title: Therapies with diverse mechanisms of action kill cells by a similar exponential process in advanced cancers.
abstract: Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor. Here, we examine theoretically different models of cell killing and analyze data from clinical trials based on these models. We show that the best description of clinical outcomes is by first-order kinetics with exponential decrease of tumor quantity. We analyzed the total tumor quantity in a diverse group of clinical trials with various cancers during the administration of different classes of anticancer agents and in all cases observed that the models that best fit the data describe the decrease of the sensitive tumor fraction exponentially. The exponential decrease suggests that all drug-sensitive cancer cells have a single rate-limiting step on the path to cell death. If there are intermediate steps in the path to cell death, they are not rate limiting in the observational time scale utilized in clinical trials--tumor restaging at 6- to 8-week intervals. On shorter time scales, there might be intermediate steps, but the rate-limiting step is the same. Our analysis, thus, points to a common pathway to cell death for cancer cells in patients. See all articles in this Cancer Research section, "Physics in Cancer Research."
authors.affiliation: National Science Foundation, Arlington, Virginia. Department of Radiology, Massachusetts General Hospital, Harvard Medical School and the Antinula Martinos Center for Biomedical Imaging, Charlestown, Massachusetts. kblagoev@nsf.gov.
authors.forename: Krastan B
authors.initials: KB
authors.lastname: Blagoev
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Hebrew University, Jerusalem, Israel.
authors.forename: Wilfred D
authors.initials: WD
authors.lastname: Stein
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: James
authors.initials: J
authors.lastname: Yang
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.affiliation: Medical Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents