Nocebo side-effects in cancer treatment

Advancements in technology and targeted agents for cancer have improved patient outcomes and reduced toxicities;1 however, serious side-effects with systemic or local therapies continue to be a major concern. Nausea, fatigue, headache, dizziness, pain, gastrointestinal irritation, depression, memory changes, urinary symptoms, and skin irritation are among the most commonly reported nonspecific toxic effects that can begin early in the course of protracted cancer therapy. The incidence and frequency of these non-specific side-effects are often correlated with objective factors such as type of therapy, total dose and duration, and physical characteristics, but accumulating clinical data suggest that patient expectations play a major part.2 Negative expectations engendered through unfiltered information disclosure can lead to physical consequences through diverse mechanisms described by the nocebo effect—Latin for I shall harm. Recognition of these potentially nocebo-inducing stimuli can help to reduce non-specific side-effects in patients with cancer. A revised ethical perspective on informed consent that takes into account this important and potentially harmful occurrence is warranted.
The physician–patient dynamic holds substantial therapeutic potential, supported by compelling clinical and basic science data in several diseases.3 Although the positive effects of this relation are shown by studies that describe them as an effect of placebo—Latin for I shall please—this term is most commonly attributed to the deceptive use of any medical intervention that has no specific activity for the disorder being treated. These effects, however, are not limited to the so-called sham administration of inert pills as used in placebo-controlled randomised trials, but are shown to encompass a more meaningful, effective, and deliberate effort to maximise treatment efficacy.4
Nocebo effects can be evoked through negative conditioning. Over the past 10 years, neurobiological pathways triggered by negative expectations have been identified and provide insight into the physiological manifestations of the nocebo effect.5 Although limited by ethical considerations, clinical data for nocebo effects collectively suggest that non-specific symptoms are highly likely to be affected by patient expectations.6
In patients with cancer, these non-specific symptoms can be triggered or exacerbated by noceboinducing stimuli, such as side-effect forms handed to patients as part of the consent process. In daily clinical practice, patients undergoing several weeks of radiotherapy can manifest non-specific symptoms during the first week of treatment. Since these symptoms—which often include nausea, headache, gastro intestinal distress, and fatigue—usually improve with reassurance alone, it is tempting to hypothesise that the anticipation of such effects can have an important role in their manifestation, as shown in other diseases. For example, in a randomised study of aspirin in patients with unstable angina, more gastrointestinal distress and a higher likelihood of study withdrawal was noted in patients taking placebo whose consent forms contained the warning of gastrointestinal irritation as a possible side-effect of treatment than in those whose consent forms did not contain this advanced warning.7