Navigating Uncertainty in Immunotherapy Regimens

I write from an unusual perspective. I am a patient who has had to cope with a challenging clinical problem, and I am an academic whose research aims to improve the evidence and methods used to inform patient care.

I have had to cope with a succession of recurrences of melanoma. Following initial diagnosis in 2012 of a tumor on my back, I experienced recurrences in 2014, 2016, and 2022. Each was surgically removed. I have been under continual surveillance.

In 2022, I was offered the opportunity to complement surveillance with adjuvant immunotherapy. The protocol called for administration of nivolumab every 4 weeks for up to 1 year or until disease recurrence or occurrence of unacceptable immune-related adverse events (irAEs). Concerned with treatment efficacy and toxicity, I inquired how this regimen (dose, schedule, and duration) was determined. I learned that the regimen was based on one evaluated in the CheckMate 238 trial,¹ revised to double the duration between doses used in the trial. I asked whether this regimen is optimal. The oncologist responded that this is unknown because phase 3 trials with other regimens have not been performed.

Having online access to medical literature, I searched to learn about the efficacy and toxicity of nivolumab. I found reason for concern when I read statements such as this: “There is still large room for improvement in the treatment of metastatic melanoma by addressing two of its major problems: resistance and treatment-related adverse events.”² I eventually agreed to initiate immunotherapy. The first three treatments were without incident. After the fourth, I felt no symptoms, but lab tests revealed a diminution in thyroid function, a common but treatable irAE. Levothyroxine stabilized the condition. After the sixth treatment, I experienced a less common irAE, a combined condition of dry mouth, lips, and eyes. A 1-week course of prednisone mitigated the issue to a limited extent but did not cure it. After considerable deliberation, I made the difficult decision to terminate treatment after 6 of 13 doses, out of concern that I would experience more severe irAEs if I were to continue.

The uncertainty with which the oncologist and I had to cope was enormous, there being no randomized controlled trial evidence on the effectiveness and toxicity I would face if I were to continue or stop. Dealing with the uncertainty as a patient was difficult. I took solace in my recognition as a researcher that medical decision-making is replete with uncertainties. Indeed, I recently published a book on the subject.³