Temozolomide Holds Promise for Patients with Advanced Metastatic Melanoma

Temozolomide Holds Promise for Patients with Advanced Metastatic Melanoma A recently approved oral treatment for brain cancer has proven to be effective against the deadliest form of skin cancer, according to a study published in the January edition of the Journal of Clinical Oncology. news pharmacotherapy,hematology/oncology, neurology/neurosurgery MedscapeWire is edited by Deborah Flapan, an associate editor at Medscape. Send press releases and comments to medscapewire2@medscapeinc.com. Medscape Portals, Inc MedscapeWire 01/28/2000 <H4>Introduction</H4> New York (MedscapeWire) Jan 28 A recently approved oral treatment for brain cancer has proven to be effective against the deadliest form of skin cancer, according to a study published in the January edition of the <cite>Journal of Clinical Oncology.</cite> The study found that temozolomide is "at least" aseffective as dacarbazine (DTIC), a current standard treatment for patients with advancedmetastatic melanoma, and that patients receiving temozolomide suffered lessfrom fatigue and insomnia. "Temozolomide shows the potential to become a significant treatment optionfor patients with metastatic melanoma because it may extend their lives, whileimproving the quality of life," said Mark Middleton, MD, senior clinicalresearch fellow for the Cancer Research Campaign, a leading British researchcharity. "As an oral formulation, temozolomide is convenient for patients,because they can swallow a capsule at home, where intravenous treatments likeDTIC require an injection at the hospital," said Middleton, lead investigatorfor the trial. Melanoma accounts for about 4% of skin cancer cases, but causes about 79%of skin cancer deaths. The number of new cases has tripled in the last 40years. The American Cancer Society estimated that about 44,200 new melanomaswould be diagnosed in 1999, and that the disease would cause 7300 deaths.Patients with the most advanced stage of the disease (stage IV) survive for anaverage of 6 months after diagnosis. Temozolomide, an oral cytotoxic alkylating agent, is the lead compound ina new class of compounds known as imidazotetrazines. Cytotoxic agents aredesigned to prevent the replication of cells that divide rapidly, includingthose in tumors.The randomized, multicenter phase III study compared the effectiveness oftemozolomide with that of DTIC, the current standard treatment, in305 patients with advanced, metastatic melanoma (intent-to-treat population).Disease-related complications caused 18 patients (10 who received temozolomide, 8 who received DTIC) tobe ineligible for treatment, and 7 more deteriorated unexpectedly or withdrewtheir consent. The remaining 280 patients made up the treated-eligible population, patients with previously untreated, advanced metastatic melanomanot involving the central nervous system who received a single dose of either studydrug. The main goals of the study were to measure overall survival,progression-free survival, objective response, and quality of life. In the intent-to-treat population, median overall survival for patientsreceiving temozolomide was 1.3 months longer than for patients receiving DTIC(average 7.7 vs 6.4 months) with a hazard ratio of 1.18. The survivaladvantage was not statistically significant (P=.20), but a 95% confidenceinterval (CI=0.92-1.52) for the hazard ratio indicated that treatmentresults with temozolomide were, statistically, at least equivalent to DTIC. The trend favoring temozolomide was also observed in the treated-eligiblepopulation, where the median survival was 2 months longer for patientsreceiving temozolomide (7.9 vs 5.7 months; P=.054). At 6 months, 61% of patients receiving temozolomide had survived, compared with 51% of patients receiving DTIC (P=.06). The tumor response rates for both drugs were similar. The percentage ofpatients responding to temozolomide (complete response plus partial response)was 13.5% (22 of 156 patients) and the complete response rate was 2.6% (4 of 156patients). In the DTIC population, the overall response rate was 12.1%(18 of 149 patients) and the complete response rate was 2.7% (4 of 149 patients).A complete response equaled resolution of the tumor for 2 consecutive months.A decrease of more than 50% in the tumor area for 2 consecutive monthsrepresented a partial response. "Both treatments use a similar chemical pathway to interfere with tumorgrowth, but temozolomide, taken orally, delivers twice as much cancer-fightingagent to the system as DTIC, an intravenous treatment, even when DTIC is givenin higher doses," Middleton said. "This may help to explain the superiorefficacy of temozolomide in parts of this study," he said. Temozolomide significantly improved quality of life when compared with DTICafter 12 weeks of treatment, according to patient questionnaires.Researchers found that 96% of patients receiving temozolomide said they hadmaintained or improved cognitive function (perception, reasoning, memory),compared with 77% of patients receiving DTIC. During the same period, 86% ofpatients receiving temozolomide reported that they had maintained or improvedphysical function, compared with 68% of patients receiving DTIC. Patientsreceiving temozolomide also reported significantly lower rates of fatigue andinsomnia. Both drugs were well tolerated, with most adverse events being mild tomoderate in severity. The most common adverse effects observed withtemozolomide were nausea (52%), vomiting (34%), pain (34%), and constipation(33%). In the DTIC group, patients most often experienced pain (39%), nausea(38%), constipation (29%), and vomiting (24%). Nausea and vomiting werereadily controlled by antiemetic therapy for both groups. Myelosuppression (thrombocytopenia and neutropenia), or reduced productionof blood cells and platelets in the bone marrow, was a dose-limiting adverseevent for both temozolomide and DTIC. The effect usually occurred withinthe first few cycles of therapy, was not cumulative, and resolved itself within9 days. Discontinuation of therapy due to adverse events was uncommon (3%for the temozolomide group vs 5% for the DTIC group). Study investigators concluded that a growing understanding of the enzyme,MGMT, which helps tumors resist the effect of temozolomide, may lead to futureimprovements in the efficacy of temozolomide. MGMT repairs tumor cell DNA astemozolomide attempts to disable the DNA (to prevent the cell from replicating).In addition, MGMT levels decrease in presence of temozolomide. Clinicaltrials are currently investigating whether subsequent doses of temozolomide,administered when MGMT levels are already reduced, will increase cytotoxityand tumor response rates.