Strahlentherapie und Onkologie Original Article Optimizing Cancer Radiotherapy with 2-Deoxy- D-Glucose Dose Escalation Studies in Patients with Glioblastoma Multiforme Dinesh Singh 1 , Ajit K. Banerji 2 , Bilikere S. Dwarakanath 3 , Rajendra P. Tripathi 3 , Jaganath P. Gupta 1 , T. Lazar Mathew 3 , Turuga Ravindranath 3 , Viney Jain 4 Background and Purpose: 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-de- oxy-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 γ-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. Patients and Methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of 60 Co γ-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evalua- tion) 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. Conclusion: 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. Key Words: 2-deoxy-D-glucose · Glioblastoma multiforme · Radiotherapy · Dose escalation · Safety and tolerance Strahlenther Onkol 2005;181:507–14 DOI 10.1007/s00066-005-1320-z Optimierte Krebsbestrahlung mit 2-Deoxy-D-Glukose. Dosiseskalationsstudien bei Patienten mit Glioblastoma multiforme Hintergrund und Ziel: Erhöhter Glukoseverbrauch und verstärkte Glykolyse korrelieren bei einigen Malignomformen generell mit schlechter Prognose. Eigene Untersuchungen an Modellsystemen zeigten, dass die nichtmetabolisierbare Glukoseverbindung 2-Deoxy-D-Glukose (2-DG) die Wirksamkeit der Strahlentherapie dosisabhängig verstärken kann, indem sie selektiv Krebszellen sensibilisiert, dagegen auf normale Zellen protektiv wirkt. Klinische Phase-I/II-Studien sprechen dafür, dass die Kombination von 2-DG (in einer oralen Dosis von 200 mg/kg Körpergewicht) mit großen Fraktionen einer γ-Strahlung von Patienten mit Hirntumo- ren gut vertragen wird. Da man erwartet, dass höhere 2-DG-Dosierungen das therapeutische Ansprechen verbessern, wurden die hier vorgestellten Untersuchungen unternommen, um an Glioblastoma-multiforme-Patienten Verträglichkeit und Sicherheit der Dosiseskalation von 2-DG in der Kombinationsbehandlung (2-DG + Radiotherapie) zu prüfen. Patienten und Methodik: In die Studie wurden nicht vorbehandelte Patienten mit histologisch belegtem Glioblastoma multi- forme (WHO-Kriterien) eingeschlossen. Das Tumorvolumen (gemäß präoperativer CT/MRT-Auswertung) plus ein 3-cm-Sicherheits- saum wurden wöchentlich mit sieben Fraktionen einer 60 Co-γ-Strahlung (5 Gy/Fraktion) behandelt. In ansteigender Dosierung Received: May 25, 2004; accepted: May 13, 2005 1 Dharmshila Cancer Hospital, New Delhi, India, 2 Vidyasagar Institute of Mental Health and Neurosciences, New Delhi, India, 3 Institute of Nuclear Medicine and Allied Sciences, Delhi, India, 4 Department of Emergency Medicine and Department of Nuclear Medicine, Kettering Medical Center, Wright State University, Dayton, OH, USA. 507 Strahlenther Onkol 2005 · No. 8 © Urban & Vogel