Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee

Abstract

Background: The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery.

Methods: Retrospective analysis was performed for patients aged <22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as <5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology.

Results: Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P < 0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1).

Conclusion: We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.

Keywords: biomarker; chemotherapy; histologic response; necrosis; osteosarcoma.

Conflict of interest statement

Nothing to declare.

© 2016 Wiley Periodicals, Inc.

Figures

Fig. 1

Induction treatment for osteosarcoma protocols are shown for (A) CCG-782 and for (B) INT0133; M, methotrexate 8–12 g/m2; V, vincristine 1.5 mg/m2; B, bleomycin 15 mg/m2/day × 2; C; cyclophosphamide 600 mg/m2/day × 2; D, dactinomycin 600 μg/m2/day × 2. (B) INT0133 induction schema; P, cisplatin 120 mg/m2; A, adriamycin (doxorubicin); 25 mg/m2/day × 3; I, ifosfamide 1.8 g/m2/day × 5; M, methotrexate 12 g/m2.

Fig. 2

CONSORT diagrams demonstrate patients enrolled on (A) CCG-782 and (B) INT0133 who were eligible for analysis, and patient events measured for those in the analytic population; SMN, second malignant neoplasm.

Fig. 3

Event-free survival (EFS) over time is demonstrated as a Kaplan–Meier curve for patients on both CCG-782 and INT0133. Curves are presented for good responders and poor responders from each trial.