Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie

Background

Uveal melanoma is characterised by a high prevalence of liver metastases and a poor prognosis.

Aim

To review the evolving surgical management of this challenging condition at a single institution over a 16-year period.

Patients and Methods

Between January 1991 and June 2007, among 3873 patients with uveal melanoma, 798 patients had liver metastases. We undertook a detailed retrospective review of their clinical records and surgical procedures. The data was evaluated with both uni- and multivariate statistical analysis for predictive survival indicators.

Results

255 patients underwent surgical resection. The median interval between ocular tumour diagnosis and liver surgery was 68 months (range 19–81). Liver surgery was either microscopically complete (R0; n = 76), microscopically incomplete (R1; n = 22) or macroscopically incomplete (R2; n = 157). The median overall postoperative survival was 14 months, but increased to 27 months when R0 resection was possible.With multivariate analysis, four variables were found to independently correlate with prolonged survival: an interval from primary tumour diagnosis to liver metastases >24 months, comprehensiveness of surgical resection (R0), number of metastases resected (≤4) and absence of miliary disease.

Conclusions

Surgical resection, when possible, is able to almost double the survival and appears at present the optimal way of improving the prognosis in metastatic uveal melanoma. Advances in medical treatments will be required to further improve survival.     

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.     

Concurrent radiotherapy: fotemustine combination for newly diagnosed malignant glioma patients, a phase II study

Purpose  Fotemustine is a nitrosourea compound used for the treatment of malignant gliomas, especially in France. Recently, an EORTC-NCIC study has shown that a concomitant combination of radiotherapy plus temozolomide (an oral cytotoxic drug) improved survival in glioblastoma patients. We set out to test a concurrent combination of radiotherapy and fotemustine for newly malignant gliomas. Methods  A prospective single-center phase II study opened for accrual in September 2004. Patients over 18 years of age able to give informed consent and with histologically proven, newly diagnosed supratentorial malignant gliomas were eligible. All patients were treated by a standard cranial irradiation (conformal irradiation, tumor bulk plus a margin of 2.5 cm) and concomitant daily administration of 10 mg/m² of fotemustine (5 days per week, 6 weeks, 1 h 30 min before radiation therapy). Adjuvant chemotherapy, fotemustine, was administered at tumor progression as standard and classic regimen. Results  Twenty-two patients were enrolled, 16 men and 6 women, median age 56 years (range 32–74), median Karnofsky performance status 70 (range 60–90). Histology included 16 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 1 mixed glioma. Eight patients underwent surgery (three total resections). Fourteen patients had a stereotactic biopsy. The concurrent radiotherapy–fotemustine combination was well tolerated: toxicity was mild and three hematologic toxicities grade 3–4 were observed. Median survival from the initial diagnosis was 9.9 months, two patients are currently alive. Median survival was 11 months for surgery and 9 months for stereotactic biopsy. Conclusions  Concomitant radiotherapy–fotemustine combination is safe and well tolerated. Overall survival of over 10 months for the whole population compares favorably with other reports.     

Initial results of fractionated CyberKnife radiosurgery for uveal melanoma

Objective To evaluate prospectively local tumor control and morbidity after fractionated CyberKnife radiosurgery for uveal melanoma unsuitable for ruthenium-106 brachytherapy or local resection. Methods This study includes melanoma ≥7 mm in initial height, or juxtapapillary and/or juxtamacular tumors (height ≥3 mm; posterior tumor margin extending to within 3 mm of optic disk rim and/or fovea). Patients were excluded if they presented evidence of echographic extrascleral tumor extension, neovascular glaucoma, or any form of pretreatment or metastases at baseline. The eye was stabilized by the same ophthalmologist via peribulbar injection of 5 cc 2% lidocaine. CyberKnife radiosurgery was performed delivering a total dose of 60 Gy to the 80% or 85% isodose line in three fractions. The planning target volume (PTV) included the contrast-enhancing lesion on MRI plus a 1-mm margin (no margin on fovea site). Results Five patients with uveal melanoma were treated by this procedure. All patients had serous retinal detachment associated with the tumor. No grade ≥2 acute toxicities were observed. Eight-month follow-up revealed a decrease in tumor thickness in three patients and reattachment of the retina in four. The tumors remained stable in two eyes and an increase in retinal detachment was noted in one eye. Vision improved minimally in two eyes and remained stable in three. Conclusion CyberKnife fractionated radiosurgery seems to be a viable alternative local treatment modality in uveal melanoma with no serious acute side effects. Further follow-up is indicated.     

Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients

The purpose of this study was to evaluate safety and efficacy of Procarbazine (PCB) and fotemustine (FTM) combination in the treatment of pre-temozolomide treated, recurrent GBM patients. The primary end-point was progression free survival at 6 months (PFS-6). Secondary end-points were overall survival, response rates (CR + PR) and toxicity. About 54 patients (41 men and 13 women) aged 26–68 years (median age, 53.5 years) with recurrent GBM were treated. PCB was administered as an oral dosage of 450 mg on days 1–2 and a total dose of 300 mg on day 3. FTM was administered on day 3, 3 h after the last PCB intake at a dose of 110 mg/mq/BSA. The treatment was repeated every 5 weeks. Treatment was continued for a maximum of six cycles or until disease progression. After two cycles of chemotherapy: 6 patients (11.2%) experienced a neuroradiographic partial response (PR), 29 patients (53.7%) had stable disease (SD), and 19 patients (35.1%) had progressive disease (PD). For the whole group of patients, the median PFS was 19.3 weeks (95% CI, 14.1–24.4 weeks), and PFS-6 was 26.7% (95% CI, 10.6–42.8%). Overall MST from the beginning of PCB + FTM chemotherapy was 28.7 weeks (95% CI, 24.8–32.7 weeks). At 6 and 12 months, 64.4% (95% CI, 51.5–77.3%) and 23.6% (95% CI, 10.1–37.1%) of patients were alive. The median survival time calculated from the first diagnosis was 20.8 months (95% CI, 16.7–24.8). We concluded that the PCB + FTM combination as done in the current trial for patients with recurrent GBM after treatment with TMZ showed some benefit with regards to increased survival and that a Phase III trial is warranted. Two errata are available for this article; the first one at , the second one at . An erratum to this article can be found at     

Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: A pilot study

Background

The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases.

Methods

In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection.

Results

Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%.

Conclusions

Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases.     

Management of uveal melanoma: a consensus-based provincial clinical practice guideline

IntroductionSurvival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure.MethodsA consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations.ResultsEighty-four publications, including five existing guidelines, formed the evidence base.SummaryKey recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.     

Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET)

Background

Microscopically complete (R0) resection of metastases from uveal melanoma prolongs median overall survival compared to incomplete surgery. The aim of this study was to compare the sensitivity of dynamic-enhanced magnetic resonance imaging (MRI) with fluorodeoxyglucose-positron emission tomography (FDG-PET) in the preoperative diagnosis of liver metastases from uveal melanoma.

Patients and methods

Fifteen consecutive patients (mean age: 56 years) underwent FDG-PET and liver MRI. Extrahepatic metastatic disease was excluded by whole body computed tomography and bone scintigraphy. MRI and FDG-PET were performed with a mean of 19 days (range: 1–30) before surgery. Imaging findings were compared with surgical (including intraoperative ultrasonography) and histological findings on a lesion by lesion analysis.

Results

R0 resection was performed in 12 patients. A total of 28 lesions were resected with 27 histologically proven metastases. Nine lesions were smaller than 5 mm, 7 measured 5–10 mm and 11 were larger than 10 mm. Sensitivity and positive predictive value were 67% and 95% for MRI compared to 41% and 100% for FDG-PET. The difference between the two modalities was statistically significant (p = 0.01; McNemar test). In remaining 3 patients, diffuse miliary disease (>10 capsular lesions) was discovered intraoperatively, and was suspected on preoperative MRI in 2 cases. Only one extrahepatic lesion identified by FDG-PET was falsely positive.

Conclusions

In this preliminary study, MRI was superior to FDG-PET for staging of liver metastases from uveal melanoma. Although miliary disease was suggested by MRI in some cases, preoperative confirmation remains imperfect.     

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

BackgroundIn uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM.Patients and methodsPatients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m² on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points.ResultsAccrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25–6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79–1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45–0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.ConclusionHIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental.EudraCT number and ClinicalTrials.gov identifier2004-002245-12 and NCT00110123.     

An anatomical study of the arteries for intraarterial chemotherapy of head and neck cancer

Background. The intraarterial approach is one of the most important routes for the administration of anticancer drugs for head and neck cancer. A profound knowledge of the anatomical characteristics and variations of the carotid artery, such as its branching pattern, length, and inner diameter, is essential to avoid complications with catheter insertion. Methods. We conducted a morphometric investigation of head and neck arteries in 29 Japanese cadavers (58 sites). Results. The branching pattern of the external carotid artery showed variations. In 65.5% of the cadavers, the lingual, facial, and superior thyroid arteries arose separately. However, in 31.0% of the cadavers, the lingual artery formed a common trunk with the facial artery, and in 3.5%, the lingual artery formed a common trunk with the superior thyroid artery. The transverse facial artery arose from the superficial temporal artery in 53.4% of the specimens, from the maxillary artery in 27.6%, and from a site central to the maxillary artery in 19.0%. The posterior auricular artery arose from the external carotid artery at the same level as the maxillary artery in 37.9% of specimens, and from a site central to the maxillary artery in 62.1%. The occipital artery arose from the external carotid artery at the same level as the maxillary artery in 55.2% of specimens, and from a site peripheral to the facial artery in 44.8%. The lengths from the auricular point to the origins of the upper branches of the external carotid artery were: 2.8 mm to the transverse facial artery, 3.2 cm to the maxillary artery, 3.8 cm to the posterior auricular artery, 6.6 cm to the occipital artery, 7.4 cm to the facial artery, 8.8 cm to the lingual artery, and 10.4 cm to the superior thyroid artery. Conclusions. These results, have led to some clarification of the clinicoanatomical basis for intraarterial infusion. These data should be helpful for assessing the approximate level of the catheter tip and for evaluating whether the catheter is placed appropriately, by transient staining of the infused area. Received: February 12, 1999 / Accepted: July 28, 1999     

The effect of perfusate buffering on toxicity and response in isolated hepatic perfusion for uveal melanoma liver metastases

Background: Isolated hepatic perfusion (IHP) is a treatment option for patients with liver metastases. Previous studies have found that liver toxicity is one of the limiting factors, and in an attempt to reduce the toxicity a buffering agent was added to the perfusate. The aim was to retrospectively analyse if this buffering reduced toxicity and complication rates.

Methods: A retrospective review of 52 consecutive patients with uveal melanoma liver metastases treated with IHP between 2005 and 2013. Patients were followed by daily liver function tests (LFT). Toxicity was graded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE; United States Department of Health &; Human Services, Washington, D.C), complications according to Clavien-Dindo and response according to RECIST-criteria.

Results: Thirty-six patients were treated with a buffered perfusate and 16 patients without buffer. There was no difference in age, gender, largest tumour size or number of tumours between the groups. There was a significantly lower mean in peak ALT, AST, PK (INR) and bilirubin when comparing buffer with no-buffer. There were five major complications without a significant difference between the groups (8.3 vs. 12.5%, p?=?0.33). There was a lower complete response (CR) rate (11 vs. 44%, p?=?0.023) and a trend for shorter time to local progression (9.2 vs. 17.6 months, p?=?0.096); however, not significant in multivariate analysis. There was no difference in survival (24.2 vs. 26.0 months, p?=?0.43) between the two groups.

Conclusions: Adding buffer to the perfusate during IHP significantly reduces postoperative LFTs; however, without a reduced complication rate. Interestingly, buffering also seems to reduce the response rate; however, this did not translate into a survival difference. To address if buffering adds any clinical benefit to the patients concerning toxicity, a larger prospective trial is necessary.     

结直肠癌肝转移的术前化疗

结直肠癌在西方国家占肿瘤患者死亡的第2位,发病率为56.1/10万。我国结直肠癌发病率约为20.6/10万,占肿瘤患者死亡的第5位。Parkin等[1]报道,2002年,全世界新诊断结直肠癌为l 020 000例,占发病率第3位,死亡529 000例,占死亡率第4位。     

MicroRNA dysregulation in uveal melanoma: a new player enters the game

Uveal melanoma is the second most common form of melanoma and a predominant intraocular malignant tumor in adults. The development of uveal melanoma is a multistep process involving genetic and epigenetic alteration of proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed a new light on the involvement of a class of noncoding RNA known as microRNAs (miRNAs) in uveal melanoma. A lot of miRNAs show differential expressions in uveal melanoma tissues and cell lines. Genes coding for these miRNAs have been characterized as novel oncogene and tumor-suppressor genes based on findings that these miRNAs control malignant phenotypes of uveal melanoma cells. Several studies have confirmed that dysregulation of miRNAs promotes cell-cycle progression, confers resistance to apoptosis, and enhances invasiveness and metastasis. Moreover, several miRNAs have also been shown to correlate with uveal melanoma initiation and progression, and thus may be used as biomarkers for early diagnosis and prognosis. Elucidating the biological aspects of miRNA dysregulation may help us better understand the pathogenesis of uveal melanoma and promote the development of miRNA directed-therapeutics against this disease.     

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.     

Isolated hepatic perfusion with oxaliplatin combined with 100 mg melphalan in patients with metastases confined to the liver: A phase I study

Aim

To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose.

Methods

Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100 mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival.

Results

Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150 mg oxaliplatin. The areas under the concentration–time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100 mg oxaliplatin ranged from 11.9 mg/L h to 16.5 mg/L h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP.

Conclusions

In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.     

Iterative treatment with surgery and radiofrequency ablation of uveal melanoma liver metastasis: Retrospective analysis of a series of very long-term survivors

BackgroundAfter treatment of primary ocular uveal melanoma (UM), up to 50% of patients will develop metastases, mostly in the liver. Systemic treatments do not provide any overall survival benefit for these patients and surgery remains the most effective therapy for selected patients. Radiofrequency ablation (RFA) alone or in combination with surgery is frequently used to spare hepatic parenchyma. When patients relapse after treatment of their first metastases, and when the liver recurrence is limited, new local liver treatment is questionable.MethodsA total of 14 patients with liver metastases from uveal melanoma (LMUM) were retrospectively evaluated. All patients had a complete first liver resection and a second treatment with RFA. Overall survival, recurrence-free interval after the first and the second treatment was evaluated.ResultsTreatment of hepatic recurrence was percutaneous RFA for ten patients and per-operative RFA for four patients associated with new metastasectomy. The median time to onset of LMUMs after ocular UM treatment was 50 months, and the median time to recurrence of hepatic metastasis after the first liver treatment was 20 months. The overall survival was 70% at five years and 35% at ten years. The recurrence-free interval was 50% and 56% at two years after the first and the second treatment, respectively.ConclusionProlonged survival can be achieved by exclusive and iterative local treatment combining surgery and RFA in a small proportion of patients with a first recurrence of isolated LMUM.     

A phase II study of fotemustine plus dacarbazine with dendritic cell vaccines as first-line therapy for Chinese patients with advanced acral lentiginous melanoma

Objective: To investigate fotemustine plus dacarbazine (DTIC) with dendritic cell (DC) vaccines on patients with advanced acral lentiginous melanoma (ALM). Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with (DTIC). DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods: This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m2, d1, 12, DTIC 400 mg/d d2(6, DC vaccines subcutaneously d7, 9, 13 repeated every 28 days. Ten HLA-A02+24+ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 (Mart-1) and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival (PFS). Secondary end-points were overall survival (OS), overall response rate (ORR) and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors (RECIST). Results: The 15 men and 13 women had a median age of 51 years. 16 patients had stage M1c disease and 11/16 had liver metastasis. Patients received an average of 3.82(1.25 cycles. Follow-up for the 18 surviving patients ranged from 7(41 months with a median of 12 months. Median PFS was 8.5 months (95% CI: 7.86(15.21) with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months (95% CI: 10.33(18.24). ORR (CR+PR) was 35.7% including 3 complete response (CR) and 7 partial response (PR). Six patients had disease stable. A total of 19 Grade III/IV toxicities were observed including thrombocytopenia (n=8), neutropenia (n=5), fatigue (n=6) and hypersensitivity reaction (n=1). One patient died of Grade IV thrombocytopenia. Conclusion: Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The regimen brings clinical benefit with a higher ORR and may provide a survival advantage. Updated survival data will be presented.