Marginal Structural Models with Dose-Delay Joint-Exposure for Assessing Variations to Chemotherapy Intensity

Marginal Structural Models (MSMs) are causal models designed to adjust for time-dependent confounders in observational studies with dynamically-adjusted treatments. They are robust tools to assess causality in complex longitudinal data. In this paper a MSM is proposed with an innovative dose-delay joint-exposure model for Inverse-Probability-of-Treatment Weighted (IPTW) estimation of the causal effect of alterations to the therapy intensity. The model is motivated by a precise clinical question concerning the possibility of reducing dosages in a regimen. It is applied to data from a randomised trial of chemotherapy in osteosarcoma, an aggressive primary bone-tumour. Chemotherapy data are complex because their longitudinal nature encompasses many clinical details like composition and organisation of multi-drug regimens, or dynamical therapy adjustments. This manuscript focuses on the clinical dynamical process of adjusting the therapy according to the patient’s toxicity history, and the causal effect on the outcome of interest of such therapy modifications. Depending on patients’ toxicity levels, variations to therapy intensity may be achieved by physicians through the allocation of either a reduction or a delay of the next planned dose. Thus, a negative feedback is present between exposure to cytotoxic agents and toxicity levels, which acts as time-dependent confounders. The construction of the model is illustrated highlighting the high complexity and entanglement of chemotherapy data. Built to address dosage reductions, the model also shows that delays should not be introduced in the therapy administration. The last aspect makes sense from the cytological point of view, but it is seldom addressed in the literature

Method to measure the mismatch between target and achieved received dose intensity of chemotherapy in cancer trials: a retrospective analysis of the MRC BO06 trial in osteosarcoma

OBJECTIVES: In cancer studies, the target received dose intensity (tRDI) for any regimen, the intended dose and time for the regimen, is commonly taken as a proxy for achieved RDI (aRDI), the actual individual dose and time for the regimen. Evaluating tRDI/aRDI mismatches is crucial to assess study results whenever patients are stratified on allocated regimen. The manuscript develops a novel methodology to highlight and evaluate tRDI/aRDI mismatches. DESIGN: Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931). SETTING: Population-based study but proposed methodology can be applied to other trial designs. PARTICIPANTS: A total of 497 patients with resectable high-grade osteosarcoma, of which 19 were excluded because chemotherapy was not started or the estimated dose was abnormally high (>1.25 × prescribed dose). INTERVENTIONS: Two regimens with the same anticipated cumulative dose (doxorubicin 6×75 mg/m2/week; cisplatin 6×100 mg/m2/week) over different time schedules: every 3 weeks in regimen-C and every 2 weeks in regimen-DI. PRIMARY AND SECONDARY OUTCOME MEASURES: tRDI distribution was measured across groups of patients derived from k-means clustering of treatment data. K-means creates groups of patients who are aRDI-homogeneous. The main outcome is the proportion of tRDI values in groups of homogeneous aRDI. RESULTS: For nearly half of the patients, there is a mismatch between tRDI and aRDI; for 21%, aRDI was closer to the tRDI of the other regimen. CONCLUSIONS: For MRC BO06, tRDI did not predict well aRDI. The manuscript offers an original procedure to highlight the presence of and quantify tRDI/aRDI mismatches. Caution is required to interpret the effect of chemotherapy-regimen intensification on survival outcome at an individual level where such a mismatch is present.The study relevance lies in the use of individual realisation of the intended treatment, which depends on individual delays and/or dose reductions reported throughout the treatment. TRIAL REGISTRATION NUMBER: ISRCTN86294690

Disease progression in osteosarcoma: a multistate model for the EURAMOS-1 (European and American Osteosarcoma Study) randomised clinical trial

Objectives Investigating the effect of prognostic factors in a multistate framework on survival in a large population of patients with osteosarcoma. Of interest is how prognostic factors affect different disease stages after surgery, with stages of local recurrence (LR), new metastatic disease (NM), LR+NM, secondary malignancy, a second NM, and death.Design An open-label, international, phase 3 randomised controlled trial.Setting 325 sites in 17 countries.Participants The subset of 1631 metastases-free patients from 1965 patients with high-grade resectable osteosarcoma, from the European and American Osteosarcoma Study.Main outcome measures The effect of prognostic factors on different disease stages, expressed as HRs; predictions of disease progression on an individual patient basis, according to patient-specific characteristics and history of intermediate events.Results Of 1631 patients, 526 experienced an intermediate event, and 305 died by the end of follow-up. An axial tumour site substantially increased the risk of LR after surgery (HR=10.84, 95% CI 8.46 to 13.86) and death after LR (HR=11.54, 95% CI 6.11 to 21.8). A poor histological increased the risk of NM (HR=5.81, 95% CI 5.31 to 6.36), which sharply declined after 3 years since surgery. Young patients (18 had a decreased risk of death after event (eg, for death after LR: HR=2.40, 95% CI 1.52 to 3.90; HR=0.35, 95% CI 0.21 to 0.56, respectively).Conclusions Our findings suggest that patients with axial tumours should be monitored for LR and patients with poor histological response for NM, and that for young patients (<12) with an LR additional treatment options should be investigated.Orthopaedics, Trauma Surgery and Rehabilitatio

Novel longitudinal Multiple Overall Toxicity (MOTox) score to quantify adverse events experienced by patients during chemotherapy treatment: a retrospective analysis of the MRC BO06 trial in osteosarcoma

Analysis and Stochastic

Survival analysis of 3 different age groups and prognostic factors among 402 patients with skeletal high-grade osteosarcoma: real world data from a single tertiary sarcoma center

Simple SummaryAge is one of many prognostic factors for overall survival in patients with skeletal osteosarcoma. This retrospective study provides an overview of survival in patients with high-grade osteosarcoma in different age groups. It shows prognostic variables for survival and local control among the overall cohort. In this study, in which 402 patients with skeletal high-grade osteosarcoma were included, poor survival was associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis at presentation, and local recurrence were independent prognostic factors associated to overall survival and event-free survival. Differences in outcome among different age groups can be partially explained by patient characteristics and treatment characteristics.Age is a known prognostic factor for many sarcoma subtypes, however in the literature there are limited data on the different risk profiles of different age groups for osteosarcoma survival. This study aims to provide an overview of survival in patients with high-grade osteosarcoma in different age groups and prognostic variables for survival and local control among the entire cohort. In this single center retrospective cohort study, 402 patients with skeletal high-grade osteosarcoma were diagnosed and treated with curative intent between 1978 and 2017 at the Leiden University Medical Center (LUMC). Prognostic factors for survival were analyzed using a Cox proportional hazard model. In this study poor overall survival (OS) and event-free survival (EFS) were associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis (DM) at presentation and local recurrence (LR) were important independent prognostic factors influencing OS and EFS. Differences in outcome among different age groups can be partially explained by patient and treatment characteristics.Experimentele farmacotherapi

Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

Abstract This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new developments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for collaborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas

Intact interferon signaling in peripheral blood leukocytes of high-grade osteosarcoma patients

High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional. We studied the molecular and functional effects of interferon treatment on peripheral blood lymphocytes and monocytes of osteosarcoma patients, both in vivo and ex vivo. In contrast to other tumor types, in osteosarcoma, interferon signaling as determined by the phosphorylation of signal transducer and activator of transcription (STAT)1 at residue 701 was intact in immune cell subsets of 33 osteosarcoma patients as compared to 19 healthy controls. Also, cytolytic activity of interferon-α stimulated natural killer cells against allogeneic (n = 7 patients) and autologous target cells (n = 3 patients) was not impaired. Longitudinal monitoring of three osteosarcoma patients on interferon-α monotherapy revealed a relative increase in the CD16-positive subpopulation of monocytes during treatment. Since interferon signaling is intact in immune cells of osteosarcoma patients, there is a potential for indirect immunological effects of interferon-α treatment in osteosarcoma