PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R–based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M–based policy ( P = .001). CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Time-varying covariates are of great interest in clinical research since they represent dynamic patterns which reflect disease progression. In cancer studies biomarkers values change as functions of time and chemotherapy treatment is modified by delaying a course or reducing the dose intensity, according to patient’s toxicity levels. In this work, a Functional covariate Cox Model (FunCM) to study the association between time-varying processes and a time-to-event outcome is proposed. FunCM first exploits functional data analysis techniques to represent time-varying processes in terms of functional data. Then, information related to the evolution of the functions over time is incorporated into functional regression models for survival data through functional principal component analysis. FunCM is compared to a standard time-varying covariate Cox model, commonly used despite its limiting assumptions that covariate values are constant in time and measured without errors. Data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma are analysed. Time-varying covariates related to alkaline phosphatase levels, white blood cell counts and chemotherapy dose during treatment are investigated. The proposed method allows to detect differences between patients with different biomarkers and treatment evolutions, and to include this information in the survival model. These aspects are seldom addressed in the literature and could provide new insights into the clinical research.

Since the mid-1980s, there has been little progress in improving survival of patients diagnosed with osteosarcoma. Survival prediction models play a key role in clinical decision-making, guiding healthcare professionals in tailoring treatment strategies based on individual patient risks. The increasing interest of the medical community in using machine learning (ML) for predicting survival has sparked an ongoing debate on the value of ML techniques versus more traditional statistical modelling (SM) approaches. This study investigates the use of SM versus ML methods in predicting overall survival (OS) using osteosarcoma data from the EURAMOS-1 clinical trial (NCT00134030). The well-established Cox proportional hazard model is compared to the extended Cox model that includes time-varying effects, and to the ML methods random survival forests and survival neural networks. The impact of eight variables on OS predictions is explored. Results are compared on different model performance metrics, variable importance, and patient-specific predictions. The article provides comprehensive insights to aid healthcare researchers in evaluating diverse survival prediction models for low-dimensional clinical data.

Objectives: This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.Design: Retrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.Setting: International multicentre population-based study.Participants: A total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).Interventions: Patients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measures: The MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.Results: A cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients’ health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient’s history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2–3 (p<0.05).Conclusions: The novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning.Trial registration number: ISRCTN86294690; Post-results.