A theoretical dose-escalation study based on biological effective dose in radioimmunotherapy with (90)Y-ibritumomab tiuxetan (Zevalin)

Abstract

Aim: To investigate the variation in biological effective dose (BED) produced by the uncertainty in absorbed dose and radiobiological parameters in Zevalin radioimmunotherapy.

Methods: Eight patients scheduled for treatment with standard administration of (90)Y-ibritumomab tiuxetan (Zevalin) were studied. Patient-specific pretherapy dosimetry was performed by injection of (111)In-ibritumomab tiuxetan. Absorbed doses and BEDs were calculated for critical organs (COs) and tumours, assuming a 30% dose uncertainty and varying the radiobiological parameters in a reasonable range. In an activity-escalation study, BEDs for the COs were compared with the BED limits of external beam radiotherapy (EBRT) and BEDs for the tumour with the EBRT dose prescriptions.

Results: At standard activities, the absorbed doses per unit activity for the COs were in agreement with those in the literature. Absorbed doses to lesions were rather variable, ranging from 1.47 to 16.7 Gy/GBq. Median tumour absorbed dose to lesions in the range 80-110 g was 9.6 Gy/GBq (range 9.2-16.7 Gy/GBq), yielding a mean BED of about 12 Gy for administration of 15 MBq/kg. For the administration of the myeloablative activity of 45 MBq/kg, risk of liver toxicity in one patient would have been foreseen by the model. Considering also the dose uncertainty, the potential risk of liver toxicity in one more patient, lung toxicity in one patient, and kidney toxicity in one patient would have been suggested. The absorbed dose uncertainty was found to be the main source of uncertainty in the BED. As for radiobiological parameters, at myeloablative activities, the increase in the repair half-time for sublethally damaged tissue (T(mu)) from 0.5 h to 5 h induced more consistent increases in mean BED/BED(limit) than alpha/beta variation from 2 Gy to 5 Gy: at 53 MBq/kg, 38% for the liver, and 34% for the lungs and kidneys (about threefold higher than that obtained for the increase alpha/beta).

Conclusion: At standard activities, absorbed doses to lesions appear to be effective, even though lower than prescribed by EBRT. At myeloablative dosages, the uncertainty associated with the absorbed doses and radiobiological parameters considerably affect BED evaluation and may account for possible "second-organ" toxicities.