LONDON, UK -- January 24, 2000 -- 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. The study found that temozolomide is "at least" as effective as DTIC, a current standard treatment for patients with advanced metastatic melanoma, and that patients receiving temozolomide suffered less from fatigue and insomnia.
"Temozolomide shows the potential to become a significant treatment
option for patients with metastatic melanoma because it may extend their
lives, while improving the quality of life," said Mark Middleton, M.D.,
Senior Clinical Research Fellow for the Cancer Research Campaign, a
leading British research charity. "As an oral formulation, temozolomide is
convenient for patients, because they can swallow a capsule at home, where
intravenous treatments like DTIC require an injection at the hospital,"
said Middleton, lead investigator for the trial.
Melanoma accounts for about 4 percent of skin cancer cases, but causes
about 79 percent of skin cancer deaths. The number of new cases has
tripled in the last 40 years. The American Cancer Society estimated that
about 44,200 new melanomas would 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 an average of six months after
Temozolomide, an oral cytotoxic alkylating agent, is the lead compound
in a new class of compounds known as imidazotetrazines. Cytotoxic agents
are designed to prevent the replication of cells that divide rapidly,
including those in tumors.
The randomized, multicenter phase III study compared the effectiveness
of temozolomide to that of dacarbazine (DTIC), the current standard
treatment, in 305 patients with advanced, metastatic melanoma
(intent-to-treat population). Disease-related complications caused 18
patients (10 temozolomide, 8 DTIC) to be ineligible for treatment, and
seven more deteriorated unexpectedly or withdrew their consent. The
remaining 280 patients made up the treated-eligible population, patients
with previously untreated advanced, metastatic melanoma not involving the
central nervous system who received one dose of either study drug. 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 patients
receiving 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
survival advantage was not statistically significant (P =.20), but a 95
percent confidence interval (CI = 0.92 - 1.52) for the hazard ratio
indicated that treatment results with temozolomide were, statistically, at
least equivalent to DTIC.
The trend favoring temozolomide was also observed in the
treated-eligible population, where the median survival was two months
longer for patients receiving temozolomide (7.9 vs. 5.7 months; P = .054).
At six months, 61 percent of patients receiving temozolomide had survived,
compared to 51 percent of patients receiving DTIC (P =.063).
The tumor response rates for both drugs were similar. The percentage of
patients responding to temozolomide (complete response plus partial
response) was 13.5 percent (22/156 patients) and the complete response
rate was 2.6 percent (4/156 patients). In the DTIC population, the overall
response rate was 12.1 percent (18/149 patients) and the complete response
rate was 2.7 percent (4/149 patients). A complete response equaled
resolution of the tumor for two consecutive months. A decrease of more
than 50 percent in the tumor area for two consecutive months represented a
"Both treatments use a similar chemical pathway to interfere with tumor
growth, but temozolomide, taken orally, delivers twice as much
cancer-fighting agent to the system as DTIC, an intravenous treatment,
even when DTIC is given in higher doses," Middleton said. "This may help
to explain the superior efficacy of temozolomide in parts of this study,"
Temozolomide significantly improved quality of life when compared to
DTIC after 12 weeks of treatment, according to patient questionnaires.
Researchers found that 96 percent of patients receiving temozolomide said
they had maintained or improved cognitive function (perception, reasoning,
memory), compared to 77 percent of patients receiving DTIC. During the
same period, 86 percent of patients receiving temozolomide reported that
they had maintained or improved physical function, compared to 68 percent
of patients receiving DTIC. Patients receiving temozolomide also reported
significantly lower rates of fatigue and insomnia.
Both drugs were well tolerated, with most adverse events being mild to
moderate in severity. The most common side effects observed with
temozolomide were nausea (52 percent), vomiting (34 percent), pain (34
percent) and constipation (33 percent). In the DTIC group, patients most
often experienced pain (39 percent), nausea (38 percent), constipation (29
percent) and vomiting (24 percent). Nausea and vomiting were readily
controlled by antiemetic therapy for both groups.
Myelosuppression (thrombocytopenia and neutropenia), or reduced
production of blood cells and platelets in the bone marrow, was a
dose-limiting adverse event for both temozolomide and DTIC. The effect
usually occurred within the first few cycles of therapy, was not
cumulative and resolved itself within nine days. Discontinuation of
therapy due to adverse events was uncommon (3 percent for the temozolomide
group vs. 5 percent 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 future improvements in the efficacy of temozolomide. MGMT repairs
tumor cell DNA as temozolomide attempts to disable the DNA (prevent the
cell from replicating). In addition, MGMT levels decrease in presence of
Clinical trials are currently investigating whether subsequent doses of temozolomide, administered when MGMT levels are already reduced, will increase cytotoxity and tumor response rates.