Original Research—Laryngology and Neurolaryngology
Exploring SEER-Medicare for Changes in the Treatment of Laryngeal Cancer among Elderly Medicare Beneficiaries
Otolaryngology– Head and Neck Surgery 2014, Vol. 150(3) 419–427 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599813518186 http://otojournal.org
Raymond A. Jean1, Dorina Kallogjeri, MD, MPH1, Seth A. Strope, MD, MPH2, Frances Mei Hardin1, Jason T. Rich, MD1, and Jay F. Piccirillo, MD1
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received September 6, 2013; revised November 11, 2013; accepted December 5, 2013.
Abstract Objective. To explore the change in frequency of treatment, and its association with 5-year survival, among elderly Medicare enrollees with squamous cell carcinoma of the larynx (SCCL).
L
Study Design. Retrospective analysis of a national cancer database. Subjects and Methods. This was an analysis of the Surveillance, Epidemiology, and End Results (SEER)–Medicare data set of elderly patients diagnosed with SCCL between 1992 and 2007. Surgical and nonsurgical treatments were identified, and changes in frequency by year of cancer diagnosis were explored. A propensity-matched multivariate Cox proportional hazards model was used to compare the impact of treatment. Results. There were 3324 cases of primary SCCL diagnosed between 1992 and 2007 studied. Most were male (n = 2605; 78%), white (n = 2845; 87%), and between 66 and 74 years of age (n = 1874; 56%). Between 1992 and 2005, there was a significant trend for increasing 5-year overall survival (43% in 1992 to 54% in 2005-2007; P \ .01). There was a significant trend for decreasing frequency of surgical therapy (47% in 1992-1995 to 41% in 2005-2007; P = .03). Surgical therapy was associated with a decreased risk of overall mortality (hazard ratio, 0.76; 95% confidence interval, 0.68-0.86) in comparison to nonsurgical treatments. Conclusion. The analysis demonstrates an increase in survival among elderly Medicare enrollees diagnosed with SCCL between 1992 and 2007. Despite a significant trend for its decreasing use, there was a significantly decreased risk of overall mortality associated with surgical therapy.
Keywords laryngeal cancer, SEER-Medicare, head and neck cancer, surgical therapy, nonsurgical therapy, propensity score, survival
aryngeal cancer is a severe, multidimensional disease that presents a serious risk of functional impairment and death to afflicted patients.1 There are approximately 89,000 individuals with laryngeal cancer currently living in the United States, and it is estimated that more than 12,000 new cases occur every year, with the median age of diagnosis being 65 years and more than 50% of new cases occurring in those aged 65 years and older.2 The treatment of these cancers involves a multidisciplinary medical and surgical team often employing some combination of chemotherapy, radiation therapy, and surgery. While surgical removal of the larynx was historically an effective definitive treatment, surgery often results in severe impairment of speech.3 Current treatment paradigms of laryngeal cancer are heavily influenced by 2 clinical studies: the Department of Veterans Affairs (VA) Laryngeal Cancer Study Group, published in 1991, and the Radiation Therapy Oncology Group 91-11 study, published in 2003.1 The VA Laryngeal Cancer Study Group research demonstrated little difference in survival between patients treated with total laryngectomy and postoperative radiation therapy and those treated with chemotherapy and radiation therapy.4 The Radiation Therapy 91-11 study found that chemotherapy and radiation therapy, when used concurrently, showed improved survival to sequential therapy or radiation therapy alone for patients with stage III or IV laryngeal cancers with low-volume tumor sizes.5 Although
1 Department of Otolaryngology, Washington University in St Louis School of Medicine, St Louis, Missouri, USA 2 Division of Urology, Department of Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
This article was presented at the 2013 AAO-HNSF Annual Meeting & OTO EXPO; September 29–October 3, 2013; Vancouver, British Columbia, Canada. Corresponding Author: Raymond A. Jean, Department of Otolaryngology, Washington University in St Louis School of Medicine, 660 S. Euclid Ave, Campus Box 8115, St Louis, MO 63110, USA. Email: [email protected]
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Table 1. Data set selection criteria. Step
No. Removed From Previous Step
Total Remaining
1. 2. 3. 4. 5. 6. 7. 8.
14,029 11,183 1358 2869 15 103 443
37,581 23,552 12,369 11,011 8142 8127 8024 7581
678 1698 257 1624
6903 5205 4948 3324
SEER-Medicare data received from NCI-CMS Age 66 to 90 years First primary and only 1 primary cancer in the data set Original and current reason for entitlement is by age only Year of diagnosis after 1992 Primary site ICD-O-3 code of the larynx (320-329) Reporting source not autopsy or death certificate only Histology ICD-O-3 code of squamous cell carcinoma (8052, 8070, 8071, 8072, 8073, 8074, 8075, 8076, 8078, 8083, 8084) 9. Medicare Part A and Part B for 1 full year preceding diagnosis 10. No HMO coverage for 1 full year preceding diagnosis 11. Cases with surgery but without valid surgery date or with unknown stage 12. Registry in greater California, Kentucky, Louisiana, and New Jersey
Abbreviations: CMS, Centers for Medicare & Medicaid Services; HMO, health maintenance organization; ICD-O-3, International Classification of Disease for Oncology, third revision; NCI, National Cancer Institute; SEER, Surveillance, Epidemiology, and End Results.
nonsurgical therapy allows the possibility of preserved voice, there is evidence that comparisons of quality of life are relatively unrelated to functional speech loss after laryngectomy.6,7 Furthermore, chemoradiation therapy has been associated with several life-altering complications, including failed healing of local tissues, pharyngeal edema and stenosis, and difficulty swallowing with aspiration.1 While this nonsurgical treatment plan can preserve voice and avoid the stigmatization of permanent tracheostomy, in many patients with advanced laryngeal cancer, Hoffman et al8 concluded that primary treatment with chemotherapy and radiation therapy resulted in a decrease in laryngeal cancer survival over the time period that these nonsurgical treatments were on the rise. This observed decrease in survival corresponds to changing paradigms in laryngeal cancer treatment, although there is evidence that these treatment changes do not totally account for the change in survival. One such example is a report by Zhang et al,9 who found that although the use of primary radiation therapy as a treatment for laryngeal cancer increased since the late 1980s, there was not a corresponding and consistent overall survival decrease for all subtypes of laryngeal cancer. To understand the impact of treatment patterns on survival, we analyzed the combined Surveillance, Epidemiology, and End Results (SEER)–Medicare data set for observational data of laryngeal cancer. From this combined SEERMedicare data set, we sought to examine the trend in survival for laryngeal cancers over a 15-year period, examine trends in the use of treatment modalities over this same time period, and compare the impact of treatments on survival.
Methods After approval by the Washington University Human Research Protection Office, we obtained linked SEER-Medicare data for
patients diagnosed with laryngeal cancer from 1992 to 2007. The SEER data set is created by the National Cancer Institute (NCI) and contains patient and tumor information about cancer cases from 17 registries throughout the United States. It represents a linkage of the SEER with Medicare claims for the population of interest, allowing for the complete claims-based tracking of cancer care. More than 95% of eligible patients in the SEER registries are successfully linked to their Medicare claims.10
Study Population The selection criteria for the final cohort are described in Table 1. Patients were included for study if squamous cell laryngeal cancer was their first malignant primary and they were at least 66 years old at the time of diagnosis. To ensure at least 1 year of complete information for the assessment of premorbid comorbidity, we included only patients diagnosed after January 1, 1992, who had a year of uninterrupted, age-related, noncapitated Medicare Part A and Part B coverage prior to diagnosis. The patient was excluded if there was evidence of a procedure with no attributable procedure date or if there was an undefined or unknown SEER stage of disease. Finally, because there were 4 SEER registries added in 2000 (greater California and the states of Kentucky, Louisiana, and New Jersey), only patients who were in the 12 data set registries available in 1992 (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Seattle–Puget Sound, Utah, Los Angeles, San Jose–Monterey, and rural Georgia) were included in the analysis.11 Because SEER records only the month and year of diagnosis, date of diagnosis was taken to be the first day of the diagnosis month. Date of last follow-up for patients was taken to be either the date of death indicated in the SEER registry or November 1, 2010, as this was the date of last
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follow-up in the SEER data set. The SEER-Medicare data set lists both a SEER date of death and a Medicare date of death. For patients listed as dead, the SEER date of death was used preferentially.
Treatment Treatment information was drawn from all claims dated after diagnosis. Information for surgical therapy was obtained by scanning the hospitalization (MEDPAR), physician (NCH), and outpatient (OUTPAT) claims files for relevant International Classification of Diseases, Ninth Revision (ICD-9) or Healthcare Common Coding Procedure Coding System (HCPCS) procedural codes (ICD-9: 30.XX; HCPCS: 31360, 31365, 31367, 31368, 31370, 31375, 31380, 31382, 31395, 31512, 31540, and 31541). Evidence for radiation therapy and chemotherapy was performed in accordance with the guidelines given on the SEER-Medicare website12 and as described in previous studies,13,14 which included scanning the MEDPAR, NCH, OUTPAT, and Durable Medical Equipment Regional Carrier (DME) claims. Interventions were considered for primary treatment designation if a claim or procedure was found that contained a valid procedure date. The earliest HCPCS or ICD-9 procedure code was taken to be definitive initial treatment. Primary modality of treatment defined the treatment patterns explored in this study. Only treatments within the first 4 months of diagnosis were considered, and treatment groupings were mutually exclusive. Primary nonsurgical treatment was defined as those cases in which there was evidence for either radiotherapy or chemotherapy preceding a surgical procedure, or cases where there was evidence for radiation or chemotherapy and no evidence for any surgical procedure. Surgical treatment was defined as the primary treatment when a defined surgical procedure was performed before any radiation therapy or chemotherapy, if there was a surgical procedure without radiotherapy and chemotherapy, or if chemotherapy preceded a surgical procedure by at most 3 months without any radiotherapy during the interim.
Patient Demographics and Tumor Characteristics Demographic and cancer-specific factors were split into discrete categories for the study. Age was separated into 5-year groups: 66 to 69, 70 to 74, 75 to 79, 80 to 84, and 85 to 90. Stage information was derived from the summary staging, when available, and categorized into SEER stages of local, regional, or distant. Race was categorized as white, black, or other. Comorbidity for each patient was determined using the Klabunde modification of the Charlson Comorbidity Index (CCI).15,16 The CCI groups were defined as follows: none (score of 0), mild (score of 1), moderate (score of 2), and severe (3 or higher).
Statistical Analysis Standard descriptive statistics were used to describe demographic and clinical characteristics of included patients. The frequency and relative frequency of each treatment by 3year groupings of year of diagnosis were calculated from
1992 to 2007. Frequencies were grouped by 3-year intervals. The 5-year survival was calculated for patient groups defined by year of diagnosis using Kaplan-Meier survival estimates. The x2 test was used for investigating distribution of demographic and clinical characteristics among different treatment groups. The Cochran-Armitage test for linear trends was used to explore the trend of change in survival and in prevalence of each treatment option with time. Coxproportional hazards regression was used to model overall survival over time and to identify the impact of demographic, tumor, and treatment factors on survival. A nearest neighbor propensity score match was used to compare the surgical and nonsurgical groups for impact on overall survival.17 The propensity score quantifies the probability of receiving a specific treatment for each patient included in the model based on certain characteristics, and adjustment allows for fair comparison among different treatment groups.18 A nominal logistic regression with stepwise selection was used with each of the nontreatment variables to generate a propensity score correlating to the probability for receiving surgical therapy vs nonsurgical therapy. The avalue for all statistical tests was set at 0.05. All data manipulation and analysis was done in the SAS 9.3 statistics program (SAS Institute, Cary, North Carolina).
Results A total of 3324 patients were included for analysis. The characteristics of those patients included in the analysis are shown in Table 2. The study population was predominantly male (n = 2605; 78%) and white (n = 2845; 87%), with a median age of 74 years. Patients had mostly local stage disease (n = 2164; 65%) at the time of diagnosis and were classified as having none (n = 1304; 39%), mild (n = 966; 29%), moderate (n = 513; 15%), or severe (n = 541; 16%) comorbidity level. Separation into primary treatment groups corresponded to 1503 (45%) receiving primary surgical therapy, 1496 (45%) receiving primary nonsurgical therapy, and 325 (10%) receiving no treatment. Cochran-Armitage test demonstrated a significant trend (Figure 1) for increasing 5-year overall survival (43% [95% linear confidence interval (CI), 40%-46%] in 19921994 to 54% [95% linear CI, 49%-58%] in 2005-2007; P for trend \.01). There was also a significant trend for decreased use of primary surgical therapy (47% in 19921995 to 41% in 2005-2007; P = .03) but no significant trend for the no treatment or nonsurgical groups. Relative frequency of treatment groups is shown in Figure 2. Age, sex, race, comorbidity, and SEER stage variables were significant predictors of survival in univariate and multivariate Cox regression models, with the exception of black race in the multivariate Cox model. In comparison to nonsurgical therapy, surgical therapy was a significant predictor for improved overall survival, offering a 23% reduction in overall mortality (hazard ratio [HR], 0.77; 95% CI, 0.71-0.84), whereas no treatment was a significant predictor for decreased overall survival (HR, 1.71; 95% CI, 1.49-1.96).
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Table 2. Univariate analysis of the study cohort. Characteristic Age, y 66-70 71-74 75-79 80-84 85-90 Sex Female Male Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant Treatment Nonsurgical Surgical None
No. (%)
Unadjusted HR (95% CI)
P Value
835 (25) 1039 (31) 773 (23) 448 (13) 229 (7)
1.00 1.16 1.47 1.75 2.39
[Reference] (1.04-1.30) (1.31-1.66) (1.53-2.00) (2.03-2.82)
.01 \.01 \.01 \.01
719 (22) 2605 (78)
1.00 [Reference] 0.82 (0.75-0.91)
\.01
2845 (86) 308 (9) 171 (5)
1.00 [Reference] 1.31 (1.14-1.50) 0.72 (0.58-0.88)
\.01 \.01
1304 966 513 541
1.00 1.27 1.49 2.15
[Reference] (1.15-1.41) (1.32-1.69) (1.91-2.42)
\.01 \.01 \.01
2164 (65) 784 (24) 376 (11)
1.00 [Reference] 2.48 (2.26-2.72) 3.33 (2.94-3.76)
\.01 \.01
1496 (45) 1503 (45) 325 (10)
1.00 [Reference] 0.76 (0.693-0.822) 1.55 (1.351-1.769)
\.01 \.01
(39) (29) (15) (16)
Abbreviations: CI, confidence interval; HR, hazard ratio; SEER, Surveillance, Epidemiology, and End Results.
Figure 1. Five-year overall survival by year of diagnosis, calculated using Kaplan-Meier survival estimates, with linear 95% confidence intervals.
The results of the multivariate Cox regression are summarized in Table 3. We explored whether there was some underlying factor that accounted for the improved overall survival over this period, despite a trend for decreased use of surgical
Figure 2. Relative frequency of treatment by year of diagnosis in 3-year intervals.
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Table 3. Multivariate Cox proportional hazards analysis. Characteristic Age, y 66-69 70-74 75-79 80-84 85-90 Sex Female Male Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant Treatment Nonsurgical Surgical None
Parameter Estimate (SE)
Adjusted HR (95% CI)
P Value
[Reference] 0.49 (0.06) 0.49 (0.06) 0.64 (0.07) 0.95 (0.08)
1.22 (1.09-1.36) 1.63 (1.44-1.83) 1.90 (1.66-2.18) 2.60 (2.20-3.06)
\.01 \.01 \.01 \.01
[Reference] –0.11 (0.05)
0.90 (0.81-0.99)
.03
[Reference] 0.10 (0.07) –0.45 (0.10)
1.10 (0.96-1.27) 0.64 (0.52-0.78)
.16 \.01
[Reference] 0.25 (0.05) 0.38 (0.06) 0.71 (0.06)
1.29 (1.16-1.43) 1.47 (1.30-1.66) 2.04 (1.81-2.30)
\.01 \.01 \.01
[Reference] 0.94 (0.05) 1.26 (0.06)
2.56 (2.34-2.81) 3.53 (3.11-3.99)
\.01 \.01
[Reference] –0.26 (0.04) 0.53 (0.07)
0.77 (0.71-0.84) 1.71 (1.49-1.96)
\.01 \.01
Abbreviations: CI, confidence interval; HR, hazard ratio; SE, standard error; SEER, Surveillance, Epidemiology, and End Results.
therapy. Comparing the trends in all covariates, we identified an increase in the frequency of local stage disease (57% in 1992-1995 to 72% in 2005-2007; P for trend \.01) and a decrease in regional stage disease (35% in 1992-1995 to 14% in 2005-2007; P for trend \.01) (Figure 3). There was a slight increase in the frequency of distant disease (8% in 1992-1995 to 14% in 2005-2007; P for trend \.01). To test the impact of SEER stage on survival over time, we examined the stage-specific 5-year overall survival rates. Survival estimates are summarized in Table 4 and Figure 4. Among patients with local stage disease, there was a significant increase in survival to 63% (95% CI, 58%-68%) after the 1999 to 2001 periods, in comparison to the 1992 to 1995 period survival of 57% (95% CI, 53%-61%). Ultimately, the overall survival during the 2005 to 2007 period for patients with local stage disease was 65% (95% CI, 60%-70%). Among regional stage, there was no significant change in overall survival over the study period, from 28% (95% CI, 23%-33%) in the 1992 to 1995 period to 27% (95% CI, 16%-37%) in the 2005 to 2007 period. There was a significant increase in distant stage overall survival from 10% (95% CI, 4%-17%) in the 1992 to 1995 period to 26% (95% CI, 17%-36%) during the 2002 to 2004 period. Among the subgroup of patients in the 2005 to 2007 period, there were
Figure 3. Frequency of Surveillance, Epidemiology, and End Results stage at time of diagnosis by 3-year groupings.
insufficient events to calculate a true 5-year overall survival, and this survival estimate was excluded. A 1:1 propensity score using age at diagnosis, stage, race, comorbidity, and sex was generated among treated
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Table 4. SEER stage-specific Kaplan-Meier survival by year of diagnosis. 5-Year Kaplan-Meier Survival, % SEER Stage Local Regional Distant
1992-1995
1996-1998
1999-2001
2002-2004
2005-2007
56.7 28.0 10.3
56.9 23.7 10.2
63.1a 21.6 12.0
62.2a 22.4 26.3a
65.0a 26.6 —b
Abbreviation: SEER, Surveillance, Epidemiology, and End Results. a Indicates a significantly different survival than the stage-specific 1992-1995 survival. b Distant-stage 5-year survival for the 2005-2007 period was excluded due to insufficient follow-up in this subset.
Figure 4. Surveillance, Epidemiology, and End Results stage-specific overall survival at time of diagnosis by 3-year groupings with 95% linear confidence intervals. Five-year survival was generated using Kaplan-Meier survival estimates. Distant stage–specific survival during the 2005 to 2007 period was excluded due to insufficient follow-up time in this subset.
patients for the probability to receive surgical therapy vs nonsurgical therapy. A propensity match was performed, resulting in 1432 pairs of matched surgical and nonsurgical cases. There were no significant differences between groups in year of diagnosis (in 3-year groupings), age, stage, comorbidity, race, or sex among the propensity-matched groups (Table 5). Multivariate Cox analysis of nonsurgical and surgical treatment groups showed that primary surgical therapy was associated with a 24% reduction in 5-year overall mortality compared with patients treated with nonsurgical therapy (HR, 0.76; 95% CI, 0.68-0.86).
Discussion Our study demonstrates that among Medicare enrollees diagnosed with squamous cell carcinoma of the larynx between 1992 and 2007, there was a significant increase in overall survival over the 15-year period. Previous work by
Hoffman et al8 found that that the relative and overall survival for patients with laryngeal cancer was steadily decreasing over the 1980s through the 1990s. In a study using the SEER data set, Cosetti et al19 demonstrated an insignificant increase in cancer-specific survival in all nonsupraglottic laryngeal cancers in patients 65 years and older between 1977 and 2002 but found a small and insignificant decrease in non–cancer-specific survival in all groups. A meta-analysis by Rudolph et al20 examined 5-year survival across several studies, including many SEER studies, and found a wide range in reported 5-year laryngeal cancer overall survival but made note of the complexity of factors associated with the disease. Several other retrospective studies have demonstrated a similar reduction in mortality with primary surgical therapy. In a study using the National Cancer Database, Chen and Halpern21 found a 30% reduction in risk mortality among patients treated with total laryngectomy compared with those treated with chemoradiation. Furthermore, this same study found an associated 30% increased risk of mortality associated with Medicare-based insurance plans among those older than 65 years.21 Despite the observed increase in survival over the period of study, there was a decrease in the utilization of surgery as a primary therapy, which was associated, in univariate and multivariate Cox regression models, with a decreased risk of overall mortality in comparison to nonsurgical therapy. It is possible that this effect is driven by the frequency changes in disease stage at diagnosis over this time period or, specifically, an increase in the frequency of local stage disease and a decrease in regional stage disease. In univariate and multivariate Cox regression, regional stage was associated with a more than doubling in the risk of overall death relative to local disease. Because the vast majority of cases (n = 2164; 65%) had local stage disease at diagnosis and the rate of local disease increased over time, we would expect this to be a significant driver for overall improved survival in this population, despite an increase in the frequency of distant disease. Changes in the frequency of disease stage over time and concomitant changes in overall survival require some investigation into the possibility of stage migration. Feinstein et al22 described the process by which an apparent improvement in survival occurs not because of change in disease treatment or response but
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Table 5. Descriptive statistics of propensity matched groups. No. (%) Characteristic Year of diagnosis 1992-1995 1996-1998 1999-2001 2002-2004 2005-2007 Age, y 66-70 71-75 76-80 81-85 86-90 Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant
Nonsurgical (n = 1432)
Surgical (n = 1432)
P Valuea .96
431 288 216 241 256
(30.1) (20.1) (15.1) (16.8) (17.9)
438 (30.6) 279 (19.5) 223 (15.6) 247 (17.2) 245 (17.1)
336 (23.5) 465 (32.5) 324 (22.6) 202 (14.1) 105 (7.3)
386 (27.0) 436 (30.4) 333 (23.3) 187 (13.1) 90 (6.3)
1231 (86.0) 120 (8.4) 81 (5.7)
1242 (86.7) 119 (8.3) 71 (5.0)
.18
.70
.84 544 427 220 241
(38.0) (29.8) (15.4) (16.8)
559 (39.0) 431 (30.1) 218 (15.2) 224 (15.6)
962 (67.2) 312 (21.8) 158 (11.0)
970 (67.7) 312 (21.8) 150 (10.5)
.89
Abbreviation: SEER, Surveillance, Epidemiology, and End Results. a Statistical difference between surgical and nonsurgical groups.
rather due to the restaging of patients with less severe disease. In calculating the stage-specific survival over this period, we observed an increase in overall survival among local and distant staged disease, with no change in overall survival among regional stage disease. The improved survival in local staged disease may be the result of multiple factors, one of which may be stage migration from in situ disease. The near doubling of survival among distant stage patients leads to the possibility of some stage migration between distant and regional stage disease, in which patients who previously were staged as having regional disease only are now being captured as having distant disease. The increased availability of new medical technologies, such as positron emission tomography scanning, may account for some of this migration.22 Given the small percentage of distant disease in comparison to regional disease, even a small amount of migration would have profound impacts on distant survival without significantly affecting regional survival. It is unclear what is driving this decrease in regional disease and relative increase in localized disease. One possibility is the improved screening or detection of laryngeal cancer over the study time period; however, because laryngeal cancer presents with distinct symptoms such as
hoarseness or irritation, there is less likelihood that a noninsidious disease progression has been improved by screening efforts. More research must be done to determine what factors are driving this protective decrease in laryngeal cancer stage. As with all large administrative data studies, our analysis is subject to several limitations. First, there is always the possibility of inherent bias present in the data set. The SEER data set represents a set of population-based cancer registries throughout the United States and therefore may not be strictly representative of national treatment patterns. Next, this study looked at a select subset of patients with primary laryngeal cancer: elderly patients older than 65 years with full Medicare coverage. Because nearly half of all laryngeal cancers occur in those younger than 65 years,2 there may be difficulty in generalizing these results to populations of patients with laryngeal cancer other than those studied. Another limitation exists in our grouping of patients into discrete categories of disease and treatment to simplify the complex nature of laryngeal cancer. Differences in laryngeal cancer location, such as those that occur in the supraglottic vs glottic region, can have a marked impact on presentation, management, and expected outcome. Likewise,
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surgical therapy for laryngeal cancer represents a wide range of procedures and associated treatment outcomes, many of which have continued to evolve over the study period. As such, there is some risk of false homogeneity and selection bias in the grouping of treatments as primarily ‘‘surgical’’ or ‘‘nonsurgical.’’ Although these categorizations were performed to facilitate data analysis, it is important to note that they are a simplification and that further studies may be needed to extract the unique and individualized qualities of laryngeal cancer disease and treatment. Further limitations include the possibility of stage differences, in that surgical patients may be more likely to undergo more accurate surgical pathology in comparison to nonsurgically treated patients. Furthermore, patients treated with multiple treatment regimens may represent more complex baseline disease that is difficult to capture. Our use of adjusted multivariate analysis and propensity-matched comparisons has attempted to account for much of this bias, but there remains the possibility that we were unable to account for all inherent differences.
Conclusion This study has demonstrated that between 1992 and 2007, there has been a significant trend for increasing 5-year overall survival among a subset of Medicare enrollees with newly diagnosed larynx cancer. Interestingly, this increase in survival over time is observed during an era when a greater number of patients were receiving nonsurgical therapies, which are associated with an increased risk of overall mortality. These results were consistent after incorporating propensity-matched comparisons. More research must be conducted to further explore drivers of increased survival over this period. Author Contributions Raymond A. Jean, design, collection, analysis, interpretation, manuscript preparation; Dorina Kallogjeri, design, analysis, interpretation, manuscript preparation; Seth A. Strope, design, interpretation, manuscript preparation; Frances Mei Hardin, data collection, manuscript preparation; Jason T. Rich, design, interpretation, manuscript preparation; Jay F. Piccirillo, design, interpretation, analysis, manuscript preparation.
Disclosures Competing interests: None. Sponsorships: None. Funding source: Raymond A. Jean was funded by a grant from the Doris Duke Charitable Foundation, Washington University Grant #2010072.
References 1. Olsen KD. Reexamining the treatment of advanced laryngeal cancer. Head Neck. 2010;32:1-7. 2. National Cancer Institute. EER cancer statistics factsheets: larynx cancer. April 2013. http://seer.cancer.gov/statfacts/html/ laryn.html. Accessed November 10, 2013.
3. Lefebvre J-L, Ang KK. Larynx preservation clinical trial design: key issues and recommendations—a consensus panel summary. Head Neck. 2009;31:429-441. 4. Wolf G, Hong WK, Gross Fisher S, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 1991;324:1685-1690. 5. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:20912098. 6. Stewart MG, Chen AY, Stach CB. Outcomes analysis of voice and quality of life in patients with laryngeal cancer. Arch Otolaryngol Head Neck Surg. 1998;124:143-148. 7. Terrell JE, Fisher SG, Wolf GT. Long-term quality of life after treatment of laryngeal cancer. The Veterans Affairs Laryngeal Cancer Study Group. Arch Otolaryngol Head Neck Surg. 1998;124:964-971. 8. 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(9, pt 2)(suppl 111):1-13. 9. Zhang H, Travis LB, Chen R, et al. Impact of radiotherapy on laryngeal cancer survival: a population-based study of 13,808 US patients. Cancer. 2012;118:1276-1287. 10. Brief description of SEER-Medicare database. October 2013. http://healthservices.cancer.gov/seermedicare/overview/. Accessed November 10, 2013. 11. Registry groupings for analyses—SEER registries. July 2013. http://seer.cancer.gov/registries/terms.html. Accessed August 14, 2013. 12. National Cancer Institute. Procedure codes for SEER-Medicare analyses. October 2013. http://healthservices.cancer.gov/seermedicare/considerations/procedure_codes.html. Accessed November 10, 2013. 13. Virnig BA, Warren JL, Cooper GS, Klabunde CN, Schussler N, Freeman J. Studying radiation therapy using SEERMedicare-linked data. Med Care. 2002;40(8)(suppl):IV-49-54. 14. Warren JL, Harlan LC, Fahey A, et al. Utility of the SEERMedicare data to identify chemotherapy use. Med Care. 2002; 40(8)(suppl):IV-55-61. 15. National Cancer Institute. SEER-Medicare: calculation of comorbidity weights. October 2013. http://appliedresearch.cancer .gov/seermedicare/program/comorbidity.html. Accessed December 19, 2013. 16. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol. 2000;53:1258-1267. 17. Parsons L. Performing a 1:N case-control match on propensity score. Paper presented at: SAS Users Group International Conference. 2004. Paper 165-29. http://www2.sas.com/pro ceedings/sugi29/165-29.pdf. Accessed August 14, 2013. 18. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.
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19. Cosetti M, Yu GP, Schantz SP. Five-year survival rates and time trends of laryngeal cancer in the US population. Arch Otolaryngol Head Neck Surg. 2008;134:370-379. 20. Rudolph E, Dyckhoff G, Becher H, Dietz A, Ramroth H. Effects of tumour stage, comorbidity and therapy on survival of laryngeal cancer patients: a systematic review and a metaanalysis. Eur Arch Otorhinolaryngol. 2011;268:165-179.
21. Chen AY, Halpern M. Factors predictive of survival in advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg. 2007;133:1270-1276. 22. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med. 1985;312:1604-1608.
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Exploring SEER-Medicare for Changes in the Treatment of Laryngeal Cancer among Elderly Medicare Beneficiaries
Otolaryngology– Head and Neck Surgery 2014, Vol. 150(3) 419–427 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599813518186 http://otojournal.org
Raymond A. Jean1, Dorina Kallogjeri, MD, MPH1, Seth A. Strope, MD, MPH2, Frances Mei Hardin1, Jason T. Rich, MD1, and Jay F. Piccirillo, MD1
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received September 6, 2013; revised November 11, 2013; accepted December 5, 2013.
Abstract Objective. To explore the change in frequency of treatment, and its association with 5-year survival, among elderly Medicare enrollees with squamous cell carcinoma of the larynx (SCCL).
L
Study Design. Retrospective analysis of a national cancer database. Subjects and Methods. This was an analysis of the Surveillance, Epidemiology, and End Results (SEER)–Medicare data set of elderly patients diagnosed with SCCL between 1992 and 2007. Surgical and nonsurgical treatments were identified, and changes in frequency by year of cancer diagnosis were explored. A propensity-matched multivariate Cox proportional hazards model was used to compare the impact of treatment. Results. There were 3324 cases of primary SCCL diagnosed between 1992 and 2007 studied. Most were male (n = 2605; 78%), white (n = 2845; 87%), and between 66 and 74 years of age (n = 1874; 56%). Between 1992 and 2005, there was a significant trend for increasing 5-year overall survival (43% in 1992 to 54% in 2005-2007; P \ .01). There was a significant trend for decreasing frequency of surgical therapy (47% in 1992-1995 to 41% in 2005-2007; P = .03). Surgical therapy was associated with a decreased risk of overall mortality (hazard ratio, 0.76; 95% confidence interval, 0.68-0.86) in comparison to nonsurgical treatments. Conclusion. The analysis demonstrates an increase in survival among elderly Medicare enrollees diagnosed with SCCL between 1992 and 2007. Despite a significant trend for its decreasing use, there was a significantly decreased risk of overall mortality associated with surgical therapy.
Keywords laryngeal cancer, SEER-Medicare, head and neck cancer, surgical therapy, nonsurgical therapy, propensity score, survival
aryngeal cancer is a severe, multidimensional disease that presents a serious risk of functional impairment and death to afflicted patients.1 There are approximately 89,000 individuals with laryngeal cancer currently living in the United States, and it is estimated that more than 12,000 new cases occur every year, with the median age of diagnosis being 65 years and more than 50% of new cases occurring in those aged 65 years and older.2 The treatment of these cancers involves a multidisciplinary medical and surgical team often employing some combination of chemotherapy, radiation therapy, and surgery. While surgical removal of the larynx was historically an effective definitive treatment, surgery often results in severe impairment of speech.3 Current treatment paradigms of laryngeal cancer are heavily influenced by 2 clinical studies: the Department of Veterans Affairs (VA) Laryngeal Cancer Study Group, published in 1991, and the Radiation Therapy Oncology Group 91-11 study, published in 2003.1 The VA Laryngeal Cancer Study Group research demonstrated little difference in survival between patients treated with total laryngectomy and postoperative radiation therapy and those treated with chemotherapy and radiation therapy.4 The Radiation Therapy 91-11 study found that chemotherapy and radiation therapy, when used concurrently, showed improved survival to sequential therapy or radiation therapy alone for patients with stage III or IV laryngeal cancers with low-volume tumor sizes.5 Although
1 Department of Otolaryngology, Washington University in St Louis School of Medicine, St Louis, Missouri, USA 2 Division of Urology, Department of Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
This article was presented at the 2013 AAO-HNSF Annual Meeting & OTO EXPO; September 29–October 3, 2013; Vancouver, British Columbia, Canada. Corresponding Author: Raymond A. Jean, Department of Otolaryngology, Washington University in St Louis School of Medicine, 660 S. Euclid Ave, Campus Box 8115, St Louis, MO 63110, USA. Email: [email protected]
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Table 1. Data set selection criteria. Step
No. Removed From Previous Step
Total Remaining
1. 2. 3. 4. 5. 6. 7. 8.
14,029 11,183 1358 2869 15 103 443
37,581 23,552 12,369 11,011 8142 8127 8024 7581
678 1698 257 1624
6903 5205 4948 3324
SEER-Medicare data received from NCI-CMS Age 66 to 90 years First primary and only 1 primary cancer in the data set Original and current reason for entitlement is by age only Year of diagnosis after 1992 Primary site ICD-O-3 code of the larynx (320-329) Reporting source not autopsy or death certificate only Histology ICD-O-3 code of squamous cell carcinoma (8052, 8070, 8071, 8072, 8073, 8074, 8075, 8076, 8078, 8083, 8084) 9. Medicare Part A and Part B for 1 full year preceding diagnosis 10. No HMO coverage for 1 full year preceding diagnosis 11. Cases with surgery but without valid surgery date or with unknown stage 12. Registry in greater California, Kentucky, Louisiana, and New Jersey
Abbreviations: CMS, Centers for Medicare & Medicaid Services; HMO, health maintenance organization; ICD-O-3, International Classification of Disease for Oncology, third revision; NCI, National Cancer Institute; SEER, Surveillance, Epidemiology, and End Results.
nonsurgical therapy allows the possibility of preserved voice, there is evidence that comparisons of quality of life are relatively unrelated to functional speech loss after laryngectomy.6,7 Furthermore, chemoradiation therapy has been associated with several life-altering complications, including failed healing of local tissues, pharyngeal edema and stenosis, and difficulty swallowing with aspiration.1 While this nonsurgical treatment plan can preserve voice and avoid the stigmatization of permanent tracheostomy, in many patients with advanced laryngeal cancer, Hoffman et al8 concluded that primary treatment with chemotherapy and radiation therapy resulted in a decrease in laryngeal cancer survival over the time period that these nonsurgical treatments were on the rise. This observed decrease in survival corresponds to changing paradigms in laryngeal cancer treatment, although there is evidence that these treatment changes do not totally account for the change in survival. One such example is a report by Zhang et al,9 who found that although the use of primary radiation therapy as a treatment for laryngeal cancer increased since the late 1980s, there was not a corresponding and consistent overall survival decrease for all subtypes of laryngeal cancer. To understand the impact of treatment patterns on survival, we analyzed the combined Surveillance, Epidemiology, and End Results (SEER)–Medicare data set for observational data of laryngeal cancer. From this combined SEERMedicare data set, we sought to examine the trend in survival for laryngeal cancers over a 15-year period, examine trends in the use of treatment modalities over this same time period, and compare the impact of treatments on survival.
Methods After approval by the Washington University Human Research Protection Office, we obtained linked SEER-Medicare data for
patients diagnosed with laryngeal cancer from 1992 to 2007. The SEER data set is created by the National Cancer Institute (NCI) and contains patient and tumor information about cancer cases from 17 registries throughout the United States. It represents a linkage of the SEER with Medicare claims for the population of interest, allowing for the complete claims-based tracking of cancer care. More than 95% of eligible patients in the SEER registries are successfully linked to their Medicare claims.10
Study Population The selection criteria for the final cohort are described in Table 1. Patients were included for study if squamous cell laryngeal cancer was their first malignant primary and they were at least 66 years old at the time of diagnosis. To ensure at least 1 year of complete information for the assessment of premorbid comorbidity, we included only patients diagnosed after January 1, 1992, who had a year of uninterrupted, age-related, noncapitated Medicare Part A and Part B coverage prior to diagnosis. The patient was excluded if there was evidence of a procedure with no attributable procedure date or if there was an undefined or unknown SEER stage of disease. Finally, because there were 4 SEER registries added in 2000 (greater California and the states of Kentucky, Louisiana, and New Jersey), only patients who were in the 12 data set registries available in 1992 (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco–Oakland, Seattle–Puget Sound, Utah, Los Angeles, San Jose–Monterey, and rural Georgia) were included in the analysis.11 Because SEER records only the month and year of diagnosis, date of diagnosis was taken to be the first day of the diagnosis month. Date of last follow-up for patients was taken to be either the date of death indicated in the SEER registry or November 1, 2010, as this was the date of last
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follow-up in the SEER data set. The SEER-Medicare data set lists both a SEER date of death and a Medicare date of death. For patients listed as dead, the SEER date of death was used preferentially.
Treatment Treatment information was drawn from all claims dated after diagnosis. Information for surgical therapy was obtained by scanning the hospitalization (MEDPAR), physician (NCH), and outpatient (OUTPAT) claims files for relevant International Classification of Diseases, Ninth Revision (ICD-9) or Healthcare Common Coding Procedure Coding System (HCPCS) procedural codes (ICD-9: 30.XX; HCPCS: 31360, 31365, 31367, 31368, 31370, 31375, 31380, 31382, 31395, 31512, 31540, and 31541). Evidence for radiation therapy and chemotherapy was performed in accordance with the guidelines given on the SEER-Medicare website12 and as described in previous studies,13,14 which included scanning the MEDPAR, NCH, OUTPAT, and Durable Medical Equipment Regional Carrier (DME) claims. Interventions were considered for primary treatment designation if a claim or procedure was found that contained a valid procedure date. The earliest HCPCS or ICD-9 procedure code was taken to be definitive initial treatment. Primary modality of treatment defined the treatment patterns explored in this study. Only treatments within the first 4 months of diagnosis were considered, and treatment groupings were mutually exclusive. Primary nonsurgical treatment was defined as those cases in which there was evidence for either radiotherapy or chemotherapy preceding a surgical procedure, or cases where there was evidence for radiation or chemotherapy and no evidence for any surgical procedure. Surgical treatment was defined as the primary treatment when a defined surgical procedure was performed before any radiation therapy or chemotherapy, if there was a surgical procedure without radiotherapy and chemotherapy, or if chemotherapy preceded a surgical procedure by at most 3 months without any radiotherapy during the interim.
Patient Demographics and Tumor Characteristics Demographic and cancer-specific factors were split into discrete categories for the study. Age was separated into 5-year groups: 66 to 69, 70 to 74, 75 to 79, 80 to 84, and 85 to 90. Stage information was derived from the summary staging, when available, and categorized into SEER stages of local, regional, or distant. Race was categorized as white, black, or other. Comorbidity for each patient was determined using the Klabunde modification of the Charlson Comorbidity Index (CCI).15,16 The CCI groups were defined as follows: none (score of 0), mild (score of 1), moderate (score of 2), and severe (3 or higher).
Statistical Analysis Standard descriptive statistics were used to describe demographic and clinical characteristics of included patients. The frequency and relative frequency of each treatment by 3year groupings of year of diagnosis were calculated from
1992 to 2007. Frequencies were grouped by 3-year intervals. The 5-year survival was calculated for patient groups defined by year of diagnosis using Kaplan-Meier survival estimates. The x2 test was used for investigating distribution of demographic and clinical characteristics among different treatment groups. The Cochran-Armitage test for linear trends was used to explore the trend of change in survival and in prevalence of each treatment option with time. Coxproportional hazards regression was used to model overall survival over time and to identify the impact of demographic, tumor, and treatment factors on survival. A nearest neighbor propensity score match was used to compare the surgical and nonsurgical groups for impact on overall survival.17 The propensity score quantifies the probability of receiving a specific treatment for each patient included in the model based on certain characteristics, and adjustment allows for fair comparison among different treatment groups.18 A nominal logistic regression with stepwise selection was used with each of the nontreatment variables to generate a propensity score correlating to the probability for receiving surgical therapy vs nonsurgical therapy. The avalue for all statistical tests was set at 0.05. All data manipulation and analysis was done in the SAS 9.3 statistics program (SAS Institute, Cary, North Carolina).
Results A total of 3324 patients were included for analysis. The characteristics of those patients included in the analysis are shown in Table 2. The study population was predominantly male (n = 2605; 78%) and white (n = 2845; 87%), with a median age of 74 years. Patients had mostly local stage disease (n = 2164; 65%) at the time of diagnosis and were classified as having none (n = 1304; 39%), mild (n = 966; 29%), moderate (n = 513; 15%), or severe (n = 541; 16%) comorbidity level. Separation into primary treatment groups corresponded to 1503 (45%) receiving primary surgical therapy, 1496 (45%) receiving primary nonsurgical therapy, and 325 (10%) receiving no treatment. Cochran-Armitage test demonstrated a significant trend (Figure 1) for increasing 5-year overall survival (43% [95% linear confidence interval (CI), 40%-46%] in 19921994 to 54% [95% linear CI, 49%-58%] in 2005-2007; P for trend \.01). There was also a significant trend for decreased use of primary surgical therapy (47% in 19921995 to 41% in 2005-2007; P = .03) but no significant trend for the no treatment or nonsurgical groups. Relative frequency of treatment groups is shown in Figure 2. Age, sex, race, comorbidity, and SEER stage variables were significant predictors of survival in univariate and multivariate Cox regression models, with the exception of black race in the multivariate Cox model. In comparison to nonsurgical therapy, surgical therapy was a significant predictor for improved overall survival, offering a 23% reduction in overall mortality (hazard ratio [HR], 0.77; 95% CI, 0.71-0.84), whereas no treatment was a significant predictor for decreased overall survival (HR, 1.71; 95% CI, 1.49-1.96).
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Table 2. Univariate analysis of the study cohort. Characteristic Age, y 66-70 71-74 75-79 80-84 85-90 Sex Female Male Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant Treatment Nonsurgical Surgical None
No. (%)
Unadjusted HR (95% CI)
P Value
835 (25) 1039 (31) 773 (23) 448 (13) 229 (7)
1.00 1.16 1.47 1.75 2.39
[Reference] (1.04-1.30) (1.31-1.66) (1.53-2.00) (2.03-2.82)
.01 \.01 \.01 \.01
719 (22) 2605 (78)
1.00 [Reference] 0.82 (0.75-0.91)
\.01
2845 (86) 308 (9) 171 (5)
1.00 [Reference] 1.31 (1.14-1.50) 0.72 (0.58-0.88)
\.01 \.01
1304 966 513 541
1.00 1.27 1.49 2.15
[Reference] (1.15-1.41) (1.32-1.69) (1.91-2.42)
\.01 \.01 \.01
2164 (65) 784 (24) 376 (11)
1.00 [Reference] 2.48 (2.26-2.72) 3.33 (2.94-3.76)
\.01 \.01
1496 (45) 1503 (45) 325 (10)
1.00 [Reference] 0.76 (0.693-0.822) 1.55 (1.351-1.769)
\.01 \.01
(39) (29) (15) (16)
Abbreviations: CI, confidence interval; HR, hazard ratio; SEER, Surveillance, Epidemiology, and End Results.
Figure 1. Five-year overall survival by year of diagnosis, calculated using Kaplan-Meier survival estimates, with linear 95% confidence intervals.
The results of the multivariate Cox regression are summarized in Table 3. We explored whether there was some underlying factor that accounted for the improved overall survival over this period, despite a trend for decreased use of surgical
Figure 2. Relative frequency of treatment by year of diagnosis in 3-year intervals.
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Table 3. Multivariate Cox proportional hazards analysis. Characteristic Age, y 66-69 70-74 75-79 80-84 85-90 Sex Female Male Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant Treatment Nonsurgical Surgical None
Parameter Estimate (SE)
Adjusted HR (95% CI)
P Value
[Reference] 0.49 (0.06) 0.49 (0.06) 0.64 (0.07) 0.95 (0.08)
1.22 (1.09-1.36) 1.63 (1.44-1.83) 1.90 (1.66-2.18) 2.60 (2.20-3.06)
\.01 \.01 \.01 \.01
[Reference] –0.11 (0.05)
0.90 (0.81-0.99)
.03
[Reference] 0.10 (0.07) –0.45 (0.10)
1.10 (0.96-1.27) 0.64 (0.52-0.78)
.16 \.01
[Reference] 0.25 (0.05) 0.38 (0.06) 0.71 (0.06)
1.29 (1.16-1.43) 1.47 (1.30-1.66) 2.04 (1.81-2.30)
\.01 \.01 \.01
[Reference] 0.94 (0.05) 1.26 (0.06)
2.56 (2.34-2.81) 3.53 (3.11-3.99)
\.01 \.01
[Reference] –0.26 (0.04) 0.53 (0.07)
0.77 (0.71-0.84) 1.71 (1.49-1.96)
\.01 \.01
Abbreviations: CI, confidence interval; HR, hazard ratio; SE, standard error; SEER, Surveillance, Epidemiology, and End Results.
therapy. Comparing the trends in all covariates, we identified an increase in the frequency of local stage disease (57% in 1992-1995 to 72% in 2005-2007; P for trend \.01) and a decrease in regional stage disease (35% in 1992-1995 to 14% in 2005-2007; P for trend \.01) (Figure 3). There was a slight increase in the frequency of distant disease (8% in 1992-1995 to 14% in 2005-2007; P for trend \.01). To test the impact of SEER stage on survival over time, we examined the stage-specific 5-year overall survival rates. Survival estimates are summarized in Table 4 and Figure 4. Among patients with local stage disease, there was a significant increase in survival to 63% (95% CI, 58%-68%) after the 1999 to 2001 periods, in comparison to the 1992 to 1995 period survival of 57% (95% CI, 53%-61%). Ultimately, the overall survival during the 2005 to 2007 period for patients with local stage disease was 65% (95% CI, 60%-70%). Among regional stage, there was no significant change in overall survival over the study period, from 28% (95% CI, 23%-33%) in the 1992 to 1995 period to 27% (95% CI, 16%-37%) in the 2005 to 2007 period. There was a significant increase in distant stage overall survival from 10% (95% CI, 4%-17%) in the 1992 to 1995 period to 26% (95% CI, 17%-36%) during the 2002 to 2004 period. Among the subgroup of patients in the 2005 to 2007 period, there were
Figure 3. Frequency of Surveillance, Epidemiology, and End Results stage at time of diagnosis by 3-year groupings.
insufficient events to calculate a true 5-year overall survival, and this survival estimate was excluded. A 1:1 propensity score using age at diagnosis, stage, race, comorbidity, and sex was generated among treated
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Table 4. SEER stage-specific Kaplan-Meier survival by year of diagnosis. 5-Year Kaplan-Meier Survival, % SEER Stage Local Regional Distant
1992-1995
1996-1998
1999-2001
2002-2004
2005-2007
56.7 28.0 10.3
56.9 23.7 10.2
63.1a 21.6 12.0
62.2a 22.4 26.3a
65.0a 26.6 —b
Abbreviation: SEER, Surveillance, Epidemiology, and End Results. a Indicates a significantly different survival than the stage-specific 1992-1995 survival. b Distant-stage 5-year survival for the 2005-2007 period was excluded due to insufficient follow-up in this subset.
Figure 4. Surveillance, Epidemiology, and End Results stage-specific overall survival at time of diagnosis by 3-year groupings with 95% linear confidence intervals. Five-year survival was generated using Kaplan-Meier survival estimates. Distant stage–specific survival during the 2005 to 2007 period was excluded due to insufficient follow-up time in this subset.
patients for the probability to receive surgical therapy vs nonsurgical therapy. A propensity match was performed, resulting in 1432 pairs of matched surgical and nonsurgical cases. There were no significant differences between groups in year of diagnosis (in 3-year groupings), age, stage, comorbidity, race, or sex among the propensity-matched groups (Table 5). Multivariate Cox analysis of nonsurgical and surgical treatment groups showed that primary surgical therapy was associated with a 24% reduction in 5-year overall mortality compared with patients treated with nonsurgical therapy (HR, 0.76; 95% CI, 0.68-0.86).
Discussion Our study demonstrates that among Medicare enrollees diagnosed with squamous cell carcinoma of the larynx between 1992 and 2007, there was a significant increase in overall survival over the 15-year period. Previous work by
Hoffman et al8 found that that the relative and overall survival for patients with laryngeal cancer was steadily decreasing over the 1980s through the 1990s. In a study using the SEER data set, Cosetti et al19 demonstrated an insignificant increase in cancer-specific survival in all nonsupraglottic laryngeal cancers in patients 65 years and older between 1977 and 2002 but found a small and insignificant decrease in non–cancer-specific survival in all groups. A meta-analysis by Rudolph et al20 examined 5-year survival across several studies, including many SEER studies, and found a wide range in reported 5-year laryngeal cancer overall survival but made note of the complexity of factors associated with the disease. Several other retrospective studies have demonstrated a similar reduction in mortality with primary surgical therapy. In a study using the National Cancer Database, Chen and Halpern21 found a 30% reduction in risk mortality among patients treated with total laryngectomy compared with those treated with chemoradiation. Furthermore, this same study found an associated 30% increased risk of mortality associated with Medicare-based insurance plans among those older than 65 years.21 Despite the observed increase in survival over the period of study, there was a decrease in the utilization of surgery as a primary therapy, which was associated, in univariate and multivariate Cox regression models, with a decreased risk of overall mortality in comparison to nonsurgical therapy. It is possible that this effect is driven by the frequency changes in disease stage at diagnosis over this time period or, specifically, an increase in the frequency of local stage disease and a decrease in regional stage disease. In univariate and multivariate Cox regression, regional stage was associated with a more than doubling in the risk of overall death relative to local disease. Because the vast majority of cases (n = 2164; 65%) had local stage disease at diagnosis and the rate of local disease increased over time, we would expect this to be a significant driver for overall improved survival in this population, despite an increase in the frequency of distant disease. Changes in the frequency of disease stage over time and concomitant changes in overall survival require some investigation into the possibility of stage migration. Feinstein et al22 described the process by which an apparent improvement in survival occurs not because of change in disease treatment or response but
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Table 5. Descriptive statistics of propensity matched groups. No. (%) Characteristic Year of diagnosis 1992-1995 1996-1998 1999-2001 2002-2004 2005-2007 Age, y 66-70 71-75 76-80 81-85 86-90 Race White Black Other Charlson comorbidity None Mild Moderate Severe SEER stage Local Regional Distant
Nonsurgical (n = 1432)
Surgical (n = 1432)
P Valuea .96
431 288 216 241 256
(30.1) (20.1) (15.1) (16.8) (17.9)
438 (30.6) 279 (19.5) 223 (15.6) 247 (17.2) 245 (17.1)
336 (23.5) 465 (32.5) 324 (22.6) 202 (14.1) 105 (7.3)
386 (27.0) 436 (30.4) 333 (23.3) 187 (13.1) 90 (6.3)
1231 (86.0) 120 (8.4) 81 (5.7)
1242 (86.7) 119 (8.3) 71 (5.0)
.18
.70
.84 544 427 220 241
(38.0) (29.8) (15.4) (16.8)
559 (39.0) 431 (30.1) 218 (15.2) 224 (15.6)
962 (67.2) 312 (21.8) 158 (11.0)
970 (67.7) 312 (21.8) 150 (10.5)
.89
Abbreviation: SEER, Surveillance, Epidemiology, and End Results. a Statistical difference between surgical and nonsurgical groups.
rather due to the restaging of patients with less severe disease. In calculating the stage-specific survival over this period, we observed an increase in overall survival among local and distant staged disease, with no change in overall survival among regional stage disease. The improved survival in local staged disease may be the result of multiple factors, one of which may be stage migration from in situ disease. The near doubling of survival among distant stage patients leads to the possibility of some stage migration between distant and regional stage disease, in which patients who previously were staged as having regional disease only are now being captured as having distant disease. The increased availability of new medical technologies, such as positron emission tomography scanning, may account for some of this migration.22 Given the small percentage of distant disease in comparison to regional disease, even a small amount of migration would have profound impacts on distant survival without significantly affecting regional survival. It is unclear what is driving this decrease in regional disease and relative increase in localized disease. One possibility is the improved screening or detection of laryngeal cancer over the study time period; however, because laryngeal cancer presents with distinct symptoms such as
hoarseness or irritation, there is less likelihood that a noninsidious disease progression has been improved by screening efforts. More research must be done to determine what factors are driving this protective decrease in laryngeal cancer stage. As with all large administrative data studies, our analysis is subject to several limitations. First, there is always the possibility of inherent bias present in the data set. The SEER data set represents a set of population-based cancer registries throughout the United States and therefore may not be strictly representative of national treatment patterns. Next, this study looked at a select subset of patients with primary laryngeal cancer: elderly patients older than 65 years with full Medicare coverage. Because nearly half of all laryngeal cancers occur in those younger than 65 years,2 there may be difficulty in generalizing these results to populations of patients with laryngeal cancer other than those studied. Another limitation exists in our grouping of patients into discrete categories of disease and treatment to simplify the complex nature of laryngeal cancer. Differences in laryngeal cancer location, such as those that occur in the supraglottic vs glottic region, can have a marked impact on presentation, management, and expected outcome. Likewise,
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surgical therapy for laryngeal cancer represents a wide range of procedures and associated treatment outcomes, many of which have continued to evolve over the study period. As such, there is some risk of false homogeneity and selection bias in the grouping of treatments as primarily ‘‘surgical’’ or ‘‘nonsurgical.’’ Although these categorizations were performed to facilitate data analysis, it is important to note that they are a simplification and that further studies may be needed to extract the unique and individualized qualities of laryngeal cancer disease and treatment. Further limitations include the possibility of stage differences, in that surgical patients may be more likely to undergo more accurate surgical pathology in comparison to nonsurgically treated patients. Furthermore, patients treated with multiple treatment regimens may represent more complex baseline disease that is difficult to capture. Our use of adjusted multivariate analysis and propensity-matched comparisons has attempted to account for much of this bias, but there remains the possibility that we were unable to account for all inherent differences.
Conclusion This study has demonstrated that between 1992 and 2007, there has been a significant trend for increasing 5-year overall survival among a subset of Medicare enrollees with newly diagnosed larynx cancer. Interestingly, this increase in survival over time is observed during an era when a greater number of patients were receiving nonsurgical therapies, which are associated with an increased risk of overall mortality. These results were consistent after incorporating propensity-matched comparisons. More research must be conducted to further explore drivers of increased survival over this period. Author Contributions Raymond A. Jean, design, collection, analysis, interpretation, manuscript preparation; Dorina Kallogjeri, design, analysis, interpretation, manuscript preparation; Seth A. Strope, design, interpretation, manuscript preparation; Frances Mei Hardin, data collection, manuscript preparation; Jason T. Rich, design, interpretation, manuscript preparation; Jay F. Piccirillo, design, interpretation, analysis, manuscript preparation.
Disclosures Competing interests: None. Sponsorships: None. Funding source: Raymond A. Jean was funded by a grant from the Doris Duke Charitable Foundation, Washington University Grant #2010072.
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