Title page
Incidence of Late-onset Pneumonia in Patients after Treatment with
Radiotherapy for Nasopharyngeal Carcinoma: a Nationwide Population-based Study
Ting-Ting Yen, M.D.1, 3; Ching-Heng Lin, Ph.D.2; Rong-San Jiang, M.D. Ph.D.1, 4; Yi-Ting Shih, M.D.5; Hung-Rong Yen, M.D. Ph.D.6, 7*; Kai-Li Liang, M.D. 1, 3, 8* 1Department of Otolaryngology and 2 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; 3 Graduate Institute of Natural Healing Sciences, Nanhua University, Chiayi, Taiwan; 4 School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Department of Radiation Oncology, Saint Martin De Porres Hospital, Chiayi, Taiwan; 6 Research Center for Traditional Chinese Medicine, Department of Medical Research and 7 Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; 6 School of Chinese Medicine, China Medical University, Taichung, Taiwan; 8Department of Medicine, National Yang-Ming Medical University, Taipei, Taiwan
* Hung-Rong Yen and Kai-Li Liang are co-corresponding authors Running title: Pneumonia in irradiated NPC patients
Key words: head and neck cancer, dysphagia, chemo-radiotherapy, nasopharyngeal carcinoma, pneumonia
Conflict of interest: none Addresses for correspondence: Hung-Rong Yen, M.D. Ph.D.
Research Center for Traditional Chinese Medicine, Department of Medical Research and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
Ｎo.2, Yuh - Der Road, Taichung, Taiwan 40447 Tel: +886-4-22052121 ext 7507
E-mail: [email protected] Kai-Li Liang, M.D.
Department of Otolaryngology, Taichung Veterans General Hospital, No. 1650, Sect. 4, Taiwan Boulevard, Taichung, Taiwan 40705 Tel: +886-4-23592525 ext 5405
Fax: +886-4-23596868
ABSTRACT
Background: To assess the incidence of late-onset pneumonia in patients with nasopharyngeal carcinoma (NPC) after radiotherapy.
Methods: Data were retrieved from the National Health Institute Research Database
of Taiwan. We identified patients diagnosed with NPC (ICD-9-CM code 147) from January 2005 to December 2008 who received curative radiotherapy as the study cohort. Incidences of pneumonia and related sequelae after 90 days of radiotherapy were calculated.
Results: A total of 3814 patients were enrolled in this study and 210 (5.5%) had late-onset pneumonia. The correlation coefficient between pneumonia and tube feeding was 0.332 (p < .001). The hazard ratio of pneumonia was 0.81 (95% CI = 0.57 - 1.15) between patients with and without chemotherapy, and was 2.37 (95% CI = 1.73 - 3.24) between patients with and without re-radiation.
Conclusions: Late-onset pneumonia is not uncommon in NPC patients after
radiotherapy. The risks of associated sequelae and mortality cannot be ignored.
KEY WORDS: head and neck cancer, dysphagia, chemo-radiotherapy, nasopharyngeal carcinoma, pneumonia
INTRODUCTION
Dysphagia is one of the late treatment side effects after chemo-radiotherapy for Head and Neck cancer, and may lead to malnutrition and aspiration pneumonia. 1-4 A comprehensive literature review in 2012 reported approximately one-third of head neck cancer patients with dysphagia devleoped pneumonia requiring treatment. 2 Another prospective study of 72 patients with oropharyngeal cancer treated with chemo-radiotherapy demonstrated that 16 (20%) developed aspiration pneumonia during a 2 years’ follow-up. 5
Nasopharyngeal carcinoma (NPC) is a common neoplasm in southern China, Hong Kong and Taiwan. 6 With the advancement of radiation techniques and chemotherapy treatment, excellent long-term survival can be achieved in most NPC patients without metastatic diseases. 7-9 However, late treatment toxicity has become an important issue among survivors. 10, 11 Chemo-radiotherapy is the primary curative treatment for NPC. Most NPC patients do not have anatomical impairment compared to other surgically treated head neck cancer patients. In addition, the risk of developing aspiration pneumonia varied with tumor sites. Characteristics of aspiration penumoina in
irradiated NPC patients may be different from those of other head neck cancer patients. Several recent articles reported that late-onset dysphagia after radiotherapy
stongly impact life quality of NPC patients, 12-15 but few studies have examed the incidence of pneumonia in irradiated NPC patients. 16, 17
Taiwan launched a National Health Insurance program in March 1995. As of 2007, over 98% of the 22.96 million people in Taiwan were enrolled in this program. The National Health Institute Research Database (NHIRD), which contains de-identified personal information derived from the registration files and original clams data of the National Health Insurance program, is maintained by the National Health Research Institutes and provided for research purposes. In this study, we retrieved data from NHIRD to investigate the incidence of late-onset toxicities in irradiated NPC patients. To the best of our knowledge, this is the first report about incidence of late-onset pneumonia in NPC patients after radiotherapy.
METHODS
Data of this study were retrieved from the NHIRD covering a period from January 2005 to December 2010. The data files in NHIRD are de-identified and further
scrambled before being released to researchers. Therefore it is impossible to query the data alone to identify individuals at any level using this database. A written agreement was submitted to study hospital declaring that none of the authors in this study have any intention of attempting to obtain information that could potentially violate the privacy of patients or care providers in this study.
The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and Procedure Coding System (ICD-9-PCS) was used to retrieve the information on diagnoses and treatment for patients. We identified cases of NPC (ICD-9-CM 147), newly diagnosed from January 2005 to December 2008 as the study cohort after excluding those who had been diagnosed with malignancy before NPC, as well as those who had another type of cancer following diagnosis of NPC. To our knowledge, most hospitals in Taiwan began using intensity-modulated radiotherapy (IMRT) technique after 2003, with a uniform radiotherapy dose for NPC that ranges from 6600 to 7200 cGy. 18-20 Among IMRT cases, only patients who received over 80% of planned curative radiotherapy (ICD-9-PCS 922 and V580) within one year after diagnoses were enrolled. The received radiotherapy amount was estimated by patients’ radiotherapy record. Furthermore, patients who had chemotherapy (ICD-9-PCS V581 and 992.5) during radiotherapy course, 90 days before the
initiation of radiotherapy, or 90 days after the completion of radiotherapy were regarded as having received chemo-radiotherapy. If patients had radiotherapy 90 days
after the complement date of 1st session of radiotherapy, they were regarded as having 2nd session radiotherapy. With the aforementioned criteria, we are confident that we selected a homogenous study cohort who received same radiotherapy technique, similar radiation dose and had at least 2 years’ follow-up.
Data files from NHIRD of the study cohort were analyzed and the incidence of late-onset respiratory toxicities including pneumonia (ICD-9-CM 480-486) and related sequelae (respiratory failure: ICD-9-CM 5188; tracheostomy: ICD-9-PCS 311-312; on endotracheal tube: ICD-9-PCS 9604; on mechanical ventilation:
ICD-9-PCS 9671-9672), and dysphagia related procedures (gastrostomy: ICD-9-PCS 430-431; nasogastric feeding ICD-9-PCS 9607) were calculated. Late-onset toxicities were defined complications that occurred or persisted beyond 90 days from the date of complement of radiotherapy.21 Patients who had hospitalized for the
aforementioned complications once or who visited the outpatient clinic 3 times for complications were regarded as having late-onset toxicities. For assessment of covariates that may be associated with the development of late toxicities, we also
retrieved the information on comorbidities including hypertension (ICD-9-CM 401-405), diabetes mellitus (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272),
cardiovascular diseases (ICD-9-CM 390-438), and chronic kidney disease
(ICD-9-CM 585). The Charlson comorbidity index 22 was calculated for each enrolled patient to estimate the prognostic effect of their comorbidity.
SAS software version 9.1 (SAS Institute, Inc., Cary, NC, USA) was used for statistical analyses. The Student’s t-test was utilized to examine differences in age between two groups. The Chi-square test was used to test for differences in comorbidities and late-onset complications between patients who received
radiotherapy or chemo-radiotherapy, and those who received one or two sessions of radiotherapy. Pearson correlation coefficient was calculated to estimate the
association between pneumonia and tube feeding. Cox-regression models were used to estimate the hazard ratio of having late-onset complications among associated factors, after controlling for certain variables. A two-sided p of < .05 was considered statistically significant.
RESULTS
The numbers of patients newly diagnosed with NPC in Taiwan from January 2005 to December 2010 are listed in Table 1. A total of 3814 patients who were diagnosed with NPC from January 2005 to December 2008 and had received curative
radiotherapy were selected as the study cohort. Among them, 3281 patients received chemo-radiotherapy (CRT group), and 533 patient received radiotherapy alone (RT group). Of the 3814 enrolled patients, 210 (5.5%) had late-onset pneumonia. The correlation coefficient between pneumonia and tube feeding (nasogastric tube or gastrostomy tube feeding) was 0.332, (p < .001). Among the 210 patients who had late-onset pneumonia, 64 (30%) died within 2 months after the episode of pneumonia. The clinical characteristics of study subjects with and without chemotherapy are listed in Table 2. Patients who received radiotherapy alone were significantly older than those who received chemo-radiotherapy (p < .001). In addition, there was a
significantly higher rate of comorbidities in the RT group than in the CRT group (p < .001). Furthermore, the incidence of late-onset pneumonia and most associated sequelae after radiotherapy were significantly higher in the RT group than in the CRT group, and more patients in the RT group received tube feeding (Table 2). Five hundred and twenty-nine patients received second-session radiotherapy. The clinical characteristics of study subjects with and without re-radiation are listed in Table 3. There were no significant differences in age, gender or comorbidities between patients with and without re-radiation. However, late-onset toxicities were significantly higher in re-radiation patients (Table 3).
Cox’s regression models were further used to analyze the risk factors for late-onset toxicities after radiotherapy, the hazard ratio of pneumonia was 0.81 (95% CI = 0.57 -1.15, p = .243, adjusted for age, gender, and comorbidities) between patients with and without chemotherapy, and was 2.37 (95% CI = 1.73 - 3.24, p < .0001, adjusted for age, gender, and comorbidities) between patients with and without re-radiation. The hazard ratios of pneumonia-related sequelae between patients with and without chemotherapy, and those with and without re-radiation are listed in Table 4. In summary, chemotherapy did not increase the risk of late-onset pneumonia and most related sequelae. In contrast, re-radiation significantly increased the risk of late-onset pneumonia and related sequelae.
DISCUSSION
Previous studies report head and neck cancer patients are at risk of aspiration
pneumonia after chemo-radiotherapy. 3, 5, 23, 24 Chen at al 25 reported a case series of 41 patients with aspiration pneumonia during chemo-radiotherapy for head and neck cancer, of whom 18 patients needed to be transferred to an intensive care unit and 7 died within 2 months. Another report estimated that the incidence of pneumonia during radiotherapy in head neck cancer patients was 4.86%. 23 The aforementioned articles reported incidence of early-onset pneumonia, which is strongly related to radiotherapy-induced mucositis and tumor sites. 23, 25 It is believed that late-onset
pneumonia after radiotherapy is associated with dysphagia and aspiration, but few studies have examined the incidence of late-onset pneumonia after radiotherapy. Hutcheson et al. 26 reported a case series of 29 irradiated head neck cancer patients
post-radiotherapy. Another study investigated the incidence of late pneumonia in a series of head and neck cancer patients treated with radiotherapy: 32% of the 324 patients developed severe dysphagia and 18 patients developed aspiration pneumonia in the first year after radiotherapy. 3 The true incidence of late-onset pneumonia in irradiated NPC is unknown. Most NPC patients are treated with chemo-radiotherapy without aerodigestive tract damage from surgery. Therefore, the incidence of
pneumonia in NPC may not be the same as in other head neck cancers. In this study, we collected data from a homogenous group of NPC patients in an endemic area with at least 2 years’ follow-up. Our results revealed the incidence of late-onset pneumonia was 5.5% in patients treated with curative radiotherapy for NPC.
Dysphagia and aspiration after radiotherapy are believed to be the main causes of late-onset pneumonia. Chang et al. 27 evaluated 184 irradiated NPC patients and found
that the swallowing function continued to deteriorate over the years after radiotherapy. The etiologies of dysphagia in irradiated patients are multifactorial. 28, 29 Saliva is
important in assisting food bolus formation and allows transport of food bolus to the pharynx. The lack of saliva in irradiated patients contributes to development of dysphagia. 30 In addition, lack of neuromuscular coordination and impairment of
pharyngeal sensation result in prolonged pharyngeal transit time and aspiration. Bilateral neck irradiation damages the neck fat, fascia and neuron axons, resulting in constriction of neck movement, and pharyngeal expansion and sensation. Furthermore, vagus and glossopharyngeal cranial palsies, other radiation-induced toxicities could impair oral and pharyngeal swallowing. 31, 32 Hughes et al. 15 conducted a study to
evaluate swallowing function of 50 NPC patients after a mean period of 56 months post-radiotherapy. The authors found abnormal patterns of swallowing in 96% of patients, and silent aspiration was present in 22% of them. We found that late tube
feeding was significant associated with development of late-onset pneumonia in NPC patients, indicating dysphagia was an important risk factor of late-onset pneumonia. Our results showed chemotherapy did not increase the risk of late-onset pneumonia and most related sequelae, whereas re-radiation significantly increased these risks. Re-radiation for recurrent head neck cancers is feasible and result in favorable survival outcomes in certain patients, but it also carries a significant risk of late complications. 33, 34 In addition to dysphagia and re-radiation, tumor stage, extension
of radiotherapy region, patients’ baseline swallowing function, performance status and smoking habit have been reported to be associated with aspiration pneumonia. 2, 5, 24 The Taiwan NHIRD data do not provide detailed information on these other factors; hence, we could not explore possible associations with late-onset pneumonia. Among the 210 pneumonia patients in this study, 30% died within two months after the onset of pneumonia. The reported mortality of aspiration pneumonia ranged from 20% to 65%. 2 In our experience, aspiration pneumonia can recur in patients with severe dysphagia and cause life-threatening infection. However, no methods have been established for prevention of aspiration in irradiated NPC patients. Ng et al. 35 suggested that early intervention with swallowing tests to detect silent aspiration may help to identify high-risk patients. For patients with severe dysphagia who are
malnourished, tube feeding provides nutritional support and avoids aspiration. 36 Lin et al. 37 reported that electrical stimulation helps to improve swallowing function and quality of life in NPC patients with dysphagia caused by radiotherapy. Although more investigation is needed on the effects of electrical stimulation, it is a promising way to help dysphagia patients. Some authors recommended swallowing-sparing
intensity-modulated radiotherapy techniques to reduce swallowing dysfunction after treatment. 30, 38
CONCLUSION
Late-onset pneumonia is not uncommon in patients after radiotherapy for NPC. The risks of associated sequelae and molality cannot be ignored. Early evaluation of swallow function to detect high-risk patients, and intervention with swallowing rehabilitation are recommended. Adjusted treatment planning with a goal to prevent post-treatment swallowing dysfunction is indicated.
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