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This article is part of the 2019 Oncology Special IssueJournal of naturopathy. Read the full issue here.
Relation
Zhou ES, Hall KT, Michaud AL, et al. Open-label placebo reduces fatigue in cancer survivors: a randomized trial.Support Care Cancer. 2019;27(6):2179-2187.
Study objective
To evaluate the effect of an open-label placebo on cancer-related fatigue (CRF) in cancer survivors and to assess whether personality traits or genetic variation in dopamine depletion (catechol-O-methyltransferase) influence placebo response
Draft
Randomized trial with participants assigned to either an open-label placebo group (i.e. participants were aware that they were receiving a placebo) or a no-treatment control group
Participant
Forty cancer survivors, all of whom had no evidence of active disease, were at least 6 months post-treatment, scored <43 on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, and were not treated or evaluated for any other medical cause of fatigue. The average age of participants was 47.3 years (range 22-74), and most were married (62.5%), non-Hispanic white (87.5%) women (92.5%), and on average had been diagnosed with breast cancer (55%). 9.3 years ago.
intervention
On day 1 of the study, all participants completed 7 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ, BIDR-7, LOT-R, and the Subjective Significance Questionnaire) and provided a saliva sample for genetic testing. Participants then met with an investigator for a 15-minute study introduction discussion, in which the investigator outlined both the rationale for the study and previous evidence indicating that placebo can improve fatigue. At the end of this discussion, participants opened a sealed envelope indicating their study assignment (either open-label placebo [OLP] or no-treatment control). OLP participants received 120 placebo pills with instructions to take 2 pills twice daily for 22 days.
On day 8 of the study, all participants repeated 3 questionnaires (FACIT-F, GLTEQ and the Subjective Significance Questionnaire). OLP participants were reminded and encouraged to continue taking their placebo pills.
On day 22 of the study, all participants repeated 5 questionnaires (FACIT-F, SF-12, POMS-SF, GLTEQ and the subjective significance questionnaire). No data were collected after day 22.
Study parameters assessed
- Fatigue: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
- Körperlicher und psychischer Gesundheitszustand: Kurzform-12 (SF-12)
- Stimmungsstörung: Profile of Mood States-Short Form (POMS-SF)
- Übungsteilnahme: Godin Leisure Time Exercise Questionnaire (GLTEQ)
- Tendenz zu sozial erwünschtem Reagieren: Balanced Inventory of Desirable Responding-Version 7 (BIDR-7)
- Generalisierter Optimismus: Lebensorientierungstest überarbeitet (LOT-R)
- Subjektive Müdigkeit und allgemeine Lebensqualität: Fragebogen zur subjektiven Signifikanz
- Catechol-O-Methyltransferase (COMT) SNPs rs4680 und rs4818: Gentests
Primary outcome measures
Differences in questionnaire results from those in the control group were assumed to reflect the influence of placebo.
Key insights
OLP significantly improved CRF, as reflected by changes in FACIT-F score between days 1 and 8 and days 1 and 22.
Changes in FACIT-F scores were not significantly correlated with measures of socially desirable responding (BIDR-7) or generalized optimism (LOT-R), suggesting that a general tendency to expect the best or present oneself in the best light is not a personality variable associated with OLP responsiveness.
Successful treatment of cancer-related fatigue is expected to improve patients' quality of life and potentially improve their survival.
The OLP response differed significantly based on COMT rs4818 genotype, suggesting that the dopamine system may play a role.
The SF-12, POMS-SF and GLTEQ questionnaires revealed no significant difference between OLP and control.
The subjective significance questionnaire revealed a significant subjective improvement in fatigue and overall quality of life in response to OLP on day 8 but not on day 22.
Practice implications
CKD is defined as “a distressing, persistent, subjective feeling of physical, emotional, and/or cognitive fatigue or exhaustion associated with cancer and/or cancer treatment that is disproportionate to recent activity and interferes with normal functioning.”1
Although descriptive in a technical sense, this academic definition does not provide a true sense of the impact of CKD on humans. Nothing compares to the words of real patients sharing their own experiences: "It's not exhaustion. I'm exhausted. I've never felt this tired before. It's not work fatigue or emotional exhaustion. It's completely different. It's incredible."2
CKD is inherently different from the fatigue experienced as part of daily life. It is not clearly associated with physical exertion, is not relieved by rest or sleep, and includes additional manifestations such as apathy, cognitive dysfunction, emotional lability, and general weakness.2
Formal estimates of the prevalence of CKD range from 4% to 91%, depending on the type of cancer examined and the assessment methods used.3A recent estimate suggests that 45% of cancer patients undergoing treatment and 29% of cancer survivors have non-trivial CKD (ie, CKD persists as a long-term problem for years).4
CKD is one of the most commonly reported concerns by cancer patients and can interfere with activities of daily living and quality of life to such an extent that it is consistently rated as more distressing than other cancer-related symptoms such as depression, nausea and pain.5.6CKD may also predict shorter survival for cancer patients.7.8Therefore, successful treatment of CKD can be expected to improve patients' quality of life and possibly also improve their survival.
Current treatment options for CKD include exercise, mind-body approaches, psychosocial interventions, and pharmaceutical therapy.9A strong argument can be made that exercise is the most effective of these treatment options.10-12However, it can be very difficult to encourage fatigued patients to exercise.
The present results from Zhou et al. can be helpful in this regard. They independently confirm the results of a similar study from 2018, positioning OLP as an interesting treatment option for CKD.13They also suggest that OLP can be used to assist patients in implementing a therapeutic exercise program. While Zhou et al. found no statistically significant evidence that OLP helped patients increase their physical activity, it is not unreasonable to suspect that a longer period of time would increase this likelihood. Placebo effects have been documented to last up to 12 months and are a valid option for patients.14
Finally, when implementing OLP in clinical practice, the clinician's approach is likely to matter. Zhou et al. approached participants very deliberately and presented information, encouragement and support. “Belief activation” could be an important element for the success of placebo in clinical practice.fifteen
restrictions
This study is limited by the majority of female participants (92.5%) and the short study duration (22 days). Further studies in a more diverse group of subjects with longer intervention are needed.
Conclusion
Even when administered open-label, placebo improved subjective cancer-related fatigue compared to no treatment in cancer survivors.