Is Dose Rounding the Answer to Cancer Drug Waste?

After he sat down with The American Journal of Managed Care^® to discuss the results of Mayo Clinic’s Dose Rounding Project, Scott A. Soefje, PharmD, MBA, BCOP, FCCP, FHOPA, director of pharmacy cancer care at the renowned center, led an insightful discussion on the history of cancer drug spend, lifting the curtain on why dose rounding should be considered.

In “Cancer Drug Dose Rounding: Decreasing Drug Cost, Minimizing Waste and Improving Efficiency,” the topics he covered ran the gamut, from the unending rise in health care costs to financial toxicity and its devastating ramifications to how drug waste has influenced the dose rounding movement for chemotherapy.

He kicked off his presentation with a discussion on the ever-increasing cost of health care.

“Unless you’ve lived in a cave, you know that health care costs are rising, and that it is anticipated by 2030, we’re going to cross $6 trillion in cost and be approaching $7 trillion in overall health care,” he stated. “In my world, in cancer, it’s a considerable cost. In 2020, the United States spent $200 billion on cancer, and over 40% of that was considered to be the cost of drugs, according to Medicare.”

In fact, he continued, overall drug costs have increased 88% in the past 5 years. Globally, in 2021 alone, over $185 billion was spent on cancer drugs alone—and by 2030, this total is expected to balloon to more than $300 billion, representing a 62% increase in less than a decade.

Further highlighting the increasing impact of drug costs, Soefje noted the increasing gap between the price of new drugs at launch and median household income in the United States, framing this relationship from 1975 to 1979 through 2010 to 2014. For this entire period, the median monthly household income of approximately $4000 remained stable; however, the median monthly cost of new anticancer drugs first rose steadily between 1975 and 1999 before beginning a steep climb that quickly outpaced median household income between 2000 and 2004.

“Anything you can do to contain costs is a good thing,” he emphasized.

So, why does health care cost so much, he asked the audience. The population is growing and living longer, there are changes in disease prevalence and incidence, and the utilization (or not) of services and their associated price. He also presented data from a study that looked at health care cost increases between 1996 and 2013:

• Service utilization rose by 2.5%
• Disease prevalence/incidence dropped 2.4%
• Population growth accounted for 23.1% of cost, and aging 11.6%
• Service price increased accounts for 50% of the cost

All too often, this translates into financial toxicity among patients.

“The number one cause of medical bankruptcies in the United States is health care debt. If you are a cancer patient, you are 6 times more likely to file for bankruptcy than if you're not a cancer patient,” he stated. “And it continues after therapy is over. That’s what’s sad about this. Medical drug waste then becomes a significant problem in the United States.”

He clarified the extent of this by laying out potential causes of drug waste—which is expected to exceed $100 billion by 2025. For example, there is a disconnect between current dosing strategies and the current marketed vial sizes of drugs; there are strict regulatory limits on single-dose vials (SDVs), and these differ among United States Pharmacopeia, CMS, the CDC, and The Joint Commission—and many oncology drugs come in SDVs, but any remaining drug from a partial dose has to be discarded.

This is where dose rounding enters the equation. There are several important questions to ask that can have an impact in this space and they relate to the phase 1 clinical trials whose goal is to determine toxicity and dose. Is the maximum tolerated dose right for the drug being dispensed? Did pharmacokinetics (PK) suggest potential for therapeutic drug monitoring? How does the phase 1 population affect results?

The current standard used to calculate drug dosage is body surface area (BSA; height and weight), and this is a process needing improvement. Just why BSA is used is not exactly clear, Soefje pointed out. At best, there are weak correlations between PK and BSA, he added; in particular, there are no correlations between BSA and hepatic functions, and multiple PK studies show no correlation between drug clearance and weight.

“BSA was developed in the '50s as a way to take the maximum lethal dose in mice and convert it to the starting dose in humans. The authors who submitted the paper to do that have published that they never intended for BSA to become the standard for calculating doses,” Soefje said. “It just became that way. In fact, in their papers they suggested that dosing should have been flat dosing and dose escalated just like every other drug we use.”

Not to mention, there are at least 18 empirical formulas that are used to calculate BSA, questions remain on which weight is appropriate to use in the calculation, and studies on fixed dosing “showed no differences in intrapatient PK variability compared with BSA dosing.

The American Society of Clinical Oncology recommends that clinicians use a patient’s actual body weight to calculate cytotoxic chemotherapy dose (intravenous and oral), regardless of obesity status, because there is no evidence that full weight-based doses increase the short- and long-term risks of treatment toxicity, Soefje noted. Further, he stated, myelosuppression is the same, or less pronounced, in obese patients with cancer vs nonobese patients and there is no increase in nonhematologic toxicity.

“What we have here is a situation where the true dose may not necessarily be the true dose, from the dose-finding studies anyway. We’re making guesses on our doses as we calculate, so why don’t we round doses a bit?” he queried the crowd. “Now the questions becomes, what would you round to, what is your comfort level for rounding, and go from there.”

All in all, dose rounding is a potential solution, but it is not the only one—at least, right now—so it’s wise to have some ground rules for chemo dose calculations. Among those that Soefje teaches his residents:

• Do not use BSA as the sole parameter of dose calculations
• Know how a drug is eliminated, and adjust dosing based on the appropriate test for elimination
• Check for drug interactions
• Know that the dose will be inaccurate up to 40% of the time
• Measure biological effect of a dose, because you may have to adjust up
• Have someone double-check your calcuations