This is the most comprehensive analysis of patient characteristics, treatment strategies, and outcomes in very young patients with osteosarcoma. Our results demonstrate differences in each of these domains for patients 5 years of age and younger compared to older patients.
Our findings confirm earlier observations from one case series in which patients 5 years and younger demonstrated a significantly higher incidence of telangiectatic osteosarcoma.[3
] This series also reported a more common tumor location in the upper limb among very young patients compared to older patients [11
]. Other case series have not specifically addressed these differences in this age group. The reason for these differences remains obscure, but suggest that osteosarcoma in these very young patients may have biological differences that drive these different clinical findings.
Surgical treatment of osteosarcoma has evolved over the past several decades [14
]. Aggressive surgery of osteosarcoma, either by amputation or by limb-sparing surgery, is essential for curative treatment and to assure local control. Currently, approximately 80% to 90% of patients with musculoskeletal tumors undergo limb-sparing surgery rather than amputation [15
]. For young skeletally immature patients, limb-sparing procedures can be especially challenging [20
]. Given the challenges of limb-sparing procedures for these children, our finding that most very young patients with appendicular tumors are treated with amputation is not surprising.
Clinical outcomes for osteosarcoma patients age 5 years or younger have not been well described. Due to rarity of this tumor under the age of 5, single institution case series have been reported for these very young children, but comprehensive data analyses are lacking [11
]. Our results indicate an unfavorable prognosis for children 5 years of age or younger at the time of initial diagnosis with osteosarcoma. Even after controlling for known prognostic factors, very young children demonstrated inferior overall survival compared to their older counterparts. This inferior outcome may reflect intrinsic biologic differences, differences in local control strategies due to extreme skeletal immaturity, or pharmacokinetic differences in drug metabolism [24
]. Evaluation of these potential explanations cannot be made using the SEER database. The inferior outcome among very young patients reinforces the need to understand the factors driving this difference. Standard treatment in osteosarcoma has been defined from clinical trials enrolling mainly adolescences and young adults. These treatment approaches may not be well-suited to very young patients [10
The impact of age on outcome in osteosarcoma has been a source of controversy. For older patients, some studies have reported equal rates of survival while others have described a worse prognosis for patients who are in adolescence or young adulthood [3
]. Other groups have reported that pre-adolescent patients may have an inferior outcome [8
]. Other studies found that the crude association of age and survival was significant, but age as prognostic factor did not maintain significance while controlling for known confounders [31
]. Our finding that outcome is different among children 5 years of age or younger compared to older pediatric patients indicates that the relationship between age and outcome is complex. This complexity may account for some of the controversy in this field.
A main strength of this study is the relatively large number of osteosarcoma cases in very young children provided by using the SEER database. These patients were treated at many different areas of the United States and selection was not based on treatment or outcome. Furthermore, our control group of older pediatric patients includes a subgroup of patients (6 – 10 years of age) that others have suggested may have a worse prognosis [8
]. The inclusion of these patients in our control group could have biased our findings towards the null hypothesis of no difference. Demonstrating a difference in survival using this control group supports our findings.
Limitations of analyzing data from SEER include those of any study relying on a tumor registry. No more data than those reported are available and the SEER database does not provide data on recurrence site. Tumor histology could not be independently confirmed. Moreover, data regarding osteosarcoma predisposition syndromes, such as Li-Fraumeni, Diamond-Blackfan anemia, and Rothmund-Thompson syndrome, were not available. A higher incidence of these syndromes among younger patients with osteosarcoma may help to explain some of the differences observed in our study [32
]. Furthermore, in order to develop a large enough cohort of very young patients, we included patients treated in the 1970’s. Both the role of chemotherapy and surgical treatments evolved significantly over the past decades and some of our findings may not apply in the setting of current practice. In order to account for these treatment changes, we controlled for year of diagnosis in our regression models and were able to confirm our univariate findings.
Another specific limitation is the scarcity of tumor size data in SEER database, since tumor size is of prognostic value in patients with osteosarcoma [31
]. In the SEER database, tumor size was unavailable in approximately half of the analyzed population and this variable was therefore not included in our analyses. Given our focus on very young children, this omission may not be as critical as in other analysis focused on larger patients. Studies in other sarcomas have shown that the risk associated with a given tumor size might not be the same in very young compared to older patients due to different body sizes [36
This study demonstrates differences in clinical presentation, treatment strategy, and outcomes according to very young age even after controlling for prognostic factors. Osteosarcoma is extremely rare in patients 5 years of age or younger. This striking difference in incidence and our findings that distinct tumor characteristics differ among very young patients suggests that these tumors arising in very young patients may be biologically different. Further investigations into developmental changes and molecular genetics are required to evaluate the observed differences in osteosarcoma among very young children. Additional efforts should be directed at adjusting treatment strategies in these very young patients to improve their outcomes.