Prognostic Factor of Severe Complications in Patients with Hypopharyngeal Cancer with Primary Concurrent Chemoradiotherapy

Discussion

The treatment strategy for a patient with hypopharyngeal cancer is complex and takes into consideration tumor stage, condition of the patient and individual preference. For the early stage of hypopharyngeal cancer, non-surgical treatment is a mainstream treatment strategy for organ preservation. For the resectable, advanced-stage hypopharyngeal cancer, non-surgical treatment has also been reported to have similar disease control and overall survival rates compared with surgery as the initial therapy; however, it has been reported to carry a high risk of non-functional larynx and hypopharynx (6). One study showed that significant acute and long-term toxic effects occur and organ preservation appears not necessarily equivalent to preservation of function and to have better quality of life (11). Therefore, we compared all the hypopharyngeal cancer patients at our hospital who received complete CCRT in order to investigate the risk factors for organ-preservation failure. For the objective evaluation, we recorded the duration of placement the feeding tube (persisted nasogastric tube or feeding gastrostomy) and persisted tracheostomy tube as prolonged tube placement significantly affects the quality of life. These objective data can exclude the different subjective evaluation on adverse symptoms, such as mucositis, dysphagia and pain. In our study, the 1-year disease control rate and severe complication rate were correlated to tumor stage and lymph node status, and were found comparable in a previous study (13). Interestingly, if we only analyzed patients who had successful disease control for at least one year, the severe complication rate would be associated with the N stage but not the tumor stage. Caudell et al. (14) have also demonstrated that N2 or N3 patients had poor function preservation and that T4 patients had a similar functional preservation compared with T2 and T3 patients.

With regards to treatment intended to preserve organ function, “function preservation” and “organ preservation” should be clearly defined. In hypopharyngeal cancer, function includes both voice and swallowing and, in a broader sense, quality of life. This may even be better preserved after removal of the organ, permitting aspiration-free deglutition and a prosthetic voice rather than leaving intact a functionless larynx. Hence, we attempted to identify the patients who were at high risk of chemoradiotherapy (CRT) toxicity leading to a non-functional larynx or hypopharynx and who would have been better advised to receive surgical therapy, especially in patients who had an invasive advanced tumor stage that was still resectable. In our study, the most common complication was dysphagia, followed by a threatened airway. Dysphagia has been reported to be induced by the toxicity of CCRT (15, 16). Stijn et al. (11) reported that 78% of patients with hypopharyngeal cancer required tube feeding during and after treatment and that the acute toxicity resolved within 3 months, even though it was the most common long-term side effect. Thus, since acute toxicity could not be resolved in 3 months, we decided to use a 6-month interval after treatment for our evaluations.

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Figure 1.

Hypopharngeal cancer directly invading the hyoid bone.

According to the AJCC classification, T4a stage is defined as a tumor invading the adjacent structure, including the hyoid bone, thyroid/cricoid cartilage, thyroid gland and neck soft tissue. Compared with T4b tumors, T4a tumors are commonly considered to be invasive but are clinically resectable. However, the treatment outcomes and related quality of life for these patients are still controversial. In addition, to the best of our knowledge, only a few studies have evaluated the benefits of non-surgical treatment in T4a patients only. In the current study, there was no difference in the disease control rate among T4a patients who were treated either non-surgically or surgically. Hence, the quality of life and treatment-related complications should be considered. For the subsites of tumor invasion in T4a patients, Wagner et al. (17) reported that patients with thyroid or cricoid cartilage invasion were not associated with a reduced overall survival rate. Two separate studies have shown no difference in local control or overall survival in patients with hyoid bone and/or cartilage invasion (18, 19). However, in our study, there is no difference in disease-free rate compared to the subsite of tumor invasion. However, if there was hyoid bone invasion (Figure 1), the complication rate was significantly higher than for other sites. Wagner et al. (19) reported that thyroid or cricoid cartilage invasion did not affect laryngeal preservation; however, they did not report on the hyoid bone. The hyoid bone is suspended by musculature connecting the mandible, styloid process, thyroid cartilage, manubrium and scapulae and, in turn, contributes to support the base of tongue. It plays an important role in swallowing and airway protection, while adequate hyoid bone dis placement is critical to swallowing safety (20). Many studies have reported that after radiation therapy, patients experience changes in swallowing and laryngeal function, including reduced tongue-base contact with the posterior pharyngeal wall, decreased laryngeal elevation, decreased anterior hyoid movement (21, 22) and decreased vestibular size and true vocal fold closure during swallowing (23). Displacement of the hyoid bone causes the epiglottis to tilt and the laryngeal vestibule to become sealed. It also helps to protect the larynx from the bolus and pulls the pharyngeal constrictor muscle to an open position (24). Hence, inadequate displacement of the hyoid bone may cause poor airway protection resulting in prolonged tracheostomy and tube feeding. Radiation can reduce hyoid bone movement (25) and damage the pharyngeal constrictors, the glottic and the supraglottic larynx, causing dysphagia and aspiration (21, 26). The radiation dose to the pharyngeal constrictor and swallowing dysfunction has been reported to be significantly associated with the aspiration rate (27). If the cancer has invaded the hyoid bone, the radiation dose should be higher on the hyoid bone and constrictor muscle. The swallowing and larynx functions may have been destroyed by the tumor or by the toxicity of the radiotherapy. In our cases of hypopharyngeal tumor with hyoid cartilage invasion, the complication rate was higher when patients received organ-preserving therapies. Although we did not compare the results with the surgical group, surgical intervention -as the primary treatment for the patients with hyoid bone invasion- may be considered.

However, there are still some issues that need to be further identified. If the hypopharyngeal tumor has invaded the hyoid bone, the tumor volume would be usually large and pretreatment tumor-related dysfunction could be present. Therefore, larger tumor volume or hypopharyngeal tumor with hyoid destruction might correlate to the dysphagia, prolonged airway problems and threatening infection as aspiration pneumonia or deep neck infection after non-surgical organ preserving therapy (28). There are also study limitations due to the limited sample size as we could only find hyoid bone invasion from hypopharynx correlated to severe complications in univariate analysis. Larger sample sizes are required for multivariate analyses. However, the findings of our study indicated that hyoid invasion in patients with hypopharyngeal cancer results in significantly higher complication rates when considering non-surgical organ preservation as initial therapy.