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The Epidemiology of Osteosarcoma

  • Giulia Ottaviani
  • Norman Jaffe
Part of the Cancer Treatment and Research book series (CTAR, volume 152)

Abstract

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5–4.6) for the range 0–14 years and 5.0 (4.6–5.6) for the range 0–19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10–14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget’s disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull or jaw (8%) and the pelvis (8%). Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference. The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.

Keywords

Childhood Cancer Ewing Sarcoma Bone Cancer Osteosarcoma Patient Pubertal Growth Spurt 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. This chapter and its companion chapter, The Etiology of Osteosarcoma, provide data from published literature in an effort to outline current concepts on the epidemiology of osteosarcoma. In our review of the literature, abstracts were identified from searches of the Web bibliographic databases, including Ovid, Medline, and PubMed, using the following combined search terms: epidemiology, osteosarcoma, children, adolescents, survival, and genetics. The updated information we present in this chapter is designed to help readers to increase their knowledge of the epidemiologic approach to osteosarcoma, to interpret and communicate research findings to patients and their families, and to enhance their own research.

Primary Osteosarcoma

Incidence

The risk of being diagnosed with cancer increases as an individual ages, and 77% of all cancers are diagnosed in persons aged 55 years and above. As a lifetime risk, the probability that an individual, over the course of a lifetime, will develop a cancer is slightly less than one in two for men and a little more than one in three for women.1, 2, 3

In the United States, for children aged 0–14, and adolescents aged 15–19 years, the overall incidence rate for all cancers is 16.5 cases per 100,000 persons per year.1,4 The childhood and adolescent cancer incidence rate has increased from 11.5 per 100,000 persons per year in 1975, to 14.8 per 100,000 in 2004. Although this trend is recognized to be the result, in part, of improved diagnosis and reporting methods, it appears that there is a true increase in the occurrence of some childhood cancers.2,5

For any newborn, the risk of developing cancer by age 20 years is about one in 300 for males and one in 333 for females.1,6 It has a peak of incidence at ages 5–14.7 Childhood cancers account for no more than 2% of all cancers.2

In the United States, it is significant that all childhood and adolescent cancers combined, affect boys more frequently than girls. Children have a significantly lower incidence rate than adolescents; white children and adolescents have the highest incidence rate among all races.4 Young people living in the Northeast of the United States have a significantly higher incidence rate compared with those in the Midwest and South census regions; this may be partially attributed to significantly higher incidence rates for central nervous system neoplasms and lymphomas in this region.4

In developing countries, it is more difficult to accurately measure the incidence rate because of the greater frequency of deaths from infectious diseases and malnutrition.2,8

According to the analysis of the Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Review of the National Cancer Institute,1 the age-adjusted incidence rate for all bone and joint cancers for all ages and all races is 0.9 per 100,000 persons per year, and the mortality rate is 0.4 per 100,000, with a 5-year overall survival rate of 67.9%. The median age at diagnosis for cancer of the bones and joints is 39 years, with the majority (28.7%) occurring below the age of 20 years. For children (aged 0–14 years), the incidence rate for all bone and joint cancers for both sexes is 0.7 per 100,000 persons per year, and the mortality rate is 0.1 per 100,000. For children and adolescents (aged 0–19 years), the incidence rate for all bone and joint cancers is 0.9 per 100,000 persons per year, while the mortality rate is 0.4 per 100,000.1 Malignancies of the bone and joint, with an average annual incidence rate of 8.7 per million children and adolescents younger than 20 years, make up about 6% of childhood and adolescent cancers (Fig. 1).3,9 The two types of malignant bone cancers that predominate in children and adolescents are osteosarcoma 1 and Ewing sarcoma, which represent about 56 and 34% of bone cancers, respectively.10
Fig. 1

Distribution of incidence by location of cancer in children and adolescents, ages 0 to 19 years, in the United States. Data are from the U.S. Cancer Statistics Working Group 2004, public-use file3

According to the most recent report from the U.S. Cancer Statistics Working Group,3 the incidence rates and 95% confidence intervals for osteosarcoma specifically, for all races and both sexes in children and adolescents under 20 years, are 4.0 (3.5–4.6) per million persons per year for the range 0–14 years, and 5.0 (4.6–5.6) per million for the range 0–19 years. Similarly, according to SEER, the incidence rate of osteosarcoma for all races and both sexes in children and adolescents is 4.7 per million persons per year, with a positive annual percentage change of 0.2.11

Cancer registry data with histologic stratification indicate that osteosarcoma is the most common primary malignant tumor of the bone among people of all ages, accounting for approximately 35% of cases, followed by chondrosarcoma (25%) and Ewing sarcoma (16%).12 Among childhood cancers, osteosarcoma is eighth in general incidence; the most common cancers, in descending order, are: leukemia (30%), brain and other nervous-system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%).6

In the United States, each year, approximately 400 new cases of osteosarcoma are diagnosed among children and adolescents younger than 20 years.10 The specific incidence trends for osteosarcoma based on age, gender, ethnicity, and site of disease are described below.

Age

Osteosarcoma is the most frequent bone cancer occurring in children and adolescents aged 10–20 years, whereas in children younger than 10 years, the most common primary bone cancer is Ewing sarcoma.13

Osteosarcoma has a bimodal age distribution; the first peak occurs during adolescence, and the second occurs in older adults.10,14, 15, 16 Osteosarcoma is rare in children younger than 5 years; only 2% of patients with osteosarcoma fall into this age group.17 There is a steady rise in the incidence rates between 5 and 10 years, and a steeper rise occurs between 11 and 15 years, coinciding with the pubertal growth spurt. The overall peak incidence of osteosarcoma occurs at the ages of 10–14 years, after which the rates decline.3 The second peak of incidence of osteosarcoma is in adults older than 65 years, in which it is more likely to represent a second malignancy, frequently related to Paget disease.14,18,19

Gender

According to the most recent publication by the U.S. Cancer Statistics Working Group,3 the incidence rates and 95% confidence intervals of childhood and adolescent osteosarcoma are 5.0 (4.4–5.8) per million persons per year for males and 5.1 (4.4–5.8) per million for females. Nonetheless, the incidence of osteosarcoma has always been considered to be higher in males than in females,10,13,16 and according to the most recent SEER data in 2008, it was a rate of 5.4 per million persons per year in males vs. 4.0 per million in females.11

Ethnicity

The National Cancer Institute SEER Study for the years 1975–1995, reported that the osteosarcoma incidence among children and adolescents younger than 20 years was higher in African Americans than in whites, with annual rates of 5.2 per million persons in African Americans, and 4.6 per million in whites.10 More recent data from SEER demonstrate that osteosarcoma occurs more often in Asians/Pacific Islanders and in Hispanics.13 Recently, the U.S. Cancer Statistics Working Group3 reported a higher incidence of osteosarcoma in blacks (6.8 per million persons per year) and in Hispanics (6.5 per million) than in whites (4.6 per million).

Site

Osteosarcoma can occur in any bone. It most often occurs near the metaphyseal growth plates of the long bones of the extremities (Fig. 2). The most common sites are the femur (42%, with 75% of these tumors in the distal femur), the tibia (19%, with 80% of these tumors in the proximal tibia), and the humerus (10%, with 90% of these tumors in the proximal humerus). Other likely locations are the skull or jaw (8%), and the pelvis (8%). Only 1.25% of osteosarcomas are located in the ribs.10,16,20, 21, 22 The most recent report from the National Cancer Data Base23 did not provide any significant additional data, as all the three long bones of the lower extremity (the femur, thetibia, and the fibula) were grouped together. Similarly, all the long bones of the upper extremity (the humerus, the radius, and the ulna) were grouped together. Furthermore, there was no distinction between the epiphyseal, metaphyseal, and diaphyseal locations.
Fig. 2

Distribution of osteosarcomas by age, sex, and skeletal site of lesion for a series of 1,274 patients from the Mayo Clinic. From Dahlin and Unni,16 by permission of Mayo Foundation for Medical Education and Research

Mortality

In the United States, cancer, of all types combined, is the second leading cause of death. Overall, one in every four deaths is due to cancer, according to the National Vital Statistics System.1, 2, 3

Cancer is the fourth most common cause of death among children and adolescents under 20 years of age, in the United States24 About 8% of all the deaths are due to cancer between birth and 20 years of age.1,6

Among persons aged 1–19 in the United States, the mortality rate is 2.8 cases per 100,000.1 The Centers for Disease Control and Prevention (CDC) reported a total of 34,500 cancer deaths among children and adolescents in the United States during the years 1990–2004.24 A total of 2,223 childhood and adolescent cancer deaths occurred in 2004, and 12% of childhood deaths are due to cancer.2,24 Death rates for childhood cancers have been declining by about 1.3% per year over the years 1990–2004.24 Overall, this trend reflects the advances that have been made in cancer treatment.4,24,25

In 1990–2004, boys (33.1 per million persons per year) had significantly higher death rates than girls (26.1 per million) for all cancers combined; adolescents (37.9 per million) had significantly higher death rates than children (26.9 per million); whites (30.1 per million) and blacks (29.3 per million) had significantly higher death rates than both Asians/Pacific Islanders (26.4 per million) and American Indian/Alaska Natives (20.0 per million); and Hispanics (30.3 per million) had significantly higher death rates than non-Hispanics (29.1 per million).24

According to the most recent data from SEER, the mortality rate for all bone and joint cancers is 0.4 per 100,000 persons per year for both sexes, all races and all ages.1

Cancer deaths due to malignant neoplasms of bone and joint represent 8.9% of all childhood and adolescent cancer deaths, compared with 25.5% for the most common type of cancers, leukemias, and 25.0% for brain and other nervous-system neoplasms (Fig. 3).24 Death rates for osteosarcoma have been declining by about 1.3% per year over the years 1990–2004, similar to the rate of decline for all other childhood cancers except leukemias (3.0% per year) and brain and other nervous-system neoplasms (1.0% per year).24,26
Fig. 3

Distribution of cancer deaths by location of disease in children and adolescents, ages 0 to 19 years. Data are from the Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Review of the National Cancer Institute public-use file1

Survival

Overall, the treatment strategy of giving preoperative chemotherapy followed by surgery and adjuvant therapy has greatly improved the survival rates of patients with osteosarcoma, over the past decades. Prior to 1970, amputation was the only surgical treatment available for osteosarcoma, and 80% of patients died of metastatic disease, mainly of the lungs.20, 21, 22 These historical cases led to the conclusion that more than 80% of patients without radiologic evidence of metastases at diagnosis had subclinical micrometastases. This assumption was the basis for the adoption of chemotherapy protocols over the past three decades, which have led to a significant increase in the overall survival rates.27, 28, 29

The National Cancer Institute SEER Study for the years 1975–1995, reported that the overall 5-year survival rate for patients with osteosarcoma diagnosed between 1974 and 1994 was 63% (59% for male patients, 70% for female patients).10 More recent SEER data demonstrate that the survival curves for the age groups younger than 45 years were nearly identical from 1975 to 2000: greater than 65%. In contrast, the 5-year survival rate for patients 45 years and older continued to be less than 45%.13 The National Cancer Data Base Report23 recently described that for the single largest series of osteosarcoma cases, the relative 5-year survival rates were 60% for patients younger than 30 years, 50% for patients between 30 and 49 years, and 30% for patients, 50 years and older. The relative 5-year survival rates by subtype were 52.6% for conventional high-grade intramedullary osteosarcoma, 85.9% for parosteal osteosarcoma, 49.5% for small-cell osteosarcoma, and 17.8% for osteosarcoma in Paget’s disease.23 Based on 648 patients treated for osteosarcoma at Massachusetts General Hospital by the orthopedic oncology group, Mankin et al.30 reported in 2004 that the overall 5-year survival rate for osteosarcoma was 68%, without a significant gender difference.

In 2002, Gatta et al.31 reported slightly higher survival rates for osteosarcoma in the United States than in Europe; however, the difference was not significant. In 2007, Lewis et al.32 reported an improvement in histologic response, but not in survival rate, in patients with osteosarcoma treated with intensified chemotherapy in Europe. Recently, Craft and Pritchard-Jones33 commented on the lower overall childhood cancer survival rate in the United Kingdom compared with that in the rest of Europe.

The age of the patient is correlated with the survival data, with the poorest survival rate for older patients.13,30 The type of surgical treatment, i.e., amputation compared with a limb-salvage procedure for nonmetastatic osteosarcoma, has no effect on the outcome.34 Tumor stage, the presence of metastases or local recurrence, the chemotherapeutic treatment, the anatomic location, the size of the tumor, and the percentage of tumor cells destroyed after neoadjuvant chemotherapy, were considered by some researchers to have a great effect on the outcome.14,30 The most significant variable affecting the osteosarcoma outcome was reported to be the date of diagnosis, with the improved survival rate trends mirroring the introduction of increasingly effective chemotherapy.35 The duration of symptoms prior to the initiation of therapy has not been shown to affect the survival rates.36

Tumor location at presentation has been correlated with the outcome. Mankin et al.30 reported the lowest survival rates for patients with osteosarcoma of the lumbar spine and pelvis (32%), the scapula and shoulder (45%), and the proximal femur (62%), and the higher survival rates for osteosarcoma of the proximal tibia (78%) and the distal femur (73%). Patients with primary osteosarcoma of the rib were reported to have an overall survival rate of only 15% at 5 years; 34% of patients affected by osteosarcoma of the rib presented with synchronous osteosarcoma lesions.37

Recently, Jeys et al.38 reported an increased survival rate in osteosarcoma patients who underwent limb salvage and had postoperative endoprosthesis infections. The 10-year survival rate for patients with endoprosthesis infection was 84.5%, compared with 62.3% in the noninfected group; infection was an independent favorable prognostic factor, as discussed more in detail in the chapter titled “Quality of life in long-term survivors of lower extremity osteosarcomas: amputation versus limb salvage.” Bramer et al.39 reported a significantly lower survival rate in osteosarcoma patients who presented with pathologic fractures compared with the rate in patients without such fractures.

Osteosarcomas Following Treatment

Radiation-induced osteosarcomas, which develop following cancer treatment with radiation, frequently for Ewing sarcoma, have been shown in some studies to have rates of local recurrence and metastasis, and functional outcomes similar to those of patients with primary osteosarcoma.40,41 Patients treated for radiation-induced osteosarcoma with limb-salvage procedures had functional outcomes similar to those of matched patients treated for primary osteosarcoma.41

A constellation of subsequent primary cancers was observed in osteosarcoma survivors.42 Bacci et al.43 reported that 2.15% of osteosarcoma patients developed a second malignant neoplasm at a median of 7.6 years (range, 1–25 years) after the primary osteosarcoma had been treated with neoadjuvant and adjuvant chemotherapy. The most common type of subsequent neoplasm was leukemia, followed by, in decreasing order of occurrence, breast, lung, kidney, central nervous system, soft-tissue, parotid, and colon cancers. The overall rate of second neoplasms in osteosarcoma survivors was significantly higher in females, and the latent period for subsequent hematologic tumors was shorter than that for subsequent solid tumors.43 The risk of subsequent breast cancer was markedly increased among females previously treated for osteosarcoma; this increased risk was probably due, in part, to thoracic radiotherapy for lung metastases, although genetic predisposition also appeared to play a role. It has been reported that a family history of sarcoma is predictive of breast-cancer risk among the survivors of bone sarcoma who have not received chest radiotherapy.44

Jaffe et al.45,46 reported the occurrence of single or multiple metachronous osteosarcoma in 4.07% of the pediatric and adolescent patients successfully treated for primary osteosarcoma. There was an increased incidence in patients who had retinoblastoma and the Li–Fraumeni syndrome. The metachronous osteosarcomas appeared as single lesions in 63.64% of cases and as multifocal in the remaining cases.45 The interval between the discovery of the primary osteosarcoma and the first metachronous osteosarcoma ranged from 11 months to 7.33 years. The histologic variant of the metachronous osteosarcoma was concordant with that of the primary osteosarcoma in 70% of cases. A total of 45% of the patients survived for periods ranging from 20 to 50 months after the treatment of the metachronous osteosarcoma.45

Conclusions

Osteosarcoma is the most common bone cancer encountered in children and adolescents. It was originally reported to be more common in males than in females; however, recent reports indicate that the incidence may be equal in both sexes. The incidence is higher in African Americans than in whites. The disease most commonly occurs in the femur. The survival rate of patients with osteosarcoma has improved over the past 30 years with the introduction of multidisciplinary therapy. Patients successfully treated for osteosarcoma may develop second malignant neoplasms, including an additional osteosarcoma.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Children’s Cancer Hospital, The University of Texas M.D. Anderson Cancer CenterHoustonUSA

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