Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA (E-mail: eisbruch@umich.edu)
Recent improvements in the therapy of head and neck cancer have largely been the result of intensification of treatment: either the delivery of radiotherapy (RT) concurrent with chemotherapy, or altered fractionated RT, notably accelerated regimens [1, 2]. Intensification of therapy has achieved improved tumor response and local/regional control rates; however, it has often been associated with higher rates of severe early and late mucosal and pharyngeal toxicities. Acute mucosal toxicity may be addressed by measures such as transient gastric tube feeding. Persistent long-term pharyngeal toxicityin some cases, a consequence of acute mucosal injuryis a major detrimental effect of some organ preservation approaches using chemotherapy-RT (chemo-RT) or aggressive accelerated RT [37]. Severe dysphagia following intensive chemo-irradiation results from a lack of specificity in the sensitization of tissues to radiation by chemotherapy. Thus, the oral, pharyngeal and laryngeal mucosal cells are sensitized to a similar extent as the cancer cells. As a result, late dysphagia limits the intensity of concurrent chemo-RT or accelerated RT regimens and reduces their therapeutic ratios [8, 9]. Late pharyngeal toxicity has recently been recognized as the main barrier to winning the battle with head and neck cancer [10].
In many articles summarizing chemo-irradiation protocols, the incidence of late dysphagia is rarely reported. The reporting of such information should be required, as it constitutes an essential element in the assessment of these regimens. In addition to reporting patients ability to eat and the prevalence of long-term tube feeding, an objective assessment of dysphagia may add a new aspect for the measurement of this toxicity.
In this issue of Annals of Oncology, Nguyen et al. present a retrospective study of modified barium swallow tests (videofluoroscopy, VF) performed in patients presenting with dysphagia after concurrent chemo-RT [11]. VF has long been considered a reliable and validated method of objective assessment of swallowing and aspiration, allowing the viewing and recording of the structure and dynamics of the swallowing process [12]. Importantly, Nguyen et al. found a high prevalence of aspiration in their studies. Many of the patients had silent aspiration, not associated with the cough reflex, that was probably due to sensory loss associated with severe mucosal and submucosal damage. These patients have a high risk of contracting pneumonia, and the lack of a cough reflex precludes their identification during clinical follow-up. Indeed, many patients suffered episodes of pneumonia following therapy, some of which were fatal. We have reported a similar experience in a prospective study of gemcitabine concurrent with irradiation [13], where the rate of silent aspiration, according to VF, was high, and patients demonstrating silent aspiration were more likely to develop clinical pneumonia when compared with those patients who did not, according to VF, demonstrate aspiration.
The prevalence of aspiration pneumonia is very rarely reported or evaluated in chemo-irradiation trials; it is likely that this morbidity is common and under-reported. For example, the chemotherapy regimen used by Nguyen et al.5-fluorouracil and cisplatin concurrent with standard fractionated RTwas similar to a regimen reported by Brizel et al. where chemotherapy was delivered concurrent with hyperfractionated (twice daily) RT [14]. Whether the difference in outcome relates to subtle differences in the treatment regimens, or to differences in the intensity of assessment of the complications, is not clear. Specific attention to dysphagia and aspiration is necessary; in addition, the objective assessment of patients presenting with dysphagia using either VF or other measures should be adopted as an essential part of all studies of intensive therapy for head and neck cancer.
What can we do to reduce the incidence of dysphagia and aspiration following intensive chemo-RT? One approach would be to use radiation sensitizers that show greater specificity to the tumor than to the non-involved mucosa when compared with standard chemotherapy. Potential candidates are drugs that inhibit the activity of the epidermal growth factor receptor (assuming that these receptors are more prevalent in tumors than in normal mucosa) or drugs that preferentially sensitize hypoxic cells [15].
Intensity modulated radiotherapy (IMRT) is a new irradiation technology that may help to reduce the incidence of late dysphagia and aspiration following intensive therapy. By producing highly conformal dose distributions around the target, IMRT may reduce the dose delivered to non-involved mucosa and to other tissues whose damage causes these sequelae. A few recent retrospective studies of intensive treatment regimens compared severe dysphagia in patients who had received either standard-technique RT or IMRT. These studies reached conflicting conclusions [1618]. Notwithstanding the uncertainties of retrospective comparisons, these conflicting results raise two important issues. First, which patients derive a benefit from IMRT? It is likely that in some tumor sites, but not in others, IMRT may achieve clinically important sparing of those structures whose damage causes dysphagia and aspiration compared with standard RT. Second, what is the best way to employ IMRT in order to gain its maximal potential benefit? Both these issues need to be addressed by the radiotherapy research community.
The radiation protector amifostine has recently been tested for mucosal protection and prevention of late dysphagia following RT of head and neck, esophagus and lung cancers with mixed results, suggesting a protective effect in one study [19] but not in another [20]. The risk of tumor cell protection by amifostine is also an issue that needs to be assessed carefully, similar to the potential risks of under-dosing subclinical tumors by IMRT. Following a relatively low dose of amifostine, there was no evidence of mucosal protection, or tumor protection, in one randomized study [21]. It is possible that higher doses of amifostine will achieve mucosal protection [22] and reduce dysphagia and aspiration following intensive chemo-RT. However, the risk of tumor cell protection with higher doses of amifostine have not yet been assessed adequately.
Until new intensive regimens emerge that are no longer associated with reduced late dysphagia and aspiration, it is crucial to identify those patients at risk. Performing VF in patients with dysphagia or, if possible, screening all patients with VF, after the subsidence of the acute side-effects of therapy, will achieve this goal. Patients with VF-assessed aspirations should be referred to speech therapy specialists who can assess whether tube feeding is recommended; in addition, they can instruct the patient in safe swallowing manoeuvres that may help to reduce the risk of pneumonia [23].
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