Biological Dose Definition
The local biological dose obtained is calculated by multiplying the absorbed energy (in grey or gy) by a weighting factor that depends on the type of radiation. The resulting equivalent dose indicates how dangerous the radiation is to the organ or tissue in question. This risk factor can range from 1 for gamma rays, X-rays and beta electrons to 10 for neutrons and even up to 20 for alpha particles. The lower risk associated with electrons, gamma rays and X-rays is due to their low ionization capacity. BT can be administered at high, medium or low dose rates or HDR, MDR or LDR. For complete manuscripts that met the eligibility criteria, we collected information on the general characteristics of the articles: article title, study phase, cancer location, molecules tested (individual or associated), type of therapeutic agents, primary and secondary targets, primary and secondary endpoints (under toxicity and efficacy), and dose determination design. We collected definitions for OBD, BAT, DLT and the observation period for the DLT assessment. Nowadays, the function of radiation sensitivity studies of energy dose (d) is described with cell survival (S), which is complementary to cell destruction (K), and probabilistically S = 1-K. These studies are largely modeled using LQ S(d) for a fraction, as radiobiological (RB) simulators show that radiation produces biological effects of radiation (RBEfs) instead of BED, which is only a mathematical result of processing the exponential part of the linear-quadratic cell survival model for fractional treatment, LQ S(n, D).
It will be a big inconsistency if we continue to use the BED, which is not an actual physical quantity. Killed and damaged subleasable cells define RBEf. The surviving cells complement each other at the former, i.e. S = 1 − K, where S: cell survival and K: cell destruction. Hariharan S, Gustafson D, Holden S, McConkey D, Davis D, Morrow M, et al. Evaluation of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist cilengitide (EMD 121974) in patients with advanced solid tumors. Ann Oncol 2007;18:1400–7. While the expression BED, equation (3), has only one parameter, α/β, the LQS(n,D) has two: α and β.
Therefore, a tissue with α = 1 Gy−1 and α/β = 10 Gy, which receives 60 Gy in 30 fractions, i.e. d = 2 Gy, has a biological radiation effect of 9.1% of cell survival. (1) represents the probability of cell survival, i.e. the average ratio of sublethal damaged cells and the sum of these when a particular living tissue marked with the parameters α and α/β is irradiated homogeneously at a fraction of dose d. For this reason, this equation can be considered for each healthy cell of a particular tissue as a probability of entering the surviving cell after irradiation. Since cell destruction is a probabilistic complement to cell survival, then the probability of cell destruction is equal to Gregorc V, Citterio G, Vitali G, Spreafico A, Scifo P, Borri A, et al. Definition of the optimal biological dose of NGR-hTNF, a selective vascular target agent, in advanced solid tumors. Eur J Cancer. 2010;46:198–206. OBD is generally defined as the lowest dose that provides the highest rate of efficacy when administered safely. However, to our knowledge, there is no consensus on the efficacy criterion to be considered in the OBD, nor on the most appropriate dose escalation strategy to use when evaluating OBD.
Dragalin V, Fedorov V. Adaptive designs for dose determination based on the efficacy-toxicity response. J Statistical inference. 2006;136:1800–23. In [4], the authors showed the use of BED in practical situations for normal tissues. For example, if a dose of 60 Gy in 30 fractions is received by a critical normal tissue, the associated BED (e.g.) can be expressed as Gy1.5, Gy2 and Gy3 (for the α/β ratios of 1.5, 2 and 3 Gy). The initial BED value for a fractionation plan of 60 Gy into 30 fractions (BED = 140Gy1.5) is used to calculate the total dose and the dose per fraction for the alternative schedule of 20 fractions. The result for the alternative fractionation scheme is obtained from the solution of d in a rearrangement of the following equation The main objective of Phase 1 clinical trials in cancer is to evaluate the maximum tolerated dose (MTD) as a function of dose-limiting toxicity (DLT), which in most cases was evaluated during the first treatment, the safety profile and recommended Phase 2 dose (RP2D) [1]. Most of the dose determination models available for Phase 1 cancer clinical trials were originally developed in the context of conventional cytotoxic agents.
These methods are based on an underlying assumption that implies that the dose of a cytotoxic drug is related to the toxic reaction via an increasing monotonous relationship [2]. With the advent of targeted molecular agents and immunotherapies, and given their specific mechanism of action, this paradigm has been changed. Severe toxicities are rare, often delayed in subsequent treatment cycles, preventing DMT from being achieved [3]. Therefore, dose determination plans based on a single toxicity parameter may no longer be appropriate. In this context, the concept of optimal biological dose (OBD) has been introduced, which takes into account not only toxicity but also efficacy. The assessment of OBD instead of conventional BAT therefore seems particularly relevant for modern Phase I studies [4]. In the region with the minimum dose per fraction of a heterogeneously irradiated tumor, there is the highest cell survival value shown by Eq. (1); That is, there is the lowest value of the probability of killing the cells.
