Response Assessment in Paediatric Phase I Trials According to RECIST Guidelines: Survival Outcomes, Patterns of Progression and Relevance of Changes in Tumour Measurements

Abstract

Introduction. RECIST guidelines constitute the reference for radiological response assessment in most paediatric trials of anticancer agents. However, these criteria have not been validated in children. We evaluated the outcomes and patterns of progression of children/adolescents enrolled in phase I trials in two paediatric drug development units. Methods. Patients aged ࣘ21 assessed with RECIST (v1.0 or v1.1) were eligible. Clinico-radiological data were analysed using Mann-Whitney U and log-rank tests to correlate response categories and sum of longest diameters (SLD) with time-toevent variables and overall survival (OS). Results. Sixty-one patients (71 enrolments) were evaluated; median age: 12.7 years (range, 3.1-20.9). Overall, 7% achieved complete/partial response (n = 5) and 31% disease stabilisation (n = 22). Median (95% CI) OS (in months) was 29.1 (27.6-30.6) with complete/partial response, 8.9 (2.0-15.8) with stable disease and 2.8 (2.3-3.3) with disease progression (P < 0.001); 32.6% patients with measurable disease presented exclusive progression of existing non-target lesions and/or new lesions. The change in SLD at best response showed a linear correlation with duration of response (r = −0.605; P = 0.004) and time on trial (r = −0.61; P = 0.003), but the change in SLD at progression did not correlate with time to progression (r = −0.219; P = 0.206). Conclusions. Response assessment according to RECIST correlated with OS in children/adolescents treated on phase I trials. The reduction in SLD at best response correlated with more prolonged responses. Tumour size did not constitute an optimal method to assess disease progression in one third of patients with measurable disease. Further refinement of current response assessment guidelines will enable the development of paediatric-specific radiological criteria.

Outcome of children and adolescents with central nervous system tumors in phase I trials

“…In pediatric phase I trials, we have previously shown that the grade of tumor shrinkage, by RECIST, also correlates with the duration of response and the OS [17]. But importantly, in agreement with previous reports [7,17], in our cohort patients with CNS tumors who achieved disease stabilization had survival rates comparable to those with objective responses. These findings suggest that novel targeted therapies, even if they cannot induce significant tumor shrinkage, may halt tumor growth sufficiently as to confer a survival advantage for some patients.…”

“…In adults enrolled in phase I trials, it has been shown a nearlinear relationship between tumor shrinkage assessed by RECIST and OS [16]. In pediatric phase I trials, we have previously shown that the grade of tumor shrinkage, by RECIST, also correlates with the duration of response and the OS [17]. But importantly, in agreement with previous reports [7,17], in our cohort patients with CNS tumors who achieved disease stabilization had survival rates comparable to those with objective responses.…”

Feasibility and applicability of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging in routine assessments of children with high-grade gliomas

“…Limitations of assessing size alone in paediatric brain tumours include interobserver variability, nonspecific enhancement, and variable correlation between decreased tumour size and survival . These issues become particularly relevant in the context of drug development, where the majority of patients deriving benefit from pediatric phase I trials present stable disease rather than objective responses . Hence, there is an increasing interest in incorporating imaging methods, capable of assessing specific tissue properties, into clinical trials to refine response assessments.…”

Predictors of response, progression‐free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high‐risk neuroblastoma

“…A retrospective review of Phase 1 adult cancer trials found that change in tumor size by RECIST had a near‐linear association with survival with no significant cutoff points. A retrospective study of Phase 1 pediatric trials found that change in tumor size by RECIST had a linear association with response duration, and was associated with overall survival (OS), but not progression‐free survival (PFS). RECIST often does not apply to patients with relapsed/refractory HR‐NB, since bone and bone marrow (BM) are the most common relapse sites, and measurable soft tissue disease may not be present.…”