The Placebo: A Controversial Element of Randomized Cancer Clinical Trials

The placebo has played a major role in the development of evidence-based therapeutic strategies. At a basic level, a placebo is used in randomized trials, either alone or in combination with a standard-of-care antineoplastic to power a control arm for comparison with an experimental drug; however, there is much about the placebo that we do not understand and must learn. For instance, its use has been suggested to remove the subjective and potentially clinically meaningful influence on study results should research participants and their physicians be aware of whether they are receiving the investigative drug.

In an appropriately designed and conducted randomized trial setting, by using a presumably biologically inactive placebo, treatment-related adverse events and symptoms suggesting disease progression will be able to be differentiated from events occurring because of the study drug. Further, in the absence of knowledge that a patient with cancer is receiving the active therapy, it is hypothesized that there will be less risk of physicians either unconsciously or intentionally searching for a justification. This justification could include looking for subjective symptoms or objective signs to ascertain that treatment used in the control arm has failed by either inducing unacceptable toxicity or a participant experiencing disease progression. Investigators could then use these insights for the purpose of permitting the patient to crossover to the experimental regimen, if permitted by the trial protocol.

The potential effectiveness of employing this approach in cancer clinical investigation is not difficult to appreciate, but the use of placebos has been, and continues to be, controversial.

Unpacking the Term

As we learn more about the “placebo effect,” it is increasingly clear several assumptions regarding placebo delivery are either somewhat inaccurate or simply incorrect. For example, the assumption that declaring an administered agent to be a placebo means it is biologically and therefore clinically inert may be wrong. This has been highlighted in the arena of trials examining cardiovascular risk reduction.^1,2 As noted by one commentator, there is limited or no formal regulatory agency oversight regarding the specific content of placebo preparations, with uncertain assurance they are, in fact, biologically inert and cannot influence either standard-of-care pharmaceuticals or a given investigative agent.¹

It is also increasingly clear that the administration of placebos may produce substantial clinical effects, including in the cancer domain.³ As noted by Kaptchuk et al in an editorial: “Placebo effects are often considered the effects of an ‘intent substance,’ but that characterization is misleading. In a broad sense, placebo effects are improvements in patients’ symptoms that are attributable to their participation in the therapeutic encounter, with its rituals, symbols, and interactions....The psychosocial factors that promote therapeutic placebo effects also have the potential to cause adverse consequences, known as nocebo effects. Not infrequently, patients perceive side effects of medications that are actually caused by anticipation of negative effects or heightened attentiveness to normal background discomforts of daily life in the context of a new therapeutic regimen.”³

Further, research efforts have begun to identify neurological pathways that mediate the placebo/nocebo effects,⁴ and provocative data suggest there may be a relevant genetic component to the magnitude of such influences.⁵ Finally, early stages of investigation have indicated the delivery of placebos as a therapeutic approach in certain settings (ie, with patient knowledge they are receiving a placebo) may have the potential to produce favorable clinical outcomes.^6,7

The point of the preceding discussion is to emphasize how much is unknown regarding the clinical effect of placebos, with the increasing realization that what may be observed is not simply the effect of an inert substance.

The Future of the Placebo

It is relevant to also question both the ethical justification for the delivery of placebos as well as the objective need for their continued use. Although space in this commentary does not permit an adequate discussion of the ethics of placebo administration in clinical investigation, this issue continues to be, an unresolved serious concern.⁸

Of course, cancer investigation is not immune to this discussion. One can inquire why according to historical record, certain studies with human participants with findings published in high-impact medical journals elected to include a placebo treatment as a control compared with an investigative study arm.^9-11 What is wrong with the control arm of a randomized trial being a therapeutic choice made by the physician and patient (assuming no standard of care is available in a given clinical setting)? Such a strategy would perhaps provide the patient with an opportunity for shortterm clinical benefit, and this approach would not prevent an objective evaluation of either efficacy or toxicity.

The issue and concern with the administration of placebos are not solely a discussion of the history of cancer investigation. Consider 2 recently published, potentially paradigm-changing studies examining the use of an immune checkpoint inhibitor in the management of advanced endometrial cancer.^12,13 The adverse effects of the checkpoint inhibitors are well known, and the availability of objective measures of disease progression in this clinical entity are well established. Therefore, was it necessary to achieve a valid study end point to require a group of patients with advanced cancer receiving a “placebo” to come to the clinic, infusion center, or physician’s office every 6 weeks (maintenance phase) for up to 14 cycles¹³ or 3 years?¹²

References

1. Golomb BA. Paradox of placebo effect. Nature. 1995;375(6532):530. doi:10.1038/375530a0
2. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with isosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792
3. Kaptchuk TJ, Miller FG. Placebo effects in medicine. N Engl J Med. 2015;373(1):8-9. doi:10.1056/ NEJMp1504023
4. Tinnermann A, Geuter S, Sprenger C, Finsterbusch J, Büchel C. Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia. Science. 2017;358(6359):105-108. doi:10.1126/science.aan1221
5. Hall KT, Loscalzo J, Kaptchuk TJ. Genetics and placebo effect: the placebome. Trends Mol Med. 2015;21(5):285-94. doi:10.1016/j.molmed.2015.02.009
6. Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One. 2010;5(12):e15591. doi:10.1371/journal.pone.0015591
7. Marchant J. Honest fakery. Nature. 2016;535(7611):S14-5. doi:10.1038/535S14a
8. Brower V. Science versus ethics. new ethical guidelines regarding the use of placebos in clinical trials have sharpened the conflict between public health and patients’ rights. EMBO Rep. 2001;2(5):365-367. doi:10.1093/embo-reports/kve103
9. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
10. Abou-Alfa CK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002
11. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068. doi:10.1200/JCO.2009.23.9764
12. Mirza MR, Chase DM, Slomovitz BM, et al; RUBY Investigators. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:1056/NEJMoa2216334
13. Esklander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2302312