had stable disease (SD), and tumor progressed in two patients (PD). The median survival time from diagnosis of liver metastasis was 24 months (range, 4 to 50+ months). Two patients survived for more than 2 years and two patients are still alive. The toxicity was low and the treatment could be administered on an outpatient basis. Conclusion. Intraarterial fotemustine treatment of uveal melanoma metastatic to the liver is well tolerated, and in some patients is associated with prolonged survival. Received: May 22, 2000 / Accpted: October 13, 2000     

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNA-repair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p = 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents.     

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.     

Efficacy and safety of ipilimumab in patients with pre-treated,uveal melanoma

BackgroundPatients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited.Patients and methodsPre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events.ResultsAmong 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma.ConclusionsThese data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.     

Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study

Uveal melanoma is the most common primary intraocular malignancy in adults and the liver is the most common site for systemic metastases. We conducted a phase II clinical trial for patients with hepatic metastases from uveal melanoma using chemoembolization of the hepatic artery with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) dissolved in ethiodized oil. Gelatin sponge particles were used as a transiently occlusive agent. The responses in hepatic metastases, overall survival, time to progression and side-effects related to chemoembolization were evaluated. Thirty patients were enrolled. Twenty-four patients completed at least one treatment to all targeted liver metastases and were evaluable for hepatic response. Eighteen of these 24 patients experienced regression or stabilization of hepatic metastases for at least 6 weeks (one complete response in hepatic metastases; four partial responses; 13 stable disease). One of the 13 patients with stable disease was rendered free of disease by surgical removal of metastases after chemoembolization (surgical complete response). The overall response rates (complete and partial responses) for intention-to-treat patients and for patients who were evaluable for response were 16.7 and 20.4%, respectively. The median overall survival of the entire intention-to-treat group of patients was 5.2 months (range, 0.1-27.6 months), for patients with complete or partial response in hepatic metastases 21.9 months (range, 7.4-27.6 months), for patients with stable disease 8.7 months (range, 2.9-14.4 months) and for patients with progressive disease 3.3 months (range, 1.6-5.6 months). Importantly, 13 of the 18 patients who achieved complete response, partial response or stable disease subsequently developed progression of extrahepatic metastases with control of hepatic metastases. Chemoembolization with BCNU is a useful palliative treatment for the control of hepatic metastases in uveal melanoma patients. However, progression in extrahepatic sites after stabilization of hepatic metastases requires further improvement in the therapeutic approach to this disease.     

Hirnmetastasen des Melanoms

Context

Brain metastases occur in the majority of patients with metastatic melanoma and are the most common cause of death. Until recently, local therapy (neurosurgery, radiosurgery and whole brain radiotherapy) was the only option for a chance of disease control in the brain. Systemic treatment options are now available.

Objective

The aim of this study is to discuss the treatment options for brain metastases from melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma and recent publications (Pubmed and manual search).

Results

In limited brain metastases, neurosurgery and radiosurgery are established treatments that can prolong survival. Immunotherapy with ipilimumab appears to have activity in patients with brain metastases, particularly when metastases are small and asymptomatic (response rate 16?% and median overall survival 7 months). The BRAF inhibitor dabrafenib achieved response rates of 30–40?% and a median overall survival of 7–8 months in patients with asymptomatic BRAF mutation brain metastases. The intracranial disease control rate was 80–90?%. In patients with symptomatic BRAF mutation brain metastases, the BRAF inhibitor vemurafenib showed activity with a disease control rate of >?80?% and a median overall survival of 5 months. In symptomatic multiple brain metastases, palliative whole brain radiotherapy is an established treatment even though it has failed to show an overall survival benefit. Corticosteroids and antiepileptic drugs are indicated for patients presenting with intracranial hypertension and epileptic seizures. Treatment of patients with metastatic melanoma and brain metastases should be discussed in a multidisciplinary team.

Conclusion

The therapeutic options for patients with brain metastases from melanoma have improved in recent years. Presently, there are several effective local and systemic treatments available.     

Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in patients with metastatic uveal melanoma

Docosahexaenoic acid (DHA)-paclitaxel is a taxane with a unique pharmacokinetic profile. We investigated the safety and response rate of DHA-paclitaxel weekly in patients with metastatic uveal melanoma. Chemotherapy-naive and previously treated patients were eligible for this open-label phase II study. DHA-paclitaxel (500?mg/m2/week) was administered by a 1-hour intravenous infusion for five consecutive weeks in a 6-weeks cycle. Response was assessed using the Response Evaluation Criteria in Solid Tumors every 6 weeks. Twenty-two patients were enrolled. The patients' median age was 56 years (range: 33-79 years). Nine patients had a systemic therapy for metastatic disease earlier. The median number of treatment cycles was 1 (range 1-7 cycles). One chemonaive patient with liver metastases had partial response lasting for 5 months. Seven patients (32%) had stable disease with a median duration of 3 months (range: 3-7 months). The median overall survival was 9.8 months. Neutropenia (23%) and musculoskeletal pain (10%) were the most common grade 3 and grade 4 toxicities. As a single-agent therapy, DHA-paclitaxel is safe and well-tolerated in metastatic uveal melanoma patients. Its efficacy in this disease is limited with 32% of patients achieving stable disease. Further evaluation of DHA-paclitaxel in combination with other chemotherapeutic agents and/or targeted agents may improve its antitumor activity.     

Treatment of metastatic malignant melanoma with dacarbazine plus fotemustine

Despite the poor prognosis of metastatic malignant melanoma, polychemotherapy with dacarbazine and fotemustine has shown promising results in several studies. We report on the clinical efficacy of a new sequential administration regimen with dacarbazine at a dose of 200 mg/m2 followed 24 h later by fotemustine 100 mg/m2 every 4 weeks in 63 patients with metastatic melanoma. A complete response was noted in 3 patients (5%), a partial response in 4 patients (6%), stable disease in 33 patients (5%) and progressive disease in 23 patients (37%). The duration of the 3 complete responses was 5, 14+ and 60+ months, for the 4 partial responses, 3, 4, 6 and 13 months. The median duration for stable disease was 4 months. The best response rates were obtained for lung and lymph node metastases. Toxicity was mild and mainly limited to haematological without pulmonary side-effects. Although there was a relatively low objective response rate, this chemotherapy regimen as a palliative treatment, is potentially valuable for patients with progressive stage IV melanoma.     

Fotemustine in the Treatment of Brain Primary Tumors and Metastases

Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma.

In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intra-arterially, with 10 objective responses observed among 26 evaluable patients.

In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising.

In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%.

Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.     

Treatment of disseminated ocular melanoma with sequential fotemustine,interferon alpha,and interleukin 2

Malignant melanoma of the uvea is remarkable for purely haematogenous dissemination and its tendency to metastasise to the liver. Although the liver is involved in up to 95% of patients, 50% of these also develop extrahepatic metastases, most often in the lungs, bone, skin, and brain. The only effective treatments reported to date relied on hepatic arterial chemoembolisation or -perfusion. The objective of this study was to establish a therapy protocol addressing patients with both sole liver involvement and systemic disease. Forty-eight patients with metastatic ocular melanoma received fotemustine 100 mg m(-2) either as 60-min infusion into the hepatic artery or as 15-min infusion via a peripheral vein, depending on the metastatic sites involved, i.e., restriction to the liver or hepatic together with extrahepatic disease. For the first treatment cycle this infusion was repeated after one week. For all cycles, subsequent to a three week resting period, patients received an immunotherapy consisting of subcutaneous interleukin 2 and interferon alpha(2). Although objective responses were more frequent within the cohort receiving intraarterial fotemustine (21.7 vs 8%), this difference did not translate into a significant benefit in overall survival, i.e., 369 and 349 days, respectively. Of note, this overall survival is much longer than that repeatedly reported for stage IV uveal melanoma not treated with fotemustine, suggesting a therapeutic activity of this cytostatic drug even after systemic administration.     

Protracted survival after resection of metastatic uveal melanoma

BACKGROUND: The objective of this study was to evaluate the usefulness of resection of metastatic uveal melanoma and to analyze the characteristics of patients who may benefit from surgical intervention. PATIENTS AND METHODS Twelve patients underwent surgical removal of metastasis between 1976 and 1998. Data regarding primary uveal melanoma, systemic metastasis, surgical procedures, and outcomes were reviewed retrospectively. RESULTS: There were seven patients with liver metastases, two with lung metastases, one with brain metastasis, and two patients with metastases in the liver and other organs. Median time to systemic metastasis was 8 years. Seven of 12 patients were asymptomatic when they were found to have metastasis. Ten patients underwent complete resection of metastasis. No significant surgical complications were experienced. Median recurrence free and overall survival periods after complete resection were 19 months (range, 6-78 months) and greater than 27 months (range, 11-86 months), respectively. Recurrence free and overall 5-year survival rates of those patients were 15.6% and 53.3%, respectively. Three of these patients had no further systemic recurrence. All patients whose time to systemic metastasis was within 5 years developed further systemic recurrence within 2 years after surgery. In contrast, in 8 patients whose time to systemic metastases was greater than 5 years, 4 patients either were recurrence free or developed second metastasis more than 4 years after surgery. CONCLUSIONS: Complete surgical removal of metastatic uveal melanoma provided unexpectedly long survival without significant morbidity for the selected patients. These results are encouraging and justify a trial in which patients eligible for resection are randomized between standard treatment and surgery.     

A pilot study of low-dose thalidomide and interferon alpha-2b in patients with metastatic melanoma who failed prior treatment

Melanoma is a hypervascular tumor and angiogenesis plays a critical role in the development/progression of metastases. As various pathways are involved in tumor angiogenesis, a combination of agents with different antiangiogenesis activities is a reasonable approach. To determine the efficacy and toxicity of combination treatment with low-dose thalidomide and low-dose interferon (IFN) in patients with stage IV melanoma who failed prior treatment(s), fifteen patients with metastatic melanoma (nine cutaneous, six uveal) received oral thalidomide (200 mg daily) with subcutaneous interferon (IFN)-alpha2b (3 MIU, 3x/week). Stabilization or regression of metastases (as evidenced by computed tomographic measurement) was the primary endpoint of the study. Patients were evaluated monthly for toxicity and every 2 months for clinical response. At a median follow-up of 22.8 months (range, 12-32 months), one patient with metastatic cutaneous melanoma achieved partial response, three patients achieved stable disease (one uveal, two cutaneous), nine patients progressed, and two were not evaluable. The time to progression was 6 months for the patient with partial response, and 2, 5.5+ and 11 months for three patients with stable disease. The estimated median overall survival was 4.7 months (confidence interval, 2.2-9.9 months; range, 0.9-31.5 months), and median progression-free survival was 1.8 months (confidence interval, 1.5-3.0 months; range, 0.5-14 months). Grade 3 toxicities related to treatment included neutropenia (n=5), elevation of transaminases (n=2), and neuropathy (n=1). No treatment-related deaths were experienced. Thalidomide+IFN is a safe and tolerable palliative treatment for previously treated stage IV melanoma.     

The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.     

Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study

Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and fotemustine in metastatic melanoma patients with or without brain metastases. The addition of fotemustine to ipilimumab does not impair its immunomodulatory activity.BackgroundIn the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination.Patients and methodsThis analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3⁺CD4⁺ICOS⁺CD45RO⁺ or CD45RA⁺ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.ResultsEighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naïve’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome.ConclusionsLong-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab.EudraCT number2010-019356-50.CinicalTrials.govNCT01654692.     

Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma]

PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.     

Metastatic uveal melanoma: is there a role for conventional chemotherapy? - A single center study based on 58 patients

Uveal melanoma metastases develop in 6.5-35% of patients, most commonly to the liver. Metastatic uveal melanoma (MUM) survival is poor, with 5-7 months of median survival. We reviewed retrospectively all patients with MUM diagnosed between January 1990 and December 2008 at our institution. We analyzed a total of 58 patients with a median age of 61 years (31-84 years). Median time for metastases development was 25.63 months (0.17-102.43 months). Fifty-six patients had hepatic involvement, 63.8% bilobar and 51.7% had more than or equal to five hepatic metastatic lesions. Sixteen patients (27.6%) had two or more organs involved. Six patients (10.71%) were treated with surgery, 25 patients (44.67%) received systemic chemotherapy, and 23 (41.07%) had best supportive care (BSC). The median overall survival (OS) for all the patients was 10.83 months [95% confidence interval (CI): 6.92-14.74]. Patients who had undergone chemotherapy presented 10.83 months (95% CI: 5.35-16.308) of median OS whereas the patients who did not undergo this treatment had an OS of 8.033 months (95% CI: 2.46-13.61). There were more patients with poor survival characteristics such as worse Eastern Cooperative Oncology Group performance status in the BSC group. OS was poor in treated and BSC patients. Differences in survival are more likely to be related to patient characteristics rather than to a chemotherapy effect. Patients with MUM should be included in clinical trials evaluating other options with newer agents.     

A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma

The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.