Dysphagia and aspiration followingchemo-irradiation of head and neck cancer: major obstacles to intensification of therapy

Abstract

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.Fu K.K. Pajak T.F. Trotti A. et al.A radiation oncology group phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck cancer.Int J Radiat Oncol Biol Phys. 2000; 48: 7-16Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar, 2.Pignon J.P. Bourhis J. Domenge C. Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data.Lancet. 2000; 355: 949-955Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar]. 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 toxicity—in some cases, a consequence of acute mucosal injury—is a major detrimental effect of some organ preservation approaches using chemotherapy-RT (chemo-RT) or aggressive accelerated RT [3.Skladowski K. Maciejewski B. Golen M. Randomized clinical trial of 7-day continuous accelerated radiation (CAIR) of head and neck cancer: report on 3-year tumor control and normal tissue toxicity.Radiother Oncol. 2000; 55: 101-110Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 4.Staar S. Rudat V. Stuetzer H. et al.Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: results of a multicenter randomized German trial in advanced head and neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 5.Delaney G.P. Fisher R.J. Smee R.J. et al.Split-course accelerated therapy in head and neck cancer: an analysis of toxicity.Int J Radiat Oncol Biol Phys. 1995; 32: 763-768Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 6.Abitbol A.A. Sridhar K.S. Lewin A.A. Hyperfractionated radiation therapy and 5-fluorouracyl, cisplatin and mitomycin C in the treatment of patients with locally advanced head and neck cancer.Cancer. 1997; 80: 266-276Crossref PubMed Scopus (39) Google Scholar, 7.Vokes E.E. Stenson K. Rosen F.R. et al.Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer.J Clin Oncol. 2003; 21: 320-326Crossref PubMed Scopus (212) Google Scholar]. 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.Kaanders J.H.M. van Daal W.A.J. Hoogenraad W.J. et al.Accelerated fractionation radiotherapy for laryngeal cancer, acute and late toxicity.Int J Radiat Oncol Biol Phys. 1992; 24: 497-503Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 9.Trotti A. Toxicity in head and neck cancer: a review of trends and issues.Int J Radiat Oncol Biol Phys. 2000; 47: 1-12Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar]. Late pharyngeal toxicity has recently been recognized as the main barrier to winning the battle with head and neck cancer [10.Robbins K.T. Barriers to winning the battle with head and neck cancer.Int J Radiat Oncol Biol Phys. 2002; 53: 4-5Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar].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.Nguyen N.P. Moltz C.C. Frank C. et al.Dysphagia following chemoradiation for locally advanced head and neck cancer.Ann Oncol. 2004; 15: 383-388Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. 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.Logemann J.A. Evaluation and treatment of swallowing disorders. second edition. Proed, Austin, TX1998Crossref Scopus (76) Google Scholar]. 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.Eisbruch A. Lyden T. Bradford C.R. et al.Objective assessment of dysphagia and aspiration following chemo-irradiation for head and neck cancer.Int J Radiat Oncol Biol Phys. 2002; 53: 23-28Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar], 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 RT—was similar to a regimen reported by Brizel et al. where chemotherapy was delivered concurrent with hyperfractionated (twice daily) RT [14.Brizel D.M. Albers M.E. Fisher R.S. et al.Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.N Engl J Med. 1998; 338: 1798-1804Crossref PubMed Scopus (997) Google Scholar]. 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.Peters L.J. Targeting hypoxia in head and neck cancer.Acta Oncol. 2001; 40: 937-940Crossref PubMed Scopus (14) Google Scholar].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 [16.Garden A.S. Morrison W.H. Wong S. et al.Preliminary results of intensity modulated radiation therapy for small primary oropharyngeal carcinoma.Proceedings of the 45th Annual Meeting of ASTRO. 2003; (Abstr 2108)Google Scholar, 17.Mittal B.B. Kepka A. Mahadevan A. et al.Use of IMRT to reduce toxicity from concurrent radiation and chemotherapy for advanced head and neck cancer.Int J Radiat Oncol Biol Phys. 2001; 51 (Abstr 147): 82Abstract Full Text Full Text PDF Google Scholar, 18.Milano M.T. Vokes E.E. Witt M.E. et al.Retrospective comparison of IMRT and conventional three-dimensional RT in advanced head and neck patients treated with definitive chemoradiation.Proc Am Soc Clin Oncol. 2003; 499: 22Google Scholar]. 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.Antonadou D. Throuvalas N. Petridis A. et al.Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small cell lung cancer.Int J Radiat Oncol Biol Phys. 2003; 57: 402-408Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar] but not in another [20.Senzer N. A phase III randomized evaluation of amifostine in non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensification: preliminary findings.Semin Oncol. 2002; 29: 38-41Crossref PubMed Scopus (32) Google Scholar]. 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.Brizel D.M. Wasserman T.H. Henke M. et al.Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.J Clin Oncol. 2000; 18: 3339-3345Crossref PubMed Scopus (684) Google Scholar]. It is possible that higher doses of amifostine will achieve mucosal protection [22.Bourhis J. Rosine D. Radioprotective effect of amifostine in patients with head and neck squamous cell carcinoma.Semin Oncol. 2002; 29: 61-62Crossref PubMed Scopus (34) Google Scholar] 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.Logemann J.A. Rademaker A.W. Pauloski B.R. et al.Effects of postural change on aspiration in head and neck patients.Otolaryngol Head Neck Surg. 1994; 110: 222-227Crossref PubMed Scopus (116) Google Scholar]. 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.Fu K.K. Pajak T.F. Trotti A. et al.A radiation oncology group phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck cancer.Int J Radiat Oncol Biol Phys. 2000; 48: 7-16Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar, 2.Pignon J.P. Bourhis J. Domenge C. Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data.Lancet. 2000; 355: 949-955Abstract Full Text Full Text PDF PubMed Scopus (2202) Google Scholar]. 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 toxicity—in some cases, a consequence of acute mucosal injury—is a major detrimental effect of some organ preservation approaches using chemotherapy-RT (chemo-RT) or aggressive accelerated RT [3.Skladowski K. Maciejewski B. Golen M. Randomized clinical trial of 7-day continuous accelerated radiation (CAIR) of head and neck cancer: report on 3-year tumor control and normal tissue toxicity.Radiother Oncol. 2000; 55: 101-110Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 4.Staar S. Rudat V. Stuetzer H. et al.Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: results of a multicenter randomized German trial in advanced head and neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 1161-1171Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 5.Delaney G.P. Fisher R.J. Smee R.J. et al.Split-course accelerated therapy in head and neck cancer: an analysis of toxicity.Int J Radiat Oncol Biol Phys. 1995; 32: 763-768Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 6.Abitbol A.A. Sridhar K.S. Lewin A.A. Hyperfractionated radiation therapy and 5-fluorouracyl, cisplatin and mitomycin C in the treatment of patients with locally advanced head and neck cancer.Cancer. 1997; 80: 266-276Crossref PubMed Scopus (39) Google Scholar, 7.Vokes E.E. Stenson K. Rosen F.R. et al.Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer.J Clin Oncol. 2003; 21: 320-326Crossref PubMed Scopus (212) Google Scholar]. 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.Kaanders J.H.M. van Daal W.A.J. Hoogenraad W.J. et al.Accelerated fractionation radiotherapy for laryngeal cancer, acute and late toxicity.Int J Radiat Oncol Biol Phys. 1992; 24: 497-503Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 9.Trotti A. Toxicity in head and neck cancer: a review of trends and issues.Int J Radiat Oncol Biol Phys. 2000; 47: 1-12Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar]. Late pharyngeal toxicity has recently been recognized as the main barrier to winning the battle with head and neck cancer [10.Robbins K.T. Barriers to winning the battle with head and neck cancer.Int J Radiat Oncol Biol Phys. 2002; 53: 4-5Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. 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.Nguyen N.P. Moltz C.C. Frank C. et al.Dysphagia following chemoradiation for locally advanced head and neck cancer.Ann Oncol. 2004; 15: 383-388Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. 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.Logemann J.A. Evaluation and treatment of swallowing disorders. second edition. Proed, Austin, TX1998Crossref Scopus (76) Google Scholar]. 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.Eisbruch A. Lyden T. Bradford C.R. et al.Objective assessment of dysphagia and aspiration following chemo-irradiation for head and neck cancer.Int J Radiat Oncol Biol Phys. 2002; 53: 23-28Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar], 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 RT—was similar to a regimen reported by Brizel et al. where chemotherapy was delivered concurrent with hyperfractionated (twice daily) RT [14.Brizel D.M. Albers M.E. Fisher R.S. et al.Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.N Engl J Med. 1998; 338: 1798-1804Crossref PubMed Scopus (997) Google Scholar]. 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.Peters L.J. Targeting hypoxia in head and neck cancer.Acta Oncol. 2001; 40: 937-940Crossref PubMed Scopus (14) Google Scholar]. 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 [16.Garden A.S. Morrison W.H. Wong S. et al.Preliminary results of intensity modulated radiation therapy for small primary oropharyngeal carcinoma.Proceedings of the 45th Annual Meeting of ASTRO. 2003; (Abstr 2108)Google Scholar, 17.Mittal B.B. Kepka A. Mahadevan A. et al.Use of IMRT to reduce toxicity from concurrent radiation and chemotherapy for advanced head and neck cancer.Int J Radiat Oncol Biol Phys. 2001; 51 (Abstr 147): 82Abstract Full Text Full Text PDF Google Scholar, 18.Milano M.T. Vokes E.E. Witt M.E. et al.Retrospective comparison of IMRT and conventional three-dimensional RT in advanced head and neck patients treated with definitive chemoradiation.Proc Am Soc Clin Oncol. 2003; 499: 22Google Scholar]. 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.Antonadou D. Throuvalas N. Petridis A. et al.Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small cell lung cancer.Int J Radiat Oncol Biol Phys. 2003; 57: 402-408Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar] but not in another [20.Senzer N. A phase III randomized evaluation of amifostine in non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensification: preliminary findings.Semin Oncol. 2002; 29: 38-41Crossref PubMed Scopus (32) Google Scholar]. 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.Brizel D.M. Wasserman T.H. Henke M. et al.Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.J Clin Oncol. 2000; 18: 3339-3345Crossref PubMed Scopus (684) Google Scholar]. It is possible that higher doses of amifostine will achieve mucosal protection [22.Bourhis J. Rosine D. Radioprotective effect of amifostine in patients with head and neck squamous cell carcinoma.Semin Oncol. 2002; 29: 61-62Crossref PubMed Scopus (34) Google Scholar] 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.Logemann J.A. Rademaker A.W. Pauloski B.R. et al.Effects of postural change on aspiration in head and neck patients.Otolaryngol Head Neck Surg. 1994; 110: 222-227Crossref PubMed Scopus (116) Google Scholar].