Radiation Injury

EXTERNAL BEAM

Radiotherapy is commonly given for patients with head and neck cancer; however, the injurious effect that this treatment modality has on the salivary glands leading to profound xerostomia, which may be permanent, is well known. The serous cells (found in the parotid gland) are extremely sensitive to apoptotic death following even moderate doses of radiation. Indeed, permanent loss of sali b

Figures 12.16b and 12.16c. Sialogram shows stricture of duct with proximal dilatation of Stenson's duct and secondary ducts and a large cystic swelling distal to the stricture.

b c vary function is seen after doses larger than approximately 3,500 cGy with little in the way of measurable parotid saliva, and 5% of patients will demonstrate a sialadenitis with gland swelling and raised amylase within 12 hours of their first treatment (Parsons 1994). However, although it is known that damage to the salivary glands will increase with radiation dose and volume of gland irradiated, there is no universal agreement over the dose required to produce xerostomia. Someya, Sakata, and Nagakura et al. (2003) found gradual recovery of function over time with doses of <5,000 cGy, while no significant recovery was seen in patients who had >5,800 cGy. The minor sali-vary/sublingual glands do not seem to play much of a role in the development of xerostomia, which seems to depend mainly on the mean dose to both the parotid and submandibular glands (Jellema, Doornaert, and Slotman et al. 2005). These authors also found that the stickiness of saliva postradiation depended mainly on the mean dose to the submandibular glands.

The exact pathogenesis and mechanism of injury to the salivary glands as a result of radiation therapy is also controversial, with no universal agreement as to cause. Based on animal studies in the rat model, a mechanism of delayed serous cell death due to sublethal DNA damage, which results in death during a reproductive phase due to highly redox-reactive metal ions (e.g., iron, copper) associated with secretion granules has been proposed (Nagler 2002, 2003). Another study showed significant increase in cytotoxic T-cells in irradiated sub-mandibular glands, suggesting cell-mediated mechanisms may be responsible for the sialadenitis with subsequent acinar cell destruction/atrophy (Teymoortash, Simolka, and Schrader et al. 2005).

Obviously once established the effects of radiation damage are difficult to treat or reverse, so much effort has been aimed at prevention. Important advances in the delivery of radiation therapy using 3-D conformal planning and intensity-modulated radiation therapy (IMRT), combined with drugs such as growth factors, cholinergic agonists, and cytoprotective agents (Amifostine), are currently the preferred modalities of prevention (Garden, Lewin, and Chambers 2006).

It has been shown with conventional radiation therapy that the ability to spare the contralateral major salivary glands or to spare the parotid by positioning of the portals can significantly increase salivary flow and reduce xerostomia (Beer et al. 2002; Malouf, Aragon, and Henson et al. 2003). The sophistication of 3-D conformal planning and IMRT allows the radiotherapist to give more radiation to the tumor target with increased sparing of normal tissue. In one study only 12% of patients developed xerostomia following IMRT for head and neck cancer, and there were no locoregional recurrences with a median follow-up of 24 months (Saarilahti, Kouri, and Collan et al. 2005). Jen, Shih, and Lin et al. (2005) compared 108 patients treated with conventional RT to 72 Gy treated with 3-D conformal RT, finding 3-D confor-mal RT delivered a higher dose to the tumor with better local control in T4 patients and improved survival with significantly better parotid function. IMRT has also been used to spare the submandibu-lar glands to prevent radiation-induced xerostomia (Saarilahti, Kouri, and Collan et al. 2006). The ability to use 3-D conformal RT and IMRT to spare the opposite parotid by excluding the contralateral level II nodes from the field was not shown to be associated with any locoregional recurrence, and no recurrence occurred in the spared area (Bussels, Maes, and Hermans et al. 2004).

A number of drugs have been investigated for preventing radiation damage. A phase III prospective randomized trial of Amifostine (Ethyol) with 315 patients showed significant reduction in grade 2 or > xerostomia and chronic xerostomia with no effect on locoregional control, disease-free survival, or overall survival. In this study, however, 53% of patients experienced nausea and/or vomiting (Brizel, Wasserman, and Henke et al. 2000). A follow-up study to review results of this study after 2 years found the significant decrease in grade 2 or > xerostomia had been maintained, as well as an increase in the proportion of patients with meaningful unstimulated saliva and reduced mouth dryness. There was no compromise of locoregional control, progression-free, or disease-free survival (Wasseman, Brizel, and Henke et al. 2005). In this study the Amifostine was given intravenously, and a recent phase II study has shown a similar radio-protective benefit for Amifostine given subcutane-ously as a simpler alternative (Anne, Machtay, and Rosenthal et al. 2007). Another approach has been to use pilocarpine, which has been used to treat xerostomia during radiotherapy as a chemopreven-tive agent. A randomized, double-blind, placebo-controlled trial of pilocarpine on 60 patients, only 39 of whom were evaluable, indicated that pilocar-pine used with radiotherapy could lead to signifi cant diminution in subsequent xerostomia (Haddad and Karimi 2002). Another randomized trial with 66 patients also concluded that patients with stimulated glands from pilocarpine during radiation had less decrease in salivary flow, which reduced radiation side effects (Nyarady, Nemeth, and Ban et al. 2006). However, the Radiation Therapy Oncology Group (RTOG) study 97-09, which was a phase III trial with 245 patients, showed that although there was a significantly increased unstimulated salivary flow in the pilocarpine group, there was no difference in parotid stimulated salivary flow, in the amelioration of mucositis, or in the quality of life between the two groups (Scarantino, LeVeque, and Swann et al. 2006). Other novel approaches to the problem have been the use of gene therapy, which has yielded promising results in animal models (Cotrim, Mineshiba, and Sugito et al. 2006; Thula et al. 2005).

Finally, a surgical approach to prevention of xerostomia has been the transfer of the sub-mandibular glands into the submental triangle out of the radiation field prior to the commencement of radiation therapy. In a phase II trial of patients who had primary surgery for oro-pharyngeal cancer followed by adjuvant RT, with or without subman-dibular gland transfer 24 of 51 patients were evaluated for swallowing. The cohort with preservation of 1 gland (13 patients) had significantly increased saliva and swallowing function (Rieger, Seikaly, and Jha et al. 2005). Similar results were reported in a small series of patients undergoing chemora-diation (Al-Qahtani et al. 2006). Regarding long-term results in 26 patients followed for 2 years, normal amounts of saliva were reported in 83% (Seikaly, Jha, and Harris et al. 2004).

RADIOACTIVE IODINE

Radioactive iodine is used in the treatment of thyroid cancer but is also concentrated in the salivary glands, particularly the parotid, and may cause sialadenitis that is immediate or begins a few months after treatment (Mandel and Mandel 2003). In a prospective study of 76 patients receiving radioactive iodine, 20 (26%) developed salivary gland toxicity, 11 developed toxicity within 48 hours, and 9 not until 3 months post-therapy. A total of 16 patients had chronic toxicity, typically xerostomia, at 12 months (Hyer et al. 2007). In seeking to quantify salivary gland dysfunction using scintigraphy in 50 patients, 46% and 42%

were found to have decreased maximum secretion and uptake ratio, respectively (Raza et al. 2006). The damage was seen more in the parotid and was dependent on the radioiodine dose. The damage and symptoms may be permanent (Mandel and Mandel 1999). The damage is most likely related to an oxidation injury indicated by an increase in prostaglandin levels (Wolfram, Palumbo, and Chehne et al. 2004).

Current management is symptomatic as for sialadenitis and xerostomia from other causes. Animal studies using the rabbit model indicate that Amifostine can significantly reduce radioiodine-induced parenchymal damage (Kutta, Kampen, and Sagowski et al. 2005). The use of sialoendo-scopic treatment in this condition for patients with partial duct stenosis has also been reported (Kim, Han, and Lee et al. 2007).

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