Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.
OBJECTIVE
Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas.


METHODS
Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria.


RESULTS
A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival.


CONCLUSIONS
Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.
Fine
H A
HA
Center for Neuro-Oncology, Dana-Farber Cancer Institute, and Departments of Neurology, Surgery, and Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Figg
W D
WD
Jaeckle
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K
Wen
P Y
PY
Kyritsis
A P
AP
Loeffler
J S
JS
Levin
V A
VA
Black
P M
PM
Kaplan
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Pluda
J M
JM
Yung
W K
WK
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003248:Constipation / Q000139:chemically induced; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012074:Remission Induction; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D006993:Hypnotics and Sedatives; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide