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Japanese Journal of Clinical Oncology Advance Access originally published online on April 20, 2009
Japanese Journal of Clinical Oncology 2009 39(7):413-417; doi:10.1093/jjco/hyp033
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© The Author (2009). Published by Oxford University Press. All rights reserved

Risk Factors for Severe Dysphagia after Concurrent Chemoradiotherapy for Head and Neck Cancers

Keiichiro Koiwai, Naoto Shikama, Shigeru Sasaki, Atsunori Shinoda and Masumi Kadoya

Department of Radiology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan

For reprints and all correspondence: Keiichiro Koiwai, Department of Radiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail: kkoiwai{at}shinshu-u.ac.jp

Received January 20, 2009; accepted March 15, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
Objective: The aim of this study was to investigate the risk factors for dysphagia induced by chemoradiotherapy for head and neck cancers.

Methods: Forty-seven patients with head and neck cancers who underwent definitive chemoradiotherapy from December 1998 to March 2006 were reviewed retrospectively. Median age was 63 years (range, 16–81). The locations of the primary lesion were as follows: larynx in 18 patients, oropharynx in 11, nasopharynx in 7, hypopharynx in 7 and others in 4. Clinical stages were as follows: Stage II in 20 and Stages III–IV in 27. Almost all patients underwent platinum-based concomitant chemoradiotherapy. The median cumulative dose of cisplatin was 100 mg/m2 (range, 80–300) and median radiation dose was 70 Gy (range, 50–70).

Results: Severe dysphagia (Grade 3–4) was observed in 22 patients (47%) as an acute toxic event. One patient required tube feeding even at 12-month follow-up. In univariate analysis, clinical stage (III–IV) (P = 0.017), primary site (oro-hypopharynx) (P = 0.041) and radiation portal size (>11 cm) (P < 0.001) were found to be associated with severe dysphagia. In multivariate analysis, only radiation portal size was found to have a significant relationship with severe dysphagia (P = 0.048).

Conclusions: Larger radiation portal field was associated with severe dysphagia induced by chemoradiotherapy.

Key Words: toxicity • combined modality therapy • head and neck neoplasm • dysphagia • radiotherapy


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
Prospective randomized clinical trials showed that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal carcinoma (1). This combined therapy is now widely used in treatment of patients with head and neck cancers. A meta-analysis conducted by Pignon et al. (2) showed a significant benefit of concurrent chemoradiotherapy, which corresponded to an absolute 5-year overall survival benefit of 8% compared with radiotherapy alone in head and neck cancers. Indication of conventional radiation-alone therapy is confined to T1 and favorable T2, N0–1 tumors. Altered fractionation alone may be indicated for unfavorable T2, N0–1 tumors (3), but more advanced and operative head and neck cancers are usually treated by surgery followed by radiotherapy or chemoradiotherapy. Patients in whom surgery is contraindicated are treated by chemoradiotherapy. This therapy is sometimes used for operative patients who wish to preserve their organs.

Concomitant addition of chemotherapy to radiotherapy not only improves the outcome but also increases toxicity of the treatment. Various toxic events, such as pain, dysgeusia, and dysphagia, are intensified. Rosenthal et al. (4) reported that 40–70% of the patients undergoing concomitant chemoradiotherapy for head and neck cancers experienced severe mucositis and 50–80% required feeding tube placement during the course of therapy. Severe dysphagia arising during the course of therapy sometimes reduces the patients' quality of life and worsens their physical condition.

A retrospective review of patients with head and neck cancers who underwent definitive chemoradiotherapy in our facility was performed along with an investigation of the risk factors for dysphagia induced by chemoradiotherapy.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
From December 1998 to March 2006, 47 patients with head and neck cancers underwent definitive chemoradiotherapy in our facility. The patients' characteristics are shown in Table 1. In our facility, definitive chemoradiotherapy had been usually eligible for the patients whose performance status was good, who had no distant metastasis and who were not so old (≤75 years, basically).


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  		Table 1. Patients' characteristics

 
All except two patients underwent platinum-based concomitant chemoradiotherapy; the two exceptions were treated by radiotherapy and docetaxel-alone chemotherapy, respectively. Various chemotherapy regimens were adopted in the treatment (Table 2). Since we had sought the optimal regimen of chemotherapy for years and had changed the way of the therapy, there had been heterogeneity as to chemotherapeutic agents in the present study. The cumulative dose of cis-diamminedichloroplatinum (cisplatin) ranged from 80 to 300 mg/m2 (median, 100 mg/m2). 5-Fluorouracil (5-FU) was administered to 43 patients. The cumulative dose of 5-FU ranged from 2000 to 12 000 mg/m2 (median, 4000 mg/m2).


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  		Table 2. Chemotherapy regimens

 
In radiation therapy, casts for immobilization and a photon beam of 4 MV were used in all patients. The fraction size was 1.5–2.0 Gy. The total dose of radiation therapy ranged from 50 to 70 Gy, and median dose was 70 Gy. Since various treatment protocols with different fraction sizes and total doses had been used in our facility, we also calculated a biologic effective dose (BED) in a linear-quadratic model (5). BED was defined as nd(1 + d/{alpha}/β), with units of Gy, where n is the fractionation number, d the daily dose and {alpha}/β was assumed to be 10 for tumors. The BED ranged from 60 to 84 Gy (median, 84 Gy). Forty-one patients were treated by a once-daily fractionation schedule and six patients were treated by an accelerated hyperfractionation schedule. In this schedule, patients initially received 40 Gy in once-daily fractionation with a fraction size of 2 Gy. After that, radiation fields were shrinked down to avoid the spinal cord and 30 Gy was added in twice-daily fractionation with a fraction size of 1.5 Gy. Lateral opposing portals alone or lateral opposing and anterior portals (three-field approach) were used according to the individual tumor spread. Stage II disease was usually treated by locally confined portals. The whole neck was included in the treatment of Stages III–IV disease initially. Spinal cord was usually avoided by cone-down field reduction after the administration of 40 Gy. Computed tomography images for radiation dose distribution were attained in 14 patients. None of the patients underwent intensity-modulated radiation therapy (IMRT). Overall treatment time ranged from 31 to 109 days (median, 50 days).

Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 3.0 (National Cancer Institute, Rockville, MD, USA). In these criteria, Grade 3 dysphagia is defined as symptomatic and severely altered eating and/or swallowing, which requires intravenous fluids, tube, feeding or total parenteral nutrition for more than 24 h. To evaluate radiation portal size, the length of the side of the equivalent square in each lateral opposing field was calculated; the median length was 11.3 cm (5.5–16.5 cm).

Statistical analyses were performed using Fisher's exact test for univariate analysis and the logistic regression model was used for multivariate analysis. Statistical significance for all analyses was set at P < 0.05. Survival rates were calculated from the start of treatment. Survival curves were calculated using the Kaplan–Meier method. These analyses were performed using the statistical software JMP version 5.1.1 (SAS Institute Inc., Cary, NC, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
Median follow-up time was 21 months (range, 3–85 months). Severe (Grade ≥3) dysphagia was observed in 22 patients (47%) as an acute toxic event. Severe (Grade ≥3) dermatitis occurred in 18 patients and severe (Grade ≥3) mucositis was observed in 18 patients.

In univariate analysis, the relationships between severe dysphagia and the following parameters were examined: age (<70 vs. ≥70 years old), performance status according to the Eastern Cooperative Oncology Group (0 vs. ≥1), pre-treatment body weight loss (<10% vs. ≥10%), smoking (<20 vs. ≥20 cigarettes per day), primary site (oro-hypopharynx vs. others), clinical stage (II vs. III–IV), radiation portal size (length of the side of the equivalent square <11 vs. ≥11 cm), cumulative dose of cisplatin (<100 vs. ≥100 mg/m2), cumulative dose of 5-FU (<4000 vs. ≥4000 mg/m2) and radiation schedule (conventional fractionation vs. hyperfractionation). The results of univariate analysis are shown in Table 3. Primary site, clinical stage and radiation portal size were found to significantly influence the rate of severe dysphagia. Four parameters were chosen for multivariate analysis: primary site, clinical stage, radiation portal size and cumulative dose of cisplatin. The results of multivariate analysis are shown in Table 4. In this analysis, only radiation portal size was found to have a significant effect on the outcome (P = 0.048).


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  		Table 3. Univariate analysis to identify risk factors for severe dysphagia

 

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  		Table 4. Multivariate analysis to identify risk factors for severe dysphagia

 
Among the 22 patients who developed severe dysphagia, opioid analgesics were administered to 13 patients and antibiotics were administered to 14 patients. As a measure for the management of severe dysphagia, total parenteral nutrition was usually adopted in our facility. Percutaneous endoscopic gastrostomy and nasogastric tubes were not usually placed. Seventeen patients required total parenteral nutrition. The median duration of severe dysphagia was 53 days (range, 21–142 days). Those patients also required prolonged hospitalization after termination of the treatment (15–117 days; median, 42). Ten patients presented some sort of dysphagia at the last follow-up. One patient had been dependent on tube feeding for more than a year.


   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
Cisplatin-based chemoradiotherapy for locally advanced head and neck cancers is now recognized as a standard therapy for patients with inoperable disease because of its larger survival benefit than radiation therapy alone (3). Sometimes, this non-surgical therapy can be adopted in operable patients to achieve better cosmetic outcome and organ preservation. There is still room for improvement of this therapy. Efforts to determine the optimal dosage of cytotoxic agents and optimal timing of chemotherapy and radiotherapy are still underway (6). Despite using a non-surgical modality, this can be a rather toxic form of therapy (7). Dysphagia caused by the therapy sometimes becomes severe and may last for a long time. This complication is thought to be one of the largest obstacles in conducting concomitant chemoradiotherapy for head and neck cancers. Few previous studies have addressed this issue (8), but some reports mentioned that more than half of the cases required enteral feeding temporarily (9) and approximately 20% required long-term enteral feeding (4). Rademaker et al. (10) reported that it took approximately 1 year for a patient whose eating ability was impaired by the therapy to recover to close to the normal level. Nguyen et al. (11,12) reported that aspiration was frequently observed during the course of therapy, sometimes leading to fatal aspiration pneumonia.

As mentioned above, it is becoming clear that concomitant chemoradiotherapy for head and neck cancers can be quite severe for patients. Therefore, care should be taken in judging whether a patient really requires concomitant chemotherapy (13). Administration of cisplatin at a dose of 100 mg/m2 is the standard therapy, but only two-thirds of the patients can receive all cycles of treatment with such a regimen (14). Improving compliance is one of the most pressing problems remaining to be resolved. Logeman et al. (15) reported that alteration of chemotherapy protocols had minimal effect on swallowing function, which may mean that arrangement of usual cytotoxic agents would not reduce the severity of this complication. Recently, the use of biologically targeted therapy has been shown to improve the outcome without increasing the common toxic effects (16). These newly emerging approaches represent promising means of improving treatment outcome in these patients.

Few studies have addressed risk factors for severe dysphagia in chemoradiotherapy for head and neck cancers. Mangar et al. (9) argued that clinical stage, general condition and history of smoking could be the risk factors for severe dysphagia. In the present study, smoking was not found to be significant. This was assumed to be due to the strict prohibition against smoking by patients during the course of therapy in the present study. Regarding general condition, this type of therapy is usually confined to patients with good performance status and this may cause selection bias. Machtay et al. (17) reported that older age was a strong risk factor for severe late toxicity. In the present study, which was aimed at early toxicity, older age was not identified as an independent risk factor. Almost all patients aged 70 or over had excellent performance status in the present study. The adaptation of this therapy is rather selective in our facility, which may result in suppression of the risk of dysphagia in aged patients. Radiation portal size was found to be a risk factor for severe dysphagia in chemoradiotherapy for head and neck cancers in the present study. Clinical stage was also associated with severe dysphagia in univariate analysis, which was similar to the previous report by Mangar et al., but not in multivariate analysis. This could be explained by a requirement of larger radiation portals for higher clinical stage, so there should be confounding factors between them. The results presented here suggest that radiotherapy plays a major role in the occurrence of dysphagia. It is supposed that broader mucous membranes and more anatomical parts important for swallowing would be affected to a greater degree by larger radiation portals, and these must be amplified by chemotherapy. Some reports suggested that primary site of disease could be an important risk factor (15,17). We also identified that primary site was associated with severe dysphagia in univariate analysis, but not in multivariate analysis. These observations may also indicate the importance of radiotherapy in the occurrence of dysphagia, as higher radiation dose is usually administered to the primary site of disease.

Accordingly, improving radiotherapy might lead to relief of this complication. IMRT has been widely used for head and neck cancers (18). Using this advanced technique, complications can be reduced without compromising therapeutic outcome. Good local control has been achieved in a number of leading institutions. Xerostomia, which arises as an late toxic event, is less severe than with conventional radiotherapy (18,19). Chemo-IMRT may cause dysphagia to some extent, but it may be less severe than chemotherapy and altered fractionation schedule (20), and requires less long-term tube feeding (21). The further development of newly emerging approaches such as IMRT may result in a decrease in the severity of dysphagia.

Dysphagia is a complication for which clinicians should be prepared. It is important to take appropriate measures for this complication. Rosenthal et al. (4) reported the importance of rehabilitation as a means of coping with dysphagia. It would be useful to identify patients at high risk of severe dysphagia in advance so that clinicians could pay attention to this complication from the early stages of therapy.


   CONCLUSIONS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
Funding
 Conflict of interest statement
 References
 
Larger radiation portal size could be a risk factor for severe dysphagia after chemoradiotherapy for head and neck cancers. Patients treated with broad radiation portals should be managed carefully during the course of therapy.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
Conflict of interest statement
 References
 
This work was supported by Health and Labor Sciences Research Grants [H19-001]; Grants-in-Aid for Cancer Research [20S-5] and a Grant-in-Aid for Scientific Research: ‘Third, term comprehensive control research for cancer [H16-039, H19-038]’ from the Ministry of Health, Labor and Welfare of Japan.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
References
 
None declared.


   Acknowledgments
 
The authors are grateful for the support of Mrs I. Koiwai and Mrs Y. Ogawa for technical assistance.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Funding
 Conflict of interest statement
 References
 
1 Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol (1998) 16:1310–7.[Abstract/Free Full Text]

2 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet (2000) 355:949–55.[Web of Science][Medline]

3 Rosenthal DI, Ang KK. Altered radiation therapy fractionation, chemoradiation, and patient selection for the treatment of head and neck squamous carcinoma. Semin Radiat Oncol (2004) 14:153–66.[CrossRef][Web of Science][Medline]

4 Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol (2006) 24:2636–43.[Abstract/Free Full Text]

5 Yaes RJ, Patel P, Maruyama Y. On using the linear-quadratic model in daily clinical practice. Int J Radiat Oncol Biol Phys (1991) 20:1353–62.[Web of Science][Medline]

6 Kawashima M. Chemoradiotherapy for head and neck cancer: current status and perspectives. Int J Clin Oncol (2004) 9:421–34.[CrossRef][Medline]

7 Shikama N, Sasaki S, Nishikawa A, Koiwai K, Kadoya M. Chemoradiation for locally advanced squamous cell carcinoma of the head and neck. Curr Top Radiol (2001) 3:27–38.

8 Lewin JS. Dysphagia after chemoradiation: prevention and treatment. Int J Radiat Oncol Biol Phys (2007) 69(Suppl_2):S86–7.[Web of Science][Medline]

9 Mangar S, Slevin N, Mais K, Sykes A. Evaluating predictive factors for determining enteral nutrition in patients receiving radical radiotherapy for head and neck cancer: a retrospective review. Radiother Oncol (2006) 78:152–8.[CrossRef][Web of Science][Medline]

10 Rademaker AW, Vonesh EF, Logemann JA, Pauloski BR, Liu D, Lazarus CL, et al. Eating ability in head and neck cancer patients after treatment with chemoradiation: a 12-month follow-up study accounting for dropout. Head Neck (2003) 25:1034–41.[CrossRef][Web of Science][Medline]

11 Nguyen NP, Frank C, Moltz CC, Vos P, Smith HJ, Bhamidipati PV, et al. Aspiration rate following chemoradiation for head and neck cancer: an underreported occurrence. Radiother Oncol (2006) 80:302–6.[CrossRef][Web of Science][Medline]

12 Nguyen NP, Moltz CC, Frank C, Vos P, Smith HJ, Karlsson U, et al. Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol (2004) 15:383–8.[Abstract/Free Full Text]

13 Garden AS, Asper JA, Morrison WH, Schechter NR, Glisson BS, Kies MS, et al. Is concurrent chemoradiation the treatment of choice for all patients with Stage III or IV head and neck carcinoma? Cancer (2004) 100:1171–8.[CrossRef][Web of Science][Medline]

14 Brizel DM, Esclamado R. Concurrent chemoradiotherapy for locally advanced, nonmetastatic, squamous carcinoma of the head and neck: consensus, controversy, and conundrum. J Clin Oncol (2006) 24:2612–7.[Abstract/Free Full Text]

15 Logemann JA, Rademaker AW, Pauloski BR, Lazarus CL, Mittal BB, Brockstein B, et al. Site of disease and treatment protocol as correlates of swallowing function in patients with head and neck cancer treated with chemoradiation. Head Neck (2006) 28:64–73.[CrossRef][Web of Science][Medline]

16 Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med (2006) 354:567–78.[Abstract/Free Full Text]

17 Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, Cooper JS, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol (2008) 26:3582–9.[Abstract/Free Full Text]

18 Lee N, Puri DR, Blanco AI, Chao KS. Intensity-modulated radiation therapy in head and neck cancers: an update. Head Neck (2007) 29:387–400.[CrossRef][Web of Science][Medline]

19 Jabbari S, Kim HM, Feng M, Lin A, Tsien C, Elshaikh M, et al. Matched case–control study of quality of life and xerostomia after intensity-modulated radiotherapy or standard radiotherapy for head-and-neck cancer: initial report. Int J Radiat Oncol Biol Phys (2005) 63:725–31.[CrossRef][Web of Science][Medline]

20 Guerrero Urbano T, Clark CH, Hansen VN, Adams EJ, A'Hern R, Miles EA, et al. A phase I study of dose-escalated chemoradiation with accelerated intensity modulated radiotherapy in locally advanced head and neck cancer. Radiother Oncol (2007) 85:36–41.[CrossRef][Web of Science][Medline]

21 de Arruda FF, Puri DR, Zhung J, Narayana A, Wolden S, Hunt M, et al. Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys (2006) 64:363–73.[CrossRef][Web of Science][Medline]


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This Article
Right arrow Abstract Freely available
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