Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology

Abstract

Radiation therapy has curative or palliative potential in roughly half of all incident solid tumours, and offers organ and function preservation in most cases. Unfortunately, early and late toxicity limits the deliverable intensity of radiotherapy, and might affect the long-term health-related quality of life of the patient. Recent progress in molecular pathology and normal-tissue radiobiology has improved the mechanistic understanding of late normal-tissue effects and shifted the focus from initial-damage induction to damage recognition and tissue remodelling. This stimulates research into new pharmacological strategies for preventing or reducing the side effects of radiation therapy.

Key Points

  • Around 50% of patients with solid malignant tumours receive radiation therapy with curative or palliative intent at some point in the course of their disease. Early and late side effects limit radiation dose and might affect the long-term health-related quality of life of the patient.

  • The classical framework for discussing early and late side effects was the target-cell hypothesis: that the severity of side effects mainly reflected cell depletion as a result of the direct cell killing of a putative target cell leading to subsequent functional deficiency. This was the prevailing biological model until the mid 1990s.

  • Recent research in radiobiology and molecular pathology has caused a change of paradigm, particularly in the understanding of late effects: radiation induces a concerted biological response at the cell and tissue level effected by the early activation of cytokine cascades.

  • Fibrogenesis and excessive extracellular matrix and collagen deposition has a key role in the development and expression of many types of late effects. This can be seen as a wound-healing response gone wrong.

  • Transforming growth factor-β is a key fibrogenic cytokine. Its activation, signalling pathway and downstream effects are understood in some detail and offer a number of potential targets for therapeutic intervention in the pathogenic process. This 'bottom-up' approach has benefited from the translation of findings from molecular pathology studies of other diseases characterized by the excessive development of fibrosis.

  • Patient-to-patient variability in the response to radiotherapy represents a 'top-down' discovery strategy whereby clinical outcome data are linked with data from high-throughput assays.

  • Radiogenomics is the study of genetic variation as an explanation for inter-individual differences in radiotherapy response. Most of the research so far has concentrated on single-nucleotide polymorphisms (SNPs) in selected candidate genes, but genome-wide approaches seem to be within reach in the near future.

  • Advances in molecular radiation pathology combined with advances in clinical radiobiology, radiation therapy planning and delivery technology are likely to improve radiation therapy outcome within the next 5–10 years.

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Figure 1: Phases of normal wound healing and radiation-induced fibrosis over time.
Figure 2: Key processes in radiation fibrogenesis.

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Acknowledgements

S.B. is supported by the University of Wisconsin Comprehensive Cancer Center.

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DATABASES

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breast cancer

FURTHER INFORMATION

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European GENEPI normal-tissue bank

Glossary

Cytokine cascade

Cytokines, low-molecular-weight intercellular messenger proteins, are often produced in a cascade: one cytokine stimulates its target cell to secrete additional cytokines.

Chemokine

Small secreted cytokines that signal for various cell types to move in a specific direction, typically up the gradient of chemokine concentration.

Bleomycin

A chemotherapeutic antibiotic that functions by inducing DNA strand breaks, and which is therefore seen as a radiation-mimetic drug. Although the initial damage induction differs from that of radiation, it is probable that the mesenchymal-response pathway is similar for the two agents. It is often used to induce lung fibrosis in mouse models.

Tissue hypoxia

A pathological condition in which a tissue region is deprived of the normal physiological oxygen concentration.

Reactive oxygen and nitrogen species

Highly reactive molecules that include oxygen or nitrogen, such as free radicals or other highly reactive forms (for example, singlet oxygen, a meta-stable state of oxygen with higher energy than the triplet ground state).

Telangiectasia

The visible dilation of small vessels under the skin or a mucosal surface that can occur after radiation therapy, perhaps as a result of radiation-induced cell killing and the loss of other small vessels in the area.

Nijmegen breakage syndrome

A rare heritable disease characterized by an abnormally small head and underdeveloped brain, associated with chromosomal instability and a predisposition to cancer, especially lymphomas.

Fanconi anaemia

A rare heritable disease in which the bone marrow fails to produce platelets, red or white blood cells or a combination of the three. It is associated with a predisposition to cancer, particularly leukaemia.

Ataxia telangiectasia

A rare heritable disease characterized by progressive dysfunction of the cerebellum, the part of the brain that coordinates voluntary motion, and a predisposition to cancer, particularly lymphomas and leukaemia.

Single nucleotide polymorphisms

(SNP) An inter-individual variation in the DNA sequence that involves the substitution of a single nucleotide that occurs in more than 1% of the population.

Candidate gene

A gene whose function indicates that it could be mechanistically involved in a specific process, such as radiation-damage repair or tissue remodelling.

Genome-wide SNP genotyping

A strategy for trying to discover associations between SNPs in any human gene and a specific phenotype; for example, patients showing atypically strong side effects after radiotherapy.

Bonferroni correction

A multiple-comparisons correction that is applied to reduce the chance of spurious ('false-positive') findings when several statistical tests are conducted to analyse a data set.

Xerostomia

Dryness of mouth caused by reduction in the secretion of saliva, a possible side effect of radiation therapy for cander of the head and neck region.

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