Osteosarcoma is the most frequent primary malignancy of the bone¹ and its management requires a multidisciplinary team of specialists, such as pediatric and medical oncologists, and orthopedic oncology surgeons.^2,3 The treatment of osteosarcoma includes resection of the primary tumor and any metastases, and also intensive systemic chemotherapy. Radiation is reserved for selected patients, such as those with unresectable tumors.³ Over the last 30 years, after the addition of chemotherapy to surgical treatment, survival after osteosarcoma has greatly improved for patients with localized disease, with 5-year event-free survival (EFS) increasing from 20% to approximately 60–70%.¹ However, 5-year EFS remains only 30% or less for those diagnosed with metastatic disease.¹ Clinical practice guidelines based on clinical trials, such as the Children’s Oncology Group (COG) and the National Comprehensive Cancer Network (NCCN), were created to help clinicians deliver the best treatment available to their patients⁴ and thus improving survival.^5–7

In the United States (US), receipt of guideline-concordant care (GCC), may vary according to primary tumor site, age at diagnosis, the presence of comorbidities, location of care, and other factors not yet identified.^4–8 However, to our knowledge, no population-based study in the US has assessed GCC patterns or associations with survival for patients diagnosed with osteosarcoma. Much of what is known about the treatment of these patients comes from single institution studies or clinical trials.^9–11 Therefore, we sought to examine factors associated with delivery of GCC in osteosarcoma patients and investigate whether GCC is associated with survival after accounting for clinical and sociodemographic factors.

In this large population-based study, we identified that GCC was associated with improved survival among patients with metastatic osteosarcoma at diagnosis, but results did not reach statistical significance for patients diagnosed at earlier stages. Despite this survival advantage with GCC, we found that patients with metastatic disease were less likely to receive GCC. Management of patients with osteosarcoma is complex, particularly for those diagnosed with metastatic disease. For example, patients with unresectable metastatic disease should undergo chemotherapy, radiation, and be reassessed as appropriate for local control. Those with resectable metastatic disease need preoperative chemotherapy followed by metastasectomy or stereotactic radiation or ablation (if pulmonary metastasectomy is not feasible).³ However, disparities in the delivery of GCC exist. The majority of patients with osteosarcoma did not receive GCC in California, with GCC varying by age at diagnosis, nSES, and location of care. Specifically, we observed that only 43% of AYAs and 30% of adults received GCC compared to 67% of children. In addition, patients who resided in the lower SES neighborhoods and those who did not receive care at SCCs were less likely to receive GCC. These findings are concerning and may contribute to disparities in survival we observed in patients with osteosarcoma.^15–17 To our knowledge, this is the first population-based study to provide information on the delivery of osteosarcoma clinical guidelines in the US and to compare the results across age groups.

Our findings of 47% of patients with osteosarcoma receiving GCC is lower than a single institution study in the US that found 67% of AYAs with osteosarcoma or Ewing sarcoma received GCC,¹⁸ but higher than a French study on patients with soft tissue sarcoma (STS).⁸ The French study examined 127 patients ages 0–25 diagnosed with STS and observed that only 41% of patients were treated according to international guidelines. Importantly, STS event-free survival was superior when the 5 guideline criteria were followed compared to ≤ 4 criteria were met.⁸ Although not on osteosarcoma, other studies reporting on treatment according to NCCN guidelines found that this varied from 80%–97% depending on the cancer site, age at diagnosis, comorbidities, and reporting facility for patients with lung, anal, rectum, cervical, and nasopharynx cancer.⁴ Our findings highlight the need for cancer care delivery interventions to improve compliance to clinical practice guidelines, especially for older patients.

We observed that patients aged less than 40 treated by medical (vs pediatric) oncologists were less likely to receive GCC, underscoring the importance of collaboration between medical and pediatric oncologists in the treatment of AYAs. A national study in France examined the impact of compulsory patient case presentation before treatment to a multidisciplinary tumor board (MDTB) on survival of patients aged >14 years diagnosed with STS and visceral sarcoma.¹⁹ The MDTB included, among others, pediatric and medical oncologists. The study found that presentation to a MDTB before treatment was associated with increased adherence to clinical guidelines and improved relapse-free survival. A more recent French study included patients with osteosarcoma and emphasized the need for presentation of patients to a MDTB that include both pediatric and medical oncologists in the diagnostic phase, before any treatment is delivered.²⁰ Our findings suggest that involvement of pediatric oncologists in the care of AYA patients with osteosarcoma could improve delivery of GCC and presentation at a MDTB inclusive of both pediatric and medical oncologists could be one way to approach this.

We demonstrated that patients who received treatment at SCCs were more likely to receive GCC. Interestingly, this finding was more pronounced among patients who received part (vs all) of their treatment at these centers. Our findings may relate to care at SCCs focusing on specific services, such as surgery or specialized diagnostics, with local facilities overseen by SCCs administering radiation and/or chemotherapy to optimize the overall treatment plan. Receiving care closer to the patient’s home may enhance adherence to GCC. In Europe¹³ and in the US³, national guidelines recommend referral of patients with osteosarcoma to SCCs. At these centers, tumor-specific cancer treatment can be delivered by a highly specialized team of clinicians. It has been shown that pre-treatment tumor biopsy, pre-treatment imaging, and neoadjuvant chemotherapy were performed more often in specialized sarcoma centers.²⁰ In addition, established treatment guidelines that are based on the results of collaborative clinical trials or established treatment protocols are more often followed at SCCs.¹³ SCCs also provide comprehensive supportive care, which include modern and innovative intensive care units, specialist nurses, and psychologists, that has been shown to be associated with improved survival.^2,21,22 Efforts should be made to increase early referral of osteosarcoma patients to SCCs in order to help improve survival outcomes in this patient population.

Our study additionally demonstrated that several sociodemographic factors influenced delivery of GCC. For example, patients of NH Asian/Pacific Islander race/ethnicity and those who resided rural areas or in higher SES neighborhoods were more likely to receive GCC. Our race/ethnicity findings differ from a study using data from the NCI-Surveillance Epidemiology and End Results (SEER) Program, which found that NH Black/African American and NH Asian/Pacific Islander patients with osteosarcoma were less likely to undergo primary surgery than NH Whites.²³ However, our study also considered radiation and systemic chemotherapy for GCC. In addition, our results are consistent with studies that found that cancer patients residing in rural areas are more likely to receive GCC (“the urban-rural paradox”), when distance to the treating facility is not consistently associated with care delivered.²⁴ This paradox has been partially explained by patients living in rural more commonly traveling longer distances²⁵ and more often have their own transportation. Further, this study demonstrated lower delivery of GCC among patients living in low and middle SES neighborhoods, which is consistent with previous reports that observed lower delivery of GCC among patients living in neighborhoods of lower SES. These findings indicate that there are factors beyond stage at diagnosis that continue to impact delivery of optimal care for patients with osteosarcoma.²⁶

Our study has several limitations. We did not have information on whether pre-treatment imaging and pre-treatment tumor biopsy were performed. We also did not have detailed data on microscopically residual disease or on the quality of surgery performed (complete resection or not). Further, treating specialty was defined by hospital first admission, therefore we may not have captured some encounters with additional specialists. This could potentially explain why a higher than anticipated proportion of patients under the age of 15 years were not recorded as being treated by a pediatric oncologist. The strengths of our study include a large population-based cohort, detailed information on first-line chemotherapy, primary surgery, and radiation data available in the CCR text fields. In addition, we examined the associations between treating physicians, location of care, and receipt of GCC and survival. Furthermore, CCR has sociodemographic data that allowed us to identify disparities in the receipt of GCC.

In conclusion, to our knowledge, this is the first population-based study to provide information on the “real world” delivery of GCC for patients with osteosarcoma in the US. Our study revealed that less than half of patients received GCC for osteosarcoma in the large and diverse state of California and confirmed that receipt of GCC was associated with improved survival for patients diagnosed with metastatic disease. However, patients with metastatic disease were less likely to receive GCC. AYAs, adults and patients residing in lower SES neighborhoods had less access to GCC, highlighting areas for interventions to improve delivery of GCC. Importantly, we reinforced the importance of referring patients newly diagnosed with osteosarcoma to SCCs, where GCC treatment is more likely to be delivered by a highly specialized multidisciplinary team.