Quantifying and reducing uncertainties in cancer therapy

Abstract

There are two basic sources of uncertainty in cancer chemotherapy: how much of the therapeutic agent reaches the cancer cells, and how effective it is in reducing or controlling the tumor when it gets there. There is also a concern about adverse effects of the therapy drug. Similarly in external-beam radiation therapy or radionuclide therapy, there are two sources of uncertainty: delivery and efficacy of the radiation absorbed dose, and again there is a concern about radiation damage to normal tissues. The therapy operating characteristic (TOC) curve, developed in the context of radiation therapy, is a plot of the probability of tumor control vs. the probability of normal-tissue complications as the overall radiation dose level is varied, e.g. by varying the beam current in external-beam radiotherapy or the total injected activity in radionuclide therapy. The TOC can be applied to chemotherapy with the administered drug dosage as the variable. The area under a TOC curve (AUTOC) can be used as a figure of merit for therapeutic efficacy, analogous to the area under an ROC curve (AUROC), which is a figure of merit for diagnostic efficacy. In radiation therapy AUTOC can be computed for a single patient by using image data along with radiobiological models for tumor response and adverse side effects. In this paper we discuss the potential of using mathematical models of drug delivery and tumor response with imaging data to estimate AUTOC for chemotherapy, again for a single patient. This approach provides a basis for truly personalized therapy and for rigorously assessing and optimizing the therapy regimen for the particular patient. A key role is played by Emission Computed Tomography (PET or SPECT) of radiolabeled chemotherapy drugs.

Assessment of an Integrative Anticancer Treatment Using an in Vitro Perfusion-Enabled 3D Breast Tumor Model

“…Such physiological and microenvironment-based factors can be location and cell specific in the tumor tissue. 8 All such forms of biological and physical heterogeneity within the tumor microenvironment can lead to a failure of treatment. Hence, requirement of appropriate computational models is to derive accurate parameters needed for treatment.…”

“…These variations are also more pronounced from tumor to tumor. Such physiological and microenvironment-based factors can be location and cell specific in the tumor tissue . All such forms of biological and physical heterogeneity within the tumor microenvironment can lead to a failure of treatment.…”

Principles of Molecular Targeting for Radionuclide Therapy

“…In both situations, design of the molecule to be retained longer in the blood depending on physical-chemical parameters of small molecules and strategies that minimize the biodistribution to normal organs are both key in improving the potential of therapeutic radiopharmaceuticals. The AUC has been the traditional approach to comparing the relative tissue complications from clinical data obtained in Phase II/III [30].…”