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

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.