Mechanism of Radiation Induced Fibrosis

The exact mechanism of late RIF has not been clearly elucidated and likely represents a complex interplay of the many different proposed mechanisms. First, repeated tissue "injury" from fractionated radiation appears to generate abnormal wound healing mechanisms and injure endothelial cells.⁵ This leads to microvascular destruction and tissue hypoxia. Altered fibroblasts and myofibroblasts have been cultured from late irradiated tissues and these cells exhibit decreased growth, shorter lifespans, and lower superoxide dismutase and catalase (free radical scavengers) activity than those in normal tissue samples.⁶ In addition, cytokine up-regulation, particularly transforming growth factor beta (TGF-β), occurs in irradiated tissues .^5,7-9 TGF- β stimulates collagen production, inhibits extracellular matrix breakdown, and inhibits epithelial cell proliferation. These mechanisms all may play a role in fibrosis development.

Scope of the Problem

Late dysphagia occurs in approximately 10 - 14% of patients with oropharyngeal tumors treated with radiotherapy (RT),^11-12 and as many as 83% of patients with pharyngeal carcinoma treated with RT may experience dysphagia.¹³

Many investigators have examined the dosimetry relationships of specific swallowing structures and predictors for the development of late onset dysphagia.^14-22 The most predictive indicators are the mean dosage to the pharyngeal constrictor muscles,^17-21,23-25 upper esophagus,^23,25 supraglottic larynx,^19-21,23 and glottic larynx.^17,20-21,23 Most studies show that when greater than 50% of the involved swallowing musculature receives >50 Gy, the risk of developing late onset dysphagia is increased.^17-21,23-25 Particularly, patients with >60 Gy dosing to the pharyngeal musculature are at increased risk for silent aspiration,^3-4 and dosage to the pharyngeal constrictor muscles >65 Gy and the laryngeal complex >50 Gy is predictive of percutaneous gastrostomy tube (PEG) dependency.^26,27 

Figure 1: View of larynx during flexible endoscopic evaluation of swallowing study in a patient 9 years after chemoradiation for base of tongue cancer. He presented with progressive dysphagia and exhibited poor pharyngeal muscular contraction, decreased sensation, and aspiration.

Treatment of DRIF

The emphasis for DRIF has primarily been on prevention because there are few treatments available. Radiation dose sparing techniques, such as 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT), have sought to reduce the incidence of DRIF by lessening radiation to surrounding tissues. Depending on the site of lesion, nodal involvement and target tissue, decreased radiation to structures vital for swallowing function may not be possible. After all, the first principle of treatment is curative intent, and few studies have examined long-term locoregional control following specific IMRT dysphagia avoidance protocols.

Prophylactic swallowing exercises have been shown to modestly improve swallowing function when compared to patients who do not follow a pre-treatment exercise program.^28,29 It is crucial for patients to begin swallowing exercises prior to treatment and
to continue them well beyond treatment on a daily basis. Unfortunately, the follow-up periods for most of these studies are relatively short and long-term effectiveness remains unknown. It must be noted as well that adherence to preventative exercise programs is surprisingly low, with only 13% of patients found to be fully adherent over a two year period.³⁰

Lastly, the maintenance of oral intake, even if supplemented with alternative nutrition, has been shown to decrease PEG dependence. At one year post RT, these patients have more advanced diets and better weight gain/maintenance than patients completely dependent on tube feedings. ³¹

Conclusion

Dysphagia due to established radiation induced fibrosis is a difficult problem to treat. Until effective medical therapies are available, prevention appears to be the best approach. Patients undergoing radiation therapy for head and neck cancer should be evaluated by a speech pathologist and begin prophylactic swallowing therapy. Patients should also be encouraged to maintain some degree of per oral intake throughout their radiation course.

Ashli K. O'Rourke , M.D.

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