Defining the role for dosimetry and radiobiology in combination therapies

Abstract

The potential of combination therapies has long been recognized, and surgery, external beam radiotherapy (EBRT) and chemotherapy are often associated to maximize the probability of curative treatment. Molecular radiotherapy (MRT) is an attractive option as it combines the tumoricidal effect of EBRT with systemic therapy. The recent article by Ferrari et al. shows that MRT can play a key role in an overall cancer management strategy, particularly if radiopharmaceutical administration is personalized according to the absorbed dose delivered and if radiobiological considerations are taken into account [1]. The combination of surgery with radiotherapy has proven to be highly successful, not only for EBRT treatments but also for the ablation of thyroid remnants with radioiodine. IART® achieves specificity with a combination of targeting via avidin/biotin affinity and locoregional administration in the tumour bed following surgical excision. The multimodality approach is completed with subsequent irradiation with EBRT, which also targets the tumour bed, but for which normal tissues at risk differ. Ferrari et al. [1] rightly raise the issue of standards, an area that has been overlooked in MRT. Whilst there are a number of guidelines emerging for quantitative imaging and dosimetry, these have yet to be accepted as standards. A brief review of the literature will readily show a large variation in image acquisition and processing procedures, as well as in the levels and frequency with which activity is administered. This indicates the critical need for the community to gather and report evidence from which standards for all aspects of treatment can be formulated [2]. This is a daunting challenge as, in contrast to the situation for EBRT, there are few centres that treat large numbers of patients. To conduct the clinical trials necessary to define these standards and to develop evidence-based protocols, close collaboration between European centres is therefore required along with significant support. This becomes an even greater challenge for combined modality therapies. Overly sophisticated dosimetry is not always necessary. Although there is a growing tendency to evaluate threedimensional distributions of absorbed dose as long-awaited software becomes available, this article demonstrates that when uptake is reasonably uniform over the target volume the calculation of a mean absorbed dose is sufficient to give a biologically meaningful result. The range of treatment regimens followed requires dosimetry methods of varying complexity. Correlations between absorbed dose and clinical effect have been demonstrated both for relatively simple and for more refined imaging and dosimetry procedures. Barone et al. [3] demonstrated a correlation between the biologically effective dose and kidney toxicity using sequential Y PET imaging, target volumes derived from pretherapy CT scans and linear quadratic modelling to obtain radiobiological parameters. Conversely, Buckley et al. [4] found a correlation between the whole-body absorbed dose and marrow toxicity using only a series of external dose rate measurements. Such results are likely to impact patient management as personalized treatment emerges to replace current population-based approaches. For the purposes of radiation protection, as well as to optimize treatment, calculation of the absorbed doses delivered from MRT is essential. If the patient subsequently undergoes EBRT, dosimetry should be assessed for both modalities. However, this alone is not sufficient. As dose M. Bardies (*) UMR 1037 INSERM/UPS, Centre de Recherche en Cancerologie, 133 Route de Narbonne, 31062, Toulouse, France e-mail: manuel.bardies@inserm.fr