Elsevier

The Lancet Oncology

Volume 4, Issue 9, September 2003, Pages 529-536
The Lancet Oncology

Review
Effects of radiation on normal tissue: consequences and mechanisms

https://doi.org/10.1016/S1470-2045(03)01191-4Get rights and content

Section snippets

General principles of normal tissue injury

The pathological processes of radiation injury begin immediately after radiation exposure, but the clinical and histological features may not become apparent for weeks, months, or even years after treatment. In the lung, for example, changes detected 6 weeks after irradiation are mild even after a high dose but by 6 months there is widespread fibrosis (figure 2). Radiation injury is commonly classified as acute, consequential, or late effects, according to the time before appearance of

Treatment-related factors

The risk, severity, and nature of early, consequential, and late reactions in a patient depend on several factors. Radiation-related treatment factors include the total dose, the dose per fraction, and schedule of treatment (ie, one versus two or three treatments per day). The current practice of fractionating radiotherapy treatments arose from observations that late effects were less severe and better local tumour control rates could be achieved with multiple, small radiation fractions than

Patient-related factors

Patient-related factors include trauma or surgery in an irradiated site and co-morbidities, particularly those involving impaired vascularity, such as diabetes and hypertension.32, 33 Age may be a factor, but age by itself must not be considered a reason for avoiding the use of a curative regimen.

Some groups of patients may have a genetic susceptibility to the development of radiation injury. For example, patients with genetic abnormalities such as ataxia telangiectasia develop severe radiation

The role of the tumour

In addition to the contribution of radiation itself, the presence of the tumour may predispose the surrounding normal tissue to injury. Tumours change their surroundings in several ways. They physically distort normal tissue architecture39, 40 resulting in defects that can add to damage produced by therapy.41 Tumours also release proteolytic enzymes that facilitate invasion and metastasis.42 Tumour vessels leak fibrinogen, which is converted to fibrin, resulting in collagen deposition and

Common clinical manifestations of radiation injury

Radiation injury varies from organ to organ, thus a comprehensive discussion is beyond the scope of this review, but is covered in other papers.5, 26, 47, 48, 49 For each area discussed here—the thorax (lung and breast tumours), head and neck, and pelvis (prostate and cervical tumours)—we describe symptoms, the histopathology underlying the symptoms, medical management of the symptoms, and future prospects for preventing or treating radiation toxicity.

Assessing normal tissue responses

When a new cancer therapy is evaluated, the toxic effects on normal tissues must be assessed and compared with standard therapy. A new scoring system has recently become available: common terminology criteria for adverse events v3·0 (CTCAE, http://ctep.cancer.gov/reporting/ctc.html). It was developed from two earlier scoring systems, the common toxicity criteria (CTC), developed by the National Cancer Institute (NCI) for evaluating acute toxicity of new chemotherapeutic agents and acute effects

Prospects for the future

Progress in cancer research is being made in many biological and technological areas. As cancer therapy improves and more patients survive longer, we need to direct research towards elucidating the processes that lead to complications of therapy. The NCI has identified long-term survival from cancer as one of the new areas of public health emphasis, particularly “studying adverse long-term or late effects of cancer and its treatment” (http://plan.cancer.gov/public/survivor.htm#studying).

It is

Search strategy and selection criteria

The references included in this review were identified by searches of PubMed, Current Contents, and citation searches on Web of Science with the search terms “IMRT”, “radiation injury”, “skin”, “salivary gland”, “lung”, “breast”, “cervix”, “prostate”, “bladder”, “rectum”, “inflammation”, “fibrosis”, “angiotensin”, “TGF-beta”, “interleukin”, “KGF”, “mechanism”, “carcinogenesis”, “hyperbaric oxygen treatment”, and “wound healing”. Reference lists in selected papers and the authors' personal

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References (89)

  • Z Vujaskovic et al.

    Radiation-induced hypoxia may perpetuate late normal tissue injury

    Int J Radiat Oncol Biol Phys

    (2001)
  • HP Rodemann et al.

    Cellular basis of radiation-induced fibrosis

    Radiother Oncol

    (1995)
  • HD Thames et al.

    Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships

    Int J Radiat Oncol Biol Phys

    (1982)
  • JW Hopewell et al.

    Volume effects in radiobiology as applied to radiotherapy

    Radiother Oncol

    (2000)
  • DM Herold et al.

    Diabetes mellitus: a predictor for late radiation morbidity

    Int J Radiat Oncol Biol Phys

    (1999)
  • HB Stone et al.

    Enhancement of radiation-induced normal tissue damage by a fibrosarcoma

    Int J Radiat Oncol Biol Phys

    (1987)
  • I Stamenkovic

    Matrix metalloproteinases in tumor invasion and metastasis

    Semin Cancer Biol

    (2000)
  • FM Kong et al.

    Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury

    Int J Radiat Oncol Biol Phys

    (2001)
  • A Försti et al.

    Loss of heterozygosity in tumour-adjacent normal tissue of breast and bladder cancer

    Eur J Cancer

    (2001)
  • RP Hill et al.

    Normal tissue radiobiology: from the laboratory to the clinic

    Int J Radiat Oncol Biol Phys

    (2001)
  • JW Denham et al.

    The radiotherapeutic injury—a complex wound

    Radiother Oncol

    (2002)
  • M Martin et al.

    TGFβ1 and radiation fibrosis: a master switch and a specific therapeutic target?

    Int J Radiat Oncol Biol Phys

    (2000)
  • GW Morgan et al.

    Radiation and the lung: a re-evaluation of the mechanisms mediating pulmonary injury

    Int J Radiat Oncol Biol Phys

    (1995)
  • S McDonald et al.

    Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems

    Int J Radiat Oncol Biol Phys

    (1995)
  • MS Anscher et al.

    Plasma transforming growth factor betal as a predictor of radiation pneumonitis

    Int J Radiat Oncol Biol Phys

    (1998)
  • MW Epperly et al.

    Manganese [correction of Magnesium] superoxide dismutase (MnSOD) plasmid/liposome pulmonary radioprotective gene therapy: modulation of irradiation-induced mRNA for IL-I, TNF-alpha, and TGF-beta correlates with delay of organizing alveolitis/fibrosis

    Biol Blood Marrow Transplant

    (1999)
  • M-C Vozenin-Brotons et al.

    Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta 1 repression and phenotypic reversion of myofibroblasts

    Free Radical Biol Med

    (2001)
  • EC Ford et al.

    Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging

    Int J Radiat Oncol Biol Phys

    (2002)
  • JO Archambeau et al.

    Pathophysiology of irradiated skin and breast

    Int J Radiat Oncol Biol Phys

    (1995)
  • W Dorr et al.

    Radiation-induced changes in cellularity and proliferation in human oral mucosa

    Int J Radiat Oncol Biol Phys

    (2002)
  • JS Cooper et al.

    Late effects of radiation therapy in the head and neck region

    Int J Radiat Oncol Biol Phys

    (1995)
  • J Bras et al.

    Osteoradionecrosis of the mandible: pathogenesis

    Am J Otolaryngol

    (1990)
  • N Jha et al.

    Submandibular salivary gland transfer prevents radiation-induced xerostomia

    Int J Radiat Oncol Biol Phys

    (2000)
  • PC O'Brien

    Radiation injury of the rectum

    Radiother Oncol

    (2001)
  • LR Coia et al.

    Late effects of radiation therapy on the gastrointestinal tract

    Int J Radiat Oncol Biol Phys

    (1995)
  • RE Peschel et al.

    Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer

    Lancet Oncol

    (2003)
  • GE Hanks et al.

    Dose response in prostate cancer with 8-12 years' follow-up

    Int J Radiat Oncol Biol Phys

    (2002)
  • JK Ryu et al.

    Interim report of toxicity from 3D conformal radiation therapy (3Dd-CRT) for prostate cancer on 3DOG/RTOg 9406, level III (79.2 Gy)

    Int J Radiat Oncol Biol Phys

    (2002)
  • MJ Zelefsky et al.

    High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localised prostate cancer

    J Urol

    (2001)
  • A Jackson et al.

    Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms

    Int J Radiat Oncol Biol Phys

    (2001)
  • KK Richter et al.

    Differential effect of radiation on endothelial cell function in rectal cancer and normal rectum

    Am J Surg

    (1998)
  • MW Skwarchuk et al.

    Changes in histology and fibrogenic cytokines in irradiated colorectum of two murine strains

    Int J Radiat Oncol Biol Phys

    (1998)
  • J Wang et al.

    Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy

    Am J Pathol

    (1998)
  • A Trotti et al.

    Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on radiotherapy

    Int J Radiat Oncol Biol Phys

    (2000)
  • Cited by (727)

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