Current dosing methods may be leaving some patients significantly underdosed, which could be causing more harm than good. [© sudok1 - Fotolia.com]
World War I was raging and the first bottles with the classic Coca-Cola formula reached stores back in 1916, when the current dosing method for many cancer patients was developed.
To this day, many cancer patients are dosed with chemotherapy based on their height and weight or body surface area (BSA), a one-size-fits-all approach to patient care that emerged from the study of only eight patients as a means of adjusting for basal metabolic rates in estimating the human starting dose from animal doses. By the 1960s, BSA dosing was adapted to chemotherapy drugs in the absence of any other dosing method.
Into the dawn of the personalized medicine era, blood level is a relatively common basis of dosing several categories of drugs, such as neurology or infectious disease. But while drugs for some childhood leukemias are similarly dosed, it hasn’t been as common in oncology, where BSA-based dosing has survived despite the numerous variables associated with it in the reaction of cancer patients—not only weight and height, but absorption as well.
BSA-based doses are recommended by manufacturers according to the maximum tolerated dose (MTD) established during Phase I studies using the Fibonacci dose escalation 3+3 schema—three patients are enrolled at each proposed dose level. If two or more patients at a given dose present a drug-limiting toxicity, doctors stop enrolling patients at that dose level, and the immediate preceding dose is deemed the MTD.
"More Harm Than Good"
“The real bad thing is, the doctor thinks the patient is tolerating the drug well, when in fact the patient could be woefully underdosed, and it’s kind of like giving somebody a low dose with an antibiotic. You’re causing really more harm than good. You might as well not treat the patient,” Salvatore Salamone, Ph.D., founder, senior VP & chief scientific officer of Saladax Biomedical, told GEN.
Saladax develops and commercializes diagnostic assays designed to improve the effectiveness of existing drugs through dosing based on the concentration of the drug in the patient’s bloodstream, or their overall exposure to the drug. Some patients may need as much as three times the dose of other patients to reach optimal concentration and obtain the best clinical efficacy, without suffering toxicity.
Of three Saladax MyCare™ assays to reach the market, one is sold in the U.S. (My 5-FU™) through a licensing deal with Myriad Genetics. Saladax is developing launch strategies for two other assays, MyPaclitaxel™ and MyDocetaxel™.
The three are among 13 oncology-focused assays by Saladax. The company has also developed two CNS antipsychotic drug dose management assays, two others are for Alzheimer’s, and two others are unannounced collaborations.
For Alzheimer’s, Saladax and Bristol-Myers Squibb originally entered into a collaboration in 2010 to develop clinical diagnostic tests for the disease for use with some BMS compounds. Last year the partnership was expanded to include a commercial partner, Johnson & Johnson’s Ortho Clinical Division.
“Back in 2004, we would call pharmaceutical companies and ask them if they were interested in companion diagnostics. And we’d never get a call back,” Dr. Salamone recalled. “Something has happened in the last two or three years or so, where pharma companies are contacting us now, asking about what our capabilities are in the companion space. So the tides have really started to turn.”
Measuring Exposure Level
Dr. Salamone and Joseph R. Bertino, M.D., a member of Saladax’ Scientific Advisory Board, contend that a more rational approach to dosing consists of defining in early drug development stages an exposure level that produces a biological effect that is associated with efficacy and/or avoidance of toxicity. For many drugs, they said, the exposure level can be determined by measuring the active form or relevant surrogate of the drug in the plasma and correlating these levels with outcomes and/or toxicity.
“By defining the exposure level where dose-limiting toxicity is presented, a maximum tolerated exposure (MTE) can be identified,” said Dr. Bertino, who is University Professor of Medicine and Pharmacology and American Cancer Society Professor at University of Medicine & Dentistry of New Jersey–Robert Wood Johnson Medical School. “If you treat to an MTE, you not only decrease toxicity but you increase the therapeutic efficacy of the drug. We talk about personalized medicine, and if you don’t give the right dose to the right person, you’re really not delivering personalized medicine. This is an important aspect of personalized medicine."
Doctors have identified MTEs for several commonly used cancer drugs such as the lung cancer drug carboplatin, fluorouracil (5-FU), and the taxanes docetaxel and paclitaxel. However, exposure for fluorouracil can vary as much as 30 to 100 fold, while docetaxel exposure can vary sevenfold.
In a Phase III study of colorectal cancer patients, a research team headed by Erick Gamelin showed that, by measuring 5-FU levels in plasma, then adjusting doses in later treatment cycles to achieve target concentrations, severe toxicities were reduced and response rates nearly doubled from 18.3% to 33.7%, with medium overall survival improved from 16 to 22 months. To achieve target levels, 68% of patients needed increased dose intensity, with another 17% requiring reduced doses.
An Issue of Cost
Given those and other promising results, why are oncologists still using BSA for dosing cancer drugs?
“There’s no doubt at all that it is very cheap to get someone’s height and weight and stick it in an iPhone app. That is certainly part of it. But we really don’t have a hard time spending money to individualize oncology care. I know we should be better at it,” Howard McLeod, PharmD, director of the Institute for Pharmacogenomics & Individualized Therapy and the Fred Eshelman Distinguished Professor of Pharmacogenomics and Individualized Therapy at the UNC Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill told GEN.
He noted that doctors will order a radiologist to perform a scan for whether patients need a different dose of chemo, in the $1,500 to $3,000 range. However, from a cost standpoint, not enough solid data exists to determine the return on investment for using these chemotherapies according to BSA-based dosages.
“With insurance companies, part of the discussion is, ‘Can we show that we’re at least giving the patient optimal blood levels, and therefore maximizing the chance of benefit?’ If you’re an insurance company, you don’t like to spend a lot of money on chemo. But you especially don’t like spending a lot of money on chemo if you don’t know if the patient’s going to benefit,” Dr. McLeod said.
“The oncologists don’t like to have that discussion. But the insurers do. They need to have that. If we’re going to spend a lot of money on chemotherapy, we need to do everything we can to make sure that it’s not being wasted.”
Indeed the cost focus of insurers may well force oncologists to join their colleagues in other medical specialties in embracing MTE-based dosing over BSA, since toxicity and underdosing often lead to costlier care for patients given the wrong dose.
Another factor that will eventually limit costlier care for misdosed patients is whole-genome screening for patients with rare tumors, where there’s no known treatment or no effective treatment. “In the future, with genomic testing to identify drugs that may work, and by appropriate dosing, I think both of those things are going to be important for really making precision medicine something that is really carried out by doctors in the future,” Dr. Bertino said.
Genomic testing is now costly—$7,000–$8,000 per whole genome, or $1,000 to test 300 genes involved in sensitivity or resistance to drugs, Dr. Bertino said. But those prices are expected to fall as the era of the $1,000 genome finally becomes reality—whether it really happens by year’s end as predicted earlier this year, or soon after.