Wyatt et al. (2017): A Randomized Clinical Trial of Caregiver-Delivered Reflexology for Symptom Management During Breast Cancer Treatment

Reference ↗
Title	Publication: A Randomized Clinical Trial of Caregiver-Delivered Reflexology for Symptom Management During Breast Cancer Treatment
Topic	Reflexology
Author	Wyatt G, Sikorskii A, Tesnjak I, Frambes D, Holmstrom A, Luo Z, Victorson D, Tamkus D
Year	2017
Journal	Journal of Pain and Symptom Management
DOI	https://doi.org/10.1016/j.jpainsymman.2017.07.037

Brief summary

Approximately 250 patients with advanced-stage breast cancer were randomly assigned to one of two arms. In one arm, the partners (or family members or friends) of the patients were trained in the technique of reflexology. They then provided reflexology to the patients about once a week for four weeks. In the other arm, the partners gave the patients some form of attention that was not further specified in the study. After four weeks, participants were free to continue the interventions. All patients were surveyed weekly on various aspects of their physical and psychological well-being. Statistical analysis was carried out rigorously. The arms were comparable in almost all aspects at the start of the study, except for age. However, this was taken into account in the statistical analyses. The quality of the patients' relationships with their study partners and the generally perceived social support were also assessed in both groups and showed no differences.

Following the treatments, particularly in the second, third, and fifth weeks of the study, the patients in the reflexology group reported a greater reduction in symptoms in two out of five areas assessed than those in the other arm. This applies to the questions from the Anderson Symptom Inventory regarding symptom severity and impairment of daily life. In particular, the questions about fatigue and pain were answered significantly more positively. At the same time, no differences could be shown in the other questionnaires, which addressed similar areas, such as physical functioning, satisfaction with social participation, and general quality of life.

One limitation of the study is that it was not stated whether the observed differences between the arms (greater improvement in fatigue and pain) were also significant in magnitude. Furthermore, interpreting the results is complicated by the fact that it was not specified what exactly the patients in the control arm received (did they also receive personal attention or even touch?). To explicitly attribute the effects to reflexology, the patients in the control arm should have been treated with a comparable, ordinary foot massage. Additionally, it should be noted that 20% of the patients dropped out within the first five weeks of the study, and 30% within the entire 11-week study period (only 3.5% due to death or severe illness). The dropout rate and reasons for dropout were comparable between the two arms, so an arm comparison was still valid. However, it can be concluded that neither attention (however it was delivered) nor reflexology in the home setting is suitable for all patients with advanced breast cancer and their study partners.

Es wurden ca. 250 Patientinnen mit Brustkrebs im fortgeschrittenen Stadium zufällig in eine von zwei Gruppen aufgeteilt. In der einen Gruppe wurden die Partner (oder Familienangehörige oder Freunde) der Patientinnen in der Technik der Reflextherapie geschult. Diese haben dann die Patientinnen für vier Wochen ungefähr einmal pro Woche mit einer Reflextherapie behandelt. In der anderen Gruppe haben die Partner den Patientinnen stattdessen irgendeine Art von Aufmerksamkeit zukommen lassen, die in der Studie nicht genauer beschrieben wird. Nach vier Wochen stand es den Teilnehmern offen, die Interventionen fortzusetzen. Alle Patientinnen wurden wöchentlich zu verschiedenen Belangen ihres physischen und psychischen Befindens befragt. Die statistische Analyse wurde nach allen Regeln der Kunst durchgeführt. Die Gruppen waren zu Beginn der Studie in fast allen Belangen außer dem Lebensalter vergleichbar. Dies wurde aber in den statistischen Analysen berücksichtigt. Auch die Qualität der Beziehung der Patientinnen zu ihrem Studienpartner und die grundsätzlich wahrgenommene soziale Unterstützung wurden in beiden Gruppen erfragt und zeigten keine Unterschiede. Nach den Behandlungen, v.a. in der zweiten, dritten und fünften Studienwoche gaben die Patientinnen der Reflextherapiegruppe in zwei von fünf erhobenen Belangen eine größere Symptomabnahme als in der anderen Gruppe an: dies betrifft die Fragen aus dem Fragebogen des Anderson Symptom Inventorys zur Symptomschwere und Beeinträchtigung des alltäglichen Lebens. V.a. die Fragen zu Fatigue und Schmerzen wurden deutlich positiver beantwortet. Gleichzeitig konnten keine Unterschiede in den anderen Fragebögen gezeigt werden, die ähnliche Belange abfragten, nämlich physisches Funktionieren, Zufriedenheit bezüglich der sozialen Teilhabe und der allgemeinen Lebensqualität. Ein Nachteil der Studie ist, dass nicht angegeben wurde, ob die gefundenen Unterschiede zwischen den Gruppen (mehr Verbesserung in Fatigue und Schmerzen) in ihrer Größenordnung auch bedeutsam sind. Desweiteren erschwert sich die Interpretation der Ergebnisse dadurch, dass nicht angegeben wurde, was genau die Patientinnen in der Kontrollgruppe bekommen haben (hat hier auch persönliche Zuwendung oder sogar Berührung stattgefunden?). Um die Effekte explizit der Reflexzonen-Massage zuschreiben zu können, hätte man die Patientinnen in der Kontrollgruppe mit einer vergleichbaren nur gewöhnlichen Fußmassage behandeln müssen. Des Weiteren ist anzumerken, dass 20% der Patientinnen die Teilnahme innerhalb der ersten fünf Studienwochen abgebrochen haben und 30% innerhalb des gesamten Studienzeitraums von 11 Wochen (davon nur 3,5 % wegen Tod oder zu starker Erkrankung). Die Abbruchrate und Abbruchgründe waren innerhalb beider Gruppen vergleichbar, so dass ein Gruppenvergleich dennoch legitim war. Allerdings lässt sich schließen, dass weder Aufmerksamkeit (wie auch immer diese stattgefunden hat) noch Reflextherapie im häuslichen Umfeld für alle fortgeschrittene Brustkrebspatientinnen und ihre Studienpartner geeignet ist.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Patient inclusion criteria were: 1) age >21, 2) stage III or IV breast cancer, 3) able to perform basic activities of daily living, 4) undergoing chemotherapy, targeted or hormonal therapy at the time of enrollment, 5) able to speak and understand English, 6) having access to a telephone, 7) able to hear normal conversation, and 8) cognitively oriented to time, place, and person (determined via recruiter). Friend/family caregiver inclusion criteria were 1) age >18, 2) able and willing to provide at least one 30-minute protocol session per week for four consecutive weeks, 3) able to speak and understand English, 4) access to a telephone, 5) able to hearnormal conversation, and 6) cognitively oriented to time, place, and person (determined via recruiter).
Exclusion criteria	Patient exclusion criteria were 1) diagnosis of major mental illness in the medical record and verified by the recruiter, 2) residing in a nursing home, 3) bedridden, 4) currently receiving reg- ular reflexology, or 5) diagnoses of symptoms of deep vein thrombosis or painful foot neuropathy. Friend/family caregiver: Exclusion criterion was unwilling to perform a return demonstration of the protocol according to training procedures.
N randomized	256
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	All statistical tests were two sided.
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0 = Baseline T1 = week 1; T2: week 2; T3: week 3; T4: week 4

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Advanced Stage
Specifications on cancer stages	Mamma carcinoma stage III-IV
Comorbidities	NI
Current cancer therapies	Chemotherapy, Hormone therapy
Specifications on cancer therapies	Chemotherapy or specific cancer therapy: 210 patients, hormone therapy only: 46 patients.
Previous cancer therapies	Diverse
Gender	Female
Gender specifications	Patients: 100 % female; Caregivers: 40,8 % female
Age groups	Adults (18+)
Age groups specification	Mean (SD): Reflexology arm: 58.09 (11.62) Control arm: 54.80 (10.30)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	128
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	N=0
Drop-out reasons	NA
Intervention	Foot reflexology
Dosage and regime	Reflex therapy by study partners who were trained 2x in a 30min. protocol for reflex therapy by reflexologists (duration: 30 min., study weeks 1-4: minimum requirement 1x/week, real average 1.1/week; SW 5-11: no requirements, average 0.6/week)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	4
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	128
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	N=0
Drop-out reasons	NA
Intervention	Attention by study partners
Dosage and regime	Attention by study partners (duration: NI, 1x week, 4 weeks in total)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	4
Side effects / Interactions	NI

Outcomes

For all: adjusted coefficient β of the arm variable of the LME model over weeks 5 and 11 (standard error of beta), p-value, adjusted mean value M for weeks 1,2,3,4,5,11 if applicable (only presentation of sig. results)

Symptom load

Outcome type As specificed by the authors	Primary
Outcome specification	Summarized scale for symptom severity (study weeks 1-4, 5, 11)
Type of measurement	MDASI (M. D. Anderson Symptom Inventory)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Sig. lower (better) values for intervention arm than control arm (β= -4.34 [1.85]; p= 0.02), especially in week 2,3 and 5 (week 2: intervention arm: M=27.50 [1.53], control arm: M=33.65 [1.55]; p<0.01; week 3: intervention arm: M= 25. 50 [1.55], control arm: M=30.98 [1.55]; p=0.01; week 5: intervention arm: M=24.64 [1.52], control arm: M=30.50 [1.48]; p<0.01), mainly explained by an improvement in the symptoms fatigue and pain.

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Functionality

Outcome type As specificed by the authors	Primary
Outcome specification	Summarized scale for restrictions of daily life (study week 1-4, 5, 11)
Type of measurement	MDASI (M. D. Anderson Symptom Inventory)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Sig. lower (better) values for intervention arm than control arm (β= -3.69 [1.39]; p<0.01) especially in weeks 2,3 and 5 (week 1: intervention arm: M= 14.60 [1.15], control arm: M= 18. 32 [1.17]; p=0.02; week 3: intervention arm: M=11.84 [1.17], control arm: M= 17.57 [1.17]; p<0.01; week 5: intervention arm: M=12.30 [1.15]; control arm: M=16.60 [1.12]; p<0.01)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Physical functioning

Outcome type As specificed by the authors	Secondary
Outcome specification	Short forms of the PROMIS: Scale for physical functioning (study weeks 3, 5, 11)
Type of measurement	PROMIS (Patient-Reported Outcomes Measurement Information System)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sig. differences between the arms (β= 0.195 [0.67]; p=0.77)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Quality of life

Outcome type As specificed by the authors	?
Outcome specification	PROMIS short forms: Satisfaction with regard to social participation (study weeks 3, 5, 11)
Type of measurement	PROMIS (Patient-Reported Outcomes Measurement Information System)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sig. differences between the arms (β= 1.659 [0.88]; p=0.06)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Study week 3,5,11
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sig. differences between the arms (β= 0.599 [0.36]; p=0.10)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Funded by NCI Grant R01 CA157459 Home-Based Symptom Management via Reflexology for Advanced Breast Cancer Patients. Principal Investigator: G. Wyatt.
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

Mediators analysed

• Perception of social support with Multidimensional Scale of Perceived Social Support (MSPSS) in study weeks 1, 5, 11: no significant differences between the arms (p=0.99)
• Quality of the patient-study partner relationship with the Quality Relationship Tool in study weeks 1, 5, 11: no significant differences between the arms (p=0.08) 

PRO:

• Large, multicenter sample
• The comparability of the groups was comprehensively checked (including the reference to the partner who carried out the reflex therapy, comorbidities, etc.) and the difference in age was controlled. In addition, statistical model with repeated measures (no multiple testing)

CONTRA:

• Reliability and validity of the short form of the Patient-Reported Outcomes Measurements Information System PROMIS has not yet been sufficiently tested
• No idea what exactly the control group did (“attention”)
• High drop-out, but equally distributed in both arms and intention-to-treat analysis carried out (nevertheless influence on external validity)
• NI about the effect sizes and the clinical relevance range