Chondrosarcoma is the second most common primary bone malignancy in the United States, representing approximately 2,000 new cases every year [
Despite being classified by some clinicians as resistant to chemotherapy and radiation therapy, one retrospective series from Princess Margaret Hospital suggested that the addition of standard doses (50 Gy) of radiation therapy to surgery leads to improved outcomes [
Given the low incidence of these tumors and the presumption of radioresistance by some clinicians, there are limited studies of large cohorts to assess the effect of radiotherapy on survival outcomes in chondrosarcoma patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to characterize the use of radiotherapy in CS patients. The NCDB is the most complete tumor registry available, capturing 70% of all newly diagnosed cancers in the United States [
The institutional review board of our institution approved this retrospective analysis of the NCDB for patients diagnosed with chondrosarcomas from 2004 to 2015. The NCDB Participant User File was searched for patients treated at NCDB-participating institutions with a primary histologic diagnosis of chondrosarcoma, treated with radiotherapy, with a reported dose and delivery modality. Radiation modalities included conventional EBRT as well as intensity-modulated radiation therapy (IMRT), proton-beam therapy (PBT), and stereotactic radiosurgery (SRS), which were all categorized as advanced modalities, given a more precise delivery of radiation to tumor tissue. The patients were identified using the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) topography codes C41.0 (bones and joints: skull, face bones), C41.2 (bones and joints: vertebral column), C41.4 (bones and joints: pelvis, sacrum, coccyx), and C40.0, C40.1, C40.2, C40.3, C40.8, and C40.9 (all bones, joints, and articular cartilage of limbs).
Data from the NCDB were available to use from 2004 to 2015. Exclusion criteria included patients that did not have a primary chondrosarcoma, patients with mesenchymal chondrosarcoma, patients with additional secondary malignancies (sequence number >1), and patients for whom it was unknown if they received beam radiation therapy. From the NCDB dataset, 5,427 chondrosarcomas were identified meeting criteria of which 680 were treated with radiotherapy at the reporting facilities between 2004 and 2015 and met our study criteria.
The chondrosarcoma patients were first divided by radiation modality (conventional (EBRT) vs. advanced (IMRT, PBTE, and SRS)). Patient characteristics, tumor characteristics, and treatment characteristics were compared between the different treatment groups. The following variables were compared: (1) patient characteristic variables: age, sex, race, Charlson Comorbidity Score (CCS), income (based on the average income level in the zip code of the patient’s home), facility type (academic/research program or community cancer program), and insurance status (none, private insurance, and government insurance including Medicare and Medicaid); (2) tumor characteristic variables: tumor size, tumor grade, and tumor site; and (3) treatment variables: surgical resection, surgical margin status, type of radiotherapy (as mentioned above), and radiation dose (<40, 40–60, and >60 Gy). In patients receiving less than 40 Gy of radiation, it was inferred this treatment was given with a palliative, rather than curative intent. The other groups were considered high-dose (>60 Gy) and low-dose (40–60 Gy) groups if the radiation modality was a type other than stereotactic radiosurgery (SRS), as this group receives lower cumulative doses in higher individual-dose fractions.
Demographic, clinical, and outcome data were compiled and presented utilizing descriptive statistics. Patient cohorts were identified by whether or not they received radiation, whether the radiation modality was conventional or advanced, and by whether the radiation dose the patient received was considered high-, low-, or palliative. Patient groups with different radiotherapy modalities for chondrosarcoma were assessed for differences in patient, tumor, and treatment characteristics using Fisher’s exact and Pearson’s chi-square tests for categorical variables and two-tailed
Multivariate proportional hazards analysis was used to identify patient, tumor, and treatment characteristics associated with increased mortality. Multiple imputation for missing data included all patient, tumor, and treatment variables examined in the analysis, as well as survival time and censoring data. Twenty imputations were performed and used in proportional hazards regression. Variables included in the base model were age (above or below median of 53 years), sex, race, Charlson Comorbidity Score, insurance type (private, government, or none), income (above or below median), facility type (academic or community), tumor size, grade, metastases at diagnosis, surgery and margin status, radiation type, and chemotherapy. Radiation types were grouped by both modality (advanced or conventional) and dose (high, low, or palliative). In a second model, the analysis was repeated including an interaction term between radiation and margin status, in which patients with positive margin status who received radiation therapy were compared to those with positive margins who did not receive adjuvant radiation. In a third model, radiation modality groups compared EBRT and IMRT together against PBT. Hazard ratios and 95% confidence intervals were computed for all covariates, with
A total of 5,427 patients with a histologic diagnosis of chondrosarcoma were identified. 52% were located in the appendicular skeleton, while 18% were within the pelvis and 4% in the spine, consistent with the previously published data. Of all the identified CS patients, 680 received some form of radiation therapy (13%).
Table
Patient characteristics.
|
No radiation ( |
Radiation ( |
High dose >60 Gy ( |
Low dose 40–60 Gy ( |
Palliative <40 Gy ( |
Conventional ( |
Advanced ( | |
---|---|---|---|---|---|---|---|---|
Age, mean (SD) in years | 52 (52-53) |
55 (53–56) |
52 (50–54) |
58 (55–60) |
60 (56–63) |
58 (56–60) |
50 (48–53) |
|
|
||||||||
Gender | Female | 2272 (48) | 308 (45) | 102 (45) | 91 (45) | 52 (49) | 139 (47) | 110 (45) |
|
||||||||
Race | Asian | 116 (3) | 18 (3) | 4 (2) | 6 (3) | 3 (3) | 6 (2) | 8 (3) |
Black | 319 (7) | 49 (7) | 10 (4) | 15 (7) | 12 (11) | 21 (7) | 14 (6) | |
White | 4129 (89) | 595 (89) | 209 (92) | 179 (89) | 89 (85) | 262 (90) | 215 (90) | |
|
||||||||
Hispanic ethnicity | 343 (8) |
67 (10) |
27 (12) | 17 (9) | 10 (10) | 27 (10) | 26 (11) | |
|
||||||||
Comorbidity | 0 | 3964 (84) | 559 (82) | 183 (80) | 165 (81) | 91 (85) | 235 (80) | 212 (87) |
1 | 616 (13) | 92 (14) | 37 (16) | 28 (14) | 12 (11) | 48 (16) | 24 (10) | |
>1 | 167 (4) | 29 (4) | 8 (4) | 11 (5) | 4 (4) | 11 (4) | 9 (4) | |
|
||||||||
Insurance | Private | 2777 (61) |
361 (54) |
122 (54) | 107 (53) | 47 (44) | 140 (48) | 150 (62) |
Government | 1564 (34) |
276 (41) |
87 (39) | 85 (42) | 55 (51) | 130 (45) | 84 (35) | |
None | 220 (5) |
35 (5) |
17 (8) | 9 (4) | 5 (5) | 21 (7) | 9 (4) | |
|
||||||||
Income above median | 2791 (60) | 416 (62) | 142 (62) | 119 (59) | 64 (60) | 173 (59) | 157 (64) | |
|
||||||||
Academic facility type | 2375 (66) |
281 (54) |
100 (60) |
74 (44) |
50 (56) |
114 (47) |
107 (64) |
For each value, the (%) reflects only the proportion of patients with known values for each variable (unknown values not included in %). Statistical comparisons included RT vs. none, palliative vs. low vs. high doses (non-SRS modalities), and conventional vs. advanced modalities. Fisher’s exact or Pearson chi-square tests were performed for categorical variables. Two-tailed t-test or ANOVA performed for numerical variables (age). Statistical significance indicated by
Tumor and treatment characteristics.
|
No radiation ( |
Radiation ( |
High dose >60 Gy ( |
Low dose 40–60 Gy ( |
Palliative <40 Gy ( |
Conventional ( |
Advanced ( | |
---|---|---|---|---|---|---|---|---|
Tumor size ≥ 5 cm | 2628 (66) |
325 (61) |
100 (53) |
122 (75) |
59 (76) |
168 (71) |
86 (45) |
|
|
||||||||
Tumor site | Axial | 2012 (44) |
507 (78) |
180 (83) |
141 (73) |
63 (64) |
190 (69) |
221 (92) |
Appendicular | 2600 (56) |
140 (22) |
37 (17) |
53 (27) |
36 (36) |
84 (31) |
20 (8) |
|
|
||||||||
Grade | Low | 1868 (45) |
144 (27) |
57 (30) |
36 (24) |
11 (13) |
48 (21) |
69 (35) |
Intermediate | 1541 (37) |
235 (45) |
90 (47) |
68 (46) |
36 (44) |
102 (45) |
94 (48) |
|
High | 773 (18) |
146 (28) |
43 (23) |
44 (30) |
35 (43) |
79 (35) |
34 (17) |
|
|
||||||||
Metastases at diagnosis | 191 (4) |
73 (11) |
7 (3) |
18 (9) |
43 (42) |
48 (17) |
9 (4) |
|
|
||||||||
Surgery | 4328 (91) |
513 (75) |
190 (83) |
152 (75) |
56 (52) |
201 (68) |
199 (81) |
|
|
||||||||
Margin | Positive | 415 (12) |
168 (44) |
68 (49) |
42 (34) |
15 (38) |
60 (38) |
80 (60) |
|
||||||||
Chemotherapy | 249 (5) |
91 (14) |
19 (9) |
27 (14) |
28 (26) |
48 (17) |
18 (8) |
For each value, the (%) reflects only the proportion of patients with known values for each variable (unknown values not included in %). Statistical comparisons included RT vs. none, palliative vs. low vs. high doses (non-SRS modalities), and conventional vs. advanced modalities. Fisher’s exact or Pearson chi-square tests were performed for categorical variables. Two-tailed t-test or ANOVA was performed for numerical variables (age). Statistical significance indicated by
Tables
Distributions for total radiation doses (top row) as well as fraction doses (bottom row) for each radiation modality. Stereotactic radiosurgery (SRS) is typically given as high-dose fractures for a lower total dose.
The 5-year survival rates of those receiving high-dose (>60 Gy) RT were 70%, significantly higher than the 57% survival rate of low-dose (40–60 Gy) RT (
Kaplan–Meier curves comparing survival between radiation treatment groups, stratified by (a) modality and (b) dose. Modalities included EBRT, IMRT, PBT, and SRS. Dose groups included high-dose (>60 Gy), low-dose (40–60 Gy), and palliative (<40 Gy). Modality and dose distributions shown to the left of survival curves. Log-rank tests comparing treatment groups included in KM curve inset, with alpha = 0.05.
Kaplan–Meier curves comparing survival for patients who received no RT and those who received conventional RT (EBRT) or advanced modality RT (IMRT, PBT, and SRS). (a) Overall 5-year survival rates were compared, as well as 5-year survival rates in patient groups with (b) positive or (c) negative surgical margins after resection.
In a multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, older age, male sex, comorbidity score >1, government insurance rather than private, nonacademic facility type, larger tumor size, higher tumor grade, lack of surgery, or positive margin surgery were all associated with worse survival. While overall RT and chemotherapy were not associated with improved survival (HR 0.96, 95% CI 0.76–1.20 for RT; HR 1.20, 95% CI 1.00–1.44 for chemotherapy), when examining just the patient cohort with positive margins, RT overall trended towards improved survival (HR 0.81, 95% CI 0.58–1.13). Compared to advanced modality RT, conventional RT was associated with significantly increased mortality, though advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (Figure
Multivariate Cox proportional hazards regression for independent predictors of mortality in patients with chondrosarcoma. Forest plot of hazard ratios and 95% confidence intervals displayed for patient, tumor, and treatment variables. Base model performed with radiation type variable categorized by both radiation modality and dose. 2Model repeated to assess the impact of margin status on the survival effect of radiation therapy. 3Radiation modalities of EBRT and IMRT were combined and compared with PBT.
As demonstrated by our review of the NCDB, despite the suggested radioresistance of chondrosarcoma, radiotherapy should be strongly considered for these patients, especially those with tumors located in difficult areas for radical resection, such as the skull base, spine, and pelvis, which are anatomic sites with a high percentage of positive margins after resection. While surgical resection should be performed with the intent of obtaining negative margins, there remains the risk of compromised function and significant morbidity when operating in these anatomic areas. Our results support a role for radiation therapy in selected high-risk CS patients with tumors in surgically challenging locations or for unplanned positive margins. Furthermore, the utilization of advanced modalities with radiation dose greater than 60 Gy in these patients is associated with an overall survival benefit.
Wide resection to achieve negative margins remains the gold standard treatment of chondrosarcoma to maximize overall patient survival and limit local recurrence [
While there is an established benefit of adjuvant radiation therapy on local recurrence of wide resection of limb soft tissue sarcomas with negative margins, Delaney et al. reported its use specifically in cases with positive margins, demonstrating improved survival and lower recurrence rates for those treated with radiation therapy [
The majority of reports of radiation therapy for chondrosarcoma have focused on skull base tumors. Given the proximity of skull base tumors to the brainstem and other cranial structures, achieving negative margins can be difficult, and the need for precise adjuvant radiation therapy is essential. As validated by our review of the NCDB, head and skull base tumors are the most common CS to receive RT. Several studies have reported positive results of adjuvant radiotherapy in skull base CS, despite its reported radioresistance [
In cases where residual tumor remains after resection given proximity to vital structures, IMRT and/or proton therapy may provide adjuvant therapy that improves survival and local recurrence rates. Recent literature has begun to investigate the use of radiation therapy in these settings; however, patient cohorts remain small given the rarity of these tumors [
Through our review of the NCDB, when treated with RT, patients with positive margins have improved survival rates when advanced modalities, such as IMRT or PBT, are utilized, with a trend towards improved survival with higher radiation doses. This highlights the importance for patients to be evaluated by radiation oncologists with experience treating sarcomas to consider the potential use of advanced modalities and higher radiation doses to sterilize tumor margins while preserving critical structures to minimize the risk of toxicity.
Although the results of our investigation are encouraging, they are not without limitations. The NCDB does not report local recurrence rates. As survival of these patients depends on metastases and other patient variables, local recurrence may provide a more straightforward indicator of the success of local adjuvant therapy, as the direct impact of radiation therapy on overall survival is difficult to surmise. Other important factors not considered in this analysis include reoperation and rehospitalization rate, as well as quality of life and functional scores. Assessing our treatment groups, although SRS is identified as an advanced modality, it is difficult to interpret the effect stratified by dose. SRS is given with a high daily radiation dose; however, the total overall dose is less than either IMRT or PBT and for this reason was excluded from the dosage analysis. In addition, for the cohort of patients with positive margins, microscopic vs. gross residual disease is not specified. This may lead to patients classified within the same cohort (positive surgical margins) having different baseline prognoses and potentially skew the survival rates.
Furthermore, the NCDB dataset is not complete for all patients included in our analyses. Patients without specific data for variables were not included in those comparisons. Given the retrospective nature of our study, many of our conclusions are inferred from the collected data. These inferences provide starting points for future studies; however, in order to truly assess the usefulness of radiation therapy in chondrosarcoma, prospective studies of larger cohorts are needed to validate these findings and investigate local recurrence rates.
Given the difficulty of obtaining negative margins in CS of the pelvis and axial skeleton, effective adjuvant therapies are imperative to improving outcomes and survival rates. With advances of radiation therapy allowing improved precision of higher radiation doses adjacent to normal critical structures, our results correlating improved survival with RT suggest that it may be a useful adjuvant modality in selected CS patients with positive margins. Successful use of these modalities may not only preserve critical structures but also allow for less morbid resections and improved limb salvage options. Larger, prospective studies focusing on advanced modalities of RT with high dose for CS of the axial skeleton and pelvis are needed to better define the role of RT in these patients.
The patient data used to support the findings of this study may be released upon application to the National Cancer Database Participant User File, who can be contacted at
This manuscript was previously presented at the 2018 Musculoskeletal Tumor Society Annual Meeting in New York, NY.
David G. Kirsch, M.D., Ph.D., is on the scientific advisory board and owns stock in Lumicell Inc., which is commercializing intraoperative imaging technology for which he holds a patent and is a cofounder and owns stock in XRAD Therapeutics, which is developing radiation sensitizers for which he has filed a patent. All other authors or any member of his or her immediate family have no funding or commercial associations (e.g., consultancies, stock ownership, equity interest, and patent/licensing arrangements) that might pose a conflict of interest in connection with the submitted article.