Radiobiology for Clinical Needs

Introduction

Knowledge of the radiobiology of tumours and normal tissues provides the basis for the practice of radiation oncology. “Kill the tumour, while sparing normal tissues” is the main strategy of radiation oncology, and it is radiobiology that points the way. There are several branches of radiobiology, which are directly relevant to clinical needs.

Tumour radiobiology deals with dose responses of cancer cell populations exposed to radiation at various dose fractionation schemes, and with potential modifications of these responses in presence of sensitizing drugs.

Biological dosimetry is a toolbox of methods, by which the changes, caused by ionizing radiation on molecular and cellular level in normal cells, can be measured, and used for the quantitative assessment of accumulated radiation dose in human body.

Biomarkers of individual radiosensitivity and radio susceptibility are mandatory for personalization of radiation treatment and in-time prevention of radiotherapy side effects, including normal tissue lesions or secondary cancers.

Basic concepts in radiation biology

The overall aim of radiobiology is to explain the phenomenon of the transformation of relatively small amount of energy brining to living objects by ionizing radiation into big effects and long-lasting consequences.

Current theory of radiobiology is rather well developed and combines the known mechanisms of various molecular, cellular, and clinical responses to radiation. The most important issues for radiation oncology and radiotherapy are:

• Initial radiochemical reactions leading to radiation-induced damage at molecular or cellular level.
• The DNA damage response.
• Chains of events leading to radiation cell killing.
• Dose response relationships for stochastic effects and threshold doses for deterministic effects.
• Relative biological effectiveness of radiation beams of different energetic quality (sparsely and densely ionizing radiations).
• Cell growth alterations after a single exposure or under fractionated irradiation.
• The role of oxygen and hypoxia, chemical radiosensitizers and radioprotectors in the development of radiation-induced effects.
• Radiation-induced mutagenesis and promotion of carcinogenesis.

Biological dosimetry

Biological dosimetry is the use of specific biomarkers to verify exposure to radiation and to estimate absorbed dose of ionizing radiation.

Introduction to Biodosimetry

Biological dosimetry is needed for timely determination of the radiation dose to the exposed individuals in the event of a radiation/nuclear emergency (i.e., exposed workers or public). In many countries it has become a routine component of national radiological protection programmes.

Biodosimetric biomarkers are quantified in the sample, taken from an exposed person, and their yield is compared to a dose response curve, which has been produced earlier by the in vitro exposure of the same biological material to a range of doses of the appropriate quality of radiation; the resultant estimate is interpreted in terms of absorbed dose for this kind of radiation.

Currently, the radiation protection community officially recognizes only four validated dosimetric biomarkers, which are cytogenetic endpoints, quantified in cultured human peripheral blood lymphocytes:

• “Unstable”^1/ aberration – dicentrics and centric rings;
• “Stable”^1/ aberration – translocations, insertions, inversions;
• Fragments and rings scored among prematurely condensed chromosomes;
• Micronuclei in binucleated lymphocytes blocked with cytochalasin B.

In the recent years the analysis of phosphorylated histones γ-H2AX, representing sites of DNA Double Strand Breaks repair in the interphase lymphocyte nuclei, has been also promoted as a supplementary biodosimeter.

Technical aspects of biological dosimetry by cytogenetic analysis are well refined and have attained international standardisation.

Footnote

^1/ Terms “stable” or “unstable” define, respectively, the ability or inability of these aberrations to pass successfully through cell division, and thus to be either preserved or eliminated in the subsequent cell generations.

The IAEA Manual

Cytogenetic Dosimetry: Applications in Preparedness for and Response to Radiation Emergencies | IAEA

International Standards

• Dicentric assay:
  
  ISO - ISO 19238:2014 - Radiological protection — Performance criteria for service laboratories performing biological dosimetry by cytogenetics
   
• Translocation assay:
  
  ISO - ISO 20046:2019 - Radiological protection — Performance criteria for laboratories using Fluorescence In Situ Hybridization (FISH) translocation assay for assessment of exposure to ionizing radiation
   
• Micronuclei assay:
  
  ISO - ISO 17099:2014 - Radiological protection — Performance criteria for laboratories using the cytokinesis block micronucleus (CBMN) assay in peripheral blood lymphocytes for biological dosimetry
   
• Triage:
  
  ISO - ISO 21243:2008 - Radiation protection — Performance criteria for laboratories performing cytogenetic triage for assessment of mass casualties in radiological or nuclear emergencies — General principles and application to dicentric assay

Applications of biodosimetry methods for clinical purposes

Current applications of biodosimetry methods in radiation oncology and medical radiology include:

• Evaluation of the therapeutic potential of radiation beams (comparison of in vitro dose response curves for chromosome aberration yields produced by radiation beams of different quality/energy).
• In vivo or in vitro assessment of the actual radiation genotoxicity of any procedure involving radiation sources in medicine, e.g., different settings of diagnostic Computed Tomography scanners.
• Revealing abnormal intrinsic chromosomal radiosensitivity in patients with adverse toxic reactions. In practice of radiation oncology, the unexpected, extreme tissue reactions are still frequently attributed to the malfunction of radiotherapy devices or erroneous dosimetry. In such situations expertise is needed to clarify the reason: the accident or patient’s intrinsic over-reactive status. Cytogenetic analysis appeared to be highly informative for confirming the radiosensitivity post factum in individual cases as identified by clinical symptoms.

Other potential approaches to use biodosimetry methods for solving clinical tasks are under active development. A strong international support is needed in this area and as such, this topic has appeared as a focus of interest of the International Atomic Energy Agency. Practical implementation of the research along with strengthening the international scientific cooperation in this area take place in the framework of the CRP E3.50.10 MEDBIODOSE (2017--2023).

Reviews on applications of radiation biomarkers for clinical purposes:

• Clinical Applications of Biomarkers of Radiation Exposure: Limitations and Possible Solutions through Coordinated Research
• Radiation Exposure Biomarkers in the Practice of Medical Radiology
• Prediction of the Acute or Late Radiation Toxicity Effects in Radiotherapy Patients Using Ex Vivo Induced Biodosimetric Markers: A Review

Radiation sterilization in tissue banking

The general purpose of tissue banks is to provide safe and effective allografts for transplantation, e.g., musculoskeletal allografts used for reconstructive surgery in orthopaedics or traumatology. Sterilisation of tissue allografts is strongly recommended to minimize the hazard of bacterial or viral contamination and thus infectious disease transmission.  

Ionizing radiation can be effectively used to sterilize tissue allografts on a large scale. Radiation sterilisation can be applied when antibiotics or heat sterilisation would cause unacceptable changes to products.  

Special studies were initiated by the IAEA to find and validate the optimal dose for sterilisation of various tissue types, providing graft sterility without compromising tissue allograft integrity or biological function for clinical applications. 

• The IAEA Code of Practice on Radiation Sterilization of Tissue Allografts

Clinical Radiobiology

Experimental findings coupled to data of respective clinical trials revealed the mechanisms of cell death and survival of tumours and normal tissues in response to radiation exposure. That allowed to generate a comprehensive formalism explaining the dose response and fractionation effect peculiarities for therapeutic radiation beams of different quality in regard of tumour growth suppression and normal tissue tolerance. 

A popular concept postulates that success or failure of standard clinical radiation treatment is determined by “the 4 R’s of radiobiology”: repair of DNA damage, redistribution of cells in the cell cycle, repopulation, and reoxygenation of hypoxic tumour areas. 

Clinical radiobiology provides the basis for current approaches to the improvement of radiotherapy including novel fractionation schemes, retreatment, IMRT, modification of hypoxia, hadron therapy, combined radiotherapy / chemotherapy, and biological modifiers of tumour and normal tissue effects. 

An important part of modern clinical radiobiology is development and validation of biomarkers – various biochemical or cellular parameters, by which clinicians can obtain prognostic or predictive information regarding tumour’s intrinsic radiosensitivity or its response to treatment, as well as regarding ongoing radiation damage in normal tissues or expected late side effects. This helps to make a right choice between different treatment options and allows to personalize radiation dosing, in trying to gain maximum possible therapeutic benefit whilst avoiding radiation-induced toxicity in patients.

Educational Resources for Radiobiology

Nowadays the study of radiobiology is important for gaining proper qualification as a radiation oncologist. In low and middle income (LMI) countries serious efforts on teaching in radiobiology are especially needed, considering the obvious deficit in knowledge of this subject.  

The IAEA offers a Handbook on Radiobiology for teachers and students. The training slide series in Radiation Biology provides further lecture material to support this course.

• Radiation Biology Handbook – Slides
• Section 1: Radiation Biology Handbook: Contents and Teaching Programme
• Section 2: Minimum Essential Syllabus for Radiobiology
• Section 3: Extra Module for Radiation Oncologists
• Section 4: Extra Module for Radiation Protection Personnel