In the realm of cancer treatment, a contentious debate is unfolding. Oncologists, researchers, and patients are increasingly questioning whether certain cancer drugs are being administered at doses higher than necessary. This practice, they argue, may be causing unnecessary toxicity without providing additional therapeutic benefits.
The discussion gained traction following a recent investigation that highlighted the experiences of patients like Chuck Manski, a Northwestern University economist who underwent treatment for advanced melanoma in 2026. Manski’s experience with nivolumab infusions left him with permanent thyroid damage and severe dryness in his eyes, lips, and mouth. Despite the protocol calling for a full year of treatment, Manski discontinued after six months, convinced that the drug had likely achieved its maximum efficacy.
Financial and Clinical Stakes
The debate over cancer drug dosing is not merely a clinical issue; it also has significant financial implications. For patients, the immediate harm is physical, with side effects ranging from permanent thyroid damage to severe dryness of the eyes and mouth. These side effects can affect eating, speaking, and sleeping, and may even push patients to discontinue drugs that were otherwise effective.
A survey of more than 1,200 people with metastatic breast cancer revealed that 86 percent reported at least one significant treatment-related side effect. Among these, about 20 percent ended up in a hospital or emergency room, and roughly 43 percent missed at least one treatment. Dose reductions brought relief for most who tried them.
From a financial perspective, the stakes are equally high. An analysis estimated that if minimum necessary dosages had been used across 29 expensive cancer drugs in 2026, the U.S. health system could have saved roughly $31 billion. Merck sold nearly $32 billion of pembrolizumab last year, highlighting the financial incentives involved in drug dosing.
Evolving Treatment Paradigms
The current dosing practices for cancer drugs are rooted in a rule designed for cytotoxic chemotherapy, where effect and toxicity generally rose together. However, targeted therapies, immunotherapies, and antibody-drug conjugates often do not follow this pattern. Their biologically effective dose can sit well below the toxicity threshold, meaning additional dose adds side effects without adding benefit.
Despite this, trial design has been slow to catch up. Friends of Cancer Research noted that among 67 novel anticancer therapies, dose-finding practice largely stayed the same, with the maximum tolerated dose typically identified using the traditional 3+3 escalation design. Donald Harvey of Emory University School of Medicine emphasized that for today’s more complex therapies, “a higher dose often does not mean a better cancer outcome.”
Evidence for lower dosing exists in specific settings, though it is uneven and contested. Oncologists in Canada, Israel, Sweden, and elsewhere have used lower nivolumab and pembrolizumab doses, shorter durations, or longer intervals than U.S. labels specify. Physicians in India have reported meaningful survival gains at one-sixth or one-twelfth of the labeled nivolumab dose.
Challenges and Controversies
The Indian evidence carries an important limit. Those studies compared ultralow-dose immunotherapy with older chemotherapy, not with standard-dose immunotherapy, so they cannot establish that the lower dose performs as well as the labeled one. Bristol Myers Squibb and Merck have expressed concerns that lower doses or shorter durations of nivolumab may harm patients and that dosing must be established through well-designed trials.
Ongoing Research and FDA Initiatives
Once a drug is approved, few parties have a commercial reason to run the study that would lower its dose. However, some efforts are underway. Researchers at Utrecht University are comparing the standard nivolumab dose in lung cancer against one up to 50 percent lower. A Dana-Farber-led group is testing whether patients who have done well on 27 weeks of pembrolizumab can stop rather than continue. At three Veterans Affairs hospitals, less frequent dosing saved about $1.5 million over two years.
The FDA has been working on the front end with Project Optimus, launched by the agency’s Oncology Center of Excellence in 2026. This initiative pushes sponsors to select doses based on efficacy, safety, and tolerability rather than maximum tolerance. The agency issued guidance on optimizing oncology dosage in 2026.
A Department of Health and Human Services spokesperson noted that these principles are now built into the review of new cancer drugs. The spokesperson also highlighted that the FDA usually cannot compel a drugmaker to run dose-ranging studies after approval and that by law the FDA does not influence drug pricing.
