Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme.
OBJECTIVE
Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of gamma-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients.


METHODS
Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of (60)Co gamma-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200-250-300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients.


RESULTS
Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who received complete treatment and survived between 11 and 46 months after treatment.


CONCLUSIONS
Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.
Singh
Dinesh
D
Dharmshila Cancer Hospital, New Delhi, India.
Banerji
Ajit K
AK
Dwarakanath
Bilikere S
BS
Tripathi
Rajendra P
RP
Gupta
Jaganath P
JP
Mathew
T Lazar
TL
Ravindranath
Turuga
T
Jain
Viney
V
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003847:Deoxyglucose / Q000008:administration & dosage* / Q000009:adverse effects; D019583:Dose Fractionation, Radiation; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality / Q000532:radiotherapy*; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000009:adverse effects; D011879:Radiotherapy Dosage; D013997:Time Factors
D003037:Cobalt Radioisotopes; D019275:Radiopharmaceuticals; D003847:Deoxyglucose