Long-term cause-specific mortality in survivors of adolescent and young adult bone and soft tissue sarcoma: A population-based study of 28,844 patients

Authors

  • Paul Youn MD,

    1. Department of Radiation Oncology and Rubin Center for Cancer Survivorship, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York
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  • Michael T. Milano MD, PhD,

    Corresponding author
    1. Department of Radiation Oncology and Rubin Center for Cancer Survivorship, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York
    • Corresponding author: Michael T. Milano, MD, PhD, Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Ave, Box 647, Rochester, NY 14642; Fax: (585) 275-1531; Michael_Milano@URMC.Rochester.edu

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  • Louis S. Constine MD,

    1. Department of Radiation Oncology and Rubin Center for Cancer Survivorship, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York
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  • Lois B. Travis MD, ScD

    1. Department of Radiation Oncology and Rubin Center for Cancer Survivorship, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York
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  • Presented in part at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO); October 2-6, 2011; Miami Beach, FL.

  • We thank Ms. Laura Finger for expert editorial assistance.

Abstract

BACKGROUND

Despite improved cure rates for bone and soft tissue sarcomas, to the authors' knowledge, no large population-based study to date has evaluated long-term cause-specific mortality in patients diagnosed in the adolescent and young adult (AYA) age range (15 years-39 years).

METHODS

A total of 28,844 survivors of AYA bone and soft tissue sarcoma, who accrued 113,206 person-years of follow-up, were identified in the population-based Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMR) and absolute excess risks (AER) (per 10,000 person-years) were calculated to evaluate associations with histology (chemotherapy-sensitive subtypes: Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma vs all other subtypes), age, and initial therapy.

RESULTS

All-cause mortality in survivors of AYA sarcoma was found to be significantly increased compared with that of the general population (SMR, 1.76; 95% confidence interval [95% CI], 1.60-1.92 [AER of 19]), and persisted for > 20 years (SMR, 1.39; 95% CI, 1.04-1.82 [AER of 20]). Significant excess mortality was observed for both second malignant neoplasms (SMR, 2.05; 95% CI, 1.71-2.43 [AER of 7]) and noncancer causes (SMR, 1.66; 95% CI, 1.49-1.85 [AER of 19]). Significant excess deaths occurred among patients with chemotherapy-sensitive (SMR, 2.76; 95% CI, 2.20-3.41 [AER of 32]) and nonchemosensitive (SMR, 1.63; 95% CI, 1.47-1.80 [AER of 17]) subtypes. Significantly elevated noncancer mortality in the former group included cardiovascular disease (SMR, 2.33) and infections (SMR, 15.6), whereas significant excess deaths in the latter group included diabetes (SMR, 2.40) and infections (SMR, 2.77).

CONCLUSIONS

Survivors of AYA bone and soft tissue sarcoma experience significant long-term mortality due to second malignant neoplasms and noncancer causes. Further research is needed to develop preventive and surveillance guidelines in this understudied population to prevent and reduce long-term excess mortality. Cancer 2014;120:2334–2342. © 2014 American Cancer Society.

INTRODUCTION

Bone and soft tissue sarcomas are potentially lethal cancers that largely affect adolescents and young adults (AYA) aged 15 years to 39 years. With combined modality treatment, 5-year disease-specific survival rates for these patients are now 50% to 70%.[1-4] However, successful therapy has been associated with several treatment-related late effects, including second malignant neoplasms(SMNs).[5-8] Several studies have evaluated long-term outcomes in pediatric and adolescent survivors of osteosarcoma,[9] Ewing sarcoma,[10] rhabdomyosarcoma,[11] and other soft tissue sarcomas,[12, 13] but were not population-based, and the majority included only those patients diagnosed aged < 21 years. To quantify long-term site-specific mortality risks, we evaluated 28,844 AYA patients reported to population-based registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program, taking into account cancer histology and initial treatment.

MATERIALS AND METHODS

Patient Database

Patients diagnosed with a histologically confirmed sarcoma as a first primary tumor between the ages of 15 years and 39 years (January 1, 1973-Deceomber 31, 2007) were identified from 12 SEER registries, with histologic types defined below.[14] The National Cancer Institute SEER program consists of population-based registries that collect data regarding patient demographics, cancer diagnosis including histology and stage of disease, first course of therapy, and survival.[14] Patients not actively followed or for whom the cause of death was not available were excluded. The final study population included 28,844 patients, who accrued 113,206 person-years (PY) of follow-up.

Diagnosis, Treatment, and Deaths

We divided sarcomas into 2 groups: those for which chemotherapy is typically used[1-3] versus those for which the routine use of chemotherapy is controversial.[15, 16] This grouping was used because the inherent chemosensitivity of several sarcoma histologies may potentially indicate differing underlying biologies than those for tumors that tend to be more chemoresistant; we also wished to examine any impact of potential acute and late treatment toxicities on long-term cause-specific mortality.

Chemosensitive sarcomas (5536 cases) were defined as Ewing sarcoma (International Classification of Diseases for Oncology 3rd Edition [ICD-O-3] code 9260), osteosarcoma (codes 9180-9200), and rhabdomyosarcoma (codes 8900-8920), types for which the use of aggressive neoadjuvant or adjuvant chemotherapy has been widely accepted based on the results of multiinstitutional prospective trials.[1-3] Nonchemosensitive sarcomas (23,308 cases) consisted of chondrosarcoma (codes 9220-9243), spindle cell sarcoma (code 8801), giant cell sarcoma (code 8802), small cell sarcoma (code 8803), epithelioid sarcoma (code 8804), desmoplastic small round cell tumor (code 8806), fibrosarcoma (code 8810-8813), liposarcoma (code 8850-8858), leiomyosarcoma (code 8890), synovial sarcoma (codes 9040-9043), clear cell sarcoma (code 9044), and other unspecified sarcoma. For both groups, the initial course of therapy was categorized as surgery only, chemotherapy with or without surgery, radiotherapy with or without surgery, and chemotherapy and radiotherapy with or without surgery. Deaths from causes other than the original sarcoma were identified using SEER cause-specific death classification. SEER obtains the cause of death from death certificates and categorizes nonmalignant causes into 26 categories, which we consolidated into broad groups as used previously.[17] Given the small numbers of patients in specific histologic groups and attendant sparse numbers of deaths in substratum defined by site-specific mortality, sex, age, latency, and other parameters, histology-specific analyses were not conducted.

Statistical Analyses

Deaths were analyzed according to overall sarcoma group (chemosensitive vs nonchemosensitive) and initial course of therapy. The numbers of expected deaths for each category were estimated by multiplying general population mortality rates for each cause of death by PY at risk, available through the Centers for Disease Control and Prevention's National Center for Health Statistics. Standardized mortality ratios (SMR) were calculated as the ratio of observed-to-expected deaths. The 95% confidence intervals (95% CI) were obtained using an approximation based on assumption of a Poisson regression model for mortality; exact methods were used when observed numbers were ≤ 5.[18] Absolute excess risk (AER) was calculated as (observed-expected deaths)/PY of observation × 10,000 to yield excess deaths per 10,000 PY.

RESULTS

Patient Characteristics

Table 1 shows patient and treatment characteristics. Among the 5536 patients with chemosensitive sarcoma, 835 were initially managed with surgery only, whereas 4481 patients received chemotherapy or radiotherapy with or without surgery (2777 treated with chemotherapy, 182 with radiotherapy, and 1522 with chemotherapy and radiotherapy). Of these, 1320 patients with chemosensitive sarcoma had died by the time of last follow-up, with 94% of deaths (1236 patients) occurring as a result of disease progression or recurrence. Among 23,308 patients with nonchemosensitive sarcoma, 15,602 were initially managed with surgery only, whereas 6651 patients received chemotherapy or radiotherapy with or without surgery (1390 treated with chemotherapy, 3620 treated with radiotherapy, and 1641 treated with chemotherapy and radiotherapy). At the time of last follow-up, 2438 patients had died, 2059 of whom (84%) died of disease progression or recurrence.

Table 1. Characteristics, Diagnoses, and Treatment of 28,844 Survivors of Sarcomas Diagnosed in Adolescence or Young Adulthooda
 No. of Patients%bPerson-Years of Follow-Up%Total Deaths%First Cancer-Specific Deaths%Second Cancer Deaths%Noncancer Deaths%
  1. Abbreviations: CT, chemotherapy; RT, radiotherapy.

  2. a

    All patients were diagnosed with bone or soft tissue sarcoma as a first primary tumor between ages 15 years and 39 years and reported to population-based registries that participate in the Surveillance, Epidemiology, and End Results program.

  3. b

    All percentages were rounded to the nearest integer.

  4. c

    Please refer to the text for definitions and International Classification of Diseases codes.

  5. d

    Other (ie, chemotherapy or RT alone) were not shown (number is 220 for chemosensitive and 1055 for nonchemosensitive).

All patients28,844 113,206 3758 3295 116 331 
Diagnostic category            
Chemosensitivec55361919,8161813203512363823205617
Nonchemosensitivec23,3088193,39082243865205962938027583
Sex            
Male14,7215156,67450221959195259564820462
Female14,1234956,53250153941134341605212738
Race            
White22,7847989,80479290777257078917823370
Black37571314,49413548154531420177222
Other23038890893038272854268
Initial treatment            
Chemosensitived5536 19,816 1320 1236 23 56 
Surgery only83515346017a907796313814
CT ± surgery277750976749a64149599488353155
RT ± surgery18236713a5745042947
CT and RT ± surgery152227508426a49137472381043916
Nonchemosensitived23,308 93,390 2438 2059 93 275 
Surgery only15,6026765,658707553152826535717263
CT ± surgery13906418245602353726910124
RT ± surgery36201614,07215456193951916174316
CT and RT ± surgery1641753776526224812313142911
Follow-up interval, y            
1-411,5164042,24737292278276084211812839
5-965952327,56724457123701126226118
10-1445971618,85017158490318164915
15-1930571112,193119834812017299
20-24195077563770217115133711
≥2511294478645311001614278

Standardized Mortality Ratios

Table 2 shows the SMR for nonrecurrence deaths grouped by year since diagnosis and SMN and noncancer deaths. Mortality from causes other than the original diagnosis was found to be significantly increased compared with the general population (SMR, 1.76; 95% CI, 1.60-1.92). SMNs accounted for 132 deaths (SMR, 2.05; 95% CI, 1.71-2.43), with mortality increased 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 19 years after diagnosis (SMRs of 5.05, 2.83, 1.65, and 1.67, respectively) with 30% nonsignificant excesses observed at ≥ 20 years. The largest number of SMN deaths were due to respiratory (26 patients; SMR, 1.65 [95% CI, 1.08-2.42]) and hematopoietic (22 patients; SMR, 3.43 [95% CI, 2.15-5.19]) cancers. Noncancer causes accounted for 331 deaths (SMR, 1.66; 95% CI, 1.49-1.85), with SMRs of 2.97, 1.52, 1.36, 0.94, and 1.44, respectively, during the intervals of 1 to 4 years, 5 to 9 years, 10 to 14 years, 15 to 19 years, and ≥ 20 years. Cardiovascular disease (CVD) comprised the most common noncancer cause of death (78 patients; SMR, 1.34 [95% CI, 1.06-1.67]). Deaths due to infections were also found to be significantly elevated (SMR, 4.01; 95% CI, 2.57-5.96), with excesses concentrated in the intervals of 1 to 4 years and 5 to 9 years (SMRs of 11.4 and 7.59, respectively; P < .05 for each interval). Patients also experienced significantly increased mortality due to diabetes (SMR, 2.20; 95% CI, 1.23-3.62).

Table 2. SMR for Nonrecurrence Death After a Sarcoma Diagnosis in Adolescence and Young Adulthood, Grouped by Time Since Sarcoma Diagnosis
  Total  1 to 4 Years 5 to 9 Years 10 to 14 Years 15 to 19 Years ≥20 Years
 ObsSMR (95% CI)AERaObsSMR (95% CI)ObsSMR (95% CI)ObsSMR (95% CI)ObsSMR (95% CI)ObsSMR (95% CI)
  1. Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk, calculated as (observed-expected)/person-years of follow-up ×10,000; CVD, cardiovascular disease; Obs, observed number of deaths; SMR, standardized mortality ratio.

  2. a

    AER (per 10,000 person-years) for sites for which significantly increased overall SMRs were observed (based on ≥20 deaths) are as follows for the latency periods of 1 to 4, 5 to 9, 10 to 14, 15 to 19, and ≥20 years, respectively: respiratory cancer (1, 1, −1, 2, and 2), hematopoetic cancer (1, 2, 2, 1, and 3), infectious disease (3, 3, 0, 1, and 0), and CVD (3, 2, 2, 3, and 2).

  3. b

    Death was not from original sarcoma.

  4. c

    P <.05.

  5. d

    Includes acute leukemia, chronic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma.

  6. e

    Other cancers include cancers of the orbit, central nervous system, and bone and soft tissue sarcoma other than the original diagnosis, and neoplasms with benign or unknown behavior.

  7. f

    Includes stomach or duodenal ulcer and chronic liver disease/cirrhosis.

  8. g

    Includes diseases of the heart, hypertension, stroke, atherosclerosis, aortic aneurysm or dissection, and other vascular diseases.

Nonrecurrence death (all)b4631.76c (1.60-1.92)191623.25c (2.77-3.79)871.77c (1.42-2.18)681.43c (1.11-1.81)501.15 (0.86-1.52)531.39c (1.04-1.82)
Second cancer (all)1322.05c (1.71-2.43)7345.05c (3.50-7.06)262.83c (1.85-4.15)191.65 (0.99-2.58)211.67c (1.03-2.55)161.3 (0.74-2.11)
Oral cavity/pharynx32.40 (0.48-7.02)018.95 (0.12-49.78)15.59 (0.07-31.09)00.00 (0.00-15.3)13.84 (0.05-21.36)00.00 (0.00-15.11)
Digestive system130.95 (0.51-1.63)010.92 (0.01-5.09)42.32 (0.62-5.94)20.84 (0.09-3.02)41.45 (0.39-3.71)00.00 (0.00-1.30)
Respiratory system261.65c (1.08-2.42)156.18c (1.99-14.41)31.84 (0.37-5.38)10.39 (0.01-2.16)61.82 (0.67-3.97)51.39 (0.45-3.25)
Melanoma31.58 (0.32-4.62)013.16 (0.04-17.56)12.77 (0.04-15.4)12.72 (0.04-15.16)00.00 (0.00-11.08)00.00 (0.00-13.18)
Breast151.73 (0.97-2.86)110.94 (0.01-5.24)21.31 (0.15-4.73)52.79 (0.90-6.52)31.73 (0.35-5.06)21.43 (0.16-5.16)
Gynecologic/female genital61.35 (0.49-2.94)011.80 (0.02-10.00)11.37 (0.02-7.64)00.00 (0.00-4.38)22.36 (0.26-8.51)11.33 (0.02-7.37)
Testicular and male genital11.16 (0.02-6.45)000.00 (0.00-38.73)00.00 (0.00-42.4)00.00 (0.00-36.2)00.00 (0.00-26.51)15.35 (0.07-29.75)
Urinary10.48 (0.01-2.69)000.00 (0.00-25.92)00.00 (0.00-15.4)00.00 (0.00-10.6)00.00 (0.00-8.76)00.00 (0.00-8.20)
Hematopoieticd223.43c (2.15-5.19)265.22c (1.91-11.4)76.23c (2.50-12.8)43.59 (0.97-9.19)21.86 (0.21-6.73)33.03 (0.61-8.85)
Other cancerse424.39c (3.16-5.93)31812.9c (7.64-20.4)74.45c (1.78-9.16)63.48c (1.27-7.58)31.73 (0.35-5.07)42.48 (0.67-6.35)
Noncancer deaths3311.66c (1.49-1.85)131282.97c (2.48-3.53)611.52c (1.17-1.96)491.36c (1.00-1.79)290.94 (0.63-1.35)371.44c (1.01-1.98)
Infectious244.01c (2.57-5.96)21111.4c (5.67-20.4)87.59c (3.27-14.95)00.00 (0.00-3.38)21.97 (0.22-7.10)11.07 (0.01-5.98)
Digestivef121.37 (0.71-2.40)010.75 (0.01-4.20)10.59 (0.01-3.26)42.20 (0.59-5.63)00.00 (0.00-2.28)53.91c (1.26-9.12)
CVDg781.34c (1.06-1.67)2172.63c (1.53-4.22)131.46 (0.78-2.50)151.40 (0.78-2.30)151.34 (0.75-2.21)121.13 (0.58-1.97)
Renal31.28 (0.26-3.74)013.60 (0.05-20.03)13.03 (0.04-16.83)00.00 (0.00-9.66)00.00 (0.00-9.15)12.29 (0.03-12.75)
Pulmonary50.95 (0.31-2.23)012.84 (0.04-15.79)12.07 (0.03-11.50)00.00 (0.00-5.34)11.07 (0.01-5.97)10.84 (0.01-4.69)
Diabetes152.20c (1.23-3.62)122.71 (0.31-9.80)11.05 (0.01-5.85)54.30c (1.38-10.0)10.77 (0.01-4.29)21.51 (0.17-5.44)
Accidents481.30 (0.96-1.73)1201.55 (0.95-2.40)90.97 (0.45-1.85)81.27 (0.55-2.51)30.74 (0.15-2.16)62.28 (0.83-4.96)
Suicide171.15 (0.67-1.84)081.65 (0.71-3.26)30.80 (0.16-2.33)31.12 (0.23-3.27)00.00 (0.00-2.09)21.82 (0.20-6.56)
Homicide90.87 (0.40-1.65)030.67 (0.14-1.97)20.69 (0.08-2.50)21.24 (0.14-4.48)00.00 (0.00-4.45)25.00 (0.56-18.06)
Other1202.41c (2.00-2.88)7645.88c (4.53-7.51)222.06c (1.29-3.11)121.24 (0.64-2.17)70.91 (0.36-1.87)50.86 (0.28-2.00)

Diagnostic Group

Table 3 shows SMRs for nonrecurrence deaths by histologic group. Mortality from all causes other than the original diagnosis were larger for patients with chemosensitive compared with nonchemosensitive sarcomas (SMR, 2.76 [95% CI, 2.20-3.41] vs SMR, 1.63 [95% CI, 1.47-1.80]). Differences between the 2 groups were greatest for SMN mortality (SMR, 5.20 [AER, 13] for patients with chemosensitive sarcoma vs SMR, 1.76 [AER, 5] for patients with nonchemosensitive sarcoma). Among the patients with chemosensitive sarcoma, 28 of 84 deaths (33%) from causes other than original diagnoses were due to SMNs. Hematopoietic malignancies comprised the most common cause of SMN death (SMR, 8.57; 95% CI, 3.13-18.6), with the majority occurring within 10 years of the sarcoma diagnosis. A total of 56 deaths were from noncancer causes (SMR, 2.23; 95% CI, 1.69-2.90) and SMRs were found to be significantly elevated for both infectious and cardiovascular causes (SMR, 15.6 [95% CI, 7.12-29.6] vs SMR, 2.33 [95% CI, 1.20-4.07]).

Table 3. SMRs for Nonrecurrence Death After a Sarcoma Diagnosis in Adolescence and Young Adulthood, Grouped by Sarcoma Histology
  Chemosensitive Histologiesa (n=5536)  Nonchemosensitive Histologiesa (n=23,308) 
 ObsSMR (95% CI)AERObsSMR (95% CI)AER
  1. Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk, calculated as (observed-expected)/person-years of follow-up ×10,000; CVD, cardiovascular disease; Obs, observed number of deaths; SMR, standardized mortality ratio.

  2. a

    Please refer to the text for definitions and International Classification of Diseases codes.

  3. b

    P <.05.

  4. Includes acute leukemia, chronic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma.

  5. c

    Includes cancers in the orbit, central nervous system, and bone and soft tissue, and neoplasms with benign or unknown behavior.

Nonrecurrence death, total842.76b (2.20-3.41)323791.63b (1.47-1.80)17
Second cancer death285.20b (3.45-7.51)131041.76b (1.44-2.13)5
Oral cavity and pharynx19.29 (0.12-51.7)121.75 (0.20-6.33)0
Digestive system21.79 (0.20-6.46)1110.88 (0.44-1.57)0
Respiratory system32.59 (0.52-7.56)1231.58 (1.00-2.37)1
Melanoma15.00 (0.07-27.81)021.18 (0.13-4.26)0
Breast23.54 (0.40-12.8)1131.61 (0.86-2.75)1
Gynecologic and female genital13.30 (0.04-18.4)051.21 (0.39-2.82)0
Testicular and male genital110.52 (0.14-58.5)100.00 (0.00-4.78) 
Urinary system00.00 (0.00-21.2) 10.53 (0.01-2.94)0
Hematopoieticc68.57b (3.13-18.7)3162.80b (1.60-4.55)1
Other cancersc1111.41b (5.69-20.4)6313.60b (2.45-5.11)3
Noncancer deaths562.23b (1.69-2.90)182751.58b (1.40-1.78)12
Infectious915.6b (7.12-29.6)5152.77b (1.55-4.57)1
Digestive33.62 (0.73-10.6)191.14 (0.52-2.16)0
CVD122.33b (1.20-4.07)4661.25 (0.96-1.58)2
Renal29.91b (1.11-35.79)110.47 (0.01-2.59)0
Pulmonary12.47 (0.03-13.77)040.83 (0.22-2.12)0
Diabetes00.00 (0.00-6.24) 152.40b (1.34-3.96)1
Accidents40.59 (0.16-1.51)−2441.46b (1.06-1.97)2
Suicide31.16 (0.23-3.38)0141.14 (0.63-1.92)0
Homicide10.48 (0.01-2.65)−180.96 (0.42-1.90)0
Other213.58b (2.22-5.47)9992.26b (1.83-2.75)6

In the patients with nonchemosensitive sarcoma, 104 of 379 deaths from causes other than the original diagnosis (27%) were from SMNs (SMR, 1.76; 95% CI, 1.44-2.13). SMN in the respiratory (23 patients; SMR, 1.58 [95% CI, 1.00-2.37]) and hematopoietic (16 patients; SMR, 2.80 [95% CI, 1.60-4.55]) systems comprised the most frequent causes of mortality. Thirteen deaths occurred due to breast cancer (SMR, 1.61; 95% CI, 0.86-2.75). Among noncancer causes of death (275 patients; SMR, 1.58 [95% CI, 1.40-1.78]), CVD (66 patients; SMR, 1.25 [95% CI, 0.96-1.58]) and accidents (44 patients; SMR, 1.46 [95% CI, 1.06-1.97]) were most frequent. Significantly increased risks of death were observed for diabetes (SMR, 2.40; 95% CI, 1.34-3.96).

Treatment

SMRs for causes of death other than the original diagnosis are shown in Table 4 according to the initial course of treatment. Among patients with chemosensitive sarcoma, mortality was found to be significantly elevated in those treated with chemotherapy (SMR, 3.18; 95% CI, 2.29-4.3), radiotherapy (SMR, 4.54; 95% CI, 1.82-9.36), or chemotherapy and radiotherapy (SMR, 2.99; 95% CI, 1.8-4.67), whereas 30% nonsignificant excesses (SMR, 1.36; 95% CI, 0.68-2.43) were observed in the group treated with surgery only. SMN mortality was elevated after chemotherapy (SMR, 5.24; 95% CI, 2.61-9.38), radiotherapy (SMR, 9.52; 95% CI, 1.91-27.8), or chemotherapy and radiotherapy (SMR, 10.5; 95% CI, 5.0-19.2). Deaths due to hematologic malignancies were found to be elevated in patients treated with chemotherapy and radiotherapy (4 patients; SMR, 28.3). Mortality from noncancer causes was found to be significantly increased after chemotherapy (SMR, 2.79; 95% CI, 1.9-3.97), with significant contributions from infectious (5 patients; SMR, 21.4) and cardiovascular (7 patients; SMR, 3.70) causes.

Table 4. SMR for Nonrecurrence Death After a Sarcoma Diagnosis in Adolescence and Young Adulthood, Grouped by Sarcoma Histology and by Initial Treatment for Sarcoma
 Initial Course of Treatment
 Surgery OnlyChemotherapy ± SurgeryRT ± SurgeryChemotherapy and RT ± Surgery
Cause of DeathObsSMR (95% CI)AERObsSMR (95% CI)AERObsSMR (95% CI)AERObsSMR (95% CI)AER
  1. Abbreviations: 95% CI, 95% confidence interval; AER, absolute excess risk, calculated as (observed-expected)/person-years of follow-up ×10,000; Obs, observed number of deaths; RT, radiotherapy; SMR, standardized mortality ratio.

  2. a

    Please refer to the text for definitions and International Classification of Diseases codes.

  3. b

    P <.05.

Nonsarcoma death            
Chemosensitivea111.36 (0.68-2.43)9423.18b (2.29-4.3)3474.54b (1.82-9.36)100192.99b (1.8-4.67)32
Nonchemosensitivea2271.28b (1.12-1.46)8233.33b (2.11-5)53612.05b (1.57-2.64)25455.05b (3.69-6.76)86
Second cancer death            
Chemosensitive31.70 (0.34-4.96)4115.24b (2.61-9.38)739.52b (1.91-27.8)311010.5b (5.0-19.2)23
Nonchemosensitive551.20 (0.9-1.54)1116.45b (3.21-11.5)24182.52b (1.5-3.99)7168.69b (4.97-14.1)27
Noncancer death            
Chemosensitive81.26 (0.54-2.48)5312.79b (1.9-3.97)2343.26 (0.88-8.34)5191.67 (0.76-3.17)9
Nonchemosensitive1721.31b (1.12-1.52)6122.31b (1.19-4.04)23431.90b (1.38-2.56)16294.10b (2.75-5.89)52
Circulatory disease death            
Chemosensitive10.55 (0.01-3.08)−373.70b (1.48-7.62)625.82 (0.65-21)3022.20 (0.25-7.94)3
Nonchemosensitive451.09 (0.8-1.46)121.39 (0.16-5.02)281.27 (0.55-2.5)174.02b (1.61-8.28)12

Among patients with nonchemosensitive sarcoma, mortality from causes other than the original diagnoses was found to be significantly elevated across all treatment groups. SMN mortality was significantly increased after chemotherapy (SMR, 6.45; 95% CI, 3.21-11.5), radiotherapy (SMR, 2.52; 95% CI, 1.5-3.99), and chemotherapy and radiotherapy (SMR, 8.69; 95% CI, 4.97-14.1). For noncancer causes, the SMR was significantly elevated in all treatment groups. Deaths due to CVD were found to be significantly elevated only after receipt of chemotherapy and radiotherapy (SMR, 4.02; 95% CI, 1.61-8.28).

DISCUSSION

To our knowledge, this is the first large (28,844 patients) population-based study to quantify long-term cause-specific mortality among survivors of AYA sarcoma. For most sarcomas (including Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma), previous investigations of long-term outcomes were based on small numbers, ranging from 32 to 97 patients.[12, 19, 20] Recently, several studies from the multiinstitutional Childhood Cancer Survivor Study have investigated treatment-related morbidity and mortality among 5-year survivors of childhood and adolescent sarcomas.[9-11] However, the Childhood Cancer Survivor Study cohort includes only 5-year survivors diagnosed with cancer before age 21 years, whereas 42% of chemosensitive sarcomas and > 90% of other sarcoma subtypes occur after this age.[14] Our population-based study includes patients with AYA sarcoma and is not restricted to 5-year survivors.

Important new findings in our investigation included significantly increased mortality among survivors of AYA sarcoma from nonrecurrent causes, which persisted for 20 years. However, it is important to note that 88% of all deaths (3295 of 3758 deaths) were due to the original sarcoma diagnosis, which remained the predominant cause of death until ≥ 20 years of follow-up.

Chemosensitive Versus Nonchemosensitive Sarcomas

We grouped together Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma because the use of aggressive chemotherapy to treat these tumors is widely accepted. Although other sarcomas such as liposarcoma[21] and synovial sarcoma[22] may demonstrate some degree of responsiveness to chemotherapy, they remain in a category of tumors for which the routine use and proven effectiveness of systemic therapy remain controversial. For patients with these tumors, the benefit of adjuvant chemotherapy is thus not fully known and there are conflicting data with regard to any improvements in survival with the use of adjuvant chemotherapy.[15, 16] As expected, 78% of patients in the chemosensitive group received chemotherapy as part of their initial course of treatment, whereas 19% of patients in the nonchemosensitive group initially received chemotherapy, most likely reflecting differing practices in population-based settings throughout the United States.

Chemosensitive Sarcomas

Significantly increased nonrecurrence mortality in AYA patients with chemosensitive sarcomas was found for both SMNs and noncancer causes, and was largely associated with the initial receipt of chemotherapy or radiotherapy. SMNs were a major contributing factor to nonrecurrence mortality in the population of patients with chemosensitive sarcoma. In recent years, treatment approaches for Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma have included surgery and/or radiotherapy to achieve local control and systemic chemotherapy to prevent disease recurrence.[1-3] Excess SMNs among cancer survivors have been associated with antecedent exposure to anthracyclines, alkylating agents, and radiotherapy.[23-26] Although several single or multiinstitutional investigations have reported an increased incidence of SMNs in the group of patients with chemosensitive sarcomas,[5-8] to the best of our knowledge the current study is the first to demonstrate an increased risk of death due to SMNs among survivors of sarcoma and to describe associations with initial therapy.

In the group of AYA patients with chemosensitive sarcoma, 21% of SMN deaths were due to hematologic malignancies, with the majority occurring within 10 years. Although not specific to survivors of sarcoma, Mertens et al,[27] in an analysis of 5-year childhood cancer survivors, reported that 27% of SMN mortality was due to hematopoietic malignancies. Treatment-related hematopoietic malignancies, such as myelodysplasia and acute myeloid leukemia, are well-documented complications of cancer treatment.[28-32] To our knowledge, Bhatia et al[33] were among the first to report excess hematopoietic malignancies among survivors of Ewing sarcoma, with a standardized incidence ratio of 127.8 and a median latency of 3 years. The results of the current study are in accord with these findings; among deaths from SMNs, 4 were due to bone or soft tissue sarcoma and 3 occurred in survivors of AYA Ewing sarcoma. Subsequent sarcoma is a known complication of treatment of Ewing sarcoma.[8, 34] Given the limitations of the SEER data, we could not ascertain detailed information regarding second sarcomas, such as whether they arose within antecedent radiotherapy fields.

Noncancer mortality was also found to be significantly elevated in the group of patients with AYA chemosensitive sarcoma, especially among patients initially treated with chemotherapy. Infection was a major cause of noncancer mortality. Although intensive chemotherapy regimens suppress bone marrow reserve and increase the risk of life-threatening infections during chemotherapy, to our knowledge there have been no studies to date that investigated bone marrow reserves in long-term survivors of AYA cancer after chemotherapy. Chemotherapeutic agents such as anthracyclines also have been associated with excess cardiac disease in survivors of childhood and adolescent cancer.[35, 36] In the current analysis, CVD was another major noncancer cause of mortality among survivors of chemosensitive sarcoma and the administration of chemotherapy was associated with a significantly increased number of deaths due to cardiovascular causes.

Nonchemosensitive Sarcomas

Unlike Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma, to our knowledge few studies to date have investigated long-term nonrecurrence mortality after therapy for other soft tissue sarcomas.[9, 13] Nonetheless, it is important to note that the incidence rate of nonchemosensitive sarcomas is higher than that of chemosensitive sarcomas in the AYA population, thereby comprising a higher percentage of survivors. We found a 1.6-fold to 1.8-fold increased risk of mortality from SMNs and noncancer causes in survivors of nonchemosensitive sarcomas. Patients whose initial course of treatment included chemotherapy demonstrated trends toward higher risks of nonrecurrence death. Although the use of chemotherapy in these patients has been limited and dependent on tumor extent, grade, and histology, it is important to note these results, which should be confirmed in analytic investigations. To the best of our knowledge, few studies to date have evaluated the risk of late SMNs and cardiac disease in patients with nonchemosensitive sarcomas. In a single-institution analysis of survivors of sarcoma, Guadagnolo et al[13] demonstrated increased mortality from SMNs, especially among patients with nonextremity sarcomas, which is in agreement with our observation of an increased SMN mortality risk. As in the study by Guadagnolo et al,[13] exposure to chemotherapy appeared to be associated with a higher SMN mortality risk. Although we also found an association between radiotherapy and SMN mortality, this observation was limited due to the lack of information regarding the anatomic site of the sarcoma and radiation fields.

Strengths and Limitations

Strengths of the current study included the large number of AYA patients with bone and soft tissue sarcomas (28,844 patients), which allowed us to evaluate the influence of major histologic groups and initial treatment on nonrecurrence mortality. The use of the SEER population-based registry allowed us to readily compare mortality risk in survivors of AYA sarcoma with that of the general population, and enabled us to avoid biases associated with hospital-specific series. Limitations of the current study are those inherent to the SEER program, including a lack of detailed data regarding chemotherapy agents and doses, radiotherapy fields and doses, and salvage therapies. When interpreting the results of this analysis, it is important to note that cause(s) of death were ascertained primarily through death certificates, which may contain some degree of misclassification, especially in deaths due to metastatic disease recurrence versus SMN. Thus, the risks of various outcomes may vary slightly from what we report, yet should not materially affect our conclusions.

Conclusions

AYA patients diagnosed with sarcomas have significantly elevated risks of nonrecurrence mortality due in part to the late effects of cancer treatment. Increases in mortality appear to be more pronounced in patients with sarcomas that require aggressive systemic treatment. The results of the current study further emphasize the importance of vigilant screening for SMNs and other late effects in this young population,[37] as well as the future conduct of analytic studies to further understand underlying mechanisms to develop preventive and interventional strategies.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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