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.

Abstract

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. Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931). Population-based study but proposed methodology can be applied to other trial designs. 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). 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. 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. 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. ISRCTN86294690.