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CANEP-863; No. of Pages 7 Cancer Epidemiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database Kyle R. Duchman, Yubo Gao, Benjamin J. Miller * Department of Orthopaedics and Rehabilitation, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 01015 JPP, Iowa City, IA 52242, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2015 Received in revised form 30 April 2015 Accepted 5 May 2015 Available online xxx
Background: The current study aims to determine cause-specific survival in patients with high-grade osteosarcoma while reporting risk factors for decreased survival out to 10 years. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with high-grade osteosarcoma from 1991 to 2010. Patient, tumor, and countylevel socioeconomic measures were analyzed to determine prognostic factors for survival. Results: Cause-specific 10-year survival for patients with local/regional disease at the time of diagnosis was 65.8%, compared to 24.0% for patients with metastatic disease. Multivariate analysis revealed metastatic disease at presentation, age 60 years, male sex, axial location, and size 10 cm as independent risk factors for decreased cause-specific survival at 10 years. Patients with the lowest socioeconomic status had a disproportionate frequency of metastatic disease and large tumors at presentation as compared to more affluent patients. Conclusions: Patients with high-grade osteosarcoma have decreased cause-specific survival at 10 years when metastatic at diagnosis, patient age 60 years, male sex, axial tumor location, and tumors measuring 10 cm. Patients living in low socioeconomic counties present more frequently with metastatic disease and large tumors. Public health efforts should focus on identifying patients with osteosarcoma prior to metastasis. ß 2015 Elsevier Ltd. All rights reserved.
Keywords: Bone neoplasms/mortality Sarcoma, Osteosarcoma/mortality SEER Program Survival analysis Risk factors
1. Introduction Osteosarcoma is the most common primary osseous sarcoma [1,2]. Since the introduction of chemotherapeutic regimens in the 1970s, neoadjuvant chemotherapy followed by surgical resection has been the standard of care for high-grade osteosarcoma [3,4]. As chemotherapeutic regimens intensified, survival for patients with high-grade osteosarcoma improved, with 5-year survival rates for patients with non-metastatic disease reported above 60% [1,2,5,6]. However, metastatic disease at presentation has consistently resulted in much poorer prognosis [1,5,7–11]. It has been reported that patients living in less affluent communities are more likely to present with metastatic disease at the time of diagnosis of osteosarcoma [12], but the effect that socioeconomic status has on survival has yet to be determined.
Healthcare disparities based on socioeconomic status and other social variables have been found to influence time to presentation, stage at presentation, treatment decisions, and, ultimately, survival in patients with other cancers [13–17]. While patient and tumor-specific characteristics are frequently non-modifiable, a patient’s socioeconomic status and subsequent access to healthcare can potentially be addressed. Established in 1973, the Surveillance, Epidemiology, and End Results (SEER) Program database collects data from seventeen cancer registries from across the United States. Using the SEER Program database, the purpose of the present study was to determine causespecific survival in patients with high-grade osteosarcoma up to 10 years after diagnosis. Additionally, we aimed to identify patient, tumor, and socioeconomic variables associated with decreased cause-specific survival in patients with high-grade osteosarcoma. 2. Materials and methods
* Corresponding author. Tel.: +1 319 384 5535; fax: +1 319 353 6754. E-mail addresses: [email protected] (K.R. Duchman), [email protected] (Y. Gao), [email protected] (B.J. Miller).
All patients with high-grade osteosarcoma listed in the SEER Program database from 1991 to 2010 were identified. This time
http://dx.doi.org/10.1016/j.canep.2015.05.001 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Duchman KR, et al. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/ j.canep.2015.05.001
G Model
CANEP-863; No. of Pages 7 2
K.R. Duchman et al. / Cancer Epidemiology xxx (2015) xxx–xxx
frame was selected for analysis as both therapeutic and imaging modalities, specifically modern chemotherapy and magnetic resonance imaging, were routinely used and available. Histologic subtypes considered high-grade osteosarcoma included osteosarcoma, NOS, chondroblastic osteosarcoma, fibroblastic osteosarcoma, telangiectatic osteosarcoma, osteosarcoma in Paget disease, small cell osteosarcoma, central osteosarcoma, high-grade surface osteosarcoma, and malignant osteosarcoma. Patients with multiple primary tumors listed within the database were excluded, leaving only patients with a single primary tumor available for analysis. Cases and associated variables of interest were identified using the SEER*Stat application (version 8.1.5). 2.1. Human subjects determination Thee SEER Program database is publicly available and provides de-identified case data. The current project was reviewed by the Institutional Review Board (IRB) at the author’s institution and was found not to meet the regulatory definition of human subjects research, and as such, did not required further IRB review. 2.2. Data elements Patient demographic variables of interest included age, sex, and race. The SEER Program database records age as a categorical variable in five-year intervals beginning at zero years and ending at 85 years. Patients were categorized into three distinct age groups (0–24 years; 25–59 years; 60 years) as has been previously reported [1,2,12]. Race was categorized as white, black, or other. Tumor specific variables of interest included histologic subtype, metastatic disease at presentation, location, and size. The high-grade osteosarcoma histologic subtypes included for analysis were categorized according to the International Classification of Disease for Oncology, 3rd Edition (IDO-O-3). Patients coded with ‘‘distant’’ disease were classified as having metastatic disease at presentation (n = 661), while patients with ‘‘localized’’ or ‘‘regional’’ disease were considered non-metastatic (n = 2188). Patients with missing data for ‘‘distant’’ or ‘‘localized/regional’’ disease were excluded. The anatomic location of the tumor was categorized as axial (pelvis, spine, and ribs) or extremity (long and short bones of the upper and lower extremity). Tumor size was categorized as small (5 cm), intermediate (>5–10 cm), large (>10 cm), or unknown. The SEER Program database provides socioeconomic measures that are collected based on a patient’s county of residence. Countylevel socioeconomic measures of interest included median family income, percent of persons living below the poverty line, percent of persons at least 25 years of age with less than a high school education, and rural or urban county setting. Using this countylevel data, we created a composite socioeconomic status (SES) variable as previously described [12,15,17]. Briefly, county-level data for median family income, percent of persons living below the poverty line, and percent of persons at least 25 years of age with less than a high school education were each divided into quartiles, with a higher number reflecting higher income, less poverty, and more education. Each of the three socioeconomic variables was equally weighted and added together to create the composite SES score. Possible scores ranged from 3 to 12 which were then further categorized as low (composite SES 3), middle (composite SES 4-10), or high (composite SES 11). The primary outcome of interest in this study was causespecific survival. The SEER Program database uses abstracted data from death certificates to determine cause of death, which are dichotomously coded as ‘‘cancer’’ or ‘‘other causes.’’ Any death resulting from cancer recurrence or metastatic disease is considered mortality attributable to ‘‘cancer.’’
2.3. Statistical analysis Estimated cause-specific survival was calculated as the time from diagnosis until death attributable to cancer. Since all patients had a single primary tumor, death attributable to cancer was considered death attributable to high-grade osteosarcoma. Using the Kaplan–Meier method, estimated cause-specific survival was calculated at 2, 5, and 10 years. The final date of follow-up for survival calculations for the study population was December 31, 2010. Patients with death attributable to cancer or incomplete follow-up for the time point of interest were censored. A sensitivity analysis was performed comparing 10-year survival estimates for the entire cohort to patients who had been completely observed, namely patients within the cohort diagnosed between 1991 and 2001. The sensitivity analysis revealed no statistical difference in survival, and as such, 10-year survival estimates are reported throughout. Association of survival with variables of interest was assessed using the log-rank test. Multivariate analyses were performed using Cox proportional hazards ratios in order to identify independent predictors of survival. The proportional assumption was tested for all variables included in the multivariate analysis, and metastatic disease was found to be non-proportional. The time-dependent covariate for metastatic disease was not included within the multivariate models, but rather, the effect was considered an average over the timeframe of the study. 2.4. Multivariate model selection Model 1 was fully adjusted and included all patient, tumor, and socioeconomic variables of interest. Model 2 utilized stepwise selection to include all variables with univariate p-values < 0.1 which included composite SES score as a clinically significant variable. A preliminary analysis revealed that patients with the lowest composite SES score (3) were more likely to present with metastatic disease at diagnosis as compared to patients with the highest composite SES score (11) (29.1 vs. 21.7%, p = 0.047), consistent with previous literature [12]. Given this finding, an interaction term between tumor stage and SES score was included in Models 1 and 2 and found to have no significant effect on predictors of survival. We did, however, elect to include an additional multivariate model, Model 3, which eliminated metastatic disease from the analysis while including all variables with univariate p-values < 0.1 in order to isolate the effect of socioeconomic status on survival. 2.5. Missing data Tumor size was the least consistently reported variable in the SEER Program database, with size data missing for 921/2849 (32.3%) of patients. Given this finding, ‘‘unknown’’ was included as a covariate within the tumor size category. This allowed for all 2849 patients available for analysis to be included in the univariate and multivariate analysis without missing data for any other variables of interest.
3. Results 3.1. Cause-specific survival There were 2849 patients with high-grade osteosarcoma identified in the SEER Program database from 1991 to 2010. Including all histologic subtypes, 661/2849 (23.2%) of patients presented with metastatic disease at diagnosis (Table 1). Causespecific survival for patients with non-metastatic disease at diagnosis was 83.6%, 71.8%, and 65.8% at 2, 5, and 10 years,
Please cite this article in press as: Duchman KR, et al. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/ j.canep.2015.05.001
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CANEP-863; No. of Pages 7 K.R. Duchman et al. / Cancer Epidemiology xxx (2015) xxx–xxx
3
Table 1 Univariate 10-year survival estimates of patient, tumor, and socioeconomic characteristics for patients with high-grade osteosarcoma identified in the SEER Program Database from 1991 to 2010. Variable Age (yrs) 0–24 25–59 60 Sex Male Female Race White Black Other Location Extremity Axial Metastatic Yes No Size 5 cm >5–10 cm 10 cm Unknown Composite SESd 3 4–10 11 Rural or urban Rural Urban Histology Osteosarcoma, NOS Central Chondroblastic Fibroblastic High-grade surface Paget Small cell Telangiectatic a b c d e
Number (%)
Survival (95% CI)a
Dead/censoredb
1825 (64.1) 676 (23.7) 348 (12.2)
62.1 (55.0–59.5) 54.1 (49.5–58.7) 29.6 (21.5–38.4)
533/1292 242/434 150/198
1604 (56.3) 1245 (43.7)
54.5 (51.4–57.5) 60.9 (57.5–64.3)
556/1048 369/876
2157 (75.7) 426 (15.0) 266 (9.3)
57.4 (54.7–60.0) 53.3 (47.1–59.5) 62.1 (55.2–68.8)
698/1459 146/280 81/185
2371 (83.2) 478 (16.8)
61.8 (59.4–64.1) 27.0 (20.8–33.8)
706/1665 219/259
661 (23.2) 2188 (76.8)
24.0 (19.4–29.0) 65.8 (63.3–68.3)
364/297 561/1627
326 760 842 921
68.8 63.3 47.6 55.8
76/250 206/554 310/532 333/588
p-Valuec
CANEP-863; No. of Pages 7 Cancer Epidemiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database Kyle R. Duchman, Yubo Gao, Benjamin J. Miller * Department of Orthopaedics and Rehabilitation, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 01015 JPP, Iowa City, IA 52242, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2015 Received in revised form 30 April 2015 Accepted 5 May 2015 Available online xxx
Background: The current study aims to determine cause-specific survival in patients with high-grade osteosarcoma while reporting risk factors for decreased survival out to 10 years. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with high-grade osteosarcoma from 1991 to 2010. Patient, tumor, and countylevel socioeconomic measures were analyzed to determine prognostic factors for survival. Results: Cause-specific 10-year survival for patients with local/regional disease at the time of diagnosis was 65.8%, compared to 24.0% for patients with metastatic disease. Multivariate analysis revealed metastatic disease at presentation, age 60 years, male sex, axial location, and size 10 cm as independent risk factors for decreased cause-specific survival at 10 years. Patients with the lowest socioeconomic status had a disproportionate frequency of metastatic disease and large tumors at presentation as compared to more affluent patients. Conclusions: Patients with high-grade osteosarcoma have decreased cause-specific survival at 10 years when metastatic at diagnosis, patient age 60 years, male sex, axial tumor location, and tumors measuring 10 cm. Patients living in low socioeconomic counties present more frequently with metastatic disease and large tumors. Public health efforts should focus on identifying patients with osteosarcoma prior to metastasis. ß 2015 Elsevier Ltd. All rights reserved.
Keywords: Bone neoplasms/mortality Sarcoma, Osteosarcoma/mortality SEER Program Survival analysis Risk factors
1. Introduction Osteosarcoma is the most common primary osseous sarcoma [1,2]. Since the introduction of chemotherapeutic regimens in the 1970s, neoadjuvant chemotherapy followed by surgical resection has been the standard of care for high-grade osteosarcoma [3,4]. As chemotherapeutic regimens intensified, survival for patients with high-grade osteosarcoma improved, with 5-year survival rates for patients with non-metastatic disease reported above 60% [1,2,5,6]. However, metastatic disease at presentation has consistently resulted in much poorer prognosis [1,5,7–11]. It has been reported that patients living in less affluent communities are more likely to present with metastatic disease at the time of diagnosis of osteosarcoma [12], but the effect that socioeconomic status has on survival has yet to be determined.
Healthcare disparities based on socioeconomic status and other social variables have been found to influence time to presentation, stage at presentation, treatment decisions, and, ultimately, survival in patients with other cancers [13–17]. While patient and tumor-specific characteristics are frequently non-modifiable, a patient’s socioeconomic status and subsequent access to healthcare can potentially be addressed. Established in 1973, the Surveillance, Epidemiology, and End Results (SEER) Program database collects data from seventeen cancer registries from across the United States. Using the SEER Program database, the purpose of the present study was to determine causespecific survival in patients with high-grade osteosarcoma up to 10 years after diagnosis. Additionally, we aimed to identify patient, tumor, and socioeconomic variables associated with decreased cause-specific survival in patients with high-grade osteosarcoma. 2. Materials and methods
* Corresponding author. Tel.: +1 319 384 5535; fax: +1 319 353 6754. E-mail addresses: [email protected] (K.R. Duchman), [email protected] (Y. Gao), [email protected] (B.J. Miller).
All patients with high-grade osteosarcoma listed in the SEER Program database from 1991 to 2010 were identified. This time
http://dx.doi.org/10.1016/j.canep.2015.05.001 1877-7821/ß 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Duchman KR, et al. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/ j.canep.2015.05.001
G Model
CANEP-863; No. of Pages 7 2
K.R. Duchman et al. / Cancer Epidemiology xxx (2015) xxx–xxx
frame was selected for analysis as both therapeutic and imaging modalities, specifically modern chemotherapy and magnetic resonance imaging, were routinely used and available. Histologic subtypes considered high-grade osteosarcoma included osteosarcoma, NOS, chondroblastic osteosarcoma, fibroblastic osteosarcoma, telangiectatic osteosarcoma, osteosarcoma in Paget disease, small cell osteosarcoma, central osteosarcoma, high-grade surface osteosarcoma, and malignant osteosarcoma. Patients with multiple primary tumors listed within the database were excluded, leaving only patients with a single primary tumor available for analysis. Cases and associated variables of interest were identified using the SEER*Stat application (version 8.1.5). 2.1. Human subjects determination Thee SEER Program database is publicly available and provides de-identified case data. The current project was reviewed by the Institutional Review Board (IRB) at the author’s institution and was found not to meet the regulatory definition of human subjects research, and as such, did not required further IRB review. 2.2. Data elements Patient demographic variables of interest included age, sex, and race. The SEER Program database records age as a categorical variable in five-year intervals beginning at zero years and ending at 85 years. Patients were categorized into three distinct age groups (0–24 years; 25–59 years; 60 years) as has been previously reported [1,2,12]. Race was categorized as white, black, or other. Tumor specific variables of interest included histologic subtype, metastatic disease at presentation, location, and size. The high-grade osteosarcoma histologic subtypes included for analysis were categorized according to the International Classification of Disease for Oncology, 3rd Edition (IDO-O-3). Patients coded with ‘‘distant’’ disease were classified as having metastatic disease at presentation (n = 661), while patients with ‘‘localized’’ or ‘‘regional’’ disease were considered non-metastatic (n = 2188). Patients with missing data for ‘‘distant’’ or ‘‘localized/regional’’ disease were excluded. The anatomic location of the tumor was categorized as axial (pelvis, spine, and ribs) or extremity (long and short bones of the upper and lower extremity). Tumor size was categorized as small (5 cm), intermediate (>5–10 cm), large (>10 cm), or unknown. The SEER Program database provides socioeconomic measures that are collected based on a patient’s county of residence. Countylevel socioeconomic measures of interest included median family income, percent of persons living below the poverty line, percent of persons at least 25 years of age with less than a high school education, and rural or urban county setting. Using this countylevel data, we created a composite socioeconomic status (SES) variable as previously described [12,15,17]. Briefly, county-level data for median family income, percent of persons living below the poverty line, and percent of persons at least 25 years of age with less than a high school education were each divided into quartiles, with a higher number reflecting higher income, less poverty, and more education. Each of the three socioeconomic variables was equally weighted and added together to create the composite SES score. Possible scores ranged from 3 to 12 which were then further categorized as low (composite SES 3), middle (composite SES 4-10), or high (composite SES 11). The primary outcome of interest in this study was causespecific survival. The SEER Program database uses abstracted data from death certificates to determine cause of death, which are dichotomously coded as ‘‘cancer’’ or ‘‘other causes.’’ Any death resulting from cancer recurrence or metastatic disease is considered mortality attributable to ‘‘cancer.’’
2.3. Statistical analysis Estimated cause-specific survival was calculated as the time from diagnosis until death attributable to cancer. Since all patients had a single primary tumor, death attributable to cancer was considered death attributable to high-grade osteosarcoma. Using the Kaplan–Meier method, estimated cause-specific survival was calculated at 2, 5, and 10 years. The final date of follow-up for survival calculations for the study population was December 31, 2010. Patients with death attributable to cancer or incomplete follow-up for the time point of interest were censored. A sensitivity analysis was performed comparing 10-year survival estimates for the entire cohort to patients who had been completely observed, namely patients within the cohort diagnosed between 1991 and 2001. The sensitivity analysis revealed no statistical difference in survival, and as such, 10-year survival estimates are reported throughout. Association of survival with variables of interest was assessed using the log-rank test. Multivariate analyses were performed using Cox proportional hazards ratios in order to identify independent predictors of survival. The proportional assumption was tested for all variables included in the multivariate analysis, and metastatic disease was found to be non-proportional. The time-dependent covariate for metastatic disease was not included within the multivariate models, but rather, the effect was considered an average over the timeframe of the study. 2.4. Multivariate model selection Model 1 was fully adjusted and included all patient, tumor, and socioeconomic variables of interest. Model 2 utilized stepwise selection to include all variables with univariate p-values < 0.1 which included composite SES score as a clinically significant variable. A preliminary analysis revealed that patients with the lowest composite SES score (3) were more likely to present with metastatic disease at diagnosis as compared to patients with the highest composite SES score (11) (29.1 vs. 21.7%, p = 0.047), consistent with previous literature [12]. Given this finding, an interaction term between tumor stage and SES score was included in Models 1 and 2 and found to have no significant effect on predictors of survival. We did, however, elect to include an additional multivariate model, Model 3, which eliminated metastatic disease from the analysis while including all variables with univariate p-values < 0.1 in order to isolate the effect of socioeconomic status on survival. 2.5. Missing data Tumor size was the least consistently reported variable in the SEER Program database, with size data missing for 921/2849 (32.3%) of patients. Given this finding, ‘‘unknown’’ was included as a covariate within the tumor size category. This allowed for all 2849 patients available for analysis to be included in the univariate and multivariate analysis without missing data for any other variables of interest.
3. Results 3.1. Cause-specific survival There were 2849 patients with high-grade osteosarcoma identified in the SEER Program database from 1991 to 2010. Including all histologic subtypes, 661/2849 (23.2%) of patients presented with metastatic disease at diagnosis (Table 1). Causespecific survival for patients with non-metastatic disease at diagnosis was 83.6%, 71.8%, and 65.8% at 2, 5, and 10 years,
Please cite this article in press as: Duchman KR, et al. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. Cancer Epidemiology (2015), http://dx.doi.org/10.1016/ j.canep.2015.05.001
G Model
CANEP-863; No. of Pages 7 K.R. Duchman et al. / Cancer Epidemiology xxx (2015) xxx–xxx
3
Table 1 Univariate 10-year survival estimates of patient, tumor, and socioeconomic characteristics for patients with high-grade osteosarcoma identified in the SEER Program Database from 1991 to 2010. Variable Age (yrs) 0–24 25–59 60 Sex Male Female Race White Black Other Location Extremity Axial Metastatic Yes No Size 5 cm >5–10 cm 10 cm Unknown Composite SESd 3 4–10 11 Rural or urban Rural Urban Histology Osteosarcoma, NOS Central Chondroblastic Fibroblastic High-grade surface Paget Small cell Telangiectatic a b c d e
Number (%)
Survival (95% CI)a
Dead/censoredb
1825 (64.1) 676 (23.7) 348 (12.2)
62.1 (55.0–59.5) 54.1 (49.5–58.7) 29.6 (21.5–38.4)
533/1292 242/434 150/198
1604 (56.3) 1245 (43.7)
54.5 (51.4–57.5) 60.9 (57.5–64.3)
556/1048 369/876
2157 (75.7) 426 (15.0) 266 (9.3)
57.4 (54.7–60.0) 53.3 (47.1–59.5) 62.1 (55.2–68.8)
698/1459 146/280 81/185
2371 (83.2) 478 (16.8)
61.8 (59.4–64.1) 27.0 (20.8–33.8)
706/1665 219/259
661 (23.2) 2188 (76.8)
24.0 (19.4–29.0) 65.8 (63.3–68.3)
364/297 561/1627
326 760 842 921
68.8 63.3 47.6 55.8
76/250 206/554 310/532 333/588
p-Valuec
