Medscape Medical News 2008. © 2008 Medscape
September 16, 2008 (Stockholm, Sweden) — One of the largest trials conducted in advanced melanoma to date has found that the oral drug temozolomide (Temodal, Schering-Plough) was no better than standard dacarbazine therapy, which is administered intravenously.
The trial, conducted in 859 patients with stage 4 melanoma, was reported here at the 33rd European Society for Medical Oncology Congress.
"Dacarbazine has been the standard therapy for this group of patients for the past 20 years or so," said lead investigator Poulam Patel, MD, from Nottingham University, in the United Kingdom, "and so far nothing has surpassed it. The results of this trial suggest that dacarbazine should remain the standard treatment."
This is the latest in a line of disappointments in the melanoma field, commented discussant Lorenz Jost, MD, from Kantonsspital Bruderholz, in Switzerland. There have been many red traffic lights on these roads, "so far we can't see a way that looks like a highway," he said.
Better Response, But No Effect on Survival
Stage 4 melanoma is generally incurable, and largely accounts for the 48,000 deaths from melanoma seen annually, Dr. Patel commented. It accounts for about 20% to 30% of all cases of melanoma that occur annually; many patients present with localized disease and can be cured with surgery.
Temozolomide is already marketed for use in various brain cancers, but in this trial it was administered at an escalated dose in an extended-dosage schedule (150 mg/m2 orally for 7 days, repeated every 14 days). "This schedule allows much more of the drug to be given," Dr. Patel said, and "our trial showed that this dosing regimen was feasible."
Temozolomide showed a significantly better overall response rate than dacarbazine (14.4% vs 9.8%; P =.05). However, progression-free survival was very similar for both drugs (2.3 months for temozolomide vs 2.17 months for dacarbazine; P = .27), as was the median overall survival (9.13 vs 9.36; P = 1.0). Both of these survival rates are very similar to what has been seen in previous trials of dacarbazine, Dr. Patel commented.
Temozolomide was "slightly more toxic" than dacarbazine, but it had an acceptable safety profile, Dr. Patel said. There was a higher rate of lymphopenia (reported by 45% of patients on temozolomide and 9% on dacarbazine), although the rates for the other hematologic adverse events (leucopenia, anemia) and nonhematologic events (such as fatigue, nausea, and vomiting) were similar for both drugs. There were no treatment-related deaths in either group.
When asked whether temozolomide might be preferred because it is an oral drug and the results suggest it is about the same as dacarbazine, Dr. Patel replied: "This trial was designed to show an improvement in survival, and it would take a larger trial to show that the oral drug is equivalent to the intravenous drug."
In his discussion, Dr. Jost said clinicians could consider using the oral drug in patients who have problematic venous access, liver failure, or asymptomatic brain metastases (although a benefit here is not proven, he pointed out). "But only if cost is not an issue," he added.
Dr. Jost also made the point that dacarbazine, although a standard treatment in this patient population for years, is unproven. "There are no data comparing this drug with best supportive care, so we do not know whether it extends survival. Even worse, there is no proof that it doesn't shorten survival," he pointed out. "So temozolomide is no better than dacarbazine, but we don't know that dacarbazine is good," he said.
Genetic Variant Linked to Melanoma
In a separate presentation, a link was reported between the cyclin D1 gene and susceptibility to melanoma. The results come from a study of 1053 people, including 161 patients with melanoma and 892 healthy controls, reported by Raquel Catarino, PhD, and colleagues from the Portuguese Institute of Oncology, in Porto.
Dr. Catarino and colleagues found that people who carry 2 copies of the gene variant were 80% more likely to develop melanoma. "Our results indicate that the proportion of melanoma cases attributable to this genetic alternation is 14%," she added.
"Our study demonstrates that cyclin D1 polymorphism is associated with a higher risk of melanoma development, indicating that this genetic variation may confer a growth advantage to cancer cells," Dr. Catarino commented. Previous studies have suggested that cyclin D1 is an important oncogene in melanoma, making it a candidate for further evaluation as a therapeutic target in this disease, the researchers commented.
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