Gourin et al.: Long-Term Outcomes of Larynx Cancer Care in the Elderly

Transcription

1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Short- and Long-Term Outcomes of Laryngeal Cancer Care in the Elderly Christine G. Gourin, MD, MPH; Heather M. Starmer, MA, CCC-SLP; Robert J. Herbert, BS; Kevin D. Frick, PhD; Arlene A. Forastiere, MD; David W. Eisele, MD; Harry Quon, MD, MS Objectives/Hypothesis: To examine associations between pretreatment variables, short-term and long-term swallowing and airway impairment, and survival in elderly patients treated for laryngeal squamous cell cancer (SCCA). Study Design: Retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data. Methods: Longitudinal data from 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 were evaluated using cross-tabulations, multivariate logistic regression, and survival analysis. Results: Dysphagia (odds ratio [OR] [ ]), weight loss (OR [ ]), esophageal stricture (OR [ ]), airway obstruction (OR 5 1.9, [ ]), tracheostomy (OR [ ]), and pneumonia (OR [ ]) increased 1 year after treatment. The odds of airway obstruction, esophageal stricture, and pneumonia increased over subsequent years, with significantly increased risk at 5 years for airway obstruction (OR [ ]) and pneumonia (OR [ ]). Pretreatment dysphagia, chemoradiation, and salvage surgery were significant predictors of long-term dysphagia, weight loss, tracheostomy, and gastrostomy, with pretreatment dysphagia and salvage surgery also associated with pneumonia. Surgery and postoperative radiation was associated with long-term dysphagia (OR [ ]) but reduced odds of long-term pneumonia (OR [ ]). Long-term dysphagia, gastrostomy or tracheostomy dependence, weight loss, airway obstruction, and pneumonia were associated with poorer survival, with pneumonia associated with the greatest risk of death at 5 years (hazard ratio [ ]). Conclusions: Airway and swallowing impairment is common after laryngeal SCCA treatment in elderly patients, increases over time, and is associated with poorer survival with pneumonia associated with the highest risk of long-term mortality. Patients with pretreatment dysphagia, initial treatment with chemoradiation, and salvage surgery represent a highrisk group with an increased risk of disability and death. Key Words: Laryngeal cancer, squamous cell cancer, treatment, surgery, radiation, chemotherapy, survival, outcomes, SEER-Medicare, elderly, dysphagia, aspiration, pneumonia, gastrostomy. Level of Evidence: 2c. Laryngoscope, 125: , 2015 INTRODUCTION Airway and swallowing impairment are significant long-term sequela of treatment for head and neck cancer. The perceived mutilation associated with primary surgery for laryngeal cancer, with effects on speech and swallowing, spurred the development of Additional Supporting Information may be found in the online version of this article. From the Department of Otolaryngology Head and Neck Surgery (C.G.G., H.M.S., D.W.E., H.Q.); the Department of Health Policy and Management, the Johns Hopkins Bloomberg School of Public Health (R.J.H., K.D.F.); the Johns Hopkins Carey Business School (K.D.F.); Johns Hopkins University, the Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (A.A.F.), and the Department of Radiation Oncology and Molecular Radiation Sciences (H.Q.), Johns Hopkins University, Baltimore, Maryland, U.S.A. Editor s Note: This Manuscript was accepted for publication September 3, Supported by an American Academy of Otolaryngology Head and Neck Surgery Percy Memorial Research Award. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Christine G. Gourin, MD, MPH, FACS, Johns Hopkins Outpatient Center Department of Otolaryngology Head and Neck Surgery, 601 N. Caroline Street Suite 6260, Baltimore, MD cgourin1@jhmi.edu DOI: /lary nonsurgical options for the treatment of this disease. This has led to a paradigm shift in the management of laryngeal cancer, with an increase in the use of nonsurgical organ preservation treatment approaches 1 3 and an increase in the proportion of laryngeal cancer surgery performed for salvage in recent years. 4 However, chemoradiation has been shown to be associated with significant severe late toxicity, including longterm severe dysphagia with aspiration, dependence on a feeding tube, and diminished quality of life. 5 More concerning, chemoradiation has been associated with an increase in late deaths not attributable to larynx cancer or treatment. 6 Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we have found a survival advantage for elderly laryngeal cancer patients treated with surgery and postoperative radiation after controlling for stage, demographic variables, and comorbidity. 7 The survival advantage for surgery with postoperative radiation persisted after controlling for quality of care using quality indicators derived from guidelines for recommended care. 8 These data suggest that the favorable outcomes of larynx preservation trials may not apply to the elderly population. We undertook 924

2 the present study to determine if long-term outcomes of swallowing and airway impairment were associated with the treatment-related survival differences seen in elderly laryngeal cancer patients. MATERIALS AND METHODS Data Source A cross-sectional analysis of patients diagnosed with larynx cancer in 2004 to 2007 was performed using discharge data from the SEER-Medicare linked database. The SEER data are a combination of population-based registries and are linked with Medicare data and data from the American Medical Association Masterfile through a collaborative effort that involves the National Cancer Institute, the SEER registries, and the Centers for Medicare and Medicaid Services. Study Population Patients with larynx (SEER site code 38) squamous cell cancer without a previous diagnosis of head and neck cancer (01 10, 37, 38, and 41) or lymphoma (68 69, 71, 72) comprised the study population. Patients with in situ disease, distant metastatic disease, diagnosis by autopsy or death certificate, and less than 1 year of continuous claims were excluded from analysis, as were patients enrolled in Medicare health maintenance organizations; health maintenance organizations do not generate claims for their care. Analyses were restricted to Medicare part A and B enrollees in the SEER-Medicare data aged 66 and older in order to include patients who were enrolled continuously in Medicare s fee-for-service program from 365 days prior to the time of diagnosis and to allow identification of prevalent comorbid conditions prior to diagnosis. Patients were followed through December 2009 until the end of data (ineligibility or end of claims) or death. Treatment Primary site, American Joint Committee on Cancer stage, subsite, age, sex, ethnicity, U.S. Census tract median income, marital status, geographic region, urban/rural location, and hospital characteristics were obtained from the SEER Patient Entitlement and Diagnosis Summary File. Age, marital status, location, and income were examined as categorical variables, with census tract median income divided into quintiles. Preexisting chronic conditions identified in claims from 365 days prior to diagnosis were used to calculate a comorbidity index using the Charlson score, 9 as implemented by Deyo et al. 10 and modified by Klabunde et al. 11 Treatment was obtained from Medicare claims files including physician (National Claims History), hospital (Medicare Provider Analysis and Review), outpatient and hospice claims files using International Classification of Disease, 9th revision (ICD-9) codes, Current Procedural Terminology codes, and Healthcare Common Procedure Coding System (HCPCS) codes for larynx cancer treatment, as previously defined. 7 Volume Hospital volumes associated with initial treatment were categorized into tertiles using the number of patients with laryngeal squamous cell cancer treated by each hospital. We examined the distribution of the number of cases per hospital, and categorized hospitals into low ( 6 cases), intermediate (7 11 cases), or high ( 12 cases) volume hospitals. Short and Long-Term Outcomes Short-term outcomes were defined as outcomes occurring during the initial treatment period using claims dating from the first date of initial treatment to 30 days after the initial treatment end date, whereas long-term outcomes were defined as those occurring after 30 days from the last initial treatment date. Long-term outcomes were categorized by year 1 (days from 30 days after the last date of initial treatment through day 365), year 2 ( days from last initial treatment date), year 3 ( days from last initial treatment date), year 4 ( days from last initial treatment date), and year 5 ( days from last initial treatment date). These outcome variables were dichotomized as present or absent if they occurred at least once during each specified time interval. Medical complications and surgical complications occurring during the initial treatment period were defined by ICD-9 diagnosis codes in claims dating from the first date of initial treatment to 30 days after the initial treatment end date (Supplemental Table SI). Medical complications were derived from codes for acute cardiac events, acute pulmonary edema or failure, acute renal failure, acute hepatic failure, acute cerebrovascular events, sepsis, pneumonia, and urinary tract infection assigned at the time of hospital discharge. Surgical complications were derived from codes for complications directly resulting from surgical procedures assigned at the time of hospital discharge. Pneumonia was removed from the definition of shortterm medical complications in the analysis of pneumonia as a short- and long-term outcome (dependent) variable. Dysphagia, weight loss, esophageal stricture, airway obstruction, tracheostomy dependence, gastrostomy dependence, and pneumonia were defined using ICD-9 and HCPCS codes in claims (Supplemental Table SII). Tracheostomy and gastrostomy dependence were adjusted for removal of tracheostomy or gastrostomy codes when codes for removal were present. Because removal may not be reimbursed, and therefore may not be documented, we considered a gastrostomy or tracheostomy to be absent unless codes for placement or use (i.e., supplies) were present. Pretreatment dysphagia, gastrostomy, tracheostomy, and weight loss were defined by the occurrence of codes in claims for these conditions on or after the diagnosis date but before the first date of initial treatment. Statistical Analysis Data were analyzed using Stata 12 (StataCorp, College Station, TX). Associations between variables were analyzed using cross-tabulations and multivariate regression modeling. Nonzero counts with fewer than 11 observations were masked in accordance with the SEER-Medicare data use agreement. Data were structured as panel data for the analysis of outcomes that were measured over time. Overall survival, defined as time from diagnosis to either last claim date or death, was analyzed using the Kaplan-Meier method and multivariate Cox proportional hazard analysis. Independent variables included age, sex, race, comorbidity, marital status, median income quintile, primary site, stage, urban/rural location, SEER region, hospital volume, initial treatment, initial treatment-related medical and surgical complications, salvage treatment, and pretreatment dysphagia, gastrostomy, tracheostomy, and weight loss. Significance was attributed to a P value of < 0.05.This protocol was reviewed and approved by the Johns Hopkins Medical Institutions Institutional Review Board. RESULTS There were 2,370 cases that met study criteria. The distribution of patients by pretreatment conditions is 925

3 Fig. 1. Overall incidence of pretreatment and posttreatment outcomes. Dysphagia, weight loss, airway obstruction, tracheostomy tube dependence, and pneumonia increased in the first year after treatment, with the incidence of airway obstruction and pneumonia remaining high in subsequent years. The incidence of gastrostomy tube use decreased over time, whereas the incidence of esophageal stricture increased over time. The incidence of esophageal stricture, gastrostomy, and tracheostomy at 5 years was suppressed because of the presence of cells with less than 11 observations to comply with the SEER- Medicare Data Use Agreement. shown in Supplemental Table SIII. Overall, pretreatment swallowing or airway impairment was present in 20% of patients. Pretreatment dysphagia was present in 371 patients (16%) and was significantly more common in patients who had supraglottic tumors (32%), advanced stage disease (29%) and who received chemoradiation as initial treatment (35%). Pretreatment weight loss was present in 129 patients (5%) and was more common in patients who had supraglottic tumors (11%), advanced stage disease (16%), black race (10%), and who received chemoradiation as initial treatment (20%). Pretreatment gastrostomy was present in 100 patients (4%) and was more common in patients with supraglottic tumors (11%), advanced stage disease (12%), black race (6%), and chemoradiation as initial treatment (17%). Pretreatment tracheostomy was present in 142 patients (6%) and was more common in patients with supraglottic tumors (11%), advanced stage disease (12%), black race (13%), advanced comorbidity (9%), and chemoradiation (20%). Patients from higher median income quintiles were less likely to have pretreatment weight loss, gastrostomy, or tracheostomy placement. There was no difference in the incidence of pretreatment variables based on age or marital status. Medical complications during the initial treatment period occurred in 763 patients (32%) and were significantly more common in patients with supraglottic (44%) and subglottic (48%) tumors; age 80 years (38%); women (37%); advanced comorbidity (61%); single, divorced, or widowed marital status (37%); advanced stage disease (55%); initial treatment with chemoradiation (44%); and low-volume hospital care (38%). There were no significant differences seen in the distribution of medical complications and race, income, or hospital location. Surgical complications occurred in 49 patients (3%) and were more common in patients with supraglottic tumors (6%) and low-volume hospital care (5%). There was no difference in the incidence of surgical complications by age, race, sex, comorbidity, or location. The incidence of posttreatment outcomes is shown in Figure 1. The incidence of dysphagia, weight loss, airway obstruction, tracheostomy tube dependence, and pneumonia were highest in the first year following treatment, with the incidence of airway obstruction and pneumonia increasing in subsequent years. The incidence of gastrostomy tube use decreased over time, whereas the incidence of esophageal stricture increased over time. Multivariate logistic regression analysis of variables that were associated with short-term outcomes during the initial treatment period are shown in Table I. After controlling for all other variables, supraglottic primary site disease and advanced tumor stage were predictors of an increased likelihood of short-term dysphagia, weight loss, pneumonia, and tracheostomy and gastrostomy placement, while pretreatment dysphagia and medical complications of initial treatment were additional predictors of short-term dysphagia, weight loss, and tracheostomy and gastrostomy placement. Multivariate logistic regression analysis of variables that were associated with long-term outcomes after the initial treatment period are shown in Table II. Pretreatment dysphagia, supraglottic disease, advanced stage, medical complications during the initial treatment period, and salvage surgery were significant predictors of long-term swallowing complications and tracheostomy as well as pneumonia. Initial treatment with chemoradiation was a significant predictor of long-term dysphagia, weight loss, and gastrostomy. Initial treatment with surgery and radiation was associated with an increased odds of dysphagia but a reduced odds of pneumonia, which remained significant even after controlling for initial total laryngectomy. High-volume hospital care was significantly associated with a reduced likelihood of shortand long-term tracheostomy use but was not significantly associated with other long-term outcomes. Because laryngectomy may be associated with a reduced risk of aspiration and pneumonia, the effect of laryngectomy on short- and long-term outcomes was examined. Total laryngectomy comprised 10% of initial surgical procedures and 38% of salvage surgery procedures. There was no significant difference in the shortterm likelihood of pneumonia or other short-term outcomes between total laryngectomy patients and all other surgical patients. Among patients treated surgically, the likelihood of long-term pneumonia was lower for those 926

4 TABLE I. Multivariate Logistic Regression Analysis of Variables Associated With Short-Term Outcomes During the Initial Treatment Period. Dysphagia Weight Loss Gastrostomy Tube Airway Obstruction Tracheostomy Tube Pneumonia Primary site Glottic Ref Ref Ref Ref Ref Ref Supraglottic 2.52 ( ) 2.16 ( ) 4.26 ( ) 1.08 ( ) 2.44 ( ) 1.94 ( ) Other larynx 1.59 ( ) 1.32 ( ) 2.64 ( ) 1.30 ( ) 3.48 ( ) 2.65 ( ) Age yrs Ref Ref Ref Ref Ref Ref yrs 1.00 ( ) 1.08 ( ) 1.03 ( ) 0.75 ( ) 0.57 ( ) 1.14 ( ) 80 yrs 0.90 ( ) 1.39 ( ) 1.05 ( ) 0.87 ( ) 1.05 ( ) 1.27 ( ) Race White Ref Ref Ref Ref Ref Ref Black 1.06 ( ) 1.10 ( ) 1.49 ( ) 1.20 ( ) 1.65 ( ) 0.98 ( ) Other 1.40 ( ) 1.96 ( ) 2.40 ( ) 1.09 ( ) 3.39 ( ) 1.82 ( ) Hispanic 0.65 ( ) 1.17 ( ) 1.38 ( ) 1.46 ( ) 1.66 ( ) 1.05 ( ) Sex Female Ref Ref Ref Ref Ref Ref Male 1.04 ( ) 0.83 ( ) 1.01 ( ) 0.83 ( ) 1.05 ( ) 1.08 ( ) Comorbidity Score 0 Ref Ref Ref Ref Ref Ref ( ) 1.31 ( ) 1.24 ( ) 1.67 ( ) 1.05 ( ) 1.49 ( ) ( ) 1.26 ( ) 0.95 ( ) 1.69 ( ) 1.31 ( ) 2.12 ( ) ( ) 1.03 ( ) 0.87 ( ) 2.09 ( ) 1.28 ( ) 2.69 ( ) Marital status Married Ref Ref Ref Ref Ref Ref Single 1.08 ( ) 0.85 ( ) 1.03 ( ) 0.92 ( ) 1.27 ( ) 1.20 ( ) Divorced/separated 1.20 ( ) 0.82 ( ) 1.39 ( ) 1.03 ( ) 1.30 ( ) 1.32 ( ) Widowed 0.90 ( ) 0.83 ( ) 0.87 ( ) 0.85 ( ) 0.79 ( ) 1.03 ( ) TNM Stage I Ref Ref Ref Ref Ref Ref II 1.53 ( ) 1.95 ( ) 2.33 ( ) 1.44 ( ) 1.97 ( ) 1.52 ( ) III 2.27 ( ) 2.73 ( ) 3.81 ( ) 2.73 ( ) 3.70 ( ) 2.41 ( ) IV 2.08 ( ) 2.55 ( ) 4.13 ( ) 2.43 ( ) 3.56 ( ) 3.90 ( ) Census Median Income Quintile Very low Ref Ref Ref Ref Ref Ref Low 0.96 ( ) 0.92 ( ) 1.50 ( ) 0.74 ( ) 0.80 ( ) 1.09 ( ) Intermediate 0.89 ( ) 0.92 ( ) 1.10 ( ) 0.86 ( ) 0.76 ( ) 0.94 ( ) High 0.86 ( ) 0.91 ( ) 1.35 ( ) 0.62 ( ) 0.82 ( ) 0.98 ( ) Very high 0.84 ( ) 0.81 ( ) 1.59 ( ) 0.57 ( ) 0.66 ( ) 1.12 ( ) Location Urban Ref Ref Ref Ref Ref Ref Rural 0.85 ( ) 0.76 ( ) 0.99 ( ) 1.42 ( ) 1.85 ( ) 1.05 ( ) Hospital volume Low Ref Ref Ref Ref Ref Ref Intermediate 1.13 ( ) 0.96 ( ) 1.11 ( ) 0.98 ( ) 0.88 ( ) 0.72 ( ) High 0.80 ( ) 0.85 ( ) 0.70 ( ) 0.75 ( ) 0.49 ( ) 0.72 ( ) Initial treatment Surgery alone Ref Ref Ref Ref Ref Ref Radiation alone 0.83 ( ) 1.85 ( ) 1.16 ( ) 0.97 ( ) 0.13 ( ) 0.62 ( ) Surgery 1 radiation 1.48 ( ) 1.93 ( ) 1.49 ( ) 1.58 ( ) 0.27 ( ) 1.12 ( ) Chemoradiation 1.44 ( ) 2.45 ( ) 1.62 ( ) 0.86 ( ) 0.11 ( ) 0.86 ( ) Medical complications during initial treatment period Yes 2.32 ( ) 3.30 ( ) 3.45 ( ) 5.66 ( ) 4.26 ( ) * 927

5 TABLE I. (Continued) Dysphagia Weight Loss Gastrostomy Tube Airway Obstruction Tracheostomy Tube Pneumonia Surgical complications during initial treatment period Yes 1.81 ( ) 1.56 ( ) 1.42 ( ) 2.80 ( ) 2.16 ( ) 5.30 ( ) Pretreatment dysphagia Yes 2.13 ( ) 1.49 ( ) 1.43 ( ) 1.34 ( ) 1.50 ( ) 1.29 ( ) Pretreatment weight loss Yes 0.92 ( ) 2.85 ( ) 1.42 ( ) 1.02 ( ) 1.44 ( ) 1.18 ( ) Pretreatment gastrostomy tube Yes 1.06 ( ) 0.69 ( ) 1.28 ( ) 5.69 ( ) 1.59 ( ) Pretreatment tracheostomy tube Yes 1.21 ( ) 1.26 ( ) 1.16 ( ) 2.27 ( ) 1.45 ( ) Data are shown as odds ratios, with a 95% confidence interval. Bold: P < 0.05 vs. reference category. *No patient with short-term pneumonia also had another medical complication. Excluded from model. who underwent initial total laryngectomy compared to all other procedures (odds ratio [OR] 0.57, 95% confidence interval [CI] ; P ) whereas patients who underwent salvage laryngectomy had a higher likelihood of long-term pneumonia (OR 4.85, 95% CI ; P < 0.001). There was no significant association between initial total laryngectomy and other airway or swallowing outcomes; however, patients who underwent salvage laryngectomy had a significantly higher likelihood of long-term dysphagia (OR 2.41, 95% CI ; P ), gastrostomy dependence (OR 3. 51, 95% CI ; P ), and airway obstruction (OR 2.96, 95% CI ; P < 0.001). Fixed effects logistic regression of long-term outcomes controlling for demographic and initial treatment variables and the time-varying effects of salvage treatment are shown in Table III. Compared to the initial treatment period, the likelihood of dysphagia, weight loss, esophageal stricture, airway obstruction, tracheostomy, and pneumonia were all increased at 1 year after treatment. The odds of airway obstruction, esophageal stricture, and pneumonia remained significantly increased over each subsequent year, with the likelihood of airway obstruction and pneumonia increasing over time, whereas the odds of dysphagia, weight loss, and tracheostomy decreased over time. Gastrostomy use was less likely after the initial treatment period for all subsequent years. Cox proportional survival analysis demonstrated that after controlling for all other variables, including pretreatment status and salvage, long-term outcomes associated with swallowing or airway impairment were associated with poorer survival, with the exception of esophageal stricture (Table IV). Pneumonia was associated with the greatest risk of death at 5 years. DISCUSSION These data show that airway and swallowing impairment is common after laryngeal squamous cell cancer (SCCA) treatment in elderly patients, increases over time, and is associated with poorer survival with pneumonia associated with the highest risk of long-term mortality. Patients with pretreatment dysphagia, initial treatment with chemoradiation, and salvage surgery represent a high-risk group with an increased risk of disability and death associated with long-term toxicity. Pneumonia was associated with the greatest risk of late deaths, and had a greater effect on survival than stage, demographic variables, treatment, and outcomes. Patients treated with surgery and postoperative radiation had a significantly reduced odds of long-term pneumonia, suggesting a possible explanation for the lower mortality that we have observed in elderly laryngeal cancer patients treated with surgery and postoperative radiation. 7 The addition of chemotherapy to radiation has been shown to improve the laryngeal preservation rate in patients with advanced laryngeal cancer, 12,13 but is associated with significant long-term toxicity. Chemoradiation is associated with a significant increase in treatment-related toxicity, with high-grade mucositis present in virtually all patients. 14 These acute treatment effects translate into a substantial burden of long-term treatment-related adverse events related to atrophy and fibrosis of the pharyngeal musculature. A meta-analysis of three Radiation Therapy Oncology Group (RTOG) studies found that 43% of long-term survivors had severe late treatment-related toxicity, after excluding patients with pretreatment severe airway or swallowing dysfunction as well as patients with recurrence. 5 The 928

6 TABLE II. Multivariate Random Effect Logistic Regression Analysis of Variables Associated With Long-Term Outcomes After the Initial Treatment Period. Dysphagia Weight Loss Esophageal Stricture Gastrostomy Tube Airway Obstruction Tracheostomy Tube Pneumonia Primary Site Glottic Ref Ref Ref Ref Ref Ref Ref Supraglottic 2.01 ( ) 1.73 ( ) 1.59 ( ) 3.52 ( ) 1.02 ( ) 1.75 ( ) 1.29 ( ) Other larynx 1.70 ( ) 1.72 ( ) 2.13 ( ) 2.89 ( ) 1.08 ( ) 2.82 ( ) 1.65 ( ) Age yrs Ref Ref Ref Ref Ref Ref Ref yrs 1.13 ( ) 1.45 ( ) 1.58 ( ) 1.23 ( ) 1.05 ( ) 0.78 ( ) 1.30 ( ) 80 yrs 1.05 ( ) 1.79 ( ) 0.83 ( ) 0.99 ( ) 1.06 ( ) 0.75 ( ) 1.45 ( ) Race White Ref Ref Ref Ref Ref Ref Ref Black 1.33 ( ) 1.15 ( ) 1.44 ( ) 1.71 ( ) 1.09 ( ) 1.42 ( ) 0.93 ( ) Other 1.16 ( ) 1.20 ( ) 1.40 ( ) 2.49 ( ) 1.19 ( ) 2.66 ( ) 1.48 ( ) Hispanic 0.98 ( ) 1.34 ( ) 1.29 ( ) 3.15 ( ) 2.09 ( ) 0.93 ( ) 2.36 ( ) Sex Female Ref Ref Ref Ref Ref Ref Ref Male 1.05 ( ) 1.02 ( ) 0.64 ( ) 1.12 ( ) 0.86 ( ) 0.95 ( ) 1.08 ( ) Comorbidity Score 0 Ref Ref Ref Ref Ref Ref Ref ( ) 1.38 ( ) 0.76 ( ) 1.27 ( ) 1.62 ( ) 1.27 ( ) 1.56 ( ) ( ) 1.37 ( ) 0.72 ( ) 0.88 ( ) 2.09 ( ) 0.98 ( ) 1.75 ( ) ( ) 1.15 ( ) 0.64 ( ) 0.95 ( ) 2.64 ( ) 0.93 ( ) 1.79 ( ) Marital Status Married Ref Ref Ref Ref Ref Ref Ref Single 0.98 ( ) 1.12 ( ) 1.03 ( ) 1.03 ( ) 0.71 ( ) 0.99 ( ) 1.06 ( ) Divorced/separated 1.18 ( ) 1.42 ( ) 1.12 ( ) 1.26 ( ) 1.02 ( ) 0.89 ( ) 1.04 ( ) Widowed 0.86 ( ) 1.13 ( ) 0.82 ( ) 0.93 ( ) 0.99 ( ) 0.70 ( ) 1.05 ( ) TNM Stage I Ref Ref Ref Ref Ref Ref Ref II 1.67 ( ) 1.50 ( ) 1.31 ( ) 2.07 ( ) 1.18 ( ) 2.32 ( ) 1.17 ( ) III 2.43 ( ) 1.95 ( ) 3.29 ( ) 4.50 ( ) 1.76 ( ) 4.78 ( ) 1.48 ( ) IV 2.55 ( ) 2.17 ( ) 2.02 ( ) 4.13 ( ) 1.91 ( ) 3.41 ( ) 1.65 ( ) Census Median Income Quintile Very low Ref Ref Ref Ref Ref Ref Ref Low 1.15 ( ) 1.19 ( ) 2.68 ( ) 1.32 ( ) 0.96 ( ) 0.99 ( ) 1.15 ( ) 929

7 TABLE II. (Continued) Dysphagia Weight Loss Esophageal Stricture Gastrostomy Tube Airway Obstruction Tracheostomy Tube Pneumonia Intermediate 1.07 ( ) 0.96 ( ) 2.12 ( ) 1.18 ( ) 0.96 ( ) 0.98 ( ) 0.97 ( ) High 1.05 ( ) 0.88 ( ) 2.96 ( ) 1.24 ( ) 0.87 ( ) 0.71 ( ) 1.02 ( ) Very high 0.88 ( ) 0.79 ( ) 1.65 ( ) 1.26 ( ) 0.79 ( ) 0.73 ( ) 1.15 ( ) Location Urban Ref Ref Ref Ref Ref Ref Ref Rural 0.79 ( ) 0.78 ( ) 0.80 ( ) 0.86 ( ) 1.10 ( ) 0.90 ( ) 0.84 ( ) Hospital Volume Low Ref Ref Ref Ref Ref Ref Ref Intermediate 1.16 ( ) 1.10 ( ) 1.07 ( ) 1.22 ( ) 1.15 ( ) 0.90 ( ) 1.24 ( ) High 0.86 ( ) 1.03 ( ) 0.70 ( ) 0.84 ( ) 0.78 ( ) 0.56 ( ) 0.85 ( ) Initial Treatment Surgery alone Ref Ref Ref Ref Ref Ref Ref Radiation alone 1.10 ( ) 1.54 ( ) 1.10 ( ) 1.28 ( ) 1.17 ( ) 0.35 ( ) 1.95 ( ) Surgery 1 radiation 1.38 ( ) 1.24 ( ) 1.53 ( ) 1.24 ( ) 1.02 ( ) 0.44 ( ) 0.70 ( ) Chemoradiation 1.70 ( ) 1.71 ( ) 1.44 ( ) 3.17 ( ) 0.98 ( ) 0.21 ( ) 1.10 ( ) Medical Complications During Initial Treatment Period Yes 2.00 ( ) 1.79 ( ) 1.21 ( ) 2.89 ( ) 2.62 ( ) 2.68 ( ) 4.18 ( ) Surgical Complications During Initial Treatment Period Yes 1.12 ( ) 1.24 ( ) 2.60 ( ) 0.75 ( ) 1.81 ( ) 1.99 ( ) 1.75 ( ) Salvage Surgery Yes 2.62 ( ) 2.14 ( ) 2.02 ( ) 6.27 ( ) 1.89 ( ) 7.11 ( ) 3.50 ( ) Salvage Radiation Yes 1.39 ( ) 0.80 ( ) 1.10 ( ) 0.97 ( ) 0.95 ( ) 1.48 ( ) 1.09 ( ) Salvage Chemotherapy Yes 1.29 ( ) 1.62 ( ) 1.54 ( ) 2.44 ( ) 1.23 ( ) 0.78 ( ) 1.12 ( ) Pretreatment Dysphagia Yes 2.52 ( ) 1.38 ( ) 2.03 ( ) 1.58 ( ) 1.28 ( ) 1.20 ( ) 1.37 ( ) 930

8 TABLE II. (Continued) Dysphagia Weight Loss Esophageal Stricture Gastrostomy Tube Airway Obstruction Tracheostomy Tube Pneumonia Pretreatment Weight Loss Yes 0.86 ( ) 2.44 ( ) 1.04 ( ) 1.38 ( ) 1.13 ( ) 1.23 ( ) 1.02 ( ) Pretreatment Gastrostomy Tube Yes 1.21 ( ) 0.88 ( ) 0.79 ( ) 1.48 ( ) 1.18 ( ) 0.73 ( ) 1.51 ( ) Pretreatment Tracheostomy Tube Yes 1.10 ( ) 1.01 ( ) 1.61 ( ) 1.13 ( ) 1.55 ( ) ( ) 1.09 ( ) Data are shown as odds ratios, with a 95% confidence interval. Bold: P < 0.05 vs. reference category. risk was increased in patients with laryngeal tumors and increased over time. A 10-year follow up of the RTOG laryngeal preservation study found that concurrent chemoradiotherapy significantly improved the larynx preservation rate, but at the expense of increased deaths unrelated to larynx cancer and without an apparent increase in late effects. 6 The authors hypothesized that this may have been due to fatal treatment-related episodes not identified with the current system employed to monitor and grade late toxicities. Similar observations have been reported in an institutional review at the University of Iowa, where severe dysphagia associated with nothing by mouth status was shown to be an independent predictor of survival, and was associated with the greatest increased risk of death, after controlling for all other variables. 15 The elderly appear to be at particular risk for chemoradiation treatment-related late toxicities. The RTOG meta-analysis found that age was a significant predictor of severe late toxicity. 5 A SEER-Medicare analysis of elderly patients with head and neck cancer found that treatment with chemoradiation was associated with the highest risks of dysphagia and pneumonia. 16 Severe long-term swallowing impairment, including gastrostomy dependence, aspiration, or stricture, has been shown to be significantly increased in the elderly with the addition of chemotherapy. 17 Our data suggest that the survival of elderly laryngeal cancer patients is significantly associated with the development of several late complications that increase with time and appear to be predominantly a consequence of chemoradiation. Collectively, these observations suggest that concurrent chemoradiation to the larynx and neck increases the risk of serious late treatment complications that can compromise patient survival in the elderly. This risk may not be limited to larynx cancers because a meta-analysis of 16,485 patients showed no benefit to the addition of chemotherapy to radiation in patients over 70 years of age. 18 One possible explanation raised by the authors included the potential for increased late complications in the elderly. We found that patients who underwent salvage surgery were also at a higher risk for long-term airway and swallowing impairment including pneumonia. Salvage laryngectomy has been shown to be associated with a reduced risk of long-term survival. 6,13 Hutcheson et al. 19 reported that salvage laryngectomy is associated with long-term gastrostomy dependence in patients with a preoperative history of recurrent pneumonia. These findings suggest that while controlling aspiration, laryngectomy does not normalize swallowing function after previous treatment, and pretreatment aspiration is a marker of more severe prelaryngectomy organ dysfunction. Salvage neck dissection has been shown to be a significant independent risk factor for severe long-term dysphagia by increasing posttreatment edema and longterm fibrosis. 5,20 It is well recognized that in addition to chemotherapy, the extent of soft-tissue injury is related to radiation dosimetry. The RTOG meta-analysis found significantly lower rates of severe long-term toxicity in 931

9 TABLE III. Fixed Effects Logistic Regression of the Odds of Long-Term Outcomes, Controlling for Time-Varying Effects of Salvage Treatment. 1 year 2 year 3 year 4 year 5 year Dysphagia 1.46 ( ) 1.15 ( ) 0.78 ( ) 0.80 ( ) 0.59 ( ) Weight Loss 1.30 ( ) 1.40 ( ) 1.31 ( ) 1.14 ( ) 1.35 ( ) Esophageal Stricture 3.84 ( ) 5.38 ( ) 5.58 ( ) 3.43 ( ) 2.46 ( ) Gastrostomy Tube 0.66 ( ) 0.37 ( ) 0.30 ( ) 0.30 ( ) 0.17 ( ) Airway Obstruction 1.90 ( ) 2.48 ( ) 2.67 ( ) 3.03 ( ) 3.25 ( ) Tracheostomy Tube 1.46 ( ) 1.38 ( ) 1.03 ( ) 1.21 ( ) 0.40 ( ) Pneumonia 1.75 ( ) 2.49 ( ) 1.86 ( ) 3.41 ( ) 5.17 ( ) Data are shown as odds ratios, with a 95% confidence interval. Bold: P < 0.05 vs. reference category (initial treatment period). patients receiving 60 Gy to the inferior hypopharynx compared to patients who received > 60 Gy. 21 Caudell et al. 22 identified that a dose of > 60 Gy to the larynx or inferior constrictor was significantly associated with gastrostomy dependence and aspiration, with higher doses were associated with an increased risk of stricture. Gokhale et al. 23 identified both a dose of 60 Gy and the volume of inferior constrictor irradiated as risk factors for long-term gastrostomy use. The influence of anatomic site suggests that injury to the larynx and hypopharynx particularly increases the risk of late complications and survival through an increased risk of organ dysfunction and subsequent aspiration injury. However, it is not entirely clear that the dose to the larynx and inferior constrictors is the main cause, as we have found that the dose and volume of irradiation to the suprahyoid muscles were more important than the constrictor muscles in multivariate modeling for the risk of aspiration. 24 These findings may partially explain our observation that patients treated with surgery and postoperative radiation had a significantly reduced odds of long-term pneumonia, even when surgery did not include total laryngectomy; postoperative radiation doses are typically 60 Gy. Because pneumonia was associated TABLE IV. Overall Survival Estimates, by Outcome Categories, Controlled for Variability of the Presence of the Outcome Over Time. Initial Treatment Period OS 1 Year OS 2 Year OS 3 Year OS 4 Year OS 5 Year OS HR Dysphagia Absent 98 (98, 98) 95 (94, 96) 87 (86, 88) 79 (78, 81) 73 (72, 75) 65 (63, 67) Present 95 (94, 96) 87 (86, 89) 74 (72, 75) 63 (61, 65) 54 (52, 57) 45 (42, 48) 1.56 (1.43, 1.71) Weight Loss Absent 98 (97, 98) 95 (94, 95) 86 (85, 87) 79 (78, 80) 73 (72, 74) 65 (63, 66) Present 94 (93, 95) 83 (91, 85) 67 (64, 69) 53 (50, 56) 43 (40, 46) 32 (28, 36) 1.89 (1.73, 2.09) Esophageal Stricture Absent 97 (92, 94) 93 (92, 94) 84 (83, 84) 75 (75, 76) 69 (68, 70) 61 (59, 62) Present 98 (95, 99) 93 (90, 96) 82 (90, 96) 72 (66, 77) 62 (55, 68) 43 (35, 52) 0.98 (0.81, 1.20) Gastrostomy Tube Absent 98 (98, 98) 95 (95, 95) 87 (86, 87) 79 (78, 80) 73 (72, 74) 64 (63, 66) Present 93 (90, 94) 79 (77, 82) 59 (56, 63) 46 (43, 49) 35 (32, 39) 28 (24, 32) 2.32 (2.08, 2.57) Airway Obstruction Absent 98 (98, 98) 95 (94, 95) 87 (86, 88) 79 (78, 80) 73 (72, 74) 65 (64, 67) Present 94 (92, 95) 84 (82, 86) 68 (66, 70) 57 (55, 60) 47 (44, 49) 36 (33, 40) 1.94 (1.77, 2.12) Tracheostomy Tube Absent 98 (97, 98) 95 (94, 95) 86 (85, 87) 78 (77, 79) 72 (71, 73) 63 (62, 65) Present 91 (88, 93) 80 (77, 82) 61 (57, 64) 50 (47, 54) 38 (35, 42) 30 (26, 35) 2.25 (2.00, 2.52) Pneumonia Absent 98 (97, 98) 95 (94, 95) 86 (85, 87) 79 (78, 80) 73 (72, 74) 65 (64, 67) Present 92 (89, 93) 79 (76, 82) 59 (56, 62) 47 (44, 50) 35 (32, 39) 22 (19, 26) 2.64 (2.39, 2.90) Values for survival probabilities are shown as percent alive, with a 95% confidence interval. Hazard ratios and corresponding confidence intervals and P values are estimated from Cox proportional hazards models and adjust for stage, age at diagnosis, site, sex, race, marital status, comorbidities, Surveillance, Epidemiology, and End Results region, hospital volume, initial treatment, subsequent salvage treatment, and pretreatment swallowing and airway dysfunction (dysphagia, weight loss, tracheostomy and gastrostomy). Bold: P < 0.05 vs. reference category (absence of outcome). HR 5 hazard ratio; OS 5 overall survival. 932

10 with the greatest risk of death in this study, these observations may in part explain the improved survival associated with surgery and postoperative radiation in this cohort. 7,8 There are well-recognized limitations of Medicare data in risk adjustment and documentation that may impact the observed differences in survival. 7,8 Poor documentation of conditions associated with airway and swallowing impairment in claims data may lead to underestimation of late toxicities. There may be significant overlap between conditions that are not reflected in claims: that is, gastrostomy has been shown to be associated with aspiration and stricture, and aspiration associated with stricture, 17 but not all diagnoses may be reflected in claims that may focus on one condition. Gastrostomy use may be a surrogate for severe dysphagia but may be underestimated in the absence of claims for nutritional support. The severity of toxicities may not be reflected in claims and in the absence of objective data. The ability to adequately control for case mix is limited when discharge diagnoses from claims data are used. Because information on recurrence is not collected, we restricted our analysis of the effect of treated recurrence by identifying claims for cancer-directed treatment following definitive initial treatment, which may underestimate the number of patients with recurrent or progressive disease who may have more severe airway and swallowing impairment. Nevertheless, these data suggest that elderly laryngeal cancer patients may be particularly susceptible to treatment-related toxicity with adverse effects on longterm survival. Severe airway and swallowing impairment were associated with worse survival, with the greatest risk of death associated with pneumonia. Pretreatment dysphagia, initial treatment with chemoradiation, and salvage surgery were associated with severe airway and swallowing impairment and poorer survival. We have previously reported that elderly larynx cancer patients treated with surgery and postoperative radiation have improved survival; and in this study, these patients had a lower incidence of pneumonia, even after controlling for total laryngectomy, suggesting a causal association. It is important to recognize that the SEER-Medicare analysis reflects the real world application of laryngeal cancer care and comprises a patient population different than the composition of clinical trial patients. Despite this, our analysis would appear to be in line with the long-term follow-up of RTOG and offers supportive evidence for the potential reasons for an increased risk of late deaths when patients are treated with chemoradiation. These data suggest that there is a need to determine the underlying causes for these observations, permit early identification of patients who are at risk for failure, and develop sensitive and valid treatment guidelines for the elderly population. CONCLUSION Airway and swallowing impairment is common after laryngeal SCCA treatment in elderly patients, increases over time, and is associated with poorer survival with pneumonia associated with the highest risk of long-term mortality. Patients with pretreatment dysphagia, initial treatment with chemoradiation, and salvage surgery represent a high-risk group with an increased risk of disability and death. BIBLIOGRAPHY 1. Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival. Laryngoscope, 2006;116(suppl 111): Chen AY, Schrag N, Hao Y, et al. Changes in treatment of advanced laryngeal cancer Otolaryngol Head Neck Surg 2006;135: Chen AY, Fedewa S, Zhu J. 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