A novel method to address the association between received dose intensity and survival outcome: benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup

Abstract

Purpose There is lack of consensus on the prognostic value of received high dose intensity in osteosarcoma survivorship. Many studies have not shown a clear survival benefit when dose intensity is increased. The aim of this study is to go beyond chemotherapy intensification by arm-wide escalation of intended dose and/or compression of treatment schedule, while conversely addressing the relationship between treatment intensity and survival at the patient level. The study focusses on the difference in outcome results, based on a novel, progressively more individualised approach to dose intensity. Methods A retrospective analysis of data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma was conducted. Three types of post hoc patient groups are formed using the intended regimen: the individually achieved cumulative dose and time on treatment, and the increase of individual cumulative dose over time. Event-free survival is investigated and compared in these three stratifications. Results The strata of intended regimen and achieved treatment yields equivalent results. Received cumulative dose over time produces groups with evident different survivorship characteristics. In particular, it highlights a group of patients with an estimated 3-year event-free survival much larger (more than 10%) than other patient groups. This group mostly contains patients randomised to an intensified regimen. In addition, adverse events reported by that group show the presence of increased preoperative myelotoxicity. Conclusions The manuscript shows the benefits of analyzing studies by using longitudinal data, e.g. recorded per cycle. This has impact on the drafting of future trials by showing why such a level of detail is needed for both treatment and adverse event data. The novel method proposed, based on cumulative dose received over time, shows that longitudinal treatment data might be used to link survival outcome with drug metabolism. This is particularly valuable when pharmacogenetics data for metabolism of cytotoxic agents are not collected. Trial registration ISRCTN86294690.

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

“…Osteosarcoma (OS) is a highly aggressive malignant bone tumor frequently occurring in children and adolescents with an annual incidence of ~4.8 per million worldwide 1 , 2 . According to WHO classification of tumors of soft tissue and bone, a minimal quantity identification of neoplastic bone is sufficient to render a diagnosis of OS 3 .…”

The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis

“…In recent years, studies co-sponsored by European and American Osteosarcoma Studies (EURAMOS), Cooperative Osteosarcoma Study Group (COSS), European Osteosarcoma Intergroup (EOI), and Scandinavian Sarcoma Group (SSG) have yielded encouraging results [44][45][46]. Smeland et al [44] enrolled 2186 patients over a 6-year period and evaluated their differences after receiving MDC chemotherapy.…”

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

“…Those findings were corroborated by pharmacokinetic studies that determined a beneficial cut-off of a plasma peak concentration of more than 1000 µM and a minimum number of six HDMTX courses [273]. Similarly, reduction of per-protocol chemotherapy intensity due to toxic complications has a negative impact on survival outcomes [274]. However, several randomized trials did not see improved survival through therapy intensification with the addition of two or more chemotherapeutic agents as compared to the standard arm [129,275,276].…”