Is Therapeutic Value a New Name for Medical Paternalism?

Maurie Markman, MD

A landmark essay by the late eminent evolutionary biologist Stephen J. Gould, PhD, entitled “The Median Isn’t the Message” serves as an excellent opening for this commentary. Gould, after receiving a diagnosis of primary peritoneal mesothelioma, what he deemed an “incurable cancer” with a median life expectancy of 8 months, responded with noting the following:

“[All] evolutionary biologists know that variation is nature’s only irreducible essence. Variation is the hard reality, not a set of imperfect measures for a central tendency. Means and medians are the abstractions. Therefore, I looked at the mesothelioma statistics quite differently— and not only because I am an optimist who tends to see the doughnut instead of the hole, but primarily because I know that variation itself is the reality. I had to place myself [amid] the variation….The [survival] distribution was, indeed, strongly right skewed, with a long tail (however small) that extended for several years above the [8]-month median. I saw no reason why I shouldn’t be in that small tail, and I breathed a very long sigh of relief. My technical knowledge had helped. I had read the graph correctly. I had asked the right question and found the answers. I had obtained, in all probability, that most precious of all possible gifts in the circumstances—substantial time.”¹

Gould survived for approximately 20 years following his diagnosis. This was likely related to an incomplete understanding of the natural history of the disease and possibly an unanticipated response to treatment. That is not the point to be highlighted here. Rather, what is noteworthy is the process whereby this patient employs both objective data and his personal beliefs to declare what he values. Further, it is reasonable to anticipate that, like Gould, other patients will carefully evaluate the risks vs benefits of various treatment options during their illness and the effect they will have on quality of life to generate a personal assessment of therapeutic value.

In discussing commercially available anticancer drugs, the term therapeutic value is often applied.² However, it is remarkable to contrast Gould’s eloquent and objectively scientific words with, in the opinion of this commentator, this misleading terminology. Consider, for example, a recent report examining drugs granted accelerated approval or conditional marketing authorization where the authors concluded that “a substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value.”²

Considering the applied connotation of therapeutic value it is appropriate to acknowledge medical paternalism, a criticized and, I hope, discarded concept where the physician makes a highly personal treatment decision on behalf of the patient.³ Among the more painful historical examples of this in the oncology arena was the routine performance of a radical mastectomy for breast cancer immediately following histological diagnosis without first providing the patient an opportunity to discuss alternative therapeutic options with a care team. Today it appears the authority to determine the therapeutic value of a new drug or cancer treatment strategy is believed by some to not reside with the rightful decision-making party—the patient. Of further concern is the notion of labeling outcomes as meaningful or not. For example, some believe that phase 3 progression-free survival outcomes that are statistically significant serve as a “surrogate end point for a meaningful clinical outcome.”^4,5 Shouldn’t patients be permitted to decide what is meaningful to them as they make decisions during their illness?

To be clear, this discussion and Gould’s words have nothing to do with the rapidly escalating costs of therapy or the disturbing effects of financial toxicity that patients with cancer and their families are experiencing.⁶ It is appropriate to challenge the unsustainable process for determining anticancer drug costs as well as the existing complex and often irrational methods of payment. Further, there is nothing inherently wrong with the academic and public policy exercise of attempting to conduct cost-vs-benefit analyses with, for example, differences in median time to disease progression or overall survival between study arms in a well-designed randomized trial to serve as an objective measure of benefit.⁷

However, it must be recognized that this difference is nothing more than a population-based number and that subsequent analyses have little or possibly no relevance to the outcome of a specific patient, specifically in terms of the value that an individual assigns to a potential objective survival or toxicity severity result or to the actual observed experience. As so eloquently stated by Gould:

“This is a personal story of statistics, properly interpreted, as profoundly nurturant and life-giving. It declares holy war on the downgrading of intellect by telling a small story to illustrate the utility of dry, academic knowledge about science. Heart and head are focal points of one body, one personality.”¹

And if that is not sufficient to make the point, consider in conclusion the following from Gould, a scientist, academic, patient with cancer, and survivor:

“Attitude clearly matters in fighting cancer. We don’t know why (from my old-style materialistic perspective, I suspect that mental states feedback upon the immune system). But match people with the same cancer for age, class, health, and socio-economic status and, in general, those with positive attitudes, with a strong will and purpose for living, with commitment to struggle, and with an active response to aiding their own treatment and not just a passive acceptance of anything doctors say tend to live longer.”¹

Who exactly should be determining the therapeutic value of a treatment program? It is a very different question than one concerning an appropriate price and payment for a regimen. In the opinion of this commentator the answer is clear: the patient.

References

1. Gould SJ. The median isn’t the message. Virtual Mentor. 2013;15(1):77-81. doi:10.1001/virtualmentor.2013.15.1.mnar1-1301
2. Vokinger KN, Kesselheim AS, Glaus CEG, Hwang TJ. Therapeutic value of drugs granted accelerated approval or conditional marketing authorization in the US and Europe from 2007 to 2021. JAMA Health Forum. 2022;3(8):e222685. doi:10.1001/jamahealthforum.2022.2685
3. Derse AR. The physician-patient relationship. N Engl J Med. 2022;387(8):669-672. doi:10.1056/NEJMp2201630
4. Frank RG, Shahzad M, Emanual EJ. Accelerated approval of cancer drugs: no economic reward for drug makers that conduct confirmatory trials. Health Aff (Millwood). 2022;41(9):1273-1280. doi:10.1377/ hlthaff.2022.00119
5. Ballreich J, Socal M, Bennett CL, et al. Medicare spending on drugs with accelerated approval. Ann Intern Med. 2022;175(7):938-944. doi:10.7326/M21-4442
6. Shankaran V, Li L, Fedorenko C, et al. Risk of adverse financial events in patients with cancer: evidence from a novel linkage between cancer registry and credit reports. J Clin Oncol. 2022;40(8):884-891. doi:10.1200/ JCO.21.01636
7. Dusetzina SB, Huskamp HA, Rothman RL, et al. Many Medicare beneficiaries do not fill high-price specialty drug prescriptions. Health Aff (Millwood). 2022;41(4):487-496. doi:10.1377/hlthaff.2021.01742