The ALLEGRO project: what is the relevance of second cancers after oncological treatment, and which information is required?

The ALLEGRO Project (Early and late health risks to normal/healthy tissues from the use of existing and emerging techniques for radiation therapy, EU Nr. 231965) addresses various aspects of radiation effects in normal tissues that are currently not well understood. For adult cancer patients, the risk for radiotherapy-induced second cancers is reported at a few percent (with large uncertainty), and hence is comparable to the usually accepted risk for severe late normal tissue complications. The risk of cancer induction from radiation therapy is not well understood. Clinical data suggest that second cancers are likely in the regions near the high-dose treatment volume, i. e. the field margins, as well as at distant sites in low-dose volumes. Indirect induction of second cancers can emerge from the radiation-induction of chronic hyperproliferative inflammatory processes (e. g. in intestine or urinary bladder), which represent pre-cancerous lesions, which occur in high dose volumes. This introduces a deterministic component into the stochastic nature of cancer development after radiation exposure. Hence, the relationship of the probability of second cancers to dose is highly complex. Moreover, several confounding factors must be considered. These include, besides an individual predisposition of the patient, persisting exposure to the initial carcinogen, but also additional chemotherapy and, more recently, administration of "biologicals". With new treatment modalities such as highly conformal photon or particle therapy, the dose distribution within the patient usually are substantially modified, which may be associated with a considerable change in the risk for secondary tumours. It is essential to be able to quantify and predict this risk for existing and evolving treatment modalities, respectively, so that an optimal treatment choice can be made. Institutional and other databases and registries of second cancers are evaluated with regard to the feasibility and ease of extraction of sufficiently detailed data on patient-related parameters, additional therapies, and treatment parameters. Examples will be presented. Options for reconstruction of radiation dose and dose distributions, both in low-dose and high-dose volumes, in relation to the site of the origin of a second tumour, based on patient files and existing documentation in the individual institutions, are tested. This includes an analysis of the uncertainties of the estimates. Dose reconstruction is compared to measurements of the distribution to the dose from photons, ions, and neutrons absorbed outside the treatment volume in cancer treatment scenarios with X-rays, protons and carbon ions. This is performed with both water phantoms as well as in realistic configurations. Factors potentially influencing the second cancer risk must be identified (e. g. age, gender, site of the primary tumour), as well as potentially confounding factors. In parallel, models to describe and predict second cancer risks after various radiotherapy modalities are designed and validated with the data processed from the databases.Results from the second cancer studies within the ALLEGRO project will be presented and discussed, and particularly the requirements with regard to databases and registries for data retrieval, as well as to procedures for dose reconstruction will be addressed.