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.

Keywords: Bone tumour; Chemotherapy; Personalised medicine; Sarcoma.

Fig. 1

a Individual standardised dose over time coloured by the allocated regimen (pink: Reg-DI; purple: Reg-C); each line is a graphical representation of the regulated RDI (rRDI) of a patient; black lines show the anticipated (target) rRDI line of a patient randomised to Reg-DI (dotted) or Reg-C (solid); divergence of coloured lines from the target black one illustrates how complicated an individual course of treatment was. b Individual cumulative standardised dose vs standardised treatment duration; each point is a graphical representation of the achieved RDI of a patient (pink circle: Reg-DI; purple square: Reg-C); two thick black markers represent two fictitious patients who completed the protocol with no delays or dose reductions (dot: Reg-DI; square: Reg-C). These black markers are a graphical representation of target RDI. The larger the distance of a coloured point from the corresponding black one, the more complicated the individual course of treatment. With respect to a, this view does not show where the complications were located in time. c As end points of rRDI lines match the pattern of achieved RDI visualised in b, regulated RDI correctly extends achieved RDI over time

Fig. 2

Individual cumulative standardised dose versus standardised treatment duration; patients are coloured in four groups determined by similarity of achieved RDI; patients are marked according to their target RDI value (circle: patient randomised to Reg-DI; square: Reg-C)

Fig. 3

Grouping of patients by similarity of regulated RDI and individual rRDI lines of each group; each line shows the growth of the standardised cumulative dose received over time. is mostly composed of patients randomised to Reg-C (92%), captures treatment discontinuations and is balanced regimen-wise; is composed only of patients allocated to Reg-DI; is composed for the large majority (72%) by patients randomised to Reg-DI. shows steeper lines than any other group, which means that patients therein reported the highest received dose intensity. In particular, presents a marked difference with in terms of line steepness that is more evident in the preoperative part of the regimen

Fig. 4

Proportion of patient cycles that required adaptations (either delays or dose reductions) according to the study protocol and corresponding cause of adaptation as reported by the case report form. The view is per rRDI-group, i.e. per group of patients with similar regulated RDI pattern. The x-axis displays cycle number, while the y-axis shows the proportion of patients in the group who required adaptations. Groups and are driven by late myelotoxicity, while groups and are driven by early myelotoxicity. In addition, seems to be driven by ‘other’ reasons (most likely doxorubicin-induced cardiotoxicity, for which a dedicated checkbox was not present on the trial’s case report form), and reports the highest proportion of adjustment due to myelotoxicity in the preoperative period. Cycles discontinued do not contribute to the plot

Fig. 5

Estimation of event-free survival in groups that are homogeneous with respect to RDI using a progressively more individualised definition of RDI. a-1 Groups defined with respect to target RDI and a-2 the corresponding Kaplan–Meier curves; b-1 groups defined with respect to achieved RDI and b-2 the corresponding survival curves; c-1 groups defined with respect to regulated RDI and c-2 the corresponding survival curves