Original Article
Aspiration Pneumonia After Concurrent Chemoradiotherapy for Head and Neck Cancer Beibei Xu, PhD1; Isabel J. Boero, BS2; Lindsay Hwang, BS2; Quynh-Thu Le, MD3; Vitali Moiseenko, PhD2; Parag R. Sanghvi, MD2; Ezra E. W. Cohen, MD4; Loren K. Mell, MD2; and James D. Murphy, MD, MS2
BACKGROUND: Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy. METHODS: Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population. RESULTS: Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P 65 years. In the current study, we observed higher rates of aspiration pneumonia than those reported in the study from Taiwan although we identified similar risk factors, such as age, male gender, and hypopharyngeal tumors. The range of incidence rates reported for aspiration pneumonia may be caused by differences in patient characteristics, treatment specifics, followup, and definitions of aspiration pneumonia. However, aspiration pneumonia is a relatively common event even among older adults without cancer. For elderly patients, the etiology of aspiration likely stems from multiple causes, although data suggest that the progressive age-related loss of protective swallowing reflexes may be contributory.27 Among patients with head and neck cancer, the etiology of aspiration pneumonia is likely multifactorial; however, radiation-induced dysphagia presumably plays a central role.28 Radiotherapy can produce fibrosis of the treated pharyngeal tissues, resulting in nerve impairment and muscular injury, and causing generalized weakness and uncoordinated swallowing. In addition, radiation-induced xerostomia reduces salivary flow which Cancer
Month 00, 2014
could also impair the swallowing mechanism thus increasing the risk of aspiration pneumonia. Radiation may also represent a unique risk factor for the development of aspiration pneumonia compared with other treatment modalities for head and neck cancer. A recent population-based study of 93,663 patients who underwent surgery for head and neck cancer reported only a 2% rate of aspiration pneumonia.29 In our study, we also observed a lower risk of aspiration pneumonia for those who underwent surgery before receiving radiation, although these findings may represent selection bias as patients who underwent surgery may have had better overall health, less comorbidity, superior performance status, or more favorable cancer characteristics compared with those who did not undergo surgery. We also identified an increased risk of aspiration pneumonia in patients who received care at a teaching hospital which may reflect differences in unmeasured patient characteristics. Teaching hospitals may care for sicker or more complex patients which could explain the increased risk of aspiration in this subpopulation. Beyond the increased risk of aspiration with chemoradiotherapy, our study highlights the potential of 7
Original Article
Figure 3. Kaplan-Meier curves illustrate overall survival (A) from the date of aspiration pneumonia among patients with head and neck cancer who developed aspiration pneumonia (N 5 801), and (B) from the date of diagnosis among patients with head and neck cancer stratified according to whether they developed aspiration pneumonia (N 5 801) or not (N 5 2712).
aspiration pneumonia to substantially impact survival. We observed significantly increased mortality after aspiration pneumonia. Other studies evaluating survival after aspiration pneumonia in patients without cancer have observed similar increases in the risk of death. A recent single-institution, retrospective study of 628 patients with aspiration pneumonia produced a 30-day mortality rate of 21%, although those patients had higher rates of hospitalization and ICU admission (99% and 38%, respectively).30 Similarly, a multicenter, retrospective cohort study of patients who were admitted with pneumonia indicated that aspiration pneumonia was the greatest risk factor for 30-day mortality with an adjusted hazard ratio of 5.69.31 The morbidity and potential impact on mortality of aspiration pneumonia after chemoradiotherapy raises the question of whether action can be taken to reduce the risk of this adverse event. Radiation techniques that spare the con8
strictor muscles involved with swallowing have the potential to reduce dysphagia which is a risk factor for aspiration pneumonia.32,33 Prospective studies to reduce the radiation dose in subsets of patients with head and neck cancer are ongoing; hopefully, the decreased radiation dose will reduce toxicity without sacrificing local tumor control. Further research should focus on reducing the volume of tissue electively irradiated in head and neck cancer for patients who have a lower risk of regional tumor spread. Beyond modifying radiation fields, a different approach could concentrate on the preservation of swallowing function with early involvement of speech therapy and rehabilitation among patients at high risk of aspiration. Routine swallowing evaluations to screen for dysphagia among this patient population also may be recommended to select patients who are at risk for this complication. These interventions deserve further study because they stand to potentially improve the survivorship of patients with head and neck cancer. Although our study characterizes the risk of aspiration pneumonia in a large cohort of patients with head and neck cancer, there are limitations to the presented results. This study population only included patients aged 66 years; therefore, the findings cannot be generalized to a younger patient population. Medicare data are collected for administration purposes; consequently, confounding factors like smoking status, dietary intake, body habitus, and performance status were not collected and could not be analyzed. Similarly, SEER-Medicare data do not include information regarding the doses of chemotherapy or radiotherapy delivered which may have an impact on the rate of aspiration pneumonia. Furthermore, the higher aspiration pneumonia rates in our patient population could have arisen from local cancer progression as opposed to radiation-induced toxicity. However, we observed no correlation between tumor stage and aspiration rates. In addition, this study could not directly assess the accuracy of the primary endpoint of aspiration pneumonia. Although separate diagnosis codes exist for aspiration pneumonia and bacterial pneumonia, distinguishing these 2 diagnoses can pose a clinical challenge with misclassification potentially impacting our findings. Finally, SEER-Medicare data do not contain information on causality; therefore, future studies with additional longitudinal data are required to fully understand what drives the increased risk of aspiration in this cohort of patients. Overall, this study represents the first US-based population study to define the incidence of aspiration pneumonia in patients with head and neck cancer who received concurrent chemoradiotherapy and to contextualize these results using a matched sample of Medicare beneficiaries without cancer. This work also identified several risk Cancer
Month 00, 2014
Aspiration Pneumonia After Radiation/Xu et al
factors that can be used to identify patients who are at a higher risk of developing aspiration pneumonia and has suggested avenues for the future mitigation of this clinically significant and potentially fatal complication of chemoradiation in head and neck cancer. FUNDING SUPPORT This study was supported by National Institutes of Health (NIH) grant KL2 RR031978 to Dr. Murphy and NIH grant T32 to Ms. Boero.
CONFLICT OF INTEREST DISCLOSURES Dr. Moiseenko reports personal fees and nonfinancial support from Varian Medical Systems outside the submitted work.
REFERENCES 1. Francis DO, Weymuller EA Jr, Parvathaneni U, Merati AL, Yueh B. Dysphagia, stricture, and pneumonia in head and neck cancer patients: does treatment modality matter? Ann Otol Rhinol Laryngol. 2010;119:391-397. 2. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344:665-671. 3. Logemann JA, Rademaker AW, Pauloski BR, 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. 4. Smith RV, Kotz T, Beitler JJ, Wadler S. Long-term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea: initial results. Arch Otolaryngol Head Neck Surg. 2000;126:384-389. 5. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2007;133:1289-1295. 6. Nguyen NP, Moltz CC, Frank C, et al. Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol. 2004;15:383-388. 7. Nguyen NP, Smith HJ, Dutta S, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res. 2007;27: 1669-1672. 8. Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys. 2002;53:23-28. 9. Nguyen NP, Frank C, Moltz CC, et al. Aspiration rate following chemoradiation for head and neck cancer: an underreported occurrence. Radiother Oncol. 2006;80:302-306. 10. Purkey MT, Levine MS, Prendes B, Norman MF, Mirza N. Predictors of aspiration pneumonia following radiotherapy for head and neck cancer. Ann Otol Rhinol Laryngol. 2009;118:811-816. 11. Hunter KU, Lee OE, Lyden TH, et al. Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck. 2014;36:120-125. 12. Mortensen HR, Jensen K, Grau C. Aspiration pneumonia in patients treated with radiotherapy for head and neck cancer. Acta Oncol. 2013;52:270-276. 13. Chu CN, Muo CH, Chen SW, Lyu SY, Morisky DE. Incidence of pneumonia and risk factors among patients with head and neck cancer undergoing radiotherapy [serial online]. BMC Cancer. 2013;13: 370.
Cancer
Month 00, 2014
14. Chen SW, Yang SN, Liang JA, Lin FJ. The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer. Eur J Cancer Care (Engl). 2010;19:631-635. 15. Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care. 2002;40:IV-3–IV-18. 16. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Available at: http://www.seer.cancer.gov. Accessed October 13, 2014. 17. VanderWalde NA, Meyer AM, Liu H, et al. Patterns of care in older patients with squamous cell carcinoma of the head and neck: a Surveillance, Epidemiology, and End Results-Medicare analysis. J Geriatr Oncol. 2013;4:262-270. 18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619. 19. Warren JL, Harlan LC, Fahey A, et al. Utility of the SEERMedicare data to identify chemotherapy use. Med Care. 2002;40:5561. 20. Virnig BA, Warren JL, Cooper GS, Klabunde CN, Schussler N, Freeman J. Studying radiation therapy using SEER-Medicare-linked data. Med Care. 2002;40:49-54. 21. Buck CJ, American Medical Association. International Classification of Diseases, Ninth Revision, Clinical Modification for Hospitals (Professional Edition). Volumes 1, 2, and 3. St Louis, MO: Elsevier; 2013. 22. McCarthy EP, Iezzoni LI, Davis RB, et al. Does clinical evidence support ICD-9-CM diagnosis coding of complications? Med Care. 2000;38:868-876. 23. Lin G, So Y, Johnston G. Analyzing Survival Data With Competing Risks Using SAS Software. Cary, NC: SAS Institute Inc.; 2012. 24. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509. 25. Kohl M, Heinze G. PSHREG: An SAS Macro for Proportional and Nonproportional Substribution Hazards Regression With Ccompeting Risk Data. Vienna, Austria: Medical University of Vienna; 2013. 26. D’Agostino RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:265-2281. 27. Pontoppidan H, Beecher HK. Progressive loss of protective reflexes in the airway with the advance of age. JAMA. 1960;174:2209-2213. 28. Russi EG, Corvo R, Merlotti A, et al. Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: review and recommendations of the Supportive Task Group of the Italian Association of Radiation Oncology. Cancer Treat Rev. 2012;38:10331049. 29. Semenov YR, Starmer HM, Gourin CG. The effect of pneumonia on short-term outcomes and cost of care after head and neck cancer surgery. Laryngoscope. 2012;122:1994-2004. 30. Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med. 2013;8:83-90. 31. Komiya K, Ishii H, Umeki K, et al. Impact of aspiration pneumonia in patients with community-acquired pneumonia and healthcareassociated pneumonia: a multicenter retrospective cohort study. Respirology. 2013;18:514-521. 32. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys. 2004;60:1425-1439. 33. van der Laan HP, Gawryszuk A, Christianen ME, et al. Swallowingsparing intensity-modulated radiotherapy for head and neck cancer patients: treatment planning optimization and clinical introduction. Radiother Oncol. 2013;107:282-287.
9
Aspiration Pneumonia After Concurrent Chemoradiotherapy for Head and Neck Cancer Beibei Xu, PhD1; Isabel J. Boero, BS2; Lindsay Hwang, BS2; Quynh-Thu Le, MD3; Vitali Moiseenko, PhD2; Parag R. Sanghvi, MD2; Ezra E. W. Cohen, MD4; Loren K. Mell, MD2; and James D. Murphy, MD, MS2
BACKGROUND: Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy. METHODS: Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population. RESULTS: Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P 65 years. In the current study, we observed higher rates of aspiration pneumonia than those reported in the study from Taiwan although we identified similar risk factors, such as age, male gender, and hypopharyngeal tumors. The range of incidence rates reported for aspiration pneumonia may be caused by differences in patient characteristics, treatment specifics, followup, and definitions of aspiration pneumonia. However, aspiration pneumonia is a relatively common event even among older adults without cancer. For elderly patients, the etiology of aspiration likely stems from multiple causes, although data suggest that the progressive age-related loss of protective swallowing reflexes may be contributory.27 Among patients with head and neck cancer, the etiology of aspiration pneumonia is likely multifactorial; however, radiation-induced dysphagia presumably plays a central role.28 Radiotherapy can produce fibrosis of the treated pharyngeal tissues, resulting in nerve impairment and muscular injury, and causing generalized weakness and uncoordinated swallowing. In addition, radiation-induced xerostomia reduces salivary flow which Cancer
Month 00, 2014
could also impair the swallowing mechanism thus increasing the risk of aspiration pneumonia. Radiation may also represent a unique risk factor for the development of aspiration pneumonia compared with other treatment modalities for head and neck cancer. A recent population-based study of 93,663 patients who underwent surgery for head and neck cancer reported only a 2% rate of aspiration pneumonia.29 In our study, we also observed a lower risk of aspiration pneumonia for those who underwent surgery before receiving radiation, although these findings may represent selection bias as patients who underwent surgery may have had better overall health, less comorbidity, superior performance status, or more favorable cancer characteristics compared with those who did not undergo surgery. We also identified an increased risk of aspiration pneumonia in patients who received care at a teaching hospital which may reflect differences in unmeasured patient characteristics. Teaching hospitals may care for sicker or more complex patients which could explain the increased risk of aspiration in this subpopulation. Beyond the increased risk of aspiration with chemoradiotherapy, our study highlights the potential of 7
Original Article
Figure 3. Kaplan-Meier curves illustrate overall survival (A) from the date of aspiration pneumonia among patients with head and neck cancer who developed aspiration pneumonia (N 5 801), and (B) from the date of diagnosis among patients with head and neck cancer stratified according to whether they developed aspiration pneumonia (N 5 801) or not (N 5 2712).
aspiration pneumonia to substantially impact survival. We observed significantly increased mortality after aspiration pneumonia. Other studies evaluating survival after aspiration pneumonia in patients without cancer have observed similar increases in the risk of death. A recent single-institution, retrospective study of 628 patients with aspiration pneumonia produced a 30-day mortality rate of 21%, although those patients had higher rates of hospitalization and ICU admission (99% and 38%, respectively).30 Similarly, a multicenter, retrospective cohort study of patients who were admitted with pneumonia indicated that aspiration pneumonia was the greatest risk factor for 30-day mortality with an adjusted hazard ratio of 5.69.31 The morbidity and potential impact on mortality of aspiration pneumonia after chemoradiotherapy raises the question of whether action can be taken to reduce the risk of this adverse event. Radiation techniques that spare the con8
strictor muscles involved with swallowing have the potential to reduce dysphagia which is a risk factor for aspiration pneumonia.32,33 Prospective studies to reduce the radiation dose in subsets of patients with head and neck cancer are ongoing; hopefully, the decreased radiation dose will reduce toxicity without sacrificing local tumor control. Further research should focus on reducing the volume of tissue electively irradiated in head and neck cancer for patients who have a lower risk of regional tumor spread. Beyond modifying radiation fields, a different approach could concentrate on the preservation of swallowing function with early involvement of speech therapy and rehabilitation among patients at high risk of aspiration. Routine swallowing evaluations to screen for dysphagia among this patient population also may be recommended to select patients who are at risk for this complication. These interventions deserve further study because they stand to potentially improve the survivorship of patients with head and neck cancer. Although our study characterizes the risk of aspiration pneumonia in a large cohort of patients with head and neck cancer, there are limitations to the presented results. This study population only included patients aged 66 years; therefore, the findings cannot be generalized to a younger patient population. Medicare data are collected for administration purposes; consequently, confounding factors like smoking status, dietary intake, body habitus, and performance status were not collected and could not be analyzed. Similarly, SEER-Medicare data do not include information regarding the doses of chemotherapy or radiotherapy delivered which may have an impact on the rate of aspiration pneumonia. Furthermore, the higher aspiration pneumonia rates in our patient population could have arisen from local cancer progression as opposed to radiation-induced toxicity. However, we observed no correlation between tumor stage and aspiration rates. In addition, this study could not directly assess the accuracy of the primary endpoint of aspiration pneumonia. Although separate diagnosis codes exist for aspiration pneumonia and bacterial pneumonia, distinguishing these 2 diagnoses can pose a clinical challenge with misclassification potentially impacting our findings. Finally, SEER-Medicare data do not contain information on causality; therefore, future studies with additional longitudinal data are required to fully understand what drives the increased risk of aspiration in this cohort of patients. Overall, this study represents the first US-based population study to define the incidence of aspiration pneumonia in patients with head and neck cancer who received concurrent chemoradiotherapy and to contextualize these results using a matched sample of Medicare beneficiaries without cancer. This work also identified several risk Cancer
Month 00, 2014
Aspiration Pneumonia After Radiation/Xu et al
factors that can be used to identify patients who are at a higher risk of developing aspiration pneumonia and has suggested avenues for the future mitigation of this clinically significant and potentially fatal complication of chemoradiation in head and neck cancer. FUNDING SUPPORT This study was supported by National Institutes of Health (NIH) grant KL2 RR031978 to Dr. Murphy and NIH grant T32 to Ms. Boero.
CONFLICT OF INTEREST DISCLOSURES Dr. Moiseenko reports personal fees and nonfinancial support from Varian Medical Systems outside the submitted work.
REFERENCES 1. Francis DO, Weymuller EA Jr, Parvathaneni U, Merati AL, Yueh B. Dysphagia, stricture, and pneumonia in head and neck cancer patients: does treatment modality matter? Ann Otol Rhinol Laryngol. 2010;119:391-397. 2. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344:665-671. 3. Logemann JA, Rademaker AW, Pauloski BR, 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. 4. Smith RV, Kotz T, Beitler JJ, Wadler S. Long-term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea: initial results. Arch Otolaryngol Head Neck Surg. 2000;126:384-389. 5. Langerman A, Maccracken E, Kasza K, Haraf DJ, Vokes EE, Stenson KM. Aspiration in chemoradiated patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2007;133:1289-1295. 6. Nguyen NP, Moltz CC, Frank C, et al. Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol. 2004;15:383-388. 7. Nguyen NP, Smith HJ, Dutta S, et al. Aspiration occurence during chemoradiation for head and neck cancer. Anticancer Res. 2007;27: 1669-1672. 8. Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys. 2002;53:23-28. 9. Nguyen NP, Frank C, Moltz CC, et al. Aspiration rate following chemoradiation for head and neck cancer: an underreported occurrence. Radiother Oncol. 2006;80:302-306. 10. Purkey MT, Levine MS, Prendes B, Norman MF, Mirza N. Predictors of aspiration pneumonia following radiotherapy for head and neck cancer. Ann Otol Rhinol Laryngol. 2009;118:811-816. 11. Hunter KU, Lee OE, Lyden TH, et al. Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck. 2014;36:120-125. 12. Mortensen HR, Jensen K, Grau C. Aspiration pneumonia in patients treated with radiotherapy for head and neck cancer. Acta Oncol. 2013;52:270-276. 13. Chu CN, Muo CH, Chen SW, Lyu SY, Morisky DE. Incidence of pneumonia and risk factors among patients with head and neck cancer undergoing radiotherapy [serial online]. BMC Cancer. 2013;13: 370.
Cancer
Month 00, 2014
14. Chen SW, Yang SN, Liang JA, Lin FJ. The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer. Eur J Cancer Care (Engl). 2010;19:631-635. 15. Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care. 2002;40:IV-3–IV-18. 16. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Available at: http://www.seer.cancer.gov. Accessed October 13, 2014. 17. VanderWalde NA, Meyer AM, Liu H, et al. Patterns of care in older patients with squamous cell carcinoma of the head and neck: a Surveillance, Epidemiology, and End Results-Medicare analysis. J Geriatr Oncol. 2013;4:262-270. 18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619. 19. Warren JL, Harlan LC, Fahey A, et al. Utility of the SEERMedicare data to identify chemotherapy use. Med Care. 2002;40:5561. 20. Virnig BA, Warren JL, Cooper GS, Klabunde CN, Schussler N, Freeman J. Studying radiation therapy using SEER-Medicare-linked data. Med Care. 2002;40:49-54. 21. Buck CJ, American Medical Association. International Classification of Diseases, Ninth Revision, Clinical Modification for Hospitals (Professional Edition). Volumes 1, 2, and 3. St Louis, MO: Elsevier; 2013. 22. McCarthy EP, Iezzoni LI, Davis RB, et al. Does clinical evidence support ICD-9-CM diagnosis coding of complications? Med Care. 2000;38:868-876. 23. Lin G, So Y, Johnston G. Analyzing Survival Data With Competing Risks Using SAS Software. Cary, NC: SAS Institute Inc.; 2012. 24. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509. 25. Kohl M, Heinze G. PSHREG: An SAS Macro for Proportional and Nonproportional Substribution Hazards Regression With Ccompeting Risk Data. Vienna, Austria: Medical University of Vienna; 2013. 26. D’Agostino RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:265-2281. 27. Pontoppidan H, Beecher HK. Progressive loss of protective reflexes in the airway with the advance of age. JAMA. 1960;174:2209-2213. 28. Russi EG, Corvo R, Merlotti A, et al. Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: review and recommendations of the Supportive Task Group of the Italian Association of Radiation Oncology. Cancer Treat Rev. 2012;38:10331049. 29. Semenov YR, Starmer HM, Gourin CG. The effect of pneumonia on short-term outcomes and cost of care after head and neck cancer surgery. Laryngoscope. 2012;122:1994-2004. 30. Lanspa MJ, Jones BE, Brown SM, Dean NC. Mortality, morbidity, and disease severity of patients with aspiration pneumonia. J Hosp Med. 2013;8:83-90. 31. Komiya K, Ishii H, Umeki K, et al. Impact of aspiration pneumonia in patients with community-acquired pneumonia and healthcareassociated pneumonia: a multicenter retrospective cohort study. Respirology. 2013;18:514-521. 32. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys. 2004;60:1425-1439. 33. van der Laan HP, Gawryszuk A, Christianen ME, et al. Swallowingsparing intensity-modulated radiotherapy for head and neck cancer patients: treatment planning optimization and clinical introduction. Radiother Oncol. 2013;107:282-287.
9
