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Open Access

Treatment patterns and survival among older adults in the United States with advanced soft-tissue sarcomas

Clinical Sarcoma Research20188:8

https://doi.org/10.1186/s13569-018-0094-x

Received: 27 October 2017

Accepted: 26 February 2018

Published: 3 May 2018

Abstract

Background

To describe patient and tumor characteristics, treatments, and survival among older adults in the United States with advanced soft-tissue sarcoma (STS), across and by categories of specifically defined histologic subtypes.

Methods

We conducted a retrospective cohort analysis using the SEER. The study population comprised patients ≥ 65 years old with advanced STS (excluding osteosarcoma, Kaposi sarcoma, and gastrointestinal stromal tumors) diagnosed from January 1, 2001 to December 31, 2011.

Results

Of 4274 study patients, 2103 (49.2%) were male. Mean age was 77.8 years, and 1539 (36.0%) had distant disease at initial diagnosis. The most common histologic categories were leiomyosarcoma (922[21.6%]), undifferentiated pleomorphic sarcoma (652[15.3%]), and liposarcoma (554[13.0%]). Overall, 1227 (28.7%) patients received first-line systemic therapy. Among these patients, 325 (26.5%) received docetaxel plus gemcitabine and 231 (18.8%) received doxorubicin alone. Only 476 patients received second-line therapy (11.1%), most commonly doxorubicin alone (n = 101). Median overall survival (95% confidence interval) from advanced STS diagnosis was 8.9 (8.3, 9.7) months.

Conclusions

Although previous studies of younger populations reported anthracycline-based therapy predominated in first line, our study of older advanced STS patients found that docetaxel plus gemcitabine was most commonly used. Despite variation by histologic category, prognosis remains poor for older adult patients with advanced STS.

Keywords

Soft-tissue sarcomaChemotherapyObservational study

Background

Soft-tissue sarcoma (STS) refers to a rare and heterogeneous group of malignant tumors comprising more than 50 histologic subtypes derived from connective tissues and other cells of mesenchymal origin. Soft-tissue sarcoma accounts for approximately 1% of all incident malignancies [1] and an estimated 13,040 new cases will be diagnosed in the United States (US) in 2018, with 7370 dying from the disease [2]. In 2014, the age-adjusted incidence rate, for STS for patients 65 years of age and older was 11.3 per 100,000, compared to 2.3 per 100,000 for patients younger than 65 years of age [3].

Among all patients diagnosed with STS, the 5-year overall survival is approximately 50% [4]. Tumor histology, stage, and primary site are prognostic factors [4, 5]; 5-year overall survival is 83% in patients with localized disease and 16% in patients with distant metastases at initial diagnosis [6]. Eventually, either at initial diagnosis or after recurrence from a more limited extent of disease, 40–50% of patients with STS will have metastatic or unresectable locally-advanced disease (collectively referred to as “advanced STS”) [7].

Treatment options for patients with advanced STS have historically been limited; cytotoxic chemotherapy has been the mainstay of therapy for decades. Active drugs include doxorubicin, ifosfamide, gemcitabine, taxanes, and several others; these may be administered either as single agents or in combination regimens [4, 8]. The intent of these treatments is palliative for the majority of patients [4, 8, 9]. Until recently, clinical trials—including those demonstrating superiority of combination chemotherapy over monotherapy and those leading to the regulatory approval of newer agents such as olaratumab, trabectedin, and pazopanib—have found improvements in response rates and progression-free survival [4, 1014]. However, olaratumab is the only newer agent to date that has also demonstrated a statistically significant improvement in overall survival [11].

Few studies have examined utilization of systemic treatments for STS in the general population of the US, especially in older patients with advanced disease. Furthermore, there is little published information on variation in outcomes according to tumor histology, especially among older adults. Thus, the objectives of this study were to describe real-world, population-based treatment patterns and survival among older adult patients with advanced STS, overall and by groupings of specific histologic subtypes (hereafter “histologic categories”).

Methods

Data source

The Surveillance, Epidemiology, and End Results (SEER), which contains administrative claims data for Medicare enrollees, was used for the study. The SEER cancer registry comprises nine state population-based and seven metropolitan or regional population-based registries that routinely collect information on 98% of newly diagnosed (incident) cancer cases, in persons residing in SEER areas [15]. SEER areas have been shown to be nationally representative [16] and capture approximately one-quarter of the total US population [15].

Along with detailed information on incident cancer, the database provides comprehensive longitudinal health care utilization data from Medicare. The Medicare claims database provides information on all services covered under Medicare Part A benefits, including inpatient, skilled nursing facility, home health care, and hospice care. In addition, the database provides information on approximately 95% of services covered under Medicare Part B, including physician visits, outpatient care, durable medical equipment, and home health care. This study was deemed exempt from Institutional Review Board review in accordance with the US Code of Federal Regulations [45CFR46.101(b)] as these data do not contain any variables that could identify an individual subject either directly or indirectly.

Study population

Patients with a new diagnosis of STS between January 1, 2001 and December 31, 2011 were eligible for this study. Medicare claims data were available through 2013. Patients with STS (except osteosarcoma, Kaposi sarcoma, and gastrointestinal stromal tumors) were identified in the SEER database using International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3), morphology codes as listed in Appendix 1: Table 6 [17]. In order to reduce the number of strata analyzed specific histologic subtypes (i.e., individual ICD-O-3 codes) were grouped into broader categories for analysis based on the 2013 World Health Organization’s (WHO) Classification of Tumours of Soft Tissue and Bone [18]: (1) leiomyosarcoma (smooth muscle tumors), (2) undifferentiated pleomorphic sarcoma (UPS; previously known as malignant fibrous histiocytoma), (3) liposarcoma (adipocytic tumors), (4) vascular sarcomas, (5) fibroblastic/myofibroblastic sarcoma, (6) nerve sheath sarcoma, (7) rhabdomyosarcoma (skeletal muscle tumors), (8) synovial sarcoma, and (9) others or not otherwise specified (NOS). The term “histologic category” was used in this study to distinguish these categories from the individual “histologic subtypes” they contain.

Advanced disease was defined as metastatic disease or as the presence of nodal metastases and no surgery (assuming patients who did not receive surgery were not suitable for surgical resection). Metastatic disease and nodal metastases were identified using the American Joint Commission on Cancer’s Cancer Staging Manual [19] or the National Cancer Institute’s (NCI’s) SEER Summary Staging Manual [20]. Patients were also considered to have advanced STS if they had an initial diagnosis of localized disease with later progression to advanced STS as identified by either a medical claim with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis code for a secondary neoplasm (ICD-9-CM 196.0-198.89) or initiation of systemic therapy more than 6 months after surgery. The 6-month lag period was chosen to avoid interpreting adjuvant therapy as treatment for advanced disease.

Additionally, eligible patients were 65 years or older at the time of advanced STS diagnosis and were enrolled in both Medicare parts A and B without any health maintenance organization (HMO) enrollment from 6 months before initial STS diagnosis to death or end of study. Patients with HMO coverage (provided outside of the Medicare system) were excluded because claims data for these patients would not be complete, as the linked data for this study were limited to Medicare. Of the patients initially diagnosed with localized or regional disease according to SEER data, only those with evidence of advanced STS in Medicare claims that occurred at a date later than the initial STS diagnosis were included in the study (i.e., patients were excluded if there were contradictory initial diagnosis codes [i.e., localized or regional STS diagnosis and secondary neoplasm claims] on the same date, or if patients had no surgery after initial STS diagnosis and no secondary neoplasm claim). Study index date for each patient (start of follow-up) was defined as the date of the first observed evidence of advanced STS.

Demographic and clinical characteristics

Demographic characteristics including age, sex, race, SEER registry location, and urban or rural residency were tabulated. Clinical characteristics that were assessed at initial STS diagnosis included cancer stage, tumor location, and histologic subtype (with subsequent categorization described previously). We also computed a modified Charlson Comorbidity Index (CCI) score to obtain a measure of each patient’s overall comorbidity burden at the time of the index diagnosis [2123]. CCI scores were calculated for each patient based on evidence of the relevant diagnoses from 6-months prior to advanced STS diagnosis to advanced STS diagnosis (i.e., during 6-month pre-index date period). ICD-9-CM diagnosis codes for cancer were excluded from the CCI calculation for this study so as to not overestimate the baseline comorbidity burden, as all patients in this study had cancer.

Treatment patterns

Treatments were identified using evidence of relevant Healthcare Common Procedure Coding System (HCPCS) codes, ICD-9-CM procedure codes, and certain ICD-9-CM diagnostic codes and administrative revenue codes. In addition to HCPCS and ICD-9-CM codes, Medicare Part D prescription data were used to identify chemotherapy use for a subset of the cohort with this data (2007–2012). Among patients who received systemic treatment, up to five lines of treatment were identified. Specific therapies were examined based upon options included in the National Comprehensive Cancer Network (NCCN) Guidelines [24]. First-line treatment was examined among all patients, with at least one claim for an HCPCS-identifiable chemotherapeutic, biologic, or targeted therapy agent after their index date. The first observed date of treatment after the index date signaled the start of first-line treatment. First-line treatment was defined as the combination of all agents observed within 21 days after (and inclusive of) treatment initiation. After the end of this 21-day period, the use of any new agent signaled the start of the next line of treatment. Discontinuation of one or more of the agents without the addition of another agent was not considered a new line of treatment. In addition, patients with at least 6 months between apparent cessation of their previous line of treatment and reuptake of an identical regimen were defined as having initiated a next line of treatment. End of a line of treatment was defined as: (1) a 6-month gap in treatment regimen, (2) interruption by next line of treatment, or (3) treatment continuation until the end of study or death. Cancer-directed therapy was defined as receipt of any of broad treatment categories of surgery, radiation, chemotherapy, biologic therapy, or targeted therapy, while supportive care was defined as no receipt of treatment from any of the broad cancer-directed therapies.

Statistical analyses

Descriptive statistics [i.e., means, medians, ranges, and standard deviations (SDs) of continuous variables and frequency counts and percentages for categorical variables] were computed. Overall survival from advanced STS diagnosis was measured using the death information available from SEER and Medicare data, and survival time end points were analyzed using the Kaplan–Meier estimates with median survival time and 95% confidence intervals (CIs) reported in months. Patients alive at the end of study period were censored for this analysis. Treatment patterns and survival were assessed in the overall advanced STS population and by histologic category. Additionally, survival was estimated separately for patients who received cancer-directed treatment and those who received supportive care only. All analyses were conducted using SAS Version 9.4 (Cary, NC: SAS Institute, Inc.; 2011). The SEER-Medicare data use agreement required that no cell sizes less than 11 be reported for any demographic or other characteristic, or combination of characteristics; thus, if sufficient sample size was not available, data were not reported and indicated with “–”.

Results

A total of 4274 patients with advanced STS met the inclusion criteria for this study (Table 1). Patients were on average 77.8 years of age (SD, 7.3; range 65–104 years) at the time of advanced STS diagnosis and 49.2% were male (Table 2). The mean (SD) CCI score was 2.8 (2.33), and 69.2, 18.3, and 6.5% of patients had a history of hypertension, congestive heart failure, and myocardial infarction, respectively.
Table 1

Study population selection process

 

Number of patients

Initial sample included in the SEER database

142,689

Initial diagnosis date on or after January 1, 2001

135,608

Patients whose first diagnosis recorded in the SEER database was STS

21,167

Patients with evidence (i.e., claim in Medicare data or diagnosis in SEER database) of metastatic disease

8537

 Initially diagnosed at metastatic stagea

3391

 Initially diagnosed at non-metastatic stagea

5146

Patients 65 years or older at time of metastatic STS diagnosis

6712

Patients who were alive at initial diagnosis of STS (i.e., reporting source other than autopsy or death certificate)

6705

Patients who were not enrolled in an HMO for at least 6 months prior to initial diagnosis of STS to end of follow-up period

5166

Patients who have continuous enrollment in Medicare Part A and B (non-HMO) for at least 6 months prior to initial diagnosis of STS until end of follow-up period

4353

Patients who are not lost to follow-up prior to the assigned advanced STS diagnosis dateb

4324

Patients with a date of advanced STS diagnosis different than initial STS diagnosis (patients excluded if no surgery after initial STS diagnosis and no secondary neoplasm claim)

4298

Patients with a date of advanced STS diagnosis different than initial STS diagnosis (patients excluded if initial STS diagnosis and secondary neoplasm claim on the same date)

4274

Final study population

4274

HMO health maintenance organization, SEER Survey, Epidemiology, and End Results, STS soft-tissue sarcoma

aOnly for descriptive purposes and no exclusion was made based on this criterion

bDay of diagnosis, which is reported as month and years, was assigned as 15th of each month and hence some patients who either die or are lost to follow-up before the 15th of the month have a negative length of follow-up

Table 2

Patient and tumor characteristics, overall and by histologic categories

 

All patients

Leiomyo-sarcomas

Undifferentiated pleomorphic sarcoma

Liposarcomas

Vascular sarcomas

Fibroblastic/myofibroblastic sarcomas

Nerve sheath sarcomas

Rhabdomyo-sarcomas

Synovial sarcomas

Others/NOS

N

4274

922

652

554

357

227

106

98

49

1309

Sex (n, %)

 Male

2103 (49.2)

307 (33.3)

390 (59.8)

329 (59.4)

195 (54.6)

122 (53.7)

64 (60.4)

43 (43.9)

28 (57.1)

625 (47.8)

 Female

2171 (50.8)

615 (66.7)

262 (40.2)

225 (40.6)

162 (45.4)

105 (46.3)

42 (39.6)

55 (56.1)

21 (42.9)

684 (52.2)

Race

 White

3729 (87.3)

783 (84.9)

576 (88.3)

499 (90.1)

309 (86.6)

203 (89.4)

96 (90.6)

82 (83.7)

43 (87.8)

1138 (86.9)

 Black

337 (7.9)

106 (11.5)

46 (7.1)

23 (4.2)

21 (5.9)

106 (8.1)

 Other

197 (4.6)

31 (3.4)

26 (4.0)

32 (5.8)

25 (7.0)

63 (4.8)

Age at advanced diagnosis

 Mean (SD)

77.8 (7.3)

76.8 (7.2)

79.4 (7.2)

77.5 (7.1)

78.2 (7.5)

77.8 (7.1)

77.7 (7.6)

76.8 (7.3)

74.1 (6.5)

78.0 (7.4)

 Median

77.4

76.1

79.7

76.6

77.9

77.8

77.3

76.6

73.5

77.5

 Min, Max

65.0, 104.1

65.0, 102.9

65.1, 99.3

65.1, 96.8

65.6, 101.8

65.7, 97.4

65.5, 95.9

65.3, 95.3

65.7, 91.0

65.1, 104.1

Pre-index date Charlson Comorbidity Index (CCI) scorea

 Mean (SD)

2.8 (2.3)

2.5 (2.2)

2.8 (2.4)

2.8 (2.3)

2.9 (2.7)

2.8 (2.2)

2.8 (2.3)

2.6 (2.1)

3.0 (2.3)

2.8 (2.4)

 Median

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

 Min, Max

0.0, 15.0

0.0, 14.0

0.0, 15.0

0.0, 12.0

0.0, 12.0

0.0, 11.0

0.0, 10.0

0.0, 9.0

0.0, 8.0

0.0, 15.0

Stage of disease at initial diagnosis of STS (n, %)

 Localized

1731 (40.5)

345 (37.4)

379 (58.1)

260 (46.9)

150 (42.0)

121 (53.3)

36 (34.0)

25 (25.5)

18 (36.7)

397 (30.3)

 Regional—direct extension only

938 (22.0)

200 (21.7)

135 (20.7)

177 (32.0)

62 (17.4)

59 (26.0)

32 (30.2)

14 (14.3)

11 (22.5)

248 (19.0)

 Regional—lymph nodes involved only

29 (0.7)

0 (0.0)

 Regional—direct extension and lymph nodes

37 (0.9)

0 (0.0)

 Distant

1539 (36.0)

363 (39.4)

133 (20.4)

114 (20.6)

138 (38.7)

45 (19.8)

36 (34.0)

53 (54.1)

20 (40.8)

637 (48.7)

Grade of cancer at time of initial diagnosis of STS (n, %)

 Well or moderately differentiated (grade 1 or 2)

646 (15.1)

152 (16.5)

36 (5.5)

239 (43.1)

40 (11.2)

50 (22.0)

116 (8.9)

 Poorly differentiated (grade 3)

908 (21.2)

192 (20.8)

151 (23.2)

101 (18.2)

81 (22.7)

35 (15.4)

16 (32.7)

294 (22.5)

 Undifferentiated (grade 4)

1310 (30.7)

250 (27.1)

228 (35.0)

129 (23.3)

61 (17.1)

63 (27.8)

28 (26.4)

34 (34.7)

510 (39.0)

 Unknown

1410 (33.0)

328 (35.6)

237 (36.4)

85 (15.3)

175 (49.0)

79 (34.8)

54 (50.9)

39 (39.8)

24 (49.0)

389 (29.7)

Total follow-up time (years)b

 Mean (SD)

1.7 (2.4)

1.8 (2.2)

2.0 (2.8)

2.6 (2.8)

1.1 (1.7)

2.5 (2.7)

1.4 (2.1)

0.8 (1.5)

1.4 (1.8)

1.3 (2.0)

 Median

0.7

1.0

0.8

1.5

0.5

1.6

0.5

0.3

0.6

0.5

 Min, Max

0.0, 12.8

0.0, 12.2

0.0, 12.3

0.0, 12.3

0.0, 12.5

0.0, 12.5

0.0, 9.9

0.0, 9.8

0.0, 8.8

0.0, 12.8

ICD-9-CM International Classification of Diseases, 9th Revision, Clinical Modification, Max maximum, Min minimum, NOS not otherwise specified, SD standard deviation, STS soft-tissue sarcoma

aBecause the objective of the CCI score was to evaluate underlying comorbidity burden independent of STS, ICD-9-CM diagnosis codes for cancer were excluded from the CCI calculation for this study

bFollow-up time calculated as the number of months between the study index date (first diagnosis of advanced STS) and the earliest of death, loss of eligibility, or end of the Medicare database (December 31, 2013)

At initial diagnosis, 36.0% of patients had metastatic (distant) disease; the remaining majority (64.0%) were diagnosed at earlier stages of disease and had claims based indicators of progression to advanced STS (Table 2) with a mean (SD) interval of 16.6 (23.0) months from initial diagnosis. Nodal disease (without any distant metastases) was observed only among 1.6% of patients at initial diagnosis. The most common histologic category was leiomyosarcoma (n = 922; 21.6%), followed by UPS (n = 652; 15.3%), liposarcoma (n = 554; 13.0%), vascular sarcoma (n = 357; 8.4%), fibroblastic/myofibroblastic sarcoma (n = 227; 5.3%), nerve sheath sarcoma (n = 106; 2.5%), rhabdomyosarcoma (n = 98; 2.3%), and synovial sarcoma (n = 49; 1.1%); the remaining 30.6% (n = 1309) had other or NOS histologic categories. A few variations in patient and tumor characteristics by tumor histology were evident: 66.7% of patients with leiomyosarcoma were female; patients with synovial sarcoma had a mean age of 74.1 years, and 54.1, 40.8, 48.7% of patients with rhabdomyosarcoma, synovial sarcoma, and other/NOS histology, respectively, had distant stage of disease at initial STS diagnosis (Table 2). Overall, the most common specified anatomic tumor site was lower limb (21.9%) (Appendix 2: Table 7), and the most common known tumor grade was undifferentiated (30.7%) (Table 2). The average observed follow-up time from advanced STS diagnosis was 1.7 years (SD, 2.36) (Table 2).

Cancer-directed treatment was received by 62.1% of patients. Radiation was received by 40.0% of patients and surgery was received by 10.3% of patients. The mean (SD) age of patients who received cancer-directed treatment was 76.5 (6.9) years and the mean (SD) CCI score was 2.5 (2.1), with hypertension, diabetes (without complications), chronic pulmonary disease, peripheral vascular disease, and congestive heart failure observed among 68.9, 28.4, 24.4, 18.1, and 14.6% of patients, respectively (Additional file 1: Table S1). Chemotherapy, biologic therapy, and targeted therapy were received by 27.5, 1.9, and 1.3% of patients, respectively. Among the 28.7% of all patients with advanced STS who received chemotherapy, biologic therapy, or targeted therapy (n = 1227), the mean duration of first-line therapy was 4.1 months (SD, 4.1) (Table 3). Second-line therapy was received by 11.1% (n = 476) of all patients; the mean duration of second-line treatment was 4.6 months (SD, 5.3). Among the 4.4% of all patients with advanced STS who received at least third-line therapy (n = 189), the mean duration of third-line therapy was 4 months (SD, 3.4). The proportion of patients receiving up to three lines of treatment and duration of each line of treatment by histologic category is shown in Table 3. First-line chemotherapy was most commonly received by patients with synovial sarcoma (42.9%), leiomyosarcoma (37.0%), and vascular sarcoma (36.4%).
Table 3

Treatment line progression, overall and by histologic categories

 

Histologic categories

All patients

Leiomyo-sarcomas

Undifferentiated pleomorphic Sarcoma

Liposarcomas

Vascular sarcomas

Fibroblastic/myofibroblastic sarcomas

Nerve sheath sarcomas

Rhabdomyo-sarcomas

Synovial sarcomas

Others/NOS

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

n (%)

All patients

4274

922

652

554

357

227

106

98

49

1309

Receiving first-line systemica treatment

1227 (28.7)

341 (37.0)

158 (24.2)

140 (25.3)

130 (36.4)

58 (25.6)

24 (22.6)

28 (28.6)

21 (42.9)

327 (25.0)

Duration, mean (SD)

4.1 (4.1)

4.1 (4.2)

4.4 (5.7)

4.3 (4.7)

4.4 (3.4)

4.2 (3.8)

3.3 (2.5)

4.5 (2.9)

3.9 (3.3)

3.8 (3.2)

Median

3.0

3.1

2.6

3.0

3.5

3.6

3.1

3.7

3.0

2.8

Receiving second-line systemica treatment

476 (11.1)

148 (16.1)

64 (9.8)

45 (8.1)

60 (16.8)

19 (8.4)

15 (15.3)

109 (8.3)

Duration, mean (SD)

4.6 (5.3)

4.5 (4.0)

5.1 (8.6)

5.5 (5.4)

4.6 (5.2)

4.7 (3.6)

3.2 (2.2)

4.3 (4.7)

Median

3.0

3.3

2.9

4.0

3.4

4.8

2.6

2.9

Receiving third-line systemica treatment

189 (4.4)

66 (7.2)

24 (3.7)

15 (2.7)

21 (5.9)

46 (3.5)

Duration, mean (SD)

4.0 (3.4)

4.6 (3.6)

3.3 (3.8)

2.8 (2.2)

5.1 (3.6)

3.4 (2.8)

Median

3.0

3.7

2.3

2.1

5.1

2.6

Oral chemotherapy was not covered by Medicare until 2007

SD standard deviation

aSystemic therapy includes chemotherapy, biologic therapy, or targeted therapy

Overall, the most common regimen during first-line therapy was docetaxel plus gemcitabine (26.5%), followed by doxorubicin monotherapy (18.8%), gemcitabine monotherapy (9.1%), paclitaxel monotherapy (5.5%), and bevacizumab monotherapy (3.3%). Docetaxel plus gemcitabine was the most common first-line therapy for patients with all histologic categories except liposarcoma (for whom it was doxorubicin monotherapy [24.3%]) and vascular sarcoma (for whom it was paclitaxel monotherapy [40.0%]) (Table 4). During first-line therapy, doxorubicin plus ifosfamide was received by 3.0% and ifosfamide monotherapy was received by 2.7% of patients. Among all patients who received doxorubicin alone or a doxorubicin-based first-line therapy (n = 371), 29.7% received liposomal doxorubicin, and 5.9% received the cardioprotective agent dexrazoxane.
Table 4

Top 5 most frequent regimens during first-, second-, and third-line therapy

First-line therapy

n (%)

Second-line therapy

n (%)

Third-line therapy

n (%)

All patients (N = 1227)

All patients (N = 476)

All patients (N = 189)

Docetaxel–gemcitabine

325 (26.5)

Doxorubicin

101 (21.2)

Doxorubicin

28 (14.8)

Doxorubicin

231 (18.8)

Docetaxel–gemcitabine

83 (17.4)

Docetaxel–gemcitabine

21 (11.1)

Gemcitabine

112 (9.1)

Gemcitabine

41 (8.6)

Gemcitabine

21 (11.1)

Paclitaxel

68 (5.5)

Paclitaxel

21 (4.4)

Ifosfamide

15 (7.9)

Bevacizumab

41 (3.3)

Ifosfamide

20 (4.2)

Dacarbazine

Leiomyosarcomas (N = 341)

 

Leiomyosarcomas (N = 148)

 

Leiomyosarcomas (N = 66)

 

Docetaxel–gemcitabine

136 (39.9)

Doxorubicin

41 (27.7)

Doxorubicin

12 (18.2)

Doxorubicin

64 (18.8)

Docetaxel–gemcitabine

35 (23.7)

Docetaxel–gemcitabine

Gemcitabine

43 (12.6)

Gemcitabine

Gemcitabine

Carboplatin-paclitaxel

Docetaxel

Carboplatin-paclitaxel

Dacarbazine-doxorubicin

Dacarbazine

Ifosfamide

Doxorubicin–ifosfamide

    

Temozolomide

    

Undifferentiated pleomorphic sarcoma (N = 158)

 

Undifferentiated pleomorphic sarcoma (N = 64)

 

Undifferentiated pleomorphic sarcoma (N = 24)

 

Docetaxel–gemcitabine

36 (22.8)

Docetaxel–gemcitabine

1 3 (20.3)

Doxorubicin

Doxorubicin

32 (20.3)

Doxorubicin

Docetaxel–gemcitabine

Gemcitabine

13 (8.2)

Ifosfamide

Dacarbazine

Ifosfamide

11 (7.0)

Gemcitabine

Ifosfamide

Doxorubicin–ifosfamide

Paclitaxel

  
  

Temozolomide

  

Liposarcomas (N = 140)

 

Liposarcomas (N = 45)

 

Liposarcomas (N = 15)

 

Doxorubicin

34 (24.3)

Docetaxel–gemcitabine

11 (24.4)

Ifosfamide

Docetaxel–gemcitabine

31 (22.1)

Doxorubicin

Gemcitabine

Bevacizumab

13 (9.3)

Gemcitabine

  

Gemcitabine

12 (8.6)

Docetaxel-doxorubicin-gemcitabine

  

Doxorubicin–ifosfamide

Ifosfamide

  

Ifosfamide

    

Vascular sarcomas (N = 130)

 

Vascular sarcomas (N = 60)

 

Vascular sarcomas (N = 21)

 

Paclitaxel

52 (40.0)

Doxorubicin

18 (30.0)

Doxorubicin

Doxorubicin

22 (16.9)

Paclitaxel

Doxorubicin–ifosfamide

Docetaxel–gemcitabine

Docetaxel–gemcitabine

Docetaxel

Doxorubicin–ifosfamide

Gemcitabine

Docetaxel–gemcitabine

Docetaxel

Docetaxel

Paclitaxel

Fibroblastic/Myofibroblastic sarcomas (N = 58)

 

Fibroblastic/Myofibroblastic sarcomas (N = 19)

 

Fibroblastic/Myofibroblastic sarcomas (N = –)

 

Docetaxel–gemcitabine

16 (27.6)

Bevacizumab

Docetaxel–gemcitabine

Doxorubicin

Docetaxel–gemcitabine

Gemcitabine

Bevacizumab

Bevacizumab-temozolomide

  

Gemcitabine

Gemcitabine

  

Cisplatin

Temozolomide

  

Doxorubicin–ifosfamide

    

Nerve sheath sarcomas (N = 24)

 

Nerve sheath sarcomas (N = –)

 

Nerve sheath sarcomas (N = –)

 

Doxorubicin

Doxorubicin

  

Docetaxel–gemcitabine

    

Gemcitabine

    

Doxorubicin–ifosfamide

    

Ifosfamide

    

Rhabdomyosarcomas (N = 28)

 

Rhabdomyosarcomas (N = 15)

 

Rhabdomyosarcomas (N = –)

 

Docetaxel–gemcitabine

Doxorubicin

  

Carboplatin-paclitaxel

Cyclophosphamide-doxorubicin-vincristine

  

Cyclophosphamide-dactinomycin-vincristine

    

Cyclophosphamide-doxorubicin

    

Cyclophosphamide-doxorubicin-vincristine

    

Doxorubicin

    

Synovial sarcomas (N = 21)

 

Synovial sarcomas (N = –)

 

Synovial sarcomas (N = –)

 

Docetaxel–gemcitabine

Dacarbazine

  

Doxorubicin

Doxorubicin

  

Temozolomide

Ifosfamide

  

Others/NOS (N = 327)

 

Others/NOS (N = 109)

 

Others/NOS (N = 46)

 

Docetaxel–gemcitabine

81 (24.8)

Docetaxel–gemcitabine

14 (12.8)

Gemcitabine

Doxorubicin

61 (18.7)

Doxorubicin

14 (12.8)

Ifosfamide

Gemcitabine

30 (9.2)

Gemcitabine

12 (11.0)

Dacarbazine

Carboplatin-paclitaxel

16 (4.9)

Carboplatin-paclitaxel

Docetaxel–gemcitabine

Paclitaxel

12 (3.7)

Docetaxel

Doxorubicin

  

Doxorubicin–ifosfamide

  
  

Ifosfamide

  

Only showing treatment regimens received by more than 1 patient

NOS not otherwise specified

Among patients who received second-line (n = 476) and third-line (n = 189) therapy, doxorubicin monotherapy (second line, 21.2%; third line, 14.8%), docetaxel plus gemcitabine (second line, 17.4%; third line, 11.1%), and gemcitabine monotherapy (second line, 8.6%; third line, 11.1%) were most common (Table 4). Among the 476 patients who received second-line therapy, the most common treatment sequence was first-line docetaxel plus gemcitabine followed by second-line doxorubicin monotherapy (n = 56, 11.8%). Among the 189 patients who received third-line therapy, the most common sequence was first-line doxorubicin followed by second-line gemcitabine and then third-line docetaxel plus gemcitabine (n ≤ 11). Among patients who received second- or third-line therapy, ≤ 11 received dexrazoxane.

Among patients who received supportive care only (n = 1618, 37.86%), the mean (SD) age was 80.0 (7.5) years (Additional file 1: Table S1). Hypertension (69.6%), diabetes without complications (28.7%), chronic pulmonary disease (28.1%), congestive heart failure (24.5%), and peripheral vascular disease (22.6%) were the most common baseline comorbidities and the mean (SD) CCI score was 3.1 (2.6).

The majority of patients (n = 3565; 83.4%) died during study follow-up, with a median survival (95% CI) of 8.9 months (8.3, 9.7) from the time of advanced STS diagnosis. Median survival (95% CI) from advanced STS diagnosis among patients who received cancer-directed therapy was 13.6 months (12.9, 14.6), and among those who received supportive care it was 2.8 months (2.6, 3.4) (Table 5 and Fig. 1). Survival estimates for each histologic category is shown in Table 5. Estimated survival from advanced STS diagnosis varied by histologic category with median survival ranging from 21.4 months (15.6, 26.8) for patients with fibroblastic/myofibroblastic sarcoma to 3.0 months (1.8, 5.7) for patients with rhabdomyosarcoma.
Table 5

Overall survival by treatment status and histologic categories

Overall

Survival from initial diagnosis of advanced STS

Total

Died

Censored

Median length of survival (in months)

95% CI

All advanced STS patients

4274

3565

709

8.9

8.3

9.7

Treatment status

 Received cancer-directed treatment

2656

2185

471

13.6

12.9

14.6

 Received supportive care only

1618

1380

238

2.8

2.6

3.4

Histologic categories

 Fibroblastic/myofibroblastic sarcomas

227

160

67

21.4

15.6

26.8

 Leiomyosarcomas

922

781

141

12.9

10.9

14.6

 Liposarcomas

554

395

159

21.1

17.4

27.1

 Nerve sheath sarcomas

106

88

18

6.2

3.6

9.3

 Rhabdomyosarcomas

98

3.0

1.8

5.7

 Synovial sarcomas

49

8.6

5.3

13.8

 Undifferentiated pleomorphic sarcomas

652

539

113

9.6

8.2

11.4

 Vascular sarcomas

357

327

30

6.0

4.8

7.3

 Others/NOS

1309

1139

170

5.4

4.8

6.1

CI confidence interval, NOS not otherwise specified, STS soft-tissue sarcoma

Figure 1
Fig. 1

Survival estimates from diagnosis of advanced soft-tissue sarcoma

Discussion

This study assessed recent real-world treatment patterns and estimated survival of a population-based cohort of older adults diagnosed with advanced STS in the US. More than 60% of patients were initially diagnosed at an earlier stage of disease and progressed to advanced STS with mean time to progression of 16.6 months. Consistent with previous studies [2527], leiomyosarcoma, UPS and liposarcoma were the most common histological categories of STS in this study population.

Among patients initiating first-line systemic therapy, the most common regimen was docetaxel plus gemcitabine combination therapy (26.5%); the next most common first-line regimen (18.8%) was doxorubicin only. Both a recent medical record review study in the US [25] and the Sarcoma Treatment and Burden of Illness in North America and Europe chart review study [26] found that anthracyclines were used most commonly among first-line therapies (either alone or in combination) in younger patient populations. In this study of older adults, docetaxel plus gemcitabine was the most commonly used first-line therapy for most histologic categories except for vascular sarcomas (for which paclitaxel was most commonly used) and liposarcoma (for which doxorubicin was most commonly used). The use of paclitaxel for vascular sarcomas is consistent with evidence suggesting that vascular sarcomas may be relatively more responsive to taxanes and as such are recommended by NCCN guidelines [24, 2830]. A relatively lower use of doxorubicin or related drugs was observed in this study, plausibly because the older age of the study population (mean age, 77.8 years) may increase concerns about adverse events, particularly doxorubicin-associated cardiotoxicity [27]. In the current study, 18.3% of the patients had a history of congestive heart failure and 25.8% of patients had a history of chronic pulmonary disease. Additionally, 69.2% of the patients in this study had hypertension that, along with age, is known to increase the risk of doxorubicin-associated cardiotoxicity [31, 32]. Prior research has addressed the issues of doxorubicin-based therapies and cardiovascular risk factors in the older adult population [3335]. It is possible that the low use of doxorubicin observed in this study cohort is related to these issues, but the study design and available data do not allow for a thorough investigation of this potential relationship. Further understanding of physician preferences with regard to administration of doxorubicin-based therapy among older adult patients is needed to adequately comprehend observed treatment patterns. Knowledge about the appropriate care of the older patient remains limited, but data from this study begin to fill this gap and suggest directions for future research related to toxicity risk, disease progression, recurrence and survival outcomes, and their relationship with patient age in the setting of advanced STS.

As observed in other studies, gemcitabine was used most commonly during second-line therapy (either alone or in combination) [25, 26]. We also noted that dexrazoxane was not at all commonly used in this population among those who were treated with doxorubicin.

Approximately 62% of the study population received cancer-directed therapy. As compared to patients receiving cancer-directed therapy, patients receiving supportive care only had a mean age of 80.0 years (cancer-directed therapy: 76.5 years) at the time of being diagnosed with advanced disease and had a baseline comorbidity burden (mean CCI score) of 3.1 (cancer-directed therapy: 2.5), and 24.5% (cancer-directed therapy: 14.6%) had a history of congestive heart failure. Therefore, it seems likely that many of these patients may have been considered to not be candidates for chemotherapy, particularly with a cardiotoxic agent. The mean non-cancer CCI scores observed in this study for the overall population, patients receiving cancer-directed treatment, and patients receiving supportive care only are in line with those reported by Davis et al. among metastatic lung cancer patients [36].

Median overall survival in the entire study population was estimated to be less than 9 months. Patients who received supportive care lived only less than 3 months. The shorter survival of the group that received only supportive care, in addition to being related to not receiving anticancer treatment per se, is likely to be confounded by selection of patients for treatment who had a more favorable prognosis or better ability to tolerate treatment.

A study by Italiano et al. [7] (median age range 53–59 years), which included patients from the time frame of this study (i.e., 2002–2006), found that patients with synchronous or metachronous metastatic STS had an overall survival of 18 months from the time of metastatic diagnosis. Patients in the study by Italiano et al. [7] had relatively longer survival than those in this study, plausibly because patients in this study were considerably older. Similar to this study, survival did vary by histologic category in the study by Italiano et al. [7]. For example, patients with leiomyosarcoma, UPS, and nerve sheath sarcoma had a median survival of 12.9, 9.6, and 6.2 months, respectively, in this study and 19.4, 11.2, and 8.6 months, respectively, in the Italiano et al. [7] study.

An array of treatments (e.g. eribulin, olaratumab, pazopanib, trabectedin) became available for this population in the last decade [11, 13, 14, 37]; however, effectiveness of these treatments specifically among older adult patients with advanced STS is yet to established. Other treatments like oral cyclophosphamide plus prednisone [34] may also be feasible for older adult patients for whom treatment with doxorubicin may not be an option. Overall survival, progression-free survival, and response rates of patients with advanced STS may improve as these treatments will become part of routine care provided to this population.

This study is subject to several limitations inherent in analyses of Medicare claims data and the use of such data in studies of advanced cancer, in particular. For patients who were not initially diagnosed at the metastatic stage of the disease, ICD-9-CM diagnosis codes were used to identify evidence of metastatic disease during the follow-up period. However, the use of ICD-9-CM codes to identify metastatic disease has been shown to have sensitivity, specificity, and positive predictive value of less than 80%, and thus the use of ICD-9-CM diagnosis codes in the Medicare claims data may have resulted in inaccurate or under-identification of an advanced STS population [38, 39]. As described in the study methods, one of the criteria used to identify progression to metastatic disease was the initiation of systemic therapy at least 6 months after surgery. This criterion may have resulted in selection bias because patients who had disease progression but did not receive systemic therapy would have been omitted from the supportive care-only group. Although, the 6-month lag period after surgery was used to avoid interpreting adjuvant therapy as treatment for advanced disease, patients who progressed and received systemic therapy for advanced disease would have been omitted from the cancer-directed therapy group. Lines of therapy are not reported in claims data; therefore, an algorithm had to be defined to estimate the lines of therapy. This may have misclassified treatments by line of therapy, as the reasons for treatment changes were not available in the data. The Medicare Part D database was available for only a subset of the cohort (32.4%); however, only a small proportion of all chemotherapy (2%) claims were identified from the Medicare Part D database, so the risk of missing important treatment data is relatively low despite this limitation. An array of treatments (i.e., eribulin, olaratumab, pazopanib, trabectedin) became available for this population in the last decade, although these agents are not fully represented in the study dataset. Future research should evaluate the use and outcomes of these novel treatments in the older adult population. Finally, this study included only patients aged 65 years or older, and although SEER-Medicare data is representative of the US population 65 years and older for age and gender, participating SEER sites may not be representative with regard to distribution of race, income, urban residence, HMO enrollment as well as cancer mortality [15] and thus the results should not be generalized to the entire population of older adult patients with advanced STS.

Despite these limitations, this study documents real-world treatment patterns that may help inform providers, researchers, and policymakers about the care of older patients with STS in the US. As real-world data including new therapeutic options become available, our results provide a basis for analyzing changes in treatment patterns and outcomes over time. This study demonstrates that the prognosis is poor for older adult patients with advanced STS, highlighting the unmet medical need in this population.

Conclusion

Although previous studies of younger populations reported anthracycline-based therapy predominated in first line, our study of older adults with advanced STS found that doxorubicin was not commonly used. Despite variation by histologic category, prognosis was observed to be poor for older adult patients with advanced STS in this study.

Abbreviations

CCI: 

Charlson Comorbidity Index

CI: 

confidence interval

HCPCS: 

Healthcare Common Procedure Coding System

ICD-9-CM: 

International Classification of Diseases, 9th Revision, Clinical Modification

ICD-O-3: 

International Classification of Diseases for Oncology, 3rd Edition

NCCN: 

National Comprehensive Cancer Network

NCI: 

National Cancer Institute

NOS: 

not otherwise specified

SD: 

standard deviation

SEER: 

The Surveillance, Epidemiology, and End Results

STS: 

soft-tissue sarcoma

UPS: 

undifferentiated pleomorphic sarcoma

US: 

United States

Declarations

Authors’ contributions

All authors have participated in the content of the manuscript from initial study design, protocol development and interpretation of the data. RP drafted the manuscript and conducted the study analyses. All other authors contributed significant scientific/intellectual content and provided critical revisions to the draft manuscript. All authors meet the criteria for authorship in accordance with the authorship standards of the International Committee of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals (http://www.ICMJE.org). All authors read and approved the final manuscript.

Acknowledgements

The authors acknowledge Eleanor Sibal (RTI Health Solutions) for medical writing support.

Competing interests

This study was performed under a research contract between RTI Health Solutions and Eli Lilly and Company and was funded by Eli Lilly and Company. RCP, SDC, and JAK are salaried employees of RTI Health Solutions. ML, LMH, and SN are salaried employees of Eli Lilly and Company.

Availability of data and materials

The SEER-Medicare dataset is available at https://healthcaredelivery.cancer.gov/seermedicare/obtain/.

Consent for publication

Not applicable.

Ethics approval and consent to participate

This study was deemed exempt from Institutional Review Board in accordance with the US Code of Federal Regulations [45CFR46.101(b)] as the public use data do not contain any variables that could identify an individual subject either directly or indirectly.

Funding

This work was funded by Eli Lilly and Company, Indianapolis, IN, United States.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
RTI Health Solutions, Research Triangle Park, USA
(2)
Eli Lilly and Company Limited, Lilly Research Centre, Erl Wood Manor, Surrey, UK
(3)
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, USA
(4)
RTI Health Solutions, Waltham, USA

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