ESOPHAGEAL STRICTURE AFTER RADIOTHERAPY IN PATIENTS WITH HEAD AND NECK CANCER: EXPERIENCE OF A SINGLE INSTITUTION OVER 2 TREATMENT PERIODS

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1 ORIGINAL ARTICLE ESOPHAGEAL STRICTURE AFTER RADIOTHERAPY IN PATIENTS WITH HEAD AND NECK CANCER: EXPERIENCE OF A SINGLE INSTITUTION OVER 2 TREATMENT PERIODS Alexander Ahlberg, MD, 1,9 Massoud al-abany, PhD, 2,7 Eleftheria Alevronta, MSc, 2,3 Signe Friesland, MD, PhD, 4 Henrik Hellborg, MSc, 5 Panayiotis Mavroidis, PhD, 3,6 Bengt K. Lind, PhD, 3 Göran Laurell, MD, PhD 1,8 1 Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden. alexander.ahlberg@karolinska.se 2 Department of Oncology Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet, Stockholm, Sweden 3 Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm, Sweden 4 Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden 5 Center of Oncology, Karolinska University Hospital, Stockholm, Sweden 6 Department of Medical Physics, Larissa University Hospital, Larissa, Greece 7 Department of Medical Physics, Karolinska University Hospital, Stockholm, Sweden 8 Department of Clinical Sciences, Umeå University, Umeå, Sweden 9 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Accepted 28 May 2009 Published online 11 August 2009 in Wiley InterScience ( DOI: /hed Abstract: Background. Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined. Methods. This was a retrospective case-control study of patients diagnosed and treated for esophageal stricture after radiotherapy for head and neck cancer. Results. The incidence of esophageal stricture after external beam radiation therapy (EBRT) was 3.3%. Seventy patients with stricture and 66 patients without stricture were identified. A multivariate analysis showed that there was increased risk of stricture in receiving enteral feeding during EBRT or in receiving a mean dose of >45 Gy to the upper esophagus. Correspondence to: A. Ahlberg VC 2009 Wiley Periodicals, Inc. Conclusions. Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated. VC 2009 Wiley Periodicals, Inc. Head Neck 32: , 2010 Keywords: esophageal stricture; esophageal stenosis; radiotherapy induced; head neck; treatment esophageal stricture During the last few decades there has been great progress in the oncological treatment of patients with squamaous cell carcinoma of the head and neck (SCCHN). The incidence of late 452 Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April 2010

2 toxicity, however, has increased as the result of more aggressive treatment. 1 One feared late adverse effect observed after external beam radiation therapy (EBRT) for SCCHN is stricture of the upper esophagus. The use of chemotherapy in conjunction with EBRT has dramatically increased the number of patients who experience stricture formation after treatment. 2 Because the number of patients who survive the treatment is increasing, more attention must be directed toward functional loss, to improve health-related quality of life (HRQL) by preventive measures and rehabilitation. 3 Radiation-induced injury to surrounding normal tissue is a common and dose-limiting side effect of EBRT. The molecular mechanisms involved in acute and delayed toxicity have still not been fully elucidated, although microvascular injury is reported to be involved in both the early and the late phases. Stricture of the upper esophagus seen after EBRT is mainly characterized by fibrosis caused by progressive obliterative endarteritis, leading to ischemia of the esophageal wall. 4 In addition to fibrosis, there is also an effect on muscle motor activity controlling swallowing through the upper segment of the esophagus. 5 Laurell et al 6 reported a variety of clinical manifestations in patients with stricture, ranging from a membranous ring to total obliteration of the esophageal lumen. The exact mechanisms and also the risk factors other than radiation for the development of stricture have not been established. There is accumulating evidence that the radiation dose and the irradiated volume of the esophagus are of greatest importance for triggering a process that leads to a stricture. 2,7 The clinical pattern of SCCHN is complex and involves a number of different anatomical sites, tumor stages, and treatment options, suggesting that EBRT and chemotherapy are not the only factors associated with this late adverse effect. Moreover, moderate to severe comorbidity is common in patients with head and neck cancer. Thus, one can speculate that other causative factors have key roles in the pathogenesis of stricture formation and, therefore, need to be defined. Impaired swallowing during EBRT has also been reported to be a risk factor. 8 As esophageal stricture after EBRT is a low-frequency complication with an incidence of <5% 6 : prospective studies on the association between the inability to swallow during EBRT and fibrosis of the esophageal wall involved are difficult to perform. However, it is well documented that a high percentage of patients with head and neck cancer receive a nasogastric (NG) feeding tube or a percutaneous endoscopic gastrostomy (PEG) even before the start of treatment, with the aim of preventing malnutrition. 9 The low number of patients in the majority of previous studies makes it difficult to draw any clear conclusions regarding risk factors in development of an irradiation-induced stricture of the upper esophagus. The present retrospective, case-control study was performed not only to identify additional risk factors but also to determine the long-term outcome of treatment of irradiation-induced stricture of the esophagus in patients after EBRT, diagnosed at 1 head and neck cancer center during the period 1992 to This study was approved by the ethical board, Stockholm, Sweden (entry no. 2006/ /3), and written consent to take part in the study was retrieved from all living participants. PATIENTS AND METHODS Patient Definitions. We continuously identified and registered all patients with esophageal stricture after EBRT at our department during the years 1992 to All patients included were initially diagnosed as having head and neck cancer at the Department of Otolaryngology and Head and Neck Surgery, Karolinska University Hospital, Solna, Sweden, between 1987 and The study sample is divided into 2 time periods based on the year of the EBRT, 1987 to 1999 and 2000 to 2005, because there was a change in EBRT treatment in 1999 to Patients diagnosed as having stricture of the upper esophagus at our institution from 1992 to 1998 all received EBRT at Radiumhemmet, Karolinska University Hospital. In 1998, surgical treatment for head and neck cancer in the County of Stockholm was centralized to our institution at Karolinska Hospital. From that year onward, all patients in Stockholm with irradiation-induced stricture were diagnosed at our institution but were given EBRT at 2 different treatment centers, Radiumhemmet at the Karolinska University Hospital or at the Stockholm South General Hospital, depending on the patient s home address. Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April

3 The diagnosis of squamous cell carcinoma was confirmed histologically in all patients. Tumor stage was classified according to the 1987, 1997, and 2002 Union Internationale Contre le Cancer (UICC) criteria, depending on the year of diagnosis. The treatment modality was decided at weekly multidisciplinary team meetings. Nutritional care was regularly given at a nurse-led outpatient clinic, and dietary counseling was provided to all patients. Clinical guidelines for enteral feeding were dysphagia and a weight loss of >5% of the pretreatment body weight (the weight taken at the initial diagnostic endoscopy) and for patients with expected nutritional problems caused by advanced tumor stage. Patients with swallowing problems and clinical signs of an esophageal obstruction were examined with conventional swallow X-ray using barium contrast and endoscopy. Diagnosis of stricture of the upper esophagus was made by an endoscopic procedure under general anesthesia, except in 1 patient in whom only an X-ray examination with swallowing of barium contrast was performed. A control group of patients without any reported swallowing problems was constructed and a case control study was conducted. Patients in the control group had answered a mailed questionnaire about dysphagia that had been sent to them 2 years after termination of EBRT. Patients in the control group were treated during 3 different years, 1992, 2000, and 2004, and all patients who fulfilled the inclusion criteria from these years were included. Inclusion criteria were that there was no esophageal stricture, the possibility of radiation to the esophagus, full-dose EBRT, and that the patient had consented to inclusion in the study. Ten patients in the control group did experience some swallowing problems but showed normal endoscopic findings or had a negative radiological examination. No further matching was done when constructing the control group. The medical records of all patients were collected and analyzed according to a data matrix, including the following parameters: EBRT dose (the given dose), survival, tumor localization and stage, use of NG tube and PEG, weight changes during EBRT, oral mucositis, and treatment of the stricture. To make a general description of the strictures of the upper esophagus, these were classified into 3 subgroups according to the findings at endoscopy for diagnosis of dysphagia or treatment of stricture. When more than 1 endoscopy was performed, the patient was classified according to the highest grade of stricture found. In grade I, the stricture could be passed with a rigid esophagoscope 7 10 mm wide and the stricture could be dilated. In grade II, the stricture could not be passed by the 7-10-mm scope but could be dilated, and after dilatation the esophagoscope could pass the stricture. In grade III, there was total obliteration of the esophagus. Exclusion Criteria. Patients treated with chemotherapy were excluded, as were patients with incomplete medical records. Patients who had had dysphagia before diagnosis of the present tumor disease were also excluded. Fourteen patients were excluded as a result of these criteria. Radiotherapy. EBRT was given at 2 different treatment centers in Stockholm Stockholm South General Hospital and Radiumhemmet at the Karolinska University Hospital and dose plans were constructed according to local guidelines. A standard 3-dimensional (3D) conformal technique was used. The treatment dose was given with 4- or 6-MV photon beams from linear accelerators in 1 daily fraction of 2 Gy 5 days a week (except for 2 patients, 1 patient from the stricture group and 1 patient from the control group, who received hyperfractioned EBRT [1.1 þ 2.0 Gy per day for 4.5 weeks, up to 68 Gy according to the Swedish ARTSCAN study]). Fields were planned according to the site of the primary tumor and the presence of neck metastases. The clinical target volume consisted of the primary gross tumor volume, the subclinical microscopic malignant disease, and the locally involved lymph nodes. A margin around the clinical target volume was included to form the planning target volume, to allow for uncertainty in its shape and variation in its location relative to the beams attributed to organ mobility, organ deformation, and variations in patient setup. The dose given at the reference point to the planning target volume was 64 to 68 Gy. The maximal accepted dose to the spinal cord was 48 to 50 Gy. After 1998, the target delineation was changed according to new guidelines from the Swedish ARTSCAN study group. These guidelines were then gradually implemented for all patients with head and neck cancer. It was decided that the irradiation volumes and the 454 Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April 2010

4 total dose given to unaffected tissue, such as the contralateral neck, should be 46 Gy. Earlier, the dose given to elective nodes was the same as that to macroscopic tumor. As a result of this change, smaller volumes were treated with high doses, and a larger proportion of normal tissue could be spared. In addition, the larynx was blocked from the anteroposterior fields if it was not included in the planning target volume. Patients had a CT scan done in supine position, with 10- or 5-mm intervals covering an area from the base of the skull down to the chest. The CT scans were transferred to the treatment-planning system (TMS; Nucleotron, Veenendaal, The Netherlands), in which the target and critical structure volumes were delineated. Dose-planning treatment data were stored for all patients. Data for a subgroup of patients with stricture and from the control group treated at Radiumhemmet were retrieved from the archive in the TMS system. This could not be done for patients treated at the Stockholm South General Hospital because of technical problems with the dose-planning system at that institution. There were also technical problems or a lack of complete medical records for some patients treated at Radiumhemmet. The upper 5 cm of the esophagus was defined anatomically as being situated 2 cm inferior to the vocal cords. The esophagus was delineated on each CT image for each patient. The differential and cumulative dose volume histograms (DVHs) of the upper 5 cm of the esophagus were assessed for each patient. DVHs summarize the information contained in the 3D dose distribution and are powerful tools for a quantitative evaluation of treatment plans. The differential DVHs, together with patient record information and statistical information about dose and volume for all defined structures, were then exported, and the corresponding cumulative DVHs were calculated for the delineated part of the esophagus. From the cumulative DVHs, it was possible to calculate the mean dose delivered to the upper 5 cm of the esophagus for this subgroup of patients. A 3D treatment plan consists of the dose-distribution information over a 3D matrix of points covering the patient s anatomy. Statistics. Test of equality of distribution was done with the chi-square test or Fisher s exact test when appropriate. Difference of means was tested with Student s t test after assessing the normal assumption. Odds ratios (ORs) for potential risk factors in developing a stricture were estimated using a logistic regression. In the logistic regression, the categories of stage and site were analyzed as separate indicator variables. A multivariate analysis was done with the most interesting and important factors from the univariate analysis. All analyses were done using SPSS for Windows version (SPSS Inc., Chicago, IL). RESULTS Patient Data. Seventy patients with irradiationinduced stricture of the upper esophagus were identified and evaluated between 1992 and All patients had received EBRT for head and neck cancer between 1987 and Sixtysix patients were included in the control group. The clinical characteristics of the patients in the stricture and control groups are presented in Table 1. Cases and controls were well matched for age and sex, but not for year of diagnosis. The total number of patients irradiated with curative intent for head and neck cancer during the 2 periods was calculated. The total number of patients treated at Radiumhemmet during 1992 to 1999 was 740 and the total number of patients treated in Stockholm at the 2 sites Radiumhemmet and Stockholm South General Hospital between 2000 and 2005 was Based on this calculation, the total incidence of irradiation-induced esophageal stricture in patients treated with radiotherapy for head and neck cancer during 1992 to 2005 was 3.3% (59/ 1805). Six patients treated with EBRT before 1992 were excluded from this calculation Parameter Table 1. Patient characteristics. Patients with stricture Patients without stricture No Mean age, y 62 (range, 30 92) 63 (range, 32 92) Males, % Females, % EBRT treatment, no. of patients, % (10) 0 (0) (47) 19 (29) (43) 47 (71) Mean total dose, Gy Abbreviations: EBRT, external beam radiation therapy; Gy, gray. Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April

5 Parameter Table 2. Analysis of risk parameters. No. of patients with stricture (%) No. of patients without stricture (%) Univariate Odds ratio Multivariate Stage UICC 6 Stage I 9 (13%) 17 (26%) 0.43 ( ) Stage II 19 (27%) 10 (15%) 2.09 ( ) Stage III 20 (29%) 10 (15%) 2.24 ( ) Stage IV 22 (31%) 22 (33%) 0.92 ( ) No stage 0 (0%) 7 (11%) Primary site of tumour Oral 21 (30%) 11 (17%) 2.14 ( ) 1.36 ( ) Oropharyngeal 22 (31%) 13 (20%) 1.87 ( ) 1.76 ( ) Epipharyngeal 5 (7%) 6 (9%) 0.77 ( ) Hypopharyngeal 5 (7%) 2 (3%) 2.46 ( ) Laryngeal 14 (20%) 24 (36%) 0.44 ( ) 0.58 ( ) Other 3 (4%) 10 (15%) 0.25 ( ) 0.22 ( ) Mucositis Stage I 49 (70%) 31 (47%) 2.63 ( ) Enteral feeding Only NG tube 31 6 PEG and/or NG tube 15 3 Total incidence of NG tube and/or PEG 46 (66%) 9 (14%) ( ) ( ) Weight Mean weight loss during EBRT 5.8% (n ¼ 41) 3.5% (n ¼ 34) <5% (ref) 16 (23%) 20 (30%) >5% 25 (36%) 14 (21%) 2.23 ( ) Missing 29 (41%) 32 (49%) 1.13 ( ) Surgery No surgery (ref) 26 (37%) 29 (44%) Surgery 44 (63%) 37 (56%) 1.33 ( ) 1.78 ( ) Postoperative EBRT (ref) 13 (19%) 19 (29%) Preoperative EBRT 31 (44%) 18 (27%) 2.52 ( ) Hemigloss-tongue 16 (23%) 3 (5%) 6.22 ( ) Radiotherapy: mean dose to upper oesophagus <45 Gy 3 (ref) 7 (10%) 25 (38%) >45 Gy 3 19 (27%) 12 (18%) 5.65 ( ) 7.01 ( ) Missing 44 (63%) 29 (44%) 5.42 ( ) 5.49 ( ) Abbreviations: UICC, Union Internationale Contre le Cancer; EBRT, external beam radiation therapy; Hemigloss-tongue, hemiglossectomy, tongue resection, base of tongue resection; NG, nasogastric; PEG, percutaneous endoscopic gastrostomy; Gy, gray. because of incomplete data. A subgroup analysis of patients treated at Radiumhemmet between 1992 and 1999, and at both treatment centers between 2000 and 2005, showed an incidence of irradiation-induced esophageal stricture of 3.8% (28/740; 5 patients treated at Stockholm South General Hospital in are not included) and 2.9% (31/1065), respectively. Thus, the difference in incidence was not statistically significant (p ¼.316). Tumor stage and primary site of the tumor are presented in Table 2. The stricture group and reference group were similar with regard to stage. To determine whether survival time is affected by stricture formation, the median survival time for cases and controls was calculated. Because all patients in the control group had survived for at least 2 years after treatment, deaths among the patients during the first 2 years after treatment were excluded. There was no significant difference in median survival time between cases (9.2 years, 95% confidence interval [CI] ¼ ) and controls (12.3 years, 95% CI ¼ ). Univariate analysis of risk parameters for developing a stricture showed a numerical but nonsignificant increase in OR for patients with oral tumors (OR ¼ 2.14, 95% CI ¼ ) and oropharyngeal tumors (OR ¼ 1.87, 95% CI ¼ ). The risk of developing a stricture was not related to having a primary tumor in the hypopharynx or epipharynx. There was a 456 Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April 2010

6 significant reduction in OR for patients with primary tumor in the larynx (OR ¼ 0.44, 95% CI ¼ ). Patients with primary tumor in sites other than the pharynx, larynx, and oral cavity (involving a number of different sites) appeared to have a lower risk of developing a stricture. We repeated all calculations with such patients excluded from both the controls and the cases, to ensure that this group did not confound the outcome. There was no significant difference to the results, however, except for wider confidence intervals. Nasogastric Tube and Percutaneous Endoscopic Gastrostomy. The numbers of patients receiving an NG tube or the combination of an NG tube followed by a PEG on a later occasion, during or within 2 weeks after termination of radiotherapy, and also the incidence of oral mucositis and weight loss during EBRT, are presented in Table 2. There was a high incidence of patients receiving tube feeding among the patients with stricture. In patients using enteral nutrition in the stricture group, 67% (31/46) used only an NG tube and 33% (15/46) used the combination of an NG tube followed later by a PEG; 2 of these patients received PEG before the start of EBRT. The OR in the univariate analysis for development of a stricture in patients receiving tube feeding before, during, or within 2 weeks of treatment was (95% CI ¼ ). This parameter was also significant in the multivariate analysis. Reliable data concerning weight loss during EBRT could be obtained for only 41 patients (41/ 70, 59%) in the stricture group and for 34 patients (34/66, 52%) in the reference group. Because there was an equal amount of missing data in both groups, a comparison of the groups could be made, even though there could be an inclusion bias in these numbers. There was higher loss of weight in the stricture group than in the reference group during EBRT, even though most patients in the stricture group received NG tube and PEG. In the stricture group, only 4.9% (2/41) gained weight during EBRT, compared with 26% (9/34) in the reference group. Surgery. In the stricture group, 44 patients (63%) underwent a surgical procedure, compared with 37 patients (56%) in the reference group. The effect of surgery on stricture formation was estimated, and the results showed no significant increase in OR for patients treated with surgery in combination with EBRT (OR ¼ 1.33, 95% CI ¼ ). However, there was an increased OR for development of stricture in patients receiving preoperative EBRT compared with patients who received postoperative EBRT (OR ¼ 2.52, 95% CI ¼ ). There was a significantly higher incidence of tongue and/or base of tongue resections in the stricture group than in the reference group (23% and 4.5%, respectively) with an OR of 6.22 (95% CI ¼ ) for development of stricture after tongue and/or base of tongue resection. Radiotherapy. It was possible to retrieve the complete dose plans and EBRT records for 26 patients in the stricture group and for 37 patients in the reference group; all of these individuals were treated at Radiumhemmet. For the remaining patients no dose volume data were available, mainly because of technical problems with the dose-planning systems. DVHs for the upper 5 cm of the esophagus are presented in Figure 1. The OR in the univariate analysis for development of stricture was 5.65 (95% CI ¼ ) in patients receiving a mean dose of >45 Gy to the superior 5 cm of the esophagus; the OR was also significant in the multivariate analysis. The limit of 45 Gy was chosen as the level at which there was a significantly increased risk of stricture. As shown in Table 3, there was a statistically significant difference in mean dose delivered to the upper 5 cm of the esophagus between the patients and controls during the whole observation period. With stratification of patients according to the 2 treatment periods, 1987 to 1999 and 2000 to 2005, as shown in Figure 1, the differences in average mean dose and the mean percentage DVHs were statistically significant between the cases and the controls for 2000 to 2005, although the differences were not significant for the period 1987 to 1999 (Table 3). Of the 8 patients with stricture in 2000 to 2005, 5 received a mean dose to the upper esophagus of >45 Gy, and 4 of these 5 had primary tumors caudal to the hyoid bone (Table 4). Multivariate Logistic Regression Analysis. A multivariate logistic regression analysis was conducted for the following parameters: mean dose to the esophagus, NG tube and/or PEG, surgery or no surgery, and primary site. This analysis Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April

7 Table 4. Primary site and T N classification of patients with stricture, 2000 to Dose to upper esophagus >45 Gy (5 patients) <45 Gy (3 patients) Larynx, T2N0 Larynx, T2N0 Epipharynx, T4N2c Hypopharynx, T2N0 Hypopharynx, T2N0 Oropharynx, T4N2b Oropharynx, T2N1 Oral, T4N0 Abbreviation: Gy, gray. tongue/base of the tongue, stage, weight, and epipharyngeal and hypopharyngeal sites, but this did not add any information concerning significant risk factors. This information is therefore excluded from Table 2. FIGURE 1. Dose volume histogram (DVH) for patients with and without stricture, stratified according to year of treatment. All patients in the first time period were treated during 1992 to showed that there was a significantly increased risk for patients receiving NG tube and/or PEG, with an OR of (95% CI ¼ ), and for receiving a mean dose of >45 Gy to the upper part of the esophagus, with an OR of 7.01 (95% CI ¼ ). For all other parameters, ORs were not significant when adjusted for in the multivariate analysis. Multivariate analysis was also performed with inclusion of mucositis, surgery of the Table 3. Mean dose to upper 5 cm of the esophagus. Parameter Patients with stricture Patients without stricture Mean difference, t test No. of patients Mean dose Gy 35.6 Gy p < Gy 44.1 Gy p ¼ Gy 29.9 Gy p ¼.006 Abbreviation: Gy, gray. Diagnosis and Treatment of Stricture in the Upper Esophagus. The duration between termination of EBRT and diagnosis of stricture ranged from 1 month to 132 months, with a mean time of 22 months and a median time of 8 months. Stricture of the upper esophagus was diagnosed by radiography with swallowing of barium contrast before esophagoscopy in 30 patients. In 2 patients, the initial radiograph did not reveal a grade I stricture, but it was later confirmed by endoscopy. In 2 cases, the radiological examination could not be performed because of aspiration of contrast. For 36 patients, no radiography was undertaken and indication for esophagoscopy was based only on clinical findings. Esophagoscopy under general anesthesia showed grade II stricture in 41 patients (59%). Grade I stricture was found in 19 patients (27%), and grade III stricture in 10 patients (14%). There was no significant association between the grade of stricture and the primary site or tumor stage. Treatment of the stricture of the upper esophagus was generally performed by endoscopic dilatations under general anesthesia. Four patients did not undergo dilatation as a result of their bad general condition and locoregional recurrence of the tumor. In 66 patients, attempted dilatations were performed using 3 different techniques. Of the 63 patients who had dilatation with Savary-guided bougies, 53 (84%) could swallow after dilatation, but in 45 of these patients dilatation had to be repeated. The average number of dilatation procedures per patient (according to grade of stricture) was 3.3 for 458 Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April 2010

8 grade I, 3.0 for grade II, and 4.5 for grade III. Five patients with grade III stricture were initially successfully treated with dilatation when they had a lower grade of stricture, but they eventually developed a grade III stricture. Endoscopic dilatation using Savary-wire-guided dilatations failed to offer any improvement of the swallowing function in 10 patients (16%). One patient with grade II stricture developed a perforation after dilatation with Savary-guided bougies. To maintain swallowing after endoscopic dilatation, mercury-weighted rubber bougies (Maloney dilators) were used in 9 patients. Five patients underwent dilatation using the through-the-scope balloon dilators; 2 of these patients were also dilated with Savary bougies. Four of these could swallow after the procedure, but 3 had to undergo dilatation more than once. Two patients (grade III) were operated on with a resection of the stricture and reconstruction with a free vascular flap. One of these patients could swallow after the surgical procedure, whereas the other had a postoperative infection and was unable to swallow. DISCUSSION The case sample in this retrospective study was composed of 70 patients with esophageal stricture after EBRT for a variety of malignant tumors in the head and neck. Patients were identified at 1 head and neck cancer center, and received EBRT as a single-modality treatment or in combination with surgery. Other studies have shown an increase in stricture formation with the use of chemotherapy and radiotherapy given concurrently, 2,10 but none of the patients in the present study received any chemotherapy. To determine whether a change in irradiation treatment technique affected the outcome of stricture of the upper esophagus after EBRT, the incidence was compared between 2 time periods, although no significant reduction in incidence could be found. However, patients who received a mean dose of >45 Gy to the upper part of the esophagus had an increased risk of stricture formation. Even though the numerically observed decrease in incidence after modification of EBRT was not statistically significant, the present data give some indication that the risk of developing this serious iatrogenic injury can be reduced with irradiation of smaller volumes, thus sparing normal tissues. This indication of a reduced risk of irradiation injury to the upper esophagus is consistent with that in other studies on patients with head and neck cancer. 6,10,11 Recent advances in better planning techniques may thus spare the normal tissue and reduce the risk of side effects such as esophageal stricture. In accordance with this, we found that laryngeal tumors were negatively associated with the risk of stricture when surgically induced strictures were excluded. A small volume is normally irradiated when treating small laryngeal tumors, which could result in fewer strictures, whereas the volumes are large when treating, say, hypopharyngeal tumors, causing early-morbidity side effects such as mucositis. 12 We have tried to identify additional factors that may increase the risk of irradiationinduced stricture of the upper esophagus, by identifying a control group of patients with head and neck cancer without stricture in the esophagus. In a univariate analysis, factors associated with the development of a stricture were: mean dose of >45 Gy to the upper esophagus, tongue, and base of tongue resection, preoperative EBRT, mucositis, and the use of NG tube or PEG during EBRT. However, the multivariate analysis identified only NG tube and/or PEG, and also a mean dose of >45 Gy to the upper esophagus, as independent risk factors for development of stricture of the upper esophagus. A multifactorial model for development of radiation-induced stricture would include not only treatment-related variables but also factors related to an individual response to radiation of normal esophageal tissue. Twelve patients in the control group received a mean dose of >45 Gy to the upper 5 cm of the esophagus, and 7 patients in the stricture group received a mean dose <45 Gy. An important question that arises is why some patients who received a low dose to the upper esophagus developed a stricture, whereas other patients who received a high dose did not. Regardless of the exact mechanisms, the fact remains that even lower doses given to spare the esophagus may be associated with stricture formation. In contrast to the findings of Lee et al, 13 who reported an association between hypopharyngeal tumors, female sex, and stricture of the upper esophagus, we found no such correlation. There was, however, an indication of increased risk of stricture formation in patients with their primary tumor in the oral cavity. For several reasons, one could hypothesize that impaired swallowing is a crucial factor for development of a stricture. Impaired swallowing in patients Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April

9 with head and neck cancer is a heterogeneous phenomenon, and a number of different factors may contribute to this, such as tube feeding, oral mucositis, dental problems, esophagitis, and surgery (eg, resection of the tongue). The relationship between mucositis and stricture is unclear. In the present study, there was a higher incidence of oral mucositis in the stricture group than that in the reference group and mucositis was found to be a significant risk factor in the univariate analysis but not in the multivariate analysis. However, in this study no classification of the level of mucositis was performed because of uncertainties in the literature concerning this parameter. The results are conflicting: Lee et al 2 and Lawson et al 13 found no clear relationship between mucositis and stricture formation. Lal et al 14 focused on the role of esophagitis and stricture formation, in which there is an obvious association. In the present study as well as in previous studies, oral mucositis was seen to cause dysphagia, and could therefore indirectly induce stricture formation. The same relation was seen with the use of tube feeding during EBRT, which was significantly higher in patients who developed esophageal stricture. Patients who receive enteral nutrition during EBRT might be less motivated to continue to swallow than patients with dysphagia, who continue with oral intake without the help of enteral feeding aids. One factor that could contribute to stricture formation is prolonged dysphagia. 8,15 According to a study by Wiggenraad et al, 16 reduced swallowing attributed to enteral nutrition might in addition to radiotherapy trigger development of an esophageal stricture. These findings are commensurate with ours, showing an increased risk when using tube feeding. Moreover, Mekhail et al 17 found indications that patients who received a PEG have a higher risk of developing a stricture than those using an NG tube, a finding that was not supported by the results of the present study, because we found a higher number of NG tube users than PEG users in patients with stricture. There is a theoretically possible cause for reflux esophagitis in patients using an NG tube, which might add to stricture formation. The management of dysphagia during radiotherapy for head and neck cancer is somewhat controversial. At some centers, tube feeding via a PEG is recommended for the majority of patients prior to radiotherapy, 9 and at our own institution, the incidence of PEG or NG tube before, during, or after EBRT was 59.4% in the period 2000 to 2004 (unpublished observations). According to the present results, one cannot exclude the possibility that use of tube feeding in the majority of patients with head and neck cancer may result in a higher percentage of stricture of the upper esophagus. However, it is very difficult to state whether PEG or NG tube is part of the cause of esophageal stricture, or whether the need for PEG or NG tube is only a sign indicating the risk of stricture development. Patients going through surgery in the oral cavity, especially tongue and base of tongue resections, and also patients undergoing reconstruction with the use of free vascular flaps are reported to have impaired swallowing. 18,19 The higher incidence of patients undergoing major surgery to the tongue and base of the tongue in the patients with stricture in this study is probably related to impaired swallowing in these patients. An increased risk of stricture formation was associated with preoperative EBRT rather than postoperative EBRT, a difference that cannot be explained by the primary tumor site or stage. Even though the number of patients studied was low, it is possible that this order of treatment impaired swallowing function more than treatment with postoperative EBRT. This association has not been thoroughly analyzed previously to our knowledge, except for surgery using free flaps. 19 There have been a number of case studies describing treatment of a stricture to the upper esophagus after radiotherapy. Many authors have successfully used the Savary Gilliard bougienage for dilatation. 5,20 Other authors have recommended balloon dilatation, which can also be used in the antegrade retrograde rendezvous technique for total obliteration of the esophagus. 21 In the present study, treatment of the esophageal stricture was successfully performed with the use of Savary Gilliard bougienage, as well as through the rigid scope balloon dilatation. These methods are safe and easily performed, with the patients hospitalized for only 24 hours. Dilatations usually have to be repeated, and the economic cost associated with this is rather low. These results are in accord with those in studies by Piotet et al 5 and Ahlawat et al. 20 No difference in mean survival was found for patients with esophageal stricture. However, HRQL is generally low in patients with dysphagia, even though no analysis of this parameter was done in this study. 22, Esophageal Stricture after Radiotherapy HEAD & NECK DOI /hed April 2010

10 One central concern in the present study was the number of confounding factors that could not be avoided in a case control study of this rare condition. Another concern was the low number of patients both cases and controls even though these numbers were high compared with other studies dealing with this treatment-related problem. Although the end goal would be to perform a prospective study on the effect of additional factors on generation of stricture of the upper esophagus in patients after EBRT, a well-designed retrospective study is most probably the only reasonable way to evaluate this low-incidence late effect. CONCLUSIONS The incidence of esophageal stricture after EBRT alone or EBRT combined with surgery for treatment of head and neck cancer was found to be 3.3%. There was a significantly increased risk of stricture formation in patients who received >45 Gy to a large volume of the upper part of the esophagus. Another independent significant risk factor identified was the use of an NG tube or PEG during or immediately after EBRT. Treatment of the stricture with Savary Gilliard bougienage or through scope balloon dilatation was safe and successful, but often had to be repeated. Esophageal stricture was not associated with reduced survival. REFERENCES 1. Lee NY, O Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69: Lawson JD, Otto K, Grist W, Johnstone PA. Frequency of esophageal stenosis after simultaneous modulated accelerated radiation therapy and chemotherapy for head and neck cancer. Am J Otolaryngol 2008;29: Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008;371: Silvain C, Barrioz T, Besson I, et al. Treatment and long-term outcome of chronic radiation esophagitis after radiation therapy for head and neck tumors. 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