Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma.
OBJECTIVE
Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma.


METHODS
One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of temozolomide 200 mg/m2 every 8 hours for five doses, or temozolomide 200 mg/m2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or temozolomide 150 mg/m2 (increased after one cycle to 200 mg/m2) daily on days 1 to 5 plus thalidomide 100 mg daily days 1 to 28.


RESULTS
The treatment arms were well balanced for known prognostic factors. Median survival was 5.3 months for 8-hourly temozolomide, 7.7 months for temozolomide/interferon, and 7.3 months for temozolomide/thalidomide; and 1-year survivals were 18%, 26%, and 24%, respectively. Response or disease stabilization occurred in 20% of patients (95% confidence interval [CI], 10% to 33%) given 8-hourly temozolomide, 21% (95% CI, 12% to 33%) given temozolomide/interferon, and 25% (95% CI, 15% to 38%) given temozolomide/thalidomide. Grade 3 or 4 nonhematologic toxicities were similar in each arm except for infection, which was more frequent with 8-hourly temozolomide. There were fewer instances of grade 3 or 4 myelotoxicity with temozolomide/thalidomide.


CONCLUSIONS
Of the three regimens tested, the combination of temozolomide and thalidomide seems the most promising for future study.
Danson
S
S
Christie Hospital, Manchester, United Kingdom. sdanson@fsmail.net
Lorigan
P
P
Arance
A
A
Clamp
A
A
Ranson
M
M
Hodgetts
J
J
Lomax
L
L
Ashcroft
L
L
Thatcher
N
N
Middleton
M R
MR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013534:Survival; D000077204:Temozolomide; D013792:Thalidomide / Q000008:administration & dosage
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013792:Thalidomide; D003606:Dacarbazine; D000077204:Temozolomide