When FDA approves a new cancer agent, oncologists usually ask: will it prolong duration of good quality life, or just prolong duration of suffering, and will the side effects profile be tolerable enough whether it works or not?
New cancer drugs are usually only for dire situations, when therapies with proven track records have failed. This CareGivingOldGuy was an oncology institutional principal investigator for Phase II and III new cancer agents, and had experiences with marginally effective and terribly expensive new drugs.
Those kinds of questions seem pertinent to the new Alzheimer’s Disease (AD) medication, lecanemab, marketed now as Leqembi ™. Several issues arise.
Swanson 2021 Fig 4ABC lecanemab efficacy CC0-BY-4.0 https///doi.org/10.1186/s13195-021-00813-8
First, there is a question of effectiveness. The efficacy of lecanemab for AD is shown above in a 2021 study, Fig 4B. It shows patients’ cognitive performance on the CDR-SB test, over time. [It’s basically the same graph shown in the 2023 NEJM paper which is copyrighted; the papers were said to have been part of FDA’s approval process.]
The stars above two of the time points denote statistical significance, but note that the downward trajectory and cognitive decline shown by the two dose lines are not substantially different from placebo, and there is almost an overlap in the error bars. About 30% of patients discontinued early in each group.
What appears to be a modest efficacy in the results led to a professional debate on “clinical meaningfulness;” the professional news item about it on AlzForum.org is followed by fascinating comments from well-known researchers in the field.
Bioethicist Norman Fost used to teach that “good medical ethics is based on good facts.” So isn’t FDA approval a fact good enough? However, it doesn’t seem that the FDA defines its approval role to include substantial clinical impacts in patients’ lives. And it can’t know about longer term efficacy on first approval.
FDA criteria are met by many agents initially. Some agents prove to be busts: think Avastin ™, pulled by the FDA in breast cancer (eventual lack of efficacy,) or Provenge ™ in prostate cancer (marginally effective; the company went bankrupt and the agent, approved by Medicare for ~$100K, hasn’t really reappeared).
For many caregivers with the Power of Attorney (POA) for Healthcare, FDA provides some facts, but doesn’t absolve some diligence in trying to figure out what might be best for the Person Living With Dementia (PLWD).
Second, the concept of “quality of life” is elusive in cancer patients, even more so in persons with cognitive and communications issues, for whom discussions of medical decisions can be hard to interpret. “Quality of life” is often used in contrast to prolonging duration of life with medical interventions.
Third, the concept of “suffering” is also elusive when communication and nuance cannot be explicit. As cognition declines, some might speculate that self-awareness of losses in function could be considered suffering, especially with a long duration.
Authors from the drug company with others published a 2023 “simulation” paper that speculates how Leqembi might temporarily delay cognitive loss and might even prolong life in a longer follow-up. Their model does show progressive severe decline in later years. In the context of suffering, would that also be prolonged?
In the background, one should understand that US medical practice, unlike medicine in other cultures, usually has a “can-do” attitude. Specialists would rather treat and risk a “sin of commission,” rather than a “sin of omission,” i.e. by not treating and letting the natural history of disease run its course.
The FDA package insert states: “LEQEMBI is indicated for the treatment of Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.”
Fourth, informed consent for people living with cognitive issues can be a dilemma. The diagnoses of Mild Cognitive Impairment or Mild Dementia don’t exactly exclude a person from making medical self-determinations, but there are no hard definitions.
For those individuals, a framework called “supported decision making” has been proposed by a group at the Penn Memory Center.
One might consider early stage cancer and early stage dementia both eventually fatal, but the timelines for patients are so different, that might not be a fair comparison. Compound those issues with an agent which might not be very effective, and the PLWD /POA / personal healthcare decision maker might be left with a very complex dilemma.
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