Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.
OBJECTIVE
To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain.


BACKGROUND
Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma.


METHODS
Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks.


RESULTS
Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months).


CONCLUSIONS
WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.
Margolin
K
K
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA. kmargolin@coh.org
Atkins
B
B
Thompson
A
A
Ernstoff
S
S
Weber
J
J
Flaherty
L
L
Clark
I
I
Weiss
G
G
Sosman
J
J
II Smith
W
W
Dutcher
P
P
Gollob
J
J
Longmate
J
J
Johnson
D
D
D000284:Administration, Oral; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy* / Q000556:secondary*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000532:radiotherapy* / Q000556:secondary*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000473:pathology*; D000077204:Temozolomide; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide