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Reuters Health Information (2014-03-26): For ocular melanoma mets to liver, intrahepatic fotemustine disappoints


For ocular melanoma mets to liver, intrahepatic fotemustine disappoints

Last Updated: 2014-03-26 11:37:11 -0400 (Reuters Health)

NEW YORK (Reuters Health) - For patients with uveal melanoma (UM) metastases in the liver, response rates and progression-free survival are only slightly better if fotemustine is given through the hepatic artery rather then intravenously, new data show.

The overall survival between the two methods is similar, and intrahepatic treatment should still be considered experimental, the authors reported online February 7 in Annals of Oncology.

"These findings provide further evidence that metastatic ocular melanoma to the liver is relatively unresponsive to traditional chemotherapy," said Dr. Hans E. Grossniklaus of Emory University School of Medicine, in an email to Reuters Health.

"New drugs and approaches are being developed that are specifically designed to target ocular melanoma molecular pathways, including the MEK inhibitor selumetinib, agents that boost immune rejection of the tumor in the liver, and agents that prevent growth of ocular melanoma micrometastases in the liver," said Dr. Grossniklaus, who was not involved in the study.

"It is a good idea to encourage patients with ocular melanoma to be treated at ocular oncology centers, especially if those centers are linked with National Cancer Institute-designated cancer centers. Ocular oncology centers generally provide the option of tumor biopsy for molecular classification, which may enable patients to be enrolled into ongoing clinical trials," he added.

To investigate the overall survival, response rate, progression-free survival (PFS), and safety of hepatic intra-arterial and IV fotemustine in patients with liver metastases from UM, lead author Dr. Serge Leyvraz of University Hospital in Lausanne, Switzerland and colleagues conducted an open-label multi-center phase III trial, EORTC 18021.

Eligible patients were at least 18 years old, untreated, with liver metastases from UM. Patients with extra-hepatic metastases, severe heart disease or active duodenal ulcer were excluded.

Eligible patients also had World Health Organization (WHO) performance status (PS) 0-2; absolute neutrophil count (ANC) at least 2.0  109/l; platelet count at least 100  109/l; and hemoglobin at least 10 g/dl. Liver enzymes had to be less than five times the upper limit of normal; and total bilirubin and serum creatinine had to be less than 1.5 times UNL.

Over six years, the researchers randomly assigned patients to receive either IV or intra-hepatic fotemustine at 100 mg/m2 on days 1, 8, 15 (and on day 22 in the intra-hepatic group only) as induction, followed by a five-week rest period, followed by maintenance every three weeks.

The researchers judged responses on the basis of tumor measurements taken by computed tomography (CT) or magnetic resonance imagery (MRI).

At the cutoff date, roughly one year after the last person was randomized, of the 171 patients studied, 155 had died and 16 were still alive. The median follow-up was 1.6 years (range 0.25 to 6).

The intra-hepatic and IV groups had similar overall survival, with a median of 14.6 and 13.8 months, respectively (hazard ratio 1.09; log-rank p=0.59).

PFS, however, was significantly better with intra-hepatic therapy, with a median of 4.5 vs 3.7 months, respectively (HR 0.62; log-rank p=0.002).

The one-year PFS rate was 24% in the intra-hepatic group compared with 8% in the IV group. The response rate was better with intra-hepatic therapy (10.5% vs 2.4%).

In the IV group, the most frequent grade 3 or higher toxicities were thrombocytopenia (42.1%) and neutropenia (62.6%), which occurred at lower rates in the intra-hepatic group (21.2% and 28.7%, respectively). The main intra-hepatic-related grade 3 or higher toxicities were catheter complications (12%), liver toxicity (4.5%), and two toxic deaths.

Dr. Ragini Kudchadkar, also of Emory University and also not involved in the study, observed in an email, "Because uveal melanoma has a tendency to involve just the liver, the theory was that if we were able to give higher doses directly to the tumor sites (i.e. intra-arterially to the liver) it would be more effective. However, this study shows that the overall outcomes are similar, despite having a slightly higher response rate with intrahepatic therapy."

"Metastatic uveal melanoma is a very clinically challenging disease," she said. "Treatments approved for metastatic cutaneous melanoma (i.e. ipilimumab, BRAF inhibitors, etc.) have not been effective in this disease. Therefore clinical trials should be the mainstay of treatment."

"Fotemustine is a nitrosurea chemotherapy agent that was not specifically developed to target ocular melanoma, and many now think that targeted therapy of metastatic ocular melanoma to the liver in its early stages using specifically designed agents hold the most promise," Dr. Grossniklaus said.

The corresponding author was unavailable for comment.


Ann Oncol 2014.

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