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Chemotherapy drug administration is a complex problem that often requires expensive clinical trials to evaluate potential regimens; one way to alleviate this burden and better inform future trials is to build reliable models for drug administration. This paper presents a mixed-integer program for combination chemotherapy (utilization of multiple drugs) optimization that incorporates various important operational constraints and, besides dose and concentration limits, controls treatment toxicity based on its effect on the count of white blood cells. To address the uncertainty of tumor heterogeneity, we also propose chance constraints that guarantee reaching an operable tumor size with a high probability in a neoadjuvant setting. We present analytical results pertinent to the accuracy of the model in representing biological processes of chemotherapy and establish its potential for clinical applications through a numerical study of breast cancer. History: Accepted by Paul Brooks, Area Editor for Applications in Biology, Medicine, & Healthcare. Funding: This work was supported by the National Science Foundation [Grants CMMI-1933369 and CMMI-1933373]. Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0207 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0207 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ . 

In radiation therapy treatment plan optimization, selecting a set of clinical objectives that are tractable and parsimonious yet effective is a challenging task. In clinical practice, this is typically done by trial and error based on the treatment planner’s subjective assessment, which often makes the planning process inefficient and inconsistent. We develop the objective selection problem that infers a sparse set of objectives for prostate cancer treatment planning based on historical treatment data. We formulate the problem as a nonconvex bilevel mixed-integer program using inverse optimization and highlight its connection with feature selection to propose multiple solution approaches, including greedy heuristics and regularized problems and application-specific methods that use anatomical information of the patients. Our results show that the proposed heuristics find objectives that are near optimal. Via curve analysis on dose-volume histograms, we show that the learned objectives closely represent latent clinical preferences.