Radiation pneumonitis

Radiation pneumonitis is an inflammation of the interstitial tissues of the lung. Its occurrence is related to both the radiation dose applied and the volume of lung irradiated. In radiotherapy, it is usually accepted that a 5-15% rate of clinical pneumonitis is acceptable in patients being treated radically for thoracic/chest wall malignancies.

There are several clinical entities of interest including an acute phase and a later phase and also fibrotic residue. According to Awwad, the lung is a FLEXIBLE tissue where the reproductive and physiological function resides in the same cells. As such, the rate of onset AND the time delay to onset of symptoms are related to dose.

Acute radiation pneumonitis usually occurs within 3 months of the start of treatment (i.e., 6 weeks after the end of 6 week course of RT). It can occur earlier but this will be a case of severe pneumonitis. The symptoms usually are a low-grade fever, wheeze and cough, although severe reactions can result in SOB, pleuritic chest pain, haemoptysis, acute respiratory distress (patients can feel very unwell from inflammatory symptoms as well as SOB), and even death. It is possible to develop a reaction in the other un-irradiated lung and this presumably occurs because of blood-borne inflammatory mediators.

Fibrosis is a late event and as far as we know permanent event which may be unaccompanied by an acute pneumonitis, although if an acute pneumonitis has occurred, subsequent fibrosis is a near certainty. The features that indicate that lung changes represent radiation pneumonitis are a geographically defined infiltrate that corresponds to the edge of the radiation field. Fibrosis can obliterate the lung tissue and make determination of tumour response almost impossible - although fibrosis should not grow on subsequent scans!

Mechanism of Injury

There are at least two separate but related mechanisms for acute radiation pneumonitis and the subsequent fibrosis. The process is poorly defined though and cell-cell communication seems to be involved. This view has only developed since the 1990s and so is not as well defined as oncologists would like. Certainly Dr Michell Anscher from Duke has been a prime mover in defining these changes and developing disease-modifying agents (see articles below).

Classical radiation pneumonitis is thought to result from a direct toxic radiation injury to the endothelial and epithelial cells and might be termed "acute alveolitis". However this reaction differs somewhat from that seem as an 'epithelitis' because of the accumulation of inflammatory and immune effector cells within the alveolar walls and spaces, disruption of the normal alveolar structures and unusually large release of lymphokines and monokines. It seems that the alveolar macrophage and fibroblasts of the interstitial tissues communicate inappropriately and chronically to maintain the inflammation. The response of tissues is relatively monotonous and so healing is by scarring/fibrosis.

There is also an 'out of field' response as described above in unirradiated lung tissue, which is sometimes called "sporadic radiation pneumonitis". current theory suggests that this is either an immunologically mediated process resulting in bilateral lymphocytic alveolitis, or the result of reaction to elevated inflammatory factors in the blood as these changes are associated with more severe acute reactions.

The changes of radiation fibrosis are usually permanent and develop over a period of months after the end of radiotherapy but usually do not change after 2 years. As in other pathologies, this pulmonary fibrosis is also a repair process following the acute inflammatory response with progressive fibrosis of the alveolar septa thickened by bundles of elastic fibers. How this process is exactly related to the acute response is unknown although the continued uncontrolled secretion of cytokines like TGF-b appears to be important clinically and has beenn shown to be predictive of toxicity.

Some of the article below indicate that fibroblast chemotactic factors for fibroblasts (e,g., transforming growth factor-beta (TGF-b) which promotes connective tissue formation), platelet-derived growth factor (PDGF) and fibronectin, although the collagen synthesis seems to be the result of TGF-b releaased from the alveolar macrophage.

Selected Readings

Pelagia G. Tsoutsou, Michael I. Koukourakis Radiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future research International Journal of Radiation Oncology * Biology * Physics 2006; 66_5:1281-1293 IJROBP66_1281_2006.pdf

Other readings

IJROBP62_255_2005.pdf IJROBP63_1448_2005.pdf IJROBP71_829_2008.pdf
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