Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long term 1-alpha-hydroxycholecalciferol.
OBJECTIVE
Classical and new therapies in anaplastic astrocytomas and glioblastomas do not yield sufficient results. Agents able to redifferentiate neoplastic cells in vitro are known. We proposed alfacalcidol, a vitamin D analog able to bind to nuclear receptors regulating mitotic activity, in the treatment of malignant gliomas.


METHODS
Patients with glioblastomas and anaplastic astrocytomas were enrolled in a phase II trial involving surgery or biopsy, radiotherapy (64 Gy), chemotherapy with VM26-CCNU or fotemustine, and alfacalcidol at the daily dose of 0.04 microg/kg. MRI took place every 6 months.


RESULTS
Eleven patients were included and completed the study. The series involved 10 glioblastomas and 1 anaplastic astrocytoma. Three patients out of 11 patients (27%), 2 glioblastomas and 1 astrocytoma grade III, exhibited a particular response, consisting in the progressive regression of the radiological lesion, with a decrease of the gadolinium-enhanced area. Simultaneously, the patients showed a complete clinical remission, observed respectively for 7, 5 and 4 years. In the series of 10 patients with glioblastomas, 2 cases showed this response; after 4 years, 2 of 10 patients with glioblastomas (20%) were alive; the median survival time is 21 months. Normal or subnormal calcemia was observed, at the dose proposed, so that no interruption of the drug was necessary.


CONCLUSIONS
Alfacalcidol, an in vitro agent of redifferentiation, is safe and seems able to induce in some patients, in synergy with classical surgery-radiotherapy-chemotherapy treatments, a particular progressive and durable regression of the tumor. The responders might represent about 20% of malignant gliomas.
Trouillas
P
P
Neurology service, H pital Neurologique, Lyon, France. paul.trouillas@chu-lyon.fr
Honnorat
J
J
Bret
P
P
Jouvet
A
A
Gerard
J P
JP
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001254:Astrocytoma / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D002454:Cell Differentiation; D004334:Drug Administration Schedule; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006887:Hydroxycholecalciferols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016019:Survival Analysis
D000276:Adjuvants, Immunologic; D016588:Anticarcinogenic Agents; D006887:Hydroxycholecalciferols; C008088:alfacalcidol