Disease progression in osteosarcoma: a multistate model for the EURAMOS-1 (European and American Osteosarcoma Study) randomised clinical trial

Abstract

Objectives: Investigating the effect of prognostic factors in a multistate framework on survival in a large population of patients with osteosarcoma. Of interest is how prognostic factors affect different disease stages after surgery, with stages of local recurrence (LR), new metastatic disease (NM), LR+NM, secondary malignancy, a second NM, and death.

Design: An open-label, international, phase 3 randomised controlled trial.

Setting: 325 sites in 17 countries.

Participants: The subset of 1631 metastases-free patients from 1965 patients with high-grade resectable osteosarcoma, from the European and American Osteosarcoma Study.

Main outcome measures: The effect of prognostic factors on different disease stages, expressed as HRs; predictions of disease progression on an individual patient basis, according to patient-specific characteristics and history of intermediate events.

Results: Of 1631 patients, 526 experienced an intermediate event, and 305 died by the end of follow-up. An axial tumour site substantially increased the risk of LR after surgery (HR=10.84, 95% CI 8.46 to 13.86) and death after LR (HR=11.54, 95% CI 6.11 to 21.8). A poor histological increased the risk of NM (HR=5.81, 95% CI 5.31 to 6.36), which sharply declined after 3 years since surgery. Young patients (<12 years) had a lower intermediate event risk (eg, for LR: HR=0.66, 95% CI 0.51 to 0.86), when compared with adolescents (12-18 years), but had an increased risk of subsequent death, while patients aged >18 had a decreased risk of death after event (eg, for death after LR: HR=2.40, 95% CI 1.52 to 3.90; HR=0.35, 95% CI 0.21 to 0.56, respectively).

Conclusions: Our findings suggest that patients with axial tumours should be monitored for LR and patients with poor histological response for NM, and that for young patients (<12) with an LR additional treatment options should be investigated.

Trial registration number: NCT00134030.

Keywords: bone diseases; clinical trials; paediatric oncology; sarcoma.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Consolidated Standards of Reporting Trials diagram of patients included in the analysis. In the boxes, we list the six exclusion criteria with the total number of patients per category. Above the arrows, we give the additional number of patients excluded on considering each criterion, in order of appearance. (a) To ensure a homogeneous study population, we excluded patients with metastases prior to surgery. For 357 patients, metastases were recorded at registration, while for 170 patients, progression of new metastatic disease was found after surgery, while no metastases were recorded at registration. These patients were retrospectively reclassified as having metastatic disease prior to surgery and excluded from the analysis; (b) 22 randomised patients were later found to be ineligible due to progression of metastatic disease or new metastatic disease (n=11), or primary and/or metastatic unresectable disease (n=11).

Figure 2

Disease progression of osteosarcoma represented in a multistate model. Seven possible states and 10 transitions are defined. For each transition, the number of patients progressing from one state to another is shown. A total of 1631 patients are present in the starting stage, Surgery. After surgery, a patient may experience a local recurrence (LR), an LR+new metastatic disease (LR +NM), an NM, a secondary malignancy (SM) or death. After any such intermediate event, a patient may progress to death. Patients with NM may experience a second new metastatic disease after remission (NM2).

Figure 3

Time-varying hazard for histological response. (A) Hazard for transitioning from surgery to new metastatic disease (NM). (B) Hazard for transitioning from NM to death. Blue: poor histological response; black: good histological response; dashed line: pointwise CI for the HR of poor histological response.

Figure 4

Stacked state occupation probabilities for patients with different characteristics. Patient characteristics are defined with respect to the reference patient, shown in 1A: patient with reference characteristics: age 12–18 years, good histological response, wide/radical excision, tumour volume <200 cm3, female, tumour location of category ‘other’. 1B: patient aged <12 years. 1C: patient aged >18 years. 2A: patient with axial tumour location. 2B: patient with poor histological response. 2C: patient with intralesional excision. 3A–3C: patient with reference characteristics experiencing a new metastatic disease (NM) at 1 year (3A), at 2 years (3B), and at 4 years (3C). 4A–4C: patient with reference characteristics experiencing local recurrence (LR) at 1 year (3A), at 2 years (3B), and at 4 years (3C). SM, secondary malignancy.