MANCHESTER, UKOral temo-zolomide (Temodar) is as effective as
intravenous dacarbazine (DTIC) in advanced metastatic malignant
melanoma and is a reasonable alternative for many patients, according
to a phase III trial. Temozolomide (TMZ) can be given as outpatient
treatment and was superior to DTIC at maintaining or improving
physical function, fatigue, and insomnia.
The agent is FDA approved in the United States for use in treating
adult patients with anaplastic astrocytoma who have relapsed after
chemotherapy including a nitrosourea and procarbazine.
An Important Role
Lead investigator Mark R. Middleton, MD, said that the improvements
in overall survival, progression-free survival, and some
quality-of-life (QOL) domains, along with the acceptable safety
profile and ability to penetrate the central nervous system (CNS),
suggest that TMZ could play an important role in the future
management of this disease.
Dr. Middleton is in the Department of Medical Oncology at Christie
Hospital, Manchester, United Kingdom.
This is an oral alternative to DTIC that requires further
evaluation with regard to schedule and combination with other agents,
and in specific indications such as intracerebral disease, Dr.
Middleton told ONI in an interview.
Treatment of advanced metastatic melanoma remains palliative. Median
survival time is about 6 months for patients with stage IV disease.
Estimated 5-year survival is 6%.
Dr. Middleton and his colleagues decided to compare TMZ to a standard
regimen of DTIC in a randomized, double-blind, phase III trial in an
attempt to increase overall survival and to improve treatment
tolerability and ease of administration. The study was powered to
detect a 3-month (50%) difference in median survival time between treatments.
Temozolomide and DTIC are both prodrugs of the alkylating agent
Temozolomide was chosen for this comparison because it has 100% oral
bioavailability and wide tissue distribution, including crossing the
blood-brain barrier and entering the cerebrospinal fluid.
The researchers enrolled 305 patients with advanced metastatic
melanoma, 287 of whom were randomized to receive either oral TMZ (200
mg/m²/d × 5 days every 28 days) or intravenous DTIC (250
mg/m²/d × 5 days every 21 days). Patients with previous
treatment for metastatic disease other than radiation were not
eligible for the study, and patients with CNS metastases were
Treatment was continued for up to 12 cycles unless there was disease
progression or intolerable toxicity. The effects of treatment were
assessed with clinical and radiologic examination and with the
European Organization for Research and Treatment of Cancer (EORTC)
quality-of-life questionnaire (QLQ-C30). The researchers also
measured plasma concentrations of TMZ, DTIC, and MTIC.
Intention-to-treat analysis showed median overall survival times of
7.7 months with TMZ vs 6.4 months with DTIC (P = .20; hazards ratio,
1.18; 95% confidence interval, 0.92 to 1.52) (J Clin Oncol
Median progression-free survival was significantly better with TMZ
(1.9 vs 1.5 months) (P = .012; hazards ratio, 1.37), but Dr.
Middleton said that this difference probably occurred because
patients treated with DTIC were examined for progression 2 weeks
earlier than those treated with TMZ.
Trying to Find a Better Treatment
We were trying to find a better treatment for melanoma than
DTIC. That TMZ is more tolerable with the same efficacy is of
benefit, but falls short of what we had hoped to discover, Dr.
Middleton said in an interview with ONI.
He continued, I dont think one can claim that TMZ might
be more effective on the basis of improved disease-free survival, as
this is largely an artifact of the protocol for disease reassessment
in the two treatment groups. That TMZ may be more effective is
possible, but our study was only powered to detect a 50% improvement
in overall survival. A larger study (requiring 600 to 1,000 patients)
would be needed to detect a smaller improvement, but such a study
will never be done.
Complete response rates and overall response rates were similar for
the two groups.
Both treatments were fairly well tolerated, with most adverse events
being mild to moderate in severity. Myelosuppres-sion was not
cumulative and resolved within 9 days. Grade 3-4 thrombocytopenia
occurred in 11% of TMZ cycles and 7% of DTIC cycles. Grade 3-4
neutropenia occurred in 11% of TMZ cycles and 13% of DTIC cycles.
The most common adverse events in the patients receiving TMZ were
nausea (52% of patients), vomiting (34%), pain (34%), and
constipation (30%). The most common adverse events with DTIC were
pain (39%), nausea (38%), constipation (29%), and vomiting (24%).
Only 3% of TMZ patients and 5% of DTIC patients discontinued
treatment due to toxicity, however.
Quality of Life Results
Patients completed questionnaires at 12 weeks after the beginning of
treatment to assess effects on health-related QOL. At 12 weeks,
statistically significant differences favoring the
temo-zolomide-treated group were observed for physical functioning,
fatigue, and insomnia. No significant differences were observed for
the remaining QLQ-C30 scores, Dr. Middleton said.
When only responders were considered, the TMZ patients reported
better physical functioning and less insomnia, and there was a
significant advantage in the physical and cognitive functioning
domains for the temozolomide-treated group, compared with the
DTIC-treated group, he said.
Pharmacokinetic analysis showed that although intravenous DTIC was
given at a higher dose, systemic exposure to the active intermediate
MTIC was twice as high in patients treated with oral temozolomide.
According to Dr. Middleton, mean systemic exposure to MTIC is so much
higher with oral temozolomide because DTIC must go through a
metabolic transformation to active MTIC, while temo-zolomide
spontaneously converts to MTIC under physiologic conditions. I
was surprised that there was so much difference in the MTIC exposure
between the two agents, he said.
In conclusion, Dr. Middleton said that the study confirmed phase II
trial data showing that temozolomide is at least as effective against
advanced metastatic melanoma as DTIC. Although the trend in overall
survival favored temozolomide, the difference did not reach the 50%
increase required for statistical significance in a sample this size.