Zhu J, Fedewa S, Chen AY. The Impact of Comorbidity on Treatment (Chemoradiation and Laryngectomy) of Advanced, Nondistant Metastatic Laryngeal CancerA Review of 16 849 Cases From the National Cancer Database (2003-2008). Arch Otolaryngol Head Neck Surg. 2012;138(12):1120–1128. doi:10.1001/jamaoto.2013.720
Author Affiliations: Department of Health Services Research, American Cancer Society (Ms Fedewa); and Department of Otolaryngology–Head and Neck Surgery, Emory University School of Medicine, Atlanta, Georgia (Dr Chen). Mr Zhu is a medical student at Emory University School of Medicine.
Objective To investigate whether patients treated with laryngectomy had less comorbidity than those treated with chemoradiation, which could help explain the improved survival for the laryngectomy cohorts in recent studies.
Design Observational cross-sectional study.
Patients Patients receiving diagnoses of primary invasive advanced squamous cell carcinoma of the larynx between 2003 and 2008 were selected from the National Cancer Database, which collects information from more than 1400 facilities accredited by the American College of Surgeons' Commission on Cancer. Patient-level independent variables included age at diagnosis, sex, diagnosis year, race/ethnicity, primary payer status, and zip code–level education.
Main Outcome Measures Primary treatment information. The association between treatment and patient clinical, sociodemographic, and facility-level and zip code–level socioeconomic status variables were analyzed using univariate statistics and multivariate models. Charlson Deyo Comorbidity and The Washington University Head and Neck Comorbidity Index scores were calculated from the hospital face sheet.
Results The study demonstrated that receipt of treatment (chemoradiation vs total laryngectomy) was significantly associated with comorbidity. Treatment was not significantly associated with insurance status, race/ethnicity, or age. Patients with comorbidity were less likely to receive chemoradiation than subtotal or total laryngectomy, with a risk ratio (RR) of 0.84 (95% CI, 0.81-0.87) for patients with 1 or more comorbidities compared with those without any comorbidity, after controlling for factors such as tumor stage, age, race/ethnicity, insurance, and socioeconomic status. Patients were also less likely to receive chemoradiation than total laryngectomy if they had stage IV disease (RR, 0.81; 95% CI, 0.79-0.83) and if they had been diagnosed at a teaching or research institution (RR, 0.80; 95% CI, 0.77-0.84). Patients were more likely to receive chemoradiation if they were diagnosed after 2003 (RR, 1.37; 95% CI, 1.30-1.45) or if they lived in a zip code with a high percentage of high school graduates (RR, 1.1; 95% CI, 1.05-1.15).
Conclusions This is the first study, to our knowledge, that demonstrates that patients with advanced laryngeal cancer with 1 or more comorbidities are more likely to receive surgery than chemoradiation compared with patients without any comorbidity, independent of numerous clinical and nonclinical variables among a large national cohort. A limitation of this study is the use of comorbidity data from the National Cancer Database, which gathers its information from hospital discharge face sheets. We recognize that the National Cancer Database may be an imperfect system for the collection of comorbidity data and encourage discussion on different methods to improve the system, including incorporating comorbidity data from the Surveillance, Epidemiology, and End Results Medicare Database and medical chart–based comorbidity data collection by cancer registrars.
Comorbidity is the presence of an underlying pathologic condition that has an impact on a patient's total burden of disease. Up to 68.7% of patients with cancer have a comorbid condition, and up to one-third of these patients have 2 or more, with hypertension, cardiovascular disease, and pulmonary disease among the most prevalent.1 The clinical implications of comorbidities range from prevention and screening to prognosis and treatment. Comorbidity has been found to have an impact on the treatment and survival of patients with prostate, breast, ovarian, colorectal, cervical, and lung cancer.2- 13 Head and neck cancer is no exception, since a history of alcohol and tobacco consumption is common among patients with head and neck cancer, increasing their risk for existing cardiac and pulmonary comorbidities.14
While the direct relationship between survival and comorbidity among patients with head and neck cancer has been well studied in the past, research correlating comorbidity status and treatment selection has been equivocal.15- 18 Singh and colleagues17 found no significant relationship between comorbidity scores and type of initial treatment among a retrospective cohort of 70 patients with head and neck squamous cell carcinoma from 3 hospitals. Similar results were observed in a single-institution retrospective analysis by Chen and colleagues,16 with 182 patients with advanced laryngeal cancer. To date, there has been no study involving national data examining the relationship between treatment and comorbidity among patients with advanced laryngeal cancer. For the treatment of late-stage laryngeal cancer, a landmark study by the Veterans Affairs Laryngeal Cancer Study Group found that chemoradiation and laryngectomy yielded equivalent survival for patients with advanced laryngeal cancer.19 However, several subsequent studies disagree, reporting improved survival for patients with advanced laryngeal cancer treated with total laryngectomy compared with chemoradiation.20,21 Hoffman and colleagues21 found a better 5-year survival rate among patients with advanced laryngeal cancer in the surgical treatment group compared with those treated with irradiation, with or without chemotherapy. Chen et al20 found similar results in an analysis of more than 7000 patients with advanced laryngeal cancer. In those studies, it is unknown if patients undergoing total laryngectomy had less comorbidity compared with those undergoing nonsurgical treatment, which could contribute to the disparity in survival. The purpose of this study was to investigate whether patients treated with laryngectomy had less comorbidity than those treated with chemoradiation, which could help explain the improved survival for the laryngectomy cohorts in the previously mentioned studies.
Data from the National Cancer Database (NCDB), a hospital-based cancer registry jointly sponsored by the American Cancer Society and the American College of Surgeons, were used in this study. The NCDB includes approximately 70% of all malignant cancers in the United States from more than 1400 facilities accredited by the American College of Surgeons' Commission on Cancer that collect and submit data to the NCDB.22 The NCDB contains standardized data elements on patient demographics, insurance status, stage at diagnosis, zip code–level socioeconomic factors, and facility-level factors. Data are entered using the standardized data dictionary of the NCDB—the Facility Oncology Registry Data Standards (FORDS) manual.23 The institutional review board of Morehouse University reviewed this study and determined that the study is exempt from institutional review board review. Patients diagnosed as having a primary invasive advanced squamous cell carcinoma of the larynx between 2003 and 2008 were selected (n = 18 708). The American Joint Commission on Cancer Cancer Staging Manual (sixth edition) was used, and “advanced” was defined as stage III or IV.24 Our categorization of patients relied primarily on reported clinical stage. If clinical staging was missing, pathologic staging was used. Patients younger than 18 years or older than 99 years were excluded (n = 5). Of 906 patients with evidence of clinical distant metastasis, those with missing data for sex (n = 7), treatment (n = 484), and facility type (n = 90), and those who listed facility type as other (n = 102), were removed from the analyses. Because of insufficient numbers, patients with other forms of government insurance (which includes the Bureau of Indian Affairs and the military [n = 265]) were also removed from analyses. The total analytic cohort included 16 849 patients.
The outcome of this study was the primary treatment. Patients were grouped into the following 6 main treatment types: chemotherapy with concurrent radiation, which was defined as having received chemotherapy and radiation within 90 days of one another; radiation alone; chemotherapy alone; invasive surgery, which included total and subtotal laryngectomy; local surgery; and no treatment. Local surgery included laser excision, stripping, and excisional biopsy. We included 2 different measures of comorbidity, which were calculated from the hospital face sheet. The Charlson Deyo Comorbidity Index (CDCI) includes 17 weighted conditions, which have been previously described and include conditions such as diabetes, myocardial infarction, and kidney failure and 2 measures of other cancers.25 The Washington University Head and Neck Comorbidity Index (WUHNCI) has been previously described and includes 7 weighted conditions, which include 2 related to cancer (other cancer controlled and cancer controlled), pulmonary disease, peripheral vascular disease, cardiac arrhythmia, congestive heart failure, and renal disease.26,27 Because we only considered patients with primary tumors, there were no patients with cancer-related comorbidity in both the CDCI and WUNCHI.
Patient-level independent variables included age at diagnosis (18-49, 50-59, 60-69, and 70-99 years), sex, diagnosis year, and race/ethnicity, which we recoded as non-Hispanic white, Hispanic, African American, other/Asian, and missing race/ethnicity. Primary payer was grouped into the following: Medicaid; uninsured, which includes not insured, charity write-off, and self-pay; private insurance plans (health maintenance organizations and preferred provider organizations); and Medicare. Because Medicare is available to most patients 65 years and older, but only for permanently disabled individuals younger than 65 years, we created a separate category for younger (age 18-64 years) Medicare patients. An area-based indicator of socioeconomic status (SES)—the proportion of the population that did not have a high school diploma—was derived at the zip code level from 2000 US census data and was included as quartiles of the observed distribution in the general US population.
On the basis of the Commission on Cancer approvals classification, we categorized facilities into the following groups: community hospitals, community cancer centers, National Cancer Institute–designated centers, and teaching or research centers. Community hospitals treat at least 300 patients with cancer per year and have a full range of services for cancer care, but patients need a referral for portions of their treatment. Community cancer centers are facilities that offer the same range of services as the community hospitals but treat at least 750 patients with cancer annually and conduct weekly cancer conferences. Teaching or research facilities have residency programs and ongoing cancer research.
Statistical analyses were performed with SAS version 9.2 (SAS Institute Inc). To analyze the relationship between the facility type and all other covariates, χ2 tests and the corresponding 2-tailed P values were calculated. Because the prevalence of our outcomes was high (>10%), we relied on multivariate log binomial models to estimate risks ratios (RRs) and 95% confidence intervals of select treatments.28 Factors related to the 2 most common treatment types (chemoradiation and total or subtotal laryngectomy) were examined in multivariable analyses.
A total of 16 849 patients were analyzed. The majority of the patients were male (76%), non-Hispanic white (67%), and older than 50 years (85%) (Table 1). Most patients (69%) lived in zip codes with high school graduation rates below 29%. Approximately 43% of patients received treatment at a teaching or research hospital, which was the most common facility type, followed by community cancer center (41%) and community hospital (16%). Private insurance was the most common insurance category (34%), followed by older Medicare (30%), younger Medicare (9%), and uninsured (9%). Slightly more than half of all patients were diagnosed as having stage IV laryngeal cancer (56%), and patients most commonly received chemoradiation (42%) or laryngectomy (31%) as the primary treatment.
In terms of CDCI scores, 69% of all patients had a score of 0, while 3% of all patients had a score of 3 or greater (Table 1). In bivariate analyses, the CDCI score varied significantly with respect to the age at diagnosis, race/ethnicity, and insurance status. The group of patients receiving diagnoses before age 50 years had a significantly lower proportion of patients with CDCI scores of 1, 2, and 3 compared with the group containing patients receiving diagnoses after age 50 years. In terms of race/ethnicity, African Americans accounted for a significantly greater proportion of patients with a CDCI score of 3 or greater. African Americans accounted for 18% of all patients but 25% of all patients with a CDCI score of 3 or greater. With respect to insurance, there were higher proportions of elevated CDCI scores among patients with Medicaid and Medicare, compared with patients with private insurance. Facility type, stage, and SES were not significantly associated with the CDCI scores.
The patient characteristics analyzed with the WUHNCI demonstrated many of the same patterns as the CDCI scores. Age, race/ethnicity, and insurance status were all significantly associated with WUHNCI scores in bivariate analyses (Table 2). Similar to the CDCI score analysis, WUHNCI scores did not vary by sex. However, several differences existed between the 2 analyses. There was a lower proportion of patients with a WUHNCI score of 3 or greater among African Americans, and a higher proportion among non-Hispanic whites. Lastly, while the type of facility was not significantly associated with the CDCI scores, it reached a level of significance with respect to the WUHNCI score.
Table 3 depicts patient characteristics by treatment. In addition to previously mentioned factors such as the age, sex, race/ethnicity, insurance status, SES, and American Joint Commission on Cancer staging of the patient, CDCI and WUHNCI scores were also associated with treatment. Results from a multivariate log binomial regression analysis comparing primary treatments of chemoradiation vs total or subtotal laryngectomy indicate that patients with a CDCI score of 1 (RR, 0.84; 95% CI, 0.81-0.87), 2 (RR, 0.86; 95% CI, 0.80-0.92), or 3 or greater (RR, 0.82; 95% CI, 0.73-0.92) were more likely to receive surgery than chemoradiation (Table 4). Race/ethnicity, insurance, and age were not associated with receipt of chemoradiation or subtotal or total laryngectomy in multivariable analyses (Table 4). However, patients with stage IV disease (RR, 0.81; 95% CI, 0.79-0.83) and those treated at teaching or research centers (RR, 0.80; 95% CI, 0.77-0.84) were less likely to receive chemoradiation. There was also a positive association between diagnosis year and receipt of chemoradiation. The same pattern held in the multivariate analysis comparing primary treatments for the different WUHNCI scores. Insurance status, race/ethnicity, and age were not associated with receipt of chemoradiation or subtotal or total laryngectomy. Patients with a WUHNCI score of 1, 2, or 3 or greater were more likely to receive subtotal or total laryngectomy than chemoradiation compared with those with a WUHNCI score of 0 (Table 4).
While there is disagreement concerning the most appropriate treatment for advanced laryngeal cancer, there is a consensus that comorbidities have a meaningful impact on survival.15,16,29,30 This study aimed to clarify whether a significant relationship exists between comorbidity and treatment using data gathered from the NCDB. Singh et al17 found no significant difference between treatment selection (surgery, radiotherapy, combination therapy) for patients with high or low comorbidity, defined using the Kaplan-Feinstein Index. Data from another study by Chen et al16 contained similar results among patients with laryngeal cancer. Our study demonstrates that comorbidity was significantly associated with treatment among patients with advanced laryngeal cancer. Patients with greater comorbidities were more likely to receive subtotal or total laryngectomy compared with chemoradiation, after controlling for factors such as tumor stage, age, race/ethnicity, insurance, and SES.
Several factors may have contributed to these discordant results. First, our study design used the CDCI classification of comorbidity and the WUHNCI, while Singh et al17 used the original Kaplan-Feinstein Index. The CDCI index has been shown to be an independent predictor of tumor-specific survival and a valid prognostic indicator in patients with head and neck malignant neoplasms.31 When compared head to head, past studies have shown that the CDCI and WUHNCI performs equally well at predicting overall survival.27 Second, the subject population in the study by Singh et al17 was restricted to patients younger than 45 years, which is very limited, since only 3% of all patients diagnosed as having laryngeal cancer between 1975 and 2008 were younger than 45 years.32 Our study included all patients between the ages of 18 and 99 years, which contains elderly patients for whom comorbidity is a bigger issue. While elderly patients are frequently considered high-risk surgical candidates, studies have shown that surgical therapy for head and neck cancer can be as effective in elderly patients as in younger patients.14,33,34 Lastly, the study by Singh et al17 had 70 patients from 3 hospitals, and Chen et al16 had 182 patients from a single teaching hospital. In our study, we used a national cancer registry database with more than 16 000 patients encompassing not only teaching and research facilities, but also community hospitals and community cancer centers. It is important to include all 3 facilities because previous studies have found significant differences between their patient populations, including the age, race/ethnicity, and insurance status.35 All 3 of these variables were significantly correlated with comorbidity in our data.
Previous studies have also demonstrated better survival in patients with advanced laryngeal cancer who had been treated with surgery compared with those without.20,21 One hypothesis to explain this survival disparity would be that the surgical candidates had been healthier than the chemoradiation and radiotherapy candidates, since comorbidity is significantly associated with survival.16 Our data demonstrate that this is not the case. Patients with comorbidities were more likely to receive subtotal or total laryngectomy than chemoradiation. This is counterintuitive, as it is often thought that those with comorbidities are poor surgical candidates. Borggreven et al36 showed that advanced comorbidity was a clear prognostic factor for complications during major oral surgery, with a clinically important complication developing in 55% of cases. Suh et al37 report a significant correlation between comorbidity level and the incidence of complications among a group of 400 cases of microvascular head and neck reconstruction. Few studies support surgery for patients with both head and neck cancer and comorbidity. Piccirillo15 showed that patients with severe comorbidity had a better 2-year survival when offered combined surgery and radiotherapy, compared with radiotherapy itself. Another study showed that in patients undergoing major surgery of the oral cavity and oropharynx, those with mild comorbidity had no significant difference in complications compared with those without comorbidity.36
Temporal trends described in previous studies found an increase in the use of chemoradiation therapy, with a concurrent decline in the use of total laryngectomy for patients with advanced laryngeal cancer.35,38 Our results support those findings, since patients receiving diagnoses between 2004 and 2008 were more likely to receive chemoradiation than surgery compared with patients receiving diagnoses in 2003. Our data also confirm that patients in the higher socioeconomic zip codes were more likely to undergo chemoradiation compared with those in the lower socioeconomic zip codes, even after controlling for comorbidity.38 This may be because of the increased barriers to care for patients in lower socioeconomic backgrounds, such as distance to a facility, access to an automobile, and availability of someone to take them to and from treatment centers.39 While these barriers apply to both surgical and nonsurgical treatments, chemoradiation may be a more difficult option because it requires many more trips over the course of several weeks compared with surgery.
Race/ethnicity was not a significant factor in predicting chemoradiation vs surgical treatment for advanced laryngeal cancer. This has not been the case in previous studies, which have shown that African Americans were more likely to have chemoradiation over laryngectomy, compared with whites.38,40 However, those studies did not control for comorbidity and did not include patient information from a large national database. It is important to control for comorbidity, since our data showed that African Americans had a significantly greater amount of comorbidity compared with whites and Hispanics in the cohort with a CDCI score of 3 or greater.
Similarly, age at diagnosis did not reach a level of significance, compared with a previous study that showed that patients in the 70- to 99-year-old age group were more likely to receive chemoradiation than laryngectomy, after controlling for several clinical and nonclinical variables.38 However, that study did not control for comorbidity. These results are congruent with the practice that elderly patients should receive standard treatment based on clinical findings and patient preference, not on chronologic age, in the absence of severe comorbidity.14
A major limitation on this study is the use of comorbidity data from the NCDB, which gathers its information from hospital discharge face sheets. Klabunde and colleagues41 found that when the face sheet of the hospital record is used as the only comorbidity data source, a significant number of comorbid conditions are underascertained—21% of patients in the study were identified as having 1 or more comorbidities by the discharge face sheet compared with 62% by a review of the full hospital record. In addition to underreporting legitimate comorbidities, the face sheet may list complications of treatment as comorbidities. While there are International Classification of Diseases, Ninth Revision codes to help differentiate between complications and comorbidities, there is not a code for every condition, and they may be underused on hospital face sheets.
Preliminary results by Robbins and colleagues42 confirm past studies questioning the ability of the NCDB to capture accurate comorbidity information.41 The Surveillance, Epidemiology, and End Results (SEER) Medicare database extrapolates comorbidities not only from inpatient claim files but also from outpatient claim files, whereas the NCDB is a hospital-based registry and depends solely on inpatient data for secondary diagnoses. Their data show a disparity in comorbidity between inpatients and outpatients, through comparing the prevalence of comorbid medical conditions among elderly patients with colorectal cancer in the NCDB and SEER Medicare database. However, for patients with late-stage laryngeal cancer, results from their SEER Medicare bivariate analysis show no significant difference in comorbidity between patients receiving chemoradiation compared with those receiving laryngectomy. This finding agrees with our multivariate analysis—the increased survival among patients treated with total laryngectomy compared with those receiving chemotherapy cannot be explained by differences in comorbidity.
Another limitation of this study is that we could not examine the survival characteristics of the different comorbidity cohorts. Not all of the cases since 2003 have been followed up, and of the available data, there is a 5-year lost-to-follow-up rate of 15%. To better discern the relationship between comorbidity and treatment, it is critical to analyze survival and quality of life in subsequent studies to gauge whether there is a difference between surgery and chemoradiation for patients with comorbidities.
In conclusion, this is the first study, to our knowledge, that demonstrates that patients with advanced laryngeal cancer with 1 or more comorbidities are more likely to receive surgery than chemoradiation, compared with patients without any comorbidity, independent of numerous clinical and nonclinical variables among a large national cohort. The differences in survival between patients treated with total laryngectomy vs chemoradiation cannot be explained by differences in comorbidity. We recognize that the NCDB is an imperfect system for the collection of comorbidity data and encourage discussion on different methods to improve the system, including incorporating comorbidity data from the SEER Medicare database. We also recommend a medical chart–based comorbidity collection by cancer registrars as an additional method of comorbidity data collection because this methodology has been tested and shown to be highly effective and valid.43,44 The selection of treatment by patients with laryngeal cancer is not an easy task and is complicated by comorbidity. To help patients with these difficult decisions, additional research is necessary to determine whether mortality and morbidity are affected by the different treatments for the different comorbidity cohorts.
Correspondence: Jason Zhu, BA, 310 Briarvista Way NE, Atlanta, GA 30329 (firstname.lastname@example.org).
Submitted for Publication: June 7, 2012; final revision received August 27, 2012; accepted September 10, 2012.
Author Contributions: Dr Chen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fedewa and Chen. Acquisition of data: Chen. Analysis and interpretation of data: Zhu, Fedewa, and Chen. Drafting of the manuscript: Zhu, Fedewa, and Chen. Critical revision of the manuscript for important intellectual content: Zhu and Chen. Statistical analysis: Fedewa and Chen. Administrative, technical, and material support: Zhu. Study supervision: Chen.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented at the Eighth International Conference on Head & Neck Cancer; July 25, 2012; Toronto, Ontario, Canada.