Abstract
Background and purpose: We tested a novel treatment approach combining (1) targeting radioresistant hypoxic tumour cells with the hypoxia-activated prodrug TH-302 and (2) inverse radiation dose painting to boost selectively non-hypoxic tumour sub-volumes having no/low drug uptake.
Material and methods: F-18-HX4 hypoxia tracer uptake measured with a clinical PET/CT scanner was used as a surrogate of TH-302 activity in rhabdomyosarcomas growing in immunoc6mpetent rats. Low or high drug uptake volume (LDUV/HDUV) was defined as 40% of the GTV with the lowest or highest F-18-HX4 uptake, respectively. Two hours post TH-302/saline administration, animals received either single dose radiotherapy (RT) uniformly (15 or 18.5 Gy) or a dose-painted non-uniform radiation (15 Gy) with 50% higher dose to LDUV or HDUV (18.5 Gy). Treatment plans were created using Eclipse treatment planning system and radiation was delivered using VMAT. Tumour response was quantified as time to reach 3 times starting tumour volume.
Results: Non-unifOrm RT boosting tumour sub-volume with low TH-302 uptake (LDUV) was superior to the same dose escalation to HDUV (p <0.0001) and uniform RT with the same mean dose 15 Gy (p = 0.0077). Noteworthy, dose escalation to LDUV required on average 3.5 Gy lower dose to the GTV to achieve similar tumour response as uniform dose escalation.
Conclusions: The results support targeted dose escalation to non-hypoxic tumour sub-volume with no/low activity of hypoxia-activated prodrugs. This strategy applies on average a lower radiation dose and is as effective as uniform dose escalation to the entire tumour. It could be applied to other type of drugs provided that their distribution can be imaged. 2017 The Author(s). Published by Elsevier Ireland Ltd.
Original language | English |
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Pages (from-to) | 513-520 |
Number of pages | 8 |
Journal | Radiotherapy and Oncology |
Volume | 124 |
Issue number | 3 |
DOIs | |
Publication status | Published - Sept 2017 |
Event | 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology - SWITZERLAND, Switzerland Duration: 17 Jun 2017 → 19 Jun 2017 |
Keywords
- Dose-painting
- HX4 PET
- Hypoxia-activated prodrug
- TH-302
- Growth delay
- Radiotherapy
- Rat rhabdomyosarcoma
- SQUAMOUS-CELL CARCINOMA
- ACTIVATED PRODRUG TH-302
- NECK-CANCER PATIENTS
- PHASE-I TRIAL
- FRACTIONATED-IRRADIATION
- PROGNOSTIC VALUE
- LUNG-CANCER
- INTERNATIONAL MULTICENTER
- LOCAL-CONTROL
- NUDE-MICE