Abstract
PurposeThere 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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 registrationISRCTN86294690.
Highlights
Extended author information available on the last page of the articleReceived dose intensity (RDI) was first described by Hryniuk as the given dose during a certain time period [1]
We performed a landmark analysis at 180 days since randomization to investigate the association between RDI and event-free survival (EFS) in the following scenarios: (i) patients are divided on the allocated regimen ( C or Reg-DI) which leads to two strata of identical target RDI (tRDI); (ii) patients are divided into four strata based on similarity of achieved RDI (aRDI); (iii) patients are divided into four strata based on similarity of Regulated RDI (rRDI)
Each rRDI line presents a sharp change in the steepness in the central part of Fig. 1 top and bottom right: this marks the last preoperative cycle whose duration includes the surgery window. rRDI lines form a tight bundle in the early phase of the treatment, but later they open up in a hand-fan shape because treatment adjustments are generally more frequent towards the end of the protocol
Summary
Received dose intensity (RDI) was first described by Hryniuk as the given dose (in mg/m2) during a certain time period [1] This definition applies to either single cytostatic agents or drug combinations [2]. RDI increase can be achieved by schedule compression supported by granulocyte colony-stimulating factor, e.g. by comparing 3-weekly doxorubicin plus cisplatin with a 2-weekly administration of the same agents at the same dosage [11]. This led to a 31% RDI increase and a significantly higher proportion of good histologic response in the intensified arm compared to the uncompressed control arm. An increase of RDI was not associated with a better survival, leading to the conclusion that histologic response was not a good surrogate marker tout court for survival outcome in osteosarcoma, because its prognostic value is limited to homogeneous groups of patients
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