MTD Practices Spotlight Shortcomings of Value-Based Care

Targeted Therapies in OncologyDecember I, 2023
Volume 12
Issue 17
Pages: 69

Leslie T. Busby, MD, discusses the shift from dose-dependent chemotherapy to the challenge of managing toxicities in biologic and targeted therapies, which are often erroneously developed using the maximum tolerated dose paradigm.

I enjoy the challenge of balancing the science of treating cancer with the art of caring for patients. A critical aspect is managing toxicities while maintaining therapy intensity. In the past, more intense chemotherapy sometimes led to a better chance of cure, so determining the maximum tolerated dose (MTD) of either a single drug or combination was important. However, biologic and targeted therapies are generally not dose dependent. Once the target is fully engaged, giving the patient additional doses only leads to toxicity. Unfortunately, these treatments are often developed and dosed using the MTD.

Empirically, when physicians have had to lower doses because of toxicity, they often found the drug worked just as well. We are aware of study results1,2 proving the effectiveness of lower doses or shorter courses, such as 1 tablet of abiraterone acetate (Zytiga) with food or 6 months of adjuvant trastuzumab (Herceptin). Despite this, adoption seems to be more the exception than the standard. Why do we continue to gravitate toward an MTD when we know microscopic benefits are often outweighed by less toxicity? I suspect the reason lies in negative incentives.

Surprisingly, some of the methods that value-based care projects use contribute to this problem. Many oncologists participate in projects such as the Enhancing Oncology Model (EOM). Problematically, EOM only enrolls patients who are on therapy in 6-month episodes3; many drug courses that are more expensive in the short term but save resources in the long term thus are disincentivized. For example, you could be punished by paying the government back if you treat a patient with chronic lymphocytic leukemia with a 2-drug, 1-year course instead of a single-agent Bruton tyrosine kinase inhibitor perpetually.

Beyond this, the strict 30-day refill quotas of payers and pharmacy benefit managers share some culpability. For example, taking 1 tablet of abiraterone per day with food has been found to be as effective as taking 4 tablets per day on an empty stomach.1 Thus a standard abiraterone prescription of 120 tablets can be made to last 4 months with just 1 copayment. Unfortunately, many specialty pharmacies will demand a new prescription every 30 days with the specific dose and instructions—do not dare to write, “Take as directed by your physician.”

This ultimately amplifies the financial burden experienced by the patient and disincentivizes physicians from using resources more effectively. To resolve this issue, manufacturers need to do better. When a dose is made up of several pills, a modification is easy to make. However, many drugs have multiple strengths, and each requires a new prescription, which might be reasonable if reducing dosage also reduced costs, but it usually doesn’t.

Regulatory bodies such as the FDA and the National Comprehensive Cancer Network also bear responsibility. When a lower dose or shorter course is shown to be just as effective and is the preferred treatment option, this information should be immediately reflected in the drug label, guidelines, and compendium.

It is good that this problem is getting more attention,4,5 but we are just beginning. Everyone needs to raise issues with the current sluggish rigidity of the system to promote what is best for the patient and health care overall.

1. Chien C, Smith M, De Porre P. Effect of food on abiraterone pharmacokinetics: a review. Int J Pharmacokinetics. 2017;2(3):183-193. doi: 10.4155/ipk-2016-0026
2. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase ii study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018;36(14):1389-1395. doi:10.1200/JCO.2017.76.4381
3. Update: Enhancing oncology model factsheet. June 27, 2023. Accessed November 1, 2023. https://www.
4. Tannock IF, Bouche G, Goldstein DA, et al. Patient-centered, self-funding dose optimization trials as a route to reduce toxicity, lower cost, and improve access to cancer therapy. Ann Oncol. 2023;34(8):638-644. doi:10.1016/j.annonc.2023.05.006
5. Project Optimus. FDA. June 30, 2022. Accessed October 25, 2023.
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