Prognosis and treatment differences between initial and second primary chondrosarcoma
- Authors:
- Published online on: May 7, 2019 https://doi.org/10.3892/ol.2019.10329
- Pages: 207-218
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Copyright: © Mao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Chondrosarcoma is a malignant tumour originating from cartilage tissue and is the second most common malignant bone tumour after osteosarcomas worldwide (1,2). Chondrosarcoma primarily occurs in individuals >50 years of age and, in the majority of cases, affects the limbs and pelvis (3). Pathological types can be divided into conventional intramedullary chondrosarcoma, clear cell chondrosarcoma, mesenchymal chondrosarcoma, juxtacortical chondrosarcoma and myxoid chondrosarcoma (4,5). Chondrosarcoma has a poor response to traditional chemotherapy and radiotherapy, and surgical resection is currently the only successful treatment available (6–8).
In recent years, second primary cancer types have become more prominent, and the incidence and risk of second primary cancer is increasing in countries such as the USA and the Netherlands (9,10). This increase may be due to a significant improvement in the survival times of those adults with cancer or the use of commonly used cancer treatments such as radiotherapy or chemotherapy (11–13). In the present study, second primary chondrosarcoma (pCS) is defined as a tumour that is different in location or histology from the initial pCS and is not derived from the metastasis or recurrence of the initial pCS. Chondrosarcoma rarely presents as a second primary tumour (10).
To the best of our knowledge, no studies have evaluated the prognosis or treatment differences between the initial pCS and the second pCS thus far. The purpose of the present study was to analyse the difference in prognosis between the initial and second pCS, and the difference in treatment outcomes on the basis of a population-level study of chondrosarcoma.
Materials and methods
Data source and patients
The Surveillance Epidemiology and End Results (SEER) database (https://seer.cancer.gov/) of the National Cancer Institute (Bethesda, MD, USA) was used as the data source in the present study. In total, 3,055 patients with initial and second pCS were identified using the International Classification of Diseases for Oncology (ICD-O-3) (http://codes.iarc.fr/) histology codes 9220/3,9221/3,9231/3,9240/3,9242/3 and 9243/3. The patients had been diagnosed between January 1, 2004, and December 31, 2015. SEER*Stat software (version 8.3.5; National Cancer Institute) was used to access the SEER 18 Regs Custom Data (with an additional treatment field) Nov 2017 Sub (1973–2015 varying) database using the client-server mode of SEER*Stat. Patients with unknown survival time, unknown American Joint Committee on Cancer (AJCC) stage or unknown Tumour-Node-Metastasis (TNM) stage (14), as well as those diagnosed at autopsy, <18 years of age or having a non-initial visit to hospital and non-osteoarticular chondrosarcoma were excluded. The National Cancer Institute's SEER database covers ~30% of the population in the USA, and collects information such as demographics, tumour histology, tumour stage at diagnosis, treatment information and survival time (15). Finally, 1,655 eligible patients were identified.
The second pCS may be synchronous or metachronous. The definitions of the second pCS met the following criteria: i) Synchronous cancer is a second pCS diagnosed simultaneously or within 6 months of diagnosis of the initial pCS (9); ii) metachronous cancer is a diagnosis of second pCS ≥6 months following the diagnosis of an initial pCS; iii) the primary site differs between the initial pCS and the second pCS; iv) histology is different if the primary site is the same as the primary site of the initial primary cancer.
Study variables
Overall survival (OS) and cancer-specific survival (CSS) were the primary outcomes in the present study. The patients in the present study were categorized into two groups: Initial pCS and second pCS. The following variables were extracted for analysis: Year of diagnosis, age at diagnosis, sex, ethnicity, marital status, area of geographical state, urban-rural residence, laterality, primary site, tumour grade, histological type, AJCC stage, extent of disease (for T and M stages), regional nodes positive (for N stage) and treatment methods (surgery, radiotherapy or chemotherapy).
Statistical analysis
The baseline data of demographics and clinicopathological characteristics of the initial and second pCS were compared using χ2 tests. Kaplan-Meier curves and log-rank tests were used for OS and CSS. Univariable analysis was performed using the log-rank test to determine the factors associated with all-cause mortality and cancer-specific mortality. Furthermore, univariable and multivariable Cox regression analyses were used to determine the factors associated with all-cause mortality and cancer-specific mortality. All statistical analyses were performed using SPSS statistics software (version 20; IBM Corp., Armonk, NY, USA). P≤0.05 was considered to indicate a statistically significant result.
Results
Demographic and clinical characteristics of the initial and second pCS
In total, 1,655 eligible patients with chondrosarcoma who were diagnosed between January 1, 2004, and December 31, 2015, were included in the cohort of the present study, with data obtained from the SEER database between January 1, 2004, and December 31, 2015. Among them, 1,455 (87.9%) patients had initial pCS and 200 (12.1%) patients had second pCS. The clinical characteristics and the χ2 test for comparison of the initial and second pCS are presented in Table I. The data presented in Table I indicates that the incidence of chondrosarcoma increases with the year of diagnosis. χ2 test revealed significant differences between the initial and second pCS in certain variables, including year of diagnosis (P=0.048), age at diagnosis (P<0.001), tumour AJCC stage (P=0.024) and M-stage (P=0.044). Patients with second pCS were more frequently diagnosed at 61–80 years of age (52.5 vs. 43.1%; P<0.001) compared with patients with initial pCS. Furthermore, the majority of patients with initial and second pCS chose to receive surgical treatment (92.0 and 91.0% respectively), and markedly less patients chose to receive radiotherapy (14.8 and 15.0%, respectively) or chemotherapy (8.0 vs. 5.5%, respectively).
Univariate survival analyses of factors associated with all-cause mortality and cancer-specific mortality
Univariate survival analyses of patients with initial and second pCS according to various clinicopathological variables (Table II). Among the 1,655 initial and second pCS patients, 390 (23.6%) were categorized as cases of all-cause mortality and 228 (13.8%) succumbed to chondrosarcoma. Univariate analyses revealed that year of diagnosis, age at diagnosis, sex, tumour grade, histological type, AJCC stage, TNM stage, surgery, radiotherapy and chemotherapy were associated with all-cause mortality and chondrosarcoma-associated mortality (all P<0.05). In addition, patients with second pCS had a higher rate of all-cause mortality compared with patients with initial pCS (P<0.001), but there was no significant difference between initial and second pCS in terms of chondrosarcoma-associated mortality (P=0.734).
Table II.Univariate survival analyses of the 1,655 patients with chondrosarcoma according to various clinicopathological variables. |
Survival
The median survival time among the entire cohort was 41.00 months, with patients with initial pCS experiencing a longer median survival time (42.00 months), and patients with second pCS experiencing a shorter median survival time (34.50 months). Fig. 1A presents the OS and CSS of the initial and second pCS. The OS rate of patients with initial pCS was significantly higher compared with that of the patients with second pCS (log-rank test, P<0.001), but the CSS rate of the patients with initial pCS was not significantly different from that of the patients with second pCS (log-rank test, P=0.428). In addition, it was also revealed that among the pathological types of chondrosarcoma, dedifferentiated chondrsarcoma exhibited the worst OS and CSS rates (Fig. 1B). Patients were stratified by primary sites and laterality, and in doing so, it was revealed that the OS rate of the patients with initial pCS was also higher compared with that of the patients with second pCS. However, there was no significant difference between the initial and second pCS in terms of chondrosarcoma-associated mortality (Fig. 2).
Risk factors for all-cause mortality and cancer-specific mortality
Univariate and multivariate Cox regression were used to analyse the factors associated with all-cause mortality and cancer-specific mortality (Table III). Age at diagnosis, sex, histological type, AJCC stage, T stage, surgery and radiotherapy were associated with all-cause mortality and chondrosarcoma-cause mortality (all P<0.05) in univariate and multivariate Cox regression. In the multivariate Cox regression analysis among patients with initial and second pCS, age 41–60 years [vs. age 18–40 years; HR, 1.80; 95% confidence interval (CI), 1.22–2.65; P=0.003], age 61–80 years (vs. age 18–40 years; HR, 2.91; 95% CI, 1.97–4.30; P<0.001), age >80 years (vs. age 18–40 years; HR, 4.04; 95% CI, 2.49–6.57; P<0.001), male (vs. female; HR, 1.50; 95% CI, 1.21–1.85; P<0.001), moderately differentiated (vs. well-differentiated; HR, 1.41; 95% CI, 1.03–1.93; P=0.033), undifferentiated (vs. well-differentiated; HR, 2.00; 95% CI, 1.09–3.68; P=0.026), mesenchymal chondrosarcoma (vs. chondrosarcoma, NOS; HR, 2.11; 95% CI, 1.03–4.33; P=0.042), dedifferentiated chondrosarcoma (vs. chondrosarcoma, NOS; HR, 3.00; 95% CI, 2.20–4.08; P<0.001), AJCC stage IV (vs. AJCC stage I; HR, 5.67; 95% CI, 3.64–8.82; P<0.001), T2 stage (vs. T1 stage; HR, 1.81; 95% CI, 1.46–2.25; P<0.001), surgery (vs. no surgery; HR, 0.39; 95% CI, 0.29–0.52; P<0.001), radiotherapy (vs. no radiotherapy; HR, 1.31; 95% CI, 1.03–1.67; P=0.030) and second pCS (vs. initial pCS; HR, 1.72; 95% CI, 1.31–2.26; P<0.001) were associated with a significant increase in all-cause mortality. However, initial and second pCS were still not associated with improved chondrosarcoma-associated survival on multivariable survival analysis (P=0.294).
Benefits of different treatment for initial and second pCS
To analyse the benefit of different treatments for all-cause mortality, patients with initial and second pCS were stratified by primary site and laterality, and multivariate analysis was used. For patients with appendicular or axial chondrosarcoma, those with initial and second pCS who underwent surgery had lower all-cause mortality (all P<0.05; Fig. 3A) compared with patients who did not receive surgery (Fig. 3A). Similarly, for left-sided or right-sided chondrosarcoma patients, those with initial and second pCS who underwent surgery had lower all-cause mortality rate (all P<0.05) compared with patients without surgery. However, the use of radiotherapy or chemotherapy did not reduce the all-cause mortality rate (Fig. 3B and C).
Discussion
The incidence of chondrosarcoma accounts for ~20% of all primary bone sarcomas (16). Above the age of 40 years, the incidence rate of chondrosarcoma gradually increases, and the incidence rate in men is higher than that in women. Rozeman et al (17) reported that common types of chondrosarcoma accounted for 85% of cases, dedifferentiation for 10%, interstitial type for 2% and clear cell type for 1%. Giuffrida et al (18) analysed 2,890 cases of chondrosarcoma between 1973 and 2003, and revealed that the highest 5-year survival rate was that of clear cell type chondrosarcoma (100%), followed by common chondrosarcoma (70%), and the lowest was that of dedifferentiated chondrosarcoma (0%). The results from the present study also revealed that dedifferentiated chondrosarcoma has the worst prognosis.
Second pCS is a rare occurrence, and, to the best of our knowledge, there are currently no studies that have assessed the prognosis and treatment differences between the initial pCS and the second pCS. Therefore, the present study is the first to report differences in prognosis and treatment between initial pCS and the second pCS.
The present study revealed that the proportion of the four age stages (18–40, 41–60, 61–80 and >80 years) of the patients with initial pCS were 26.3, 43.1, 26.5 and 4.2%, respectively, while the proportion of the patients with second pCS in the four age stages was 5.0,32.0,52.5 and 10.5%, respectively. It was demonstrated that patients with second pCS were at an older age when diagnosed compared with patients with initial pCS. The difference may be due to a significant improvement in survival for patients with cancer.
As one of the multiple primary malignancies (MPMs), the second primary cancer has received greater attention. MPMs are rarely encountered in different organs and tissues in the same patient, and the incidence of MPMs ranges from 0.7–11.0%, as determined through the statistical analysis of several national cancer registries (10,19,20). The most common subsequent types of cancer are squamous cell skin cancer, colorectal cancer and breast cancer (13). Patients with MPMs exhibit a worse 5-year OS rate compared with patients with a single malignancy (21). This may be associated with genetic, environmental and immunological factors, as well as the application of radiotherapy or chemotherapy (22,23).
The risk of developing a subsequent cancer in patients with MPMs was 1.4 to 3.0 times higher compared to the general population (13). There are a number of studies that have focused on second primary tumours. By investigating 2,462 patients with hepatocellular carcinoma who underwent liver transplantation, Heo et al (24) revealed that patients with hepatocellular carcinoma who had received a liver transplantation had a longer life expectancy and higher risk of second primary cancer compared with the general population (standardized incidence ratios, 2.79; 95% CI, 2.27–3.38). Chen et al (25) demonstrated that the prognosis of patients with second primary colorectal cancer was worse than that of patients with initial primary colorectal cancer, and the therapeutic benefit on colorectal cancer prognosis was generally similar for the patients with initial and second primary colorectal cancer. The present study revealed similar results; it was identified that patients with second pCS had a worse prognosis compared with patients with initial pCS, and the treatment benefits were similar for patients with initial and second pCS. Surgery can significantly reduce all-cause mortality, while the use of radiotherapy or chemotherapy does not reduce all-cause mortality.
Furthermore, in terms of demographic and clinical characteristics, χ2 tests revealed a significant difference in the age at diagnosis for patients with initial pCS and those patients with second pCS; patients with second pCS were diagnosed at an older age compared with patients with initial pCS.
The present study does have certain limitations. First, the research is based on the SEER database, a retrospective dataset that therefore has inherent limitations. Secondly, the patients’ physical condition was unclear; patients with excessive comorbidities may pursue more conservative treatment. In addition, the number of patients included in the present study was small, so further prospective studies are necessary.
The results of the present study revealed that patients with second pCS were more frequently diagnosed at an older age and had a worse prognosis compared with patients with initial pCS. For patients with initial and second pCS, surgery was the main treatment method.
Acknowledgements
Not applicable.
Funding
The present study was supported by grant from the Tongji University (grant no. 1501219143) and the National Natural Science Foundation of China (grant no. 81001134.
Availability of data and materials
All the data generated or analyzed during the present study are included in this published article.
Authors' contributions
WM, JF and JG designed the research. HY and MK acquired the data. DW, XH and XY analyzed the results. WM wrote the article. JF and JG revised and provided critical comments. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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