Causal effect of chemotherapy received dose intensity on survival outcome: a retrospective study in osteosarcoma.

Background: This study aims to analyse the effects of reducing Received Dose Intensity (RDI) in chemotherapy treatment for osteosarcoma patients on their survival by using a novel approach. Previous research has highlighted discrepancies between planned and actual RDI, even among patients randomized to the same treatment regimen. To mitigate toxic side effects, treatment adjustments, such as dose reduction or delayed courses, are necessary. Toxicities are therefore risk factors for mortality and predictors of future exposure levels. Toxicity introduces post-assignment confounding when assessing the causal effect of chemotherapy RDI on survival outcomes, a topic of ongoing debate.

Methods: Chemotherapy administration data from BO03 and BO06 Randomized Clinical Trials (RCTs) in ostosarcoma are employed to emulate a target trial with three RDI-based exposure strategies: 1) standard, 2) reduced, and 3) highly-reduced RDI. Investigations are conducted between subgroups of patients characterised by poor or good Histological Responses (HRe), i.e., the strongest known prognostic factor for survival in osteosarcoma. Inverse Probability of Treatment Weighting (IPTW) is first used to transform the original population into a pseudo-population which mimics the target randomized cohort. Then, a Marginal Structural Cox Model with effect modification is employed. Conditional Average Treatment Effects (CATEs) are ultimately measured as the difference between the Restricted Mean Survival Time of reduced/highly-reduced RDI strategy and the standard one. Confidence Intervals for CATEs are obtained using a novel IPTW-based bootstrap procedure.

Results: Significant effect modifications based on HRe were found. Increasing RDI-reductions led to contrasting trends for poor and good responders: the higher the reduction, the better (worsen) was the survival in poor (good) reponders. Due to their intrinsic resistance to chemotherapy, poor reponders could benefit from reduced RDI, with an average gain of 10.2 and 15.4 months at 5-year for reduced and highly-reduced exposures, respectively.

Conclusions: This study introduces a novel approach to (i) comprehensively address the challenges related to the analysis of chemotherapy data, (ii) mitigate the toxicity-treatment-adjustment bias, and (iii) repurpose existing RCT data for retrospective analyses extending beyond the original trials' intended scopes.