Sage Journals: Discover world-class research

Abstract

Background

We describe the study design and protocol of a pragmatic randomized controlled trial (RCT) Acupressure for Children in Treatment for a Childhood Cancer (ACT-CC).

Objective

To describe the feasibility and effectiveness of an acupressure intervention to decrease treatment-related symptoms in children in treatment for cancer or recipients of a chemotherapy-based hematopoietic stem cell transplant (HSCT).

Design

Two-armed RCTs with enrollment of 5 to 30 study days.

Setting

Two pediatric teaching hospitals.

Patients

Eighty-five children receiving cancer treatment or a chemotherapy-based HSCT each with 1 parent or caregiver.

Intervention

Patients are randomized 1:1 to receive either usual care plus daily professional acupressure and caregiver delivered acupressure versus usual care alone for symptom management. Participants receive up to 20 professional treatments.

Main Outcome

A composite nausea/vomiting measure for the child.

Secondary Outcomes

Child’s nausea, vomiting, pain, fatigue, depression, anxiety, and positive affect.

Parent Outcomes

Depression, anxiety, posttraumatic stress symptoms, caregiver self-efficacy, and positive affect. Feasibility of delivering the semistandardized intervention will be described. Linear mixed models will be used to compare outcomes between arms in children and parents, allowing for variability in diagnosis, treatment, and age.

Discussion

Trial results could help childhood cancer and HSCT treatment centers decide about the regular inclusion of trained acupressure providers to support symptom management.

Keywords

childhood cancer symptom management nausea vomiting pain acupuncture acupressure

Introduction

Background and Rationale

Despite advances in pharmacologic symptom management, most children with cancer^1,2 or receiving a hematopoietic stem cell transplant (HSCT)^3–6 suffer from multiple treatment-related symptoms including nausea, vomiting,⁷ pain,⁸ and fatigue.³ Pharmacologic symptom management can be effective, but can have side effects that decrease quality of life.^9,10 Symptom distress is an important predictor of poor health-related quality of life among children treated for cancer¹¹ or receiving HSCT.^6,12 Severe symptoms can result in interruptions in planned treatment, dose reductions, or other therapy changes with the potential to compromise survival.^13,14 A systematic review documented frequent undertreated symptoms during oncology and HSCT treatment.¹

A growing body of high-quality evidence from large meta-analyses and systematic reviews of adult acupuncture point stimulation supports the use of acustimulation for the management of adult pain,^15–19 headache,^20–22 postoperative nausea/vomiting (PONV),²³ presurgery anxiety, chemotherapy-related nausea/vomiting (CINV),^24–35 cancer-related pain,^24,36 cancer-related anxiety,^32,37,38 chemotherapy-related fatigue,^38,39 and cancer treatment-related symptoms.²⁴ (The term acustimulation is used throughout the protocol and refers to the use of needles, laser, or pressure stimulation.) A National Institutes of Health (NIH) Consensus Conference assessed acupuncture as effective in reducing CINV and PONV.⁴⁰ Compared to pharmacologic symptom management alone, in adults, acustimulation may provide equivalent⁴¹ or superior³⁰ symptom relief and decreased the use of rescue antiemetics and opioids.²⁹

Fewer studies support the use of acustimulation in children. Systematic reviews reported that acupuncture decreased pain,⁴² and a Cochrane review reported decreased PONV.⁴¹ Three randomized controlled trials (RCTs) reported no statistically significant effect of acupressure on CINV^43–45 or PONV.^46,47 Two well-designed, but small RCTs of children receiving highly emetogenic chemotherapy for treatment of a childhood cancer reported decreased nausea and vomiting^48,49 as well as reduced the use of antiemetic medications following acupuncture.⁵⁰ An RCT of children with leukemia showed decreased postchemotherapy fatigue with the application of acupressure to a single point (St36), but results lasted less than 24 hours.⁵¹ A review article of acustimulation for nausea, vomiting, or rescue antiemetics describes the quality of evidence as low but having nonsignificant moderate effect sizes (ESs) in acupuncture versus sham in children.⁵² Studies consistently report few side effects and a strong safety profile.^41,42,48,53 Most acustimulation studies described side effects from acupuncture (not acupressure), and these included pain on needle insertion, redness, irritation, bleeding, swelling, itching, or fatigue.^42,48,53

In its supportive care guidelines The Children’s Oncology Group (COG) states “that acupuncture, acupressure … may be effective in children receiving antineoplastic agents” to reduce CINV.⁵⁴ However, the strength of the COG recommendation is rated as “weak” and the quality of evidence is categorized as “very low.”⁵⁴ Acustimulation has the potential strengths of being safe, having few side effects, and addressing multiple symptoms with one treatment. However, the majority of systematic reviews have concluded that additional high-quality trials are needed among children to assess the effectiveness of acustimulation to reduce pain, nausea, and vomiting in general populations,^42,55–59 as well as in childhood cancer.^29,30,60,61

Trial Objectives/Aims

The primary objective of Acupressure for Children in Treatment for a Childhood Cancer (ACT-CC) is to describe the feasibility, benefits, and risks of an acupressure intervention plus usual care versus usual care alone for symptom management in children in treatment for a childhood cancer and/or receiving a chemotherapy-based HSCT. Aim 1 assesses whether patients in the acupressure arm, compared to usual care alone arm, will report decreased nausea/vomiting (primary outcome) and improved management of treatment-related symptoms such as nausea, vomiting (separately), pain interference and intensity, fatigue, anxiety, depression, and greater positive affect (secondary outcomes). It is hypothesized that rescue antiemetic and analgesic use will be lower in the acupressure arm and that greater acupressure dose will lead to greater improvement of primary and secondary outcomes. Aim 2 investigates whether parent involvement in the delivery of acupressure reduces posttraumatic stress symptoms, anxiety and depression, and increases positive affect and caregiving self-efficacy.

This protocol manuscript is based on the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines to ensure comprehensiveness of reporting⁶² with recommended additions from the SPIRIT protocol to Traditional Chinese Medicine (TCM).⁶³ The study protocol will be made available on the ACT-CC study website once the trial is complete.

Trial Design

This is a 2.5-year pragmatic RCT among children receiving treatment for a childhood cancer or a HSCT. We will enroll 85 dyads consisting of a child with a parent/caregiver for a total of 170 participants. Study staff and health-care providers are blinded to study arm assignment. Participants will be randomized 1:1 into the 2 arms and will be followed for up to 30 days of hospital-based oncology or HSCT treatment (continuous or intermittent days) within 2 calendar months from enrollment. If a patient finishes treatment before 30 study days (ie, end of stem cell transplant hospitalization), the study enrollment period ends. Children in Arm A will receive professional acupressure 5 days/week along with usual care, and their parent/caregiver will be trained in how to provide additional acupressure to manage symptoms. Arm B participants will receive usual care alone. (The caregiver will be trained in how to provide acupressure at the end of study participation.)

Stakeholder Involvement

Stakeholders were engaged with the original design for the pilot study during study development, and have ongoing involvement in the study implementation (recruitment, outreach, intervention, and reviewing patient materials). Stakeholders will continue their involvement in the interpretation of the results and in discussions on framing or interpretation of findings.

Methods: Participants, Intervention, and Outcomes

Study Setting

Inpatients and outpatients are enrolled from a United States, Northern California Pediatric Teaching Hospital with 2 sites. Patients are enrolled from hematology-oncology, neuro-oncology, or HSCT units.

Participants’ Eligibility Criteria

The ACT-CC study aims to enroll 85 patients, most with 1 caregiver. Recruitment started in October 2017. Inclusion criteria for ACT-CC require that the child is either receiving treatment for childhood cancer (curative or supportive care) or a chemotherapy-based HSCT (nonmalignant central nervous system tumors are considered a childhood cancer); be age 5 through 24 years old; be receiving hospital-based treatment (inpatient or outpatient); English or Spanish speaking; and availability and willingness of a parent or caregiver to deliver acupressure for patients aged 5 to 17 years. (For young adults aged 18–24 years, participation of a parent, close friend, or family member/caregiver is preferred but not required.) Children are excluded if the treating oncologist, health-care provider, or a study investigator advises against study participation for physical health, mental health (parent or child), or logistical reasons. Examples of exclusion reasons include when the health-care provider thinks participation might be burdensome, there are serious mental health issues for child or caregiver, family stress, a child is receiving a radioactive treatment and is in isolation, or hospital visits are not long enough or frequent enough to provide the intervention.

Intervention

The protocol is based on adherence to the STRICTA reporting guidelines (Standards for Reporting Interventions in Clinical Trials of Acupuncture)⁶⁴ which are an extension of the CONSORT Statement⁶⁵ and the CONSORT guidelines for nonpharmacologic interventions.⁶⁶ The STRICTA guidelines were developed to improve the completeness and transparency of reporting acupuncture interventions (see Table 1).⁶⁴

Table 1.

Summary of the Semistandardized Intervention Details.

Acupuncture rationale: Style of acupuncture and reasoning for treatment provided	The intervention is a semi-standardized acupressure protocol based on TCM theory. From a Western medical perspective, chemotherapy-related symptoms are associated, with inflammatory processes.^13,14,67,68 Acupuncture acts on the neuroendocrine system⁶⁹ or through anti-inflammatory effects.^70–75 TCM will be used with points chosen based on peer reviewed research, TCM texts, and consensus of licensed acupressure provider experts (see Appendix 1).
Point stimulation details: Number of points, names, and technique of stimulation	The practitioner takes a history, feels the patient’s pulse, observes the tongue, forms a TCM diagnosis, and chooses from a platform of points and additional points (listed in Table 2). A mean of 6 acupoints (range 2–10) unilateral and bilaterally^a are stimulated using fingers for 3 minutes each using a pressing and circling motion until di qi is achieved.Parent acupressure can be offered daily, 3 minutes per point for ∼2 points bilaterally using similar techniques.
Treatment regimen: number, frequency, and duration of sessions	Approximately 20 (15–20 min) professional sessions are offered to participants over 30 study days. Sessions are offered 5 days/week.Acupressure providers record delivery of the intervention including symptoms treated and points stimulated. If a participant does not receive the intervention the reason is recorded. Data is collected for each intervention.
Other components of treatment	No other components of the acupressure intervention.
Practitioner qualifications	Licensed acupuncturist trained in TCM.2+ years of acupuncture clinical experience.Successful completion of supervised clinical internship.Successful completion of exam by State of California Acupuncture Board or Acupuncture MD training.
Rationale and description of control group intervention	The control group receives usual care for symptom management. Participants will not be coenrolled in studies testing the effectiveness of antiemetics or studies testing the effectiveness of massage or acupuncture. While enrolled in the ACT-CC study families agree to refrain from non-study-related massage, acustimulation, TENS units, and sea band use unless medically indicated.

Abbreviations: ACT-CC, Acupressure for Children in Treatment for a Childhood Cancer; TCM, Traditional Chinese Medical; TENS, Transcutaneous Clectrical Nerve Stimulation.

^aBarriers to use of bilateral points include limb amputation and medical equipment obstructing access.

Acupoint treatment order

Most points used are located distal to the elbows or knees. Treatment is applied based on primary symptom/complaint using standard points (termed “platform points”) prescribed for each symptom. Additional points (+) are included in the protocol and can be chosen based on secondary symptoms, experience, and TCM diagnosis (see Table 2).^76,77

Table 2.

Points for Each Symptom/TCM Diagnosis.

Symptom(s)	TCM Diagnosis	AcuPoints^a
Nausea and Vomiting^{23,41,49,50,52,56,78–83}	Rebellious Stomach Qi (this diagnosis applies to all nausea/vomiting)	Platform Points: P6 → SP4 → ST36 → REN 12
	Excess Condition: Accumulation of Heat, Cold or Food in Stomach	(+) ST44/Nei Ting (extra point) → ST41 → GB34
	Deficient Condition: Spleen Qi Def	(+) UB20 → Ren 6 → ST25
	Deficient Condition: Stomach Yin Def	(+) KI6 → UB21 → Ren4
Pain^61,84–90	Qi and Blood Stagnation in the Channel (true for most cases)	Platform Points: LV3 → HT7 → LI4Head Pain (+): LI4 → SJ5 → GB41Chest Pain (+): P6 → Ren 17 → KI27 → LU1Stomach Pain (+): UB 40 → ST36 → REN12Hypochondria Pain (+): SJ5 → GB34 → LV8 → LV14Upper Limb Pain (+): LI4 → LI11 → LI15Lower Limb Pain (+): ST40 → GB34 → SP10
Fatigue^{15,38,39,51,85,89,91–93}	Deficiency of Qi, Blood, Yin, Yang	Platform Points: SP6 → ST36 → DU20Qi Deficient (+): LU9 → UB13 → REN6Blood Deficiency (+): HT7 → SP4 → LV8 → UB17 → UB18Yin Deficiency (+): LU7 → KI6 → UB23Yang Deficiency (+): KI7 → UB23 → DU14
Depression^{38,85,89,91,94}	Excess Diagnosis: Liver Qi Stagnation	Platform Points: LI4 → P6 → LV3
	Deficient Diagnosis: Deficiency of Qi, Blood, Yin, Yang	Platform Points: SP6 → ST36 → DU20
Anxiety^38,39,85	Excess Diagnosis: Qi Stagnation	Platform Points: Ki1 → HT7 → P6 → Yintang → Du20
	Deficient Diagnosis: Deficiency of Qi, Blood, Yin, Yang	Platform Points: SP6 → ST36 → DU20
General Well-Being^38,95		Platform Points: LU7 → LI4 → LI11 → SP6 → ST36Additional Points: KI1 → Yintang → DU2

Abbreviations: TCM, Traditional Chinese Medical; +, additional points that can be used to supplement the platform of points.

^aParents only use bolded points.

Acupressure points are applied in the following order:

Upper limbs—yin (medial) side (distal to proximal) then yang (outer) side (distal to proximal)

Lower limbs—yin side (distal to proximal) then yang side (distal to proximal)

Prone (face down)—lower torso working up to head

Supine (face up)—abdomen working up to chest and then face

Delivery of Intervention for Each Group

Intervention precautions

Before proceeding with the acupressure session, the provider verifies platelet counts, assesses for skin breakdown associated with graft versus host disease (GVHD), or infection precautions. If platelet counts are <10 000/mL, usual supportive care guidelines recommend a transfusion. If the patient has not received a transfusion, the acupressure provider instructs parents to defer acupressure until platelets recover. Professional acupressure will continue to be delivered by the practitioner using gentle touch as per recommendations from the oncology team. In the case of infection precautions, the acupressure provider follows designated institutional infection control protocols including wearing gloves, mask, and gown as indicated. Acupressure will not be performed when there is skin breakdown or performed only on unaffected areas.

Patients are treated in their clothing or hospital gowns either lying in bed or seated in a chair according to patient preference. Lotion is not used. To assess intervention fidelity, randomly selected sessions are observed by study investigators.

Parent acupressure intervention

Caregivers are trained by the acupressure providers in the performance of acupressure for the patient. The training occurs at the same time as the professional acupressure intervention is initiated. Parents are encouraged to provide acupressure on a daily basis or as requested by the child. Teaching materials include a brochure with instructions including pictures of each point, a description of recommended points for each symptom, and point names (in English and Chinese). Video teaching instructions are also available on the study website for parents in Arm A (using a website log-in). During the first week of regular child acupressure, the provider begins by teaching parents the safety precautions and acupressure points for specific symptoms (eg, nausea, vomiting, pain, and fatigue). Teaching is updated each time the acupressure provider gives a session until parents are confident. Parents in Arm B (controls) are given acupressure instructions and materials when they complete the study.

Usual care for symptom management applied to both groups

Usual care is defined according to Children’s Oncology Group endorsed supportive care guidelines for nausea or vomiting⁵⁴ with updated guidelines^7,96–100 and guidelines for management of pain¹⁰¹ and fatigue.¹⁰² Usual care for symptom management to reduce nausea and vomiting involves the classification of the antineoplastic agents into varying levels of emetogenicity (highly emetogenic chemotherapy [HEC], moderately emetogenic chemotherapy [MEC], low and minimal emetic risk) and the provision of appropriate antiemetic agents on a regular schedule. The goal is to achieve optimal control of acute CINV, defined as “no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention, no nausea-related change in the child’s usual appetite and diet.”¹⁰³ Different antiemetic agents are recommended based on the age of the child, treatment factors (ie, avoidance of drug interactions), and the emetic risk. Guidelines to treat anticipatory and breakthrough nausea and for the prevention of refractory nausea are also followed.^7,99

Discontinuation of Intervention

The intervention will be discontinued if continued participation is no longer in the patient’s best interest (ie, in response to an adverse event as needed; emergence of skin breakdown due to GVHD), upon patient or caregiver request, when exclusion criteria occurs (even mid-enrollment) or in the case of concurrent illness that prevents acupressure from being delivered (ie, when a patient is moved to the Pediatric Intensive Care Unit).

Intervention Fidelity

The principal investigator (PI) does periodic observations of the acupressure providers for fidelity to the written intervention protocol.

Outcomes

Patient-Reported Outcomes Measurement Information System (PROMIS) measures are used when available consistent with the study interest in patient-reported outcomes (PROs). They are valid, easily understood and interpreted,¹⁰⁴ comparable across studies, often used in clinical trials,¹⁰⁵ demonstrate strong reliability (≥.85) for each domain measured,^106–108 and when a repeated measure, are responsive to changes in status in pediatric cancer patients¹⁰⁹ and in adults.¹¹⁰ Both adult and pediatric measures are designed for those with chronic health conditions (as well as general populations), aged 8 to 17 years,¹¹¹ and child proxy measures can be filled out by parents to assess symptoms in children aged 5 to 7 years or when children are unable to fill out forms.^103,112 Studies have verified the feasibility and efficiency¹¹³ of administering PROMIS instruments via tablet computers (see Table 3).¹¹⁴

Table 3.

Study Child and Parent Outcomes.

Measure	Description	Frequency
Primary Child Outcome
Demographic and other covariates	Age, sex, race, ethnicity, highest years of education, socioeconomic status, family structure, siblings (number and ages), and single parenthood,¹¹⁵ diagnosis, COG study protocol.	Baseline
Nausea/vomiting	Composite measure capturing the continuum of nausea/vomiting with a range of 1 to 8. The raw number will be assessed. The measures are defined for 2 age groups.	Daily
PeNAT and vomiting question	Among children age 5 to 17, nausea is measured using the PeNAT¹¹⁶ which is validated for ages 5 to 17. The 1 to 4 scale = none, mild, moderate, and severe using faces is a preferred method of measuring distress among children.¹¹⁷ Daily vomiting is assessed with one question (no. of episodes 1 min apart) with a range of 0 to 4+, capped at 4.^118,119	Daily
MAT	For young adults ages 18 to 24, the MAT is used to assess both nausea and vomiting domains.¹²⁰ MAT nausea responses are on a 0-10 scale and can be re-categorized on a 1 to 4 scale for comparability. The MAT nausea question has been adapted by deleting the phrase “. . . since your last chemotherapy” given the current study is interested in nausea and vomiting from any source. The number of MAT vomiting episodes are recorded and later capped so the range will be 0 to 4+ episodes in a 24-hour period. Together, the scale represents a continuum from complete control (value = 1), partial control (value = 2–4), and severe nausea and vomiting (value = 5–8).	Daily
Secondary Child Outcomes
PeNAT, MAT, and vomiting	These measures will be used separately as secondary outcomes (described above).	Daily
Pain interference and intensity	PROMIS: 4 items assess pain interference,¹⁰⁸ and a single item assesses pain intensity¹²¹ in children ages 8+.	Daily
Faces Pain Intensity	FPS-R: 1 item assesses pain in children ages 5 to 7.¹²² Scores range from 0 to 10.^123–127	Daily
Fatigue	PROMIS: 4 items assess fatigue.¹²⁸	Twice/week
Depression, anxiety	PROMIS: 4 items each assess depression and anxiety.¹⁰⁷	Once/week
Positive affect	PROMIS: 4 items each assess well-being.^129,130	Once/week
SSPedi	SSPedi is a pediatric cancer-specific symptom screening and assessment scale measuring physical and psychological symptoms (eg, feeling angry, sad or worried, tired, mouth sores, headache, constipation or diarrhea, problems thinking or remembering, body changes, or appetite loss, among others) in 15 questions.^131–133 with a proxy version.¹³⁴ The SSPedi is also used in a pediatric HSCT population.⁴ This instrument provides a brief measure of the most burdensome pediatric symptoms with minimal respondent burden.	Twice/week
Prior and current acustimulation exposure	Children age 10+ are asked about child’s previous experience with acustimulation at baseline. Parents are asked about same when for children age 5 to 9 years. At the final interview data on exposure to acustimulation or massage from nonstudy providers during study enrollment will be collected including number of times and symptoms treated.	Baseline and final interview
Acupressure expectations	Will be assessed at baseline consistent with previous research²⁸ scoring on a 5-point scale with 1 = not at all effective and 5 = very effective. Treatment outcome expectations have been reported to influence outcomes.^135,136	Baseline, at 1 week, and final interview
Rescue pain and antiemetics	Extracted from EMR.	Daily
Parent Outcomes: parents receive baseline, week 1 and a final survey
Demographics	For child, parent, and household	Baseline
Prior experience	Parents are asked about child’s prior experience with acupuncture.	Baseline
Acupressure expectations	Four questions each on expectations of effectiveness of the professional acupuncture and the parent performed acupressure are included.¹³⁷	Baseline and week 1
Depression and anxiety	PROMIS 4 item depression and 4 item anxiety measures from the PROMIS Adult Profile Bank.^138,139	Baseline, week 1 and final
PANAS	Positive Affect Subscale of the PANAS (5-items): This positive affect sub-scale of the 10-item PANAS scale (i-PANAS-SF) assessed positive or pleasurable engagement with the environment, well-being, and satisfaction with life. The scale can be used cross-culturally and has acceptable internal reliability, temporal stability, convergent, and criterion-related validity.¹⁴⁰ A Spanish translation is available. A translation exists for the full 20 item version¹⁴¹ and the study translator used that version to create the shorter 5-item Spanish version.¹⁴²	Baseline, 1 week and final
PTSS	Posttraumatic stress disorder Checklist (PCL-5) (20 items): updated to meet DSM5 criteria, responses assess frequency and intensity of symptoms (strong internal consistency, test-retest reliability and validity).¹⁴³	Baseline and final
PSES	Parent’s Self-Efficacy Scale (PSES)¹⁴⁴ (6 items): adapted from Bandura¹⁴⁵ and Lorig,^146,147 and previously used in parents of children with disabilities (excellent psychometric reliability and validity).^144,148	Baseline and final
Parent delivered acupressure	Parent-delivered acupressure data: frequency, duration, acupoints used, and child symptoms being treated.	Daily
Acupressure expectation-met?	One item assesses whether acupressure expectations were met using 5-item Likert scale.	Final
Patient satisfaction	Two items assess satisfaction with hospital stay¹⁴⁹ and with intervention¹⁵⁰	Final
Experience (open-ended)	One open question asked at the final interview: “Can you tell us in a few words how it was for you to learn and do acupressure on your child?	Final
Rewards and burden	Parent rewards and burdens of delivering acupressure: 2 questions use Likert scale to assess parent reward and burden in delivering acupressure.	Final
Acupressure Provider Information
Intervention details	The acupressure provider documents each session: chief complaint/symptom, secondary complaints, observation of the pulse and tongue, TCM diagnosis, points used, total minutes of acupressure, and patient response. The provider also asks parents about delivery of acupressure to their child: minutes of acupressure delivered each day, points used, symptoms treated, and child’s reaction.	At each intervention session

Abbreviations: COG, Children’s Oncology Group; EMR, electronic medical record; FPS-R, Faces Pain (Intensity) Scale-Revised; HSCT, hematopoietic stem cell transplant; MASCC, Multinational Association of Supportive Care in Cancer; MAT, MASCC Anti-emesis Tool; PeNAT, Pediatric Nausea Assessment Tool; PANAS, positive and negative affect schedule; PROMIS, Patient-Reported Outcomes Measurement Information System; PTSS, posttraumatic stress disorder Checklist; SSPedi, The Symptom Screening in Pediatrics; TCM, Traditional Chinese Medical.

Additional data related to child outcomes are collected from the electronic medical records (EMRs) including supportive care pain and antiemetic medications; medications for sleep; vomiting episodes; pain; ability to drink; parenteral nutrition; fever; chemotherapy complications (infection/sepsis, bleeding, GVHD, or hepatic veno-occlusive disease). Laboratory data being collected include the absolute neutrophil count (ANC) and platelet count. Additional information will be collected on likely precipitants for nausea/vomiting including chemotherapy (agent, dose, timing), surgery (length of surgery, length of time since surgery, and body location), and investigational drugs. Related to the timing of treatment, variables will be created based on the following conditions: CINV will be categorized for children reporting nausea during administration and up to 24 hours following chemotherapy.^151,152 For delayed CINV, we will analyze CINV scores in groups (HEC, MEC, vs lower intensity) up to 4 days after the end of chemotherapy administration based on recommendations from a National Institute for Health Research report.¹⁵¹ For PONV, we will categorize a participant at risk for nausea/vomiting following surgery for up to 24 hours.¹⁵³

Participant Timeline

Table 4 details the participant timeline.

Table 4.

Participant Timeline: Schedule of Enrollment, Interventions, Assessments, and Visits to Participants.

			−1	0	T1–T30	F1
Activity/Assessment	Staff Member(s)	Approximate Time/Frequency	Prestudy (Screening and Consent)	Prestudy (Baseline/Randomization)	Study Days (Over ≤ 2 Months)	Follow-Up: 1 Month Post Last Study Day
Identification and Screening	Study Nurse CRC, PI	10 minutes	X
Eligibility Documents	CRC, PI, Study Nurse	10 minutes	X
Consent Prep	CRC, PI	15 minutes	X
Bill of Rights, HIPPA, Informed Consent/Assent	CRC	30 minutes		X
Consent Note	CRC	5 minutes		X
Baseline (Parent and Child)	CRC	15 minutesOnce		X
Randomization	Study Nurse	2 minutes		X
Acupressure Intervention (Arm A)	Acupressure Provider	20 minutesWeek days			X
Acupressure Provider Log	Acupressure Provider	10 minutesEach session			X
Week 1 (Parent and Child) Survey	CRC	5 minutes Once			X
Nausea/vomiting and Pain Survey	CRC	2 minutes Daily			X
Sx Assess-Long Form Survey	CRC	5 minutes1/week			X
Sx Assess-Short Form Survey	CRC	4 minutes1/week			X
Follow-up (Parent and Child)	CRC	20 minutesOnce				X
Parent Acupressure Training (Arm B)	Acupressure Provider	20 minutes1–2 times				X
APeX EMR Record Capture-CTSI	CTSI^a	Done digitally				X
SAE (Serious Adverse Event) Form				As needed throughout protocol
Note to File	CRC, PI	15 minutes		As needed throughout protocol
Study Progress Tracking	CRC	10 minutesDaily	X	X	X	X

Abbreviations: CRC, clinical research coordinators; CTSI, Clinical & Translational Science Institute; EMR, electronic medical record; HIPPA, Health Insurance Portability and Accountability Act; PI, principal investigator.

^aClinical and Translational Science Institute services doing digital downloads of specified data.

Sample size

The target sample size is 85 participants along with ∼85 parents/caregivers. Participants are randomized on a 1:1 basis into each of the 2 study arms. Under some simplifying assumptions, detailed below, we estimate that this sample of 85 patients, randomized 1:1 to acupressure versus usual symptom management, will provide 80% power in 2-sided tests with α of .05 to detect average reductions of 0.52 to 0.58 standard deviations (SDs) in pairwise comparisons between the acupressure arm and the usual care only arm, depending on the intraclass correlation (ICC) of the repeated outcome measures (assumed to be 0.6–0.8). (With a more conservative assumption where ICC = 0.9, the minimal detectable effects [MDE] would increase to 0.61.)

MDEs in context

In a systematic review of acupressure studies of CINV, the standardized ES for vomiting episodes was 0.53 SDs, for retching episodes ES = 0.44 SDs, for severity of nausea, ES = 0.73 SDs, for the use of rescue antiemetics ES = 0.46 SD’s,³⁵ child-reported pain ES = 0.42 SDs, and fatigue ES = 0.78 SDs.⁹⁰ A composite score for nausea/vomiting should fall within the ES range for CINV in previous studies. Additional ESs for secondary symptoms fall within a similar range where pain ES = 0.37–0.55.⁹³ Thus, our calculations suggest that, in the case where the ICC = 0.6, with a sample size of 85 we expect to have 80% power to detect plausible and clinically significant effects for nausea, vomiting, and fatigue outcomes and may be able to detect differences in pain. If the ICC = 0.8, we expect to be able to detect differences for nausea and fatigue.

Recruitment

Patients are identified and recruited at varying stages of their disease course: at the time of diagnosis; during a new or repeat hospitalization, mid-treatment, or at relapse.

The study nurse monitors all planned and unplanned admissions and outpatient appointments, and prescreens for eligibility including age, diagnosis, language, and availability of a parent/caregiver. Approval of a treating health-care provider is sought before eligible patients are approached during inpatient or outpatient visits to the hospital. Consent is obtained from parents/caregivers and patients who are 18 years and older, and assent is obtained from patients aged 8 to 17 years following UCSF institutional review board (IRB) guidelines (see Figure 1).

Methods: Assignment of Interventions for Controlled Trials

Randomization, Allocation Concealment Mechanism, and Blinding

After collection of baseline data, the study nurse (who does not see study patients) performs 1:1 simple randomization into 2 groups: acupressure + usual care versus usual care alone using a Qualtrics computer-based assignment program in which the study nurse enters the participant ID number before randomization is revealed. Assignment is immediately locked into the database. Study staff who carry out the symptom assessments and health-care providers are blinded to study arm assignment. The use of simple randomization is considered the strongest design to prevent selection bias.¹⁵⁴ The acupressure provider, floor nurses, patients, and caregivers are not blinded due to the type of intervention. Floor nurses are informed before the acupressure provider enters the room to ensure that there are no medical issues that need to be addressed. Families are asked not to disclose their study arm to the staff and periodic checks assure us that the physicians remain unaware of allocation. Allocation is communicated to the family by the acupressure provider who naturally knows the allocation.

Methods: Data Collection, Management, and Analysis

Data Collection

Study staff were trained in the collection of survey data. Data are monitored post interview for accuracy and completeness. Survey data collection can occur in 4 ways: paper survey administered by staff, paper survey filled out by patient or parent, staff administered assessment using a portable device (ipad) with a link to a programmed questionnaire, or patient/parent filling out survey using link to the online questionnaire. See Table 3 for survey outcomes and timing. Study assessments are allowed a window of ±3 weekdays, ±4 days between consent and baseline, and ±10 days for final surveys. Electronic Medical data for each patient participant for each study day are collected using digital methods.

Patient retention is promoted by efforts of study staff to form a trusting relationship with participants, the use of a financial incentive of $50 each (caregiver and child) upon study completion, and, for the control arm, by providing instruction and training for caregivers to deliver acupressure at the end of participation.

Data Management

Survey data are entered into the Qualtrics database and recruitment and enrollment tracking data are recorded and stored using secure HIPAA compliant software. The study project manager monitors data entry for accuracy and completeness for both sites. Survey data include study ID with no protected health information (PHI) with the exception of the baseline and follow-up survey. Baseline and follow-up surveys are deidentified before the analysis phase. Information linking the study ID and patient PHI are kept in a HIPAA secured environment separate from survey data. Physical records are kept in an area accessible only to research staff and in a locked file cabinet. No names or individual identities will be used in publications resulting from the study. Research data are stored on a secure, HIPAA-compliant server and drive with monitored and controlled access for study staff and investigators.

Statistical Analysis

Aim 1: Child Outcomes

Summary of proposed modeling approach

This study will use linear mixed models (LMMs), an extension of least squares regression to longitudinal data. Among other advantages, this approach will accommodate differences in treatment timing, intensity and emetogenicity between the treatment groups, and differences related to treatment uptake and the semistandardized intervention, while also accounting for within-patient correlation of repeated measures, optimally weighting data for patients with different numbers of responses, and providing valid estimates in the presence of missing data under relatively mild assumptions about how the missing data arise.¹⁵⁵ In brief, we will flexibly model the time course of the composite nausea/vomiting severity scale for each treatment group and by emetogenicity, which will allow us to estimate average differences between these trajectories by randomized study intervention assignment (acupressure vs usual care). The model will intrinsically weight patients in proportion to the length of the course of treatment.

Technical description of analysis approach

We will flexibly model the average time course of composite nausea/vomiting scores (and severity of symptoms for other outcomes) for each combination of treatment modality and intervention assignment, using group-specific restricted cubic splines (RCS) in time since the start of study enrollment. The model will also include random intercepts and RCS components, to flexibly model patient-specific departures from the average group-specific trajectory. In addition, to capture spikes in symptom severity in the first few days after surgery or chemotherapy, the model will include time-dependent covariates flexibly modeling the effect of time since the most recent chemotherapy, surgery, and/or radiation, depending on the outcome (ie, for CINV chemotherapy will be dominantly factored in). The function of these adjustments is to explain variability in the outcome, increasing model efficiency. Normalizing transformation of the composite nausea/vomiting symptom severity scale will be used if necessary. We will assess the adequacy of both the fixed and random parts of the model and check for modification of the effects of the acupressure by both time and treatment modality. We will perform intent-to-treat analyses (by original assigned groups), which is the recommended method for describing clinical trial results,⁶⁵ and additional analyses will report on groups as treated.

Assumptions and sensitivity analyses

This approach relies on the plausible assumption that the timing and duration of treatment will not be affected by assignment to or intensity of the use of acupressure. Sensitivity analyses will be conducted assessing evidence for violations of this assumption, using between-arm comparisons of treatment patterns, as well as models for the association of lagged acupressure intensity with the timing of subsequent treatments.

Dose–response analysis using marginal structural models (Aim 1)

Our primary analyses for each symptom will be by intent-to-treat, according to allocation assignment, without regard to the intensity or duration of acupressure actually received. To assess dose effects as an exploratory analysis, the effects of total minutes of professional acupressure (as well as total minutes of professional plus caregiver provided acupressure) received per week, treated as an ordinal category with 3 to 4 levels, will be estimated in a secondary analysis. Because acupressure duration may depend on earlier levels of the outcome, marginal structural models will be used.

Aim 2: Parent Outcomes

We will determine whether parents differ in posttraumatic stress symptoms (total symptom scores), depression, and anxiety (T scores) and caregiver self-efficacy (score) between groups at 2 points: at week 1 for both arms regardless of pattern of hospital-based treatment; and at 1 month post-study enrollment, which will vary depending on whether patients have 1 month of continuous hospitalization followed by 1 month for follow-up or intermittent hospitalization or outpatient treatment over 2 months followed by a 1 month follow-up. In both cases, analysis will control for baseline values as appropriate. We will use similar analytic approaches as in Aim 1, with LMM as the primary analysis approach.

Exploratory analysis of heterogeneity of treatment effects

Using LMMs we will explore heterogeneity of treatment effects by demographics (age, sex, race/ethnicity), diagnosis, treatment agent/modality, or initiation of most recent treatment dose, with the goal of assessing variation in benefit from acupressure by subgroup. Our overall hypothesis in regard to heterogeneity of treatment effect is that groups with more severe symptoms of nausea and vomiting will experience greater benefit.¹⁵⁶ If certain groups benefit more from acupressure, recommendations may target provision of the intervention to these groups. Given our anticipated sample size of n = 85, within-subgroup effect estimates will likely have wide confidence intervals, and power to detect between-subgroup differences may be low. Since previous research has not documented point estimates for differences between subsamples within pediatric populations, these findings will provide preliminary estimates of ESs within subgroups which will be the basis for future studies of subsamples.

Missing Data Approaches

Some outcome data may be missing not at random (MNAR)—in particular, when missing symptom assessments occur due to early hospital discharge, moving into hospice care, severe symptoms or illness, refusal to answer, or conflicts with other medical procedures. To address this difficulty, we will perform sensitivity analyses using multiple imputation of missing outcomes under plausible MNAR scenarios as well as under the standard MAR assumptions for key outcomes. Where feasible, we will utilize appropriate information on nausea, vomiting, and pain available in the EMR in multiple imputation models to take advantage of data that may be available even when patient-reported symptom data cannot be collected directly.

Definition of populations

Intent to treat is defined as the entire randomized sample.

Methods: Monitoring

Data Safety Monitoring and Audits

The study is monitored by the Helen Diller Family Comprehensive Cancer Center (HDFCCC) Regulatory Unit for quality and regulatory compliance with yearly audits of 20% of participants (guideline for minimal risk trial) and biannual review by the Data Safety Monitoring Board (DSMB) reporting on data quality, subject safety, serious adverse reactions, and yearly accrual. The DSMB is independent from PCORI and the Investigators have no competing interests. The DSMB is made up of members who are knowledgeable in the conduct of research, with backgrounds in cancer, biostatistics, experimental design, or bioethics. The HDFCCC DSMB charter can be found at http://cancer.ucsf.edu/itr/itr-dsm.

Interim Analyses and Stopping Rules

The primary clinical outcome variable, nausea/vomiting, is a symptom associated with exposure to pediatric cancer treatment and HSCT conditioning. Continued nausea/vomiting is not an outcome that would justify early termination rules for a study of this nature, and it is highly unlikely that there would be differences in mortality or any other major health difference between arms. No interim analyses related to outcome will be performed and we do not anticipate stopping the trial early.

Adverse Events

Any adverse events (AEs) related to the administration of acupressure, specifically including bruising or skin irritation, are recorded. AEs can be reported by the family or the medical provider. All AEs are entered into the study records. Study AEs are graded. Serious (grade 3 and above) AEs are reported to IRB and the DSMB. AEs are monitored and discussed at every study staff and Co-Investigator meeting.

Ethics and Dissemination

The ACT-CC study has been approved by UCSF Helen Diller Family Comprehensive Cancer Center Protocol Review Committee and the IRB at UCSF Benioff Children’s Hospital Mission Bay site (9-26-17) and Benioff Children’s Hospital-Oakland site (11/3/17). HIPAA permissions, Patient Bill of Rights and consent/assent is obtained by trained study staff who receive 6 weeks of Cancer Center training in addition to training from the PI. No biological samples are collected for this trial.

This study includes a vulnerable population of children with life-threatening conditions. Thus efforts are made to reduce patient burden in the following way: after baseline regular assessments are short (<5 min) and enrolled patients can decline acupressure sessions or assessments; parents in Arm A are taught to provide acupressure and training is available throughout enrollment; surveys can be performed using the most convenient survey method. A pediatric cancer or HSCT population can be challenging to access given severe symptoms, fatigue, the need to have both the child and parent present for consent and intervention delivery for the youngest group, and the need to work around curative treatment procedures, medical equipment, and health-care personnel visits to the room. Thus, study staff receive training and ongoing monitoring as recruitment and enrollment occurs to ensure that patient needs are honored and study procedures are transparent, clear, and optional. Acupressure training is provided to caregivers in the control arm after the family finishes the trial to ensure that everyone enrolled has the opportunity to benefit from the intervention if desired. We ask participants to refrain from receiving acupuncture, acupressure or massage from outside providers during the trial unless medically indicated, in which case, patients can remain in the trial and receive integrative medicine services. The use of integrative medicine services is documented.

Protocol changes related to eligibility or any significant change in study procedures are reported to the study funder, the HDFCCC Site Committee, the IRB, and updated on clinicaltrials.gov.

Study results will first be presented to our stakeholders for evaluation and discussion. After incorporating stakeholder feedback, final study results related to primary and secondary outcomes will be published in peer-reviewed journals and presented at one or more scientific conferences.

Confidentiality

At recruitment, personal information is collected through secure e-mails (to get treating health-care provider permission to approach). Enrollment tracking is recorded using HIPAA compliant software or stored in HIPAA compliant secure folders. No names or personal identifiers are available during the analysis phase.

Access to Data

Access to the data involves a formal request including an abstract, proposed aims, background, outcomes, analysis plan, and investigator qualifications. Upon approval a complete, cleaned, and de-identified copy of the final dataset will be provided. Data sharing will be coordinated to avoid overlapping analyses.

Discussion

The results of the ACT-CC trial will provide both feasibility and effectiveness data so that Hematology-Oncology and HSCT treatment centers can assess the logistics, risks, and benefits of integrating acupressure into symptom management along with usual care in inpatient and outpatient settings treating childhood cancer or providing a chemotherapy-based HSCT. To our knowledge, this study represents the largest study employing a semistandardized daily acupressure intervention for pediatric oncology and HSCT-patients.

In 2002, the NIH convened a 14-member multidisciplinary expert panel to examine symptom management dilemmas for patients with cancer.^157,158 The panel stated that all patients should have optimal symptom control throughout the course of their illness and suggested that pain, depression, and fatigue are inadequately treated in most cancer patients. Additional data show that effective management of nausea and vomiting in children remains challenging.^3,96 This trial will provide data on an integrative medicine approach to improve symptom management.

Although the trail has employed rigorous methodology, nonetheless, it has limitations. A sample size of 85 may make it harder to detect differences between groups for pain. It is likely to be difficult to determine the effectiveness of the intervention between subgroups such as those receiving inpatient versus outpatient care, hematology-oncology versus HSCT, by age, or by diagnosis. A future larger multisite trial would be important to increase the sample size so that the effectiveness in subgroups could be explored in more depth.

Trail Status

The trial is currently active enrolling and was opened in October 2017. No posttrial care is required.

Footnotes

Appendix 1 Author Contributions

EAL drafted the manuscript. All remaining authors reviewed and edited versions.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by: Patient Centered Outcomes Research Institute (PCORI) R-1602-34557 (Lown); Pierre’s Birthday Fund for acupressure delivery; National Cancer Institute, P30CA082103 (UCSF Helen Diller Family Comprehensive Cancer Center); and UCSF Clinical & Translational Science Institute (CTSI) UL1 TR991872. The scientific direction and publication is determined by the investigator team.

References

Kestler

LoBiondo-Wood

Review of symptom experiences in children and adolescents with cancer.

Cancer Nurs. 2012; 35(2):E31–E49.

Rodgers

Hooke

Hockenberry

MJ.

Symptom clusters in children.

Curr Opin Support Palliat Care. 2013; 7(1):67–72.

Flank

Sparavalo

Vol

, et al. The burden of chemotherapy-induced nausea and vomiting in children receiving hematopoietic stem cell transplantation conditioning: a prospective study. Bone Marrow Transpl. 2017; 52(9):1294–1299.

Johnston

Hyslop

Tomlinson

, et al. Describing symptoms using the Symptom Screening in Pediatrics Tool in hospitalized children with cancer and hematopoietic stem cell transplant recipients. Cancer Med. 2018; 7(5):1750–1755.

Phipps

Dunavant

Garvie

Lensing

Rai

SN.

Acute health-related quality of life in children undergoing stem cell transplant: I. Descriptive outcomes.

Bone Marrow Transplant. 2002; 29(5):425–434.

Rodgers

Highberger

Powers

Voigt

Douglas

Symptom trajectories of adolescents during hematopoietic stem cell recovery [published online ahead of print October 17, 2018]. Cancer Nurs. doi:10.1097/NCC.0000000000000643

Dupuis

Robinson

Boodhan

, et al. Guideline for the prevention and treatment of anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. Pediatr Blood Cancer. 2014; 61(8):1506–1512.

Dupuis

Mitchell

, et al. Anxiety, pain, and nausea during the treatment of standard-risk childhood acute lymphoblastic leukemia: a prospective, longitudinal study from the Children’s Oncology Group. Cancer. 2016; 122(7):1116–1125.

Tomlinson

Robinson

Oberoi

, et al. Pharmacologic interventions for fatigue in cancer and transplantation: a meta-analysis. Curr Oncol. 2018; 25(2):e152–e167.

10.

Chow

Chiu

Navari

, et al. Efficacy and safety of olanzapine for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) as reported in phase I and II studies: a systematic review. Support Care Cancer. 2016; 24(2):1001–1008.

11.

Rosenberg

Orellana

Ullrich

, et al. Quality of life in children with advanced cancer: a report from the PediQUEST study. J Pain Symptom Manage. 2016; 52(2):243–253.

12.

Rodgers

Krance

Street

Hockenberry

MJ.

Symptom prevalence and physiologic biomarkers among adolescents using a mobile phone intervention following hematopoietic stem cell transplantation.

Oncol Nurs Forum. 2014; 41(3):229–236.

13.

Cleeland

CS.

Symptom burden: multiple symptoms and their impact as patient-reported outcomes.

J Natl Cancer Inst Monogr. 2007;(37):16–21.

14.

Wang

Shi

Williams

, et al. Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy. Brain Behav Immun. 2010; 24(6):968–974.

15.

Lee

Frazier

SK.

The efficacy of acupressure for symptom management: a systematic review. J Pain Symptom Manage. 2011; 42(4):589–603.

16.

Vickers

Cronin

Maschino

, et al. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med. 2012; 172(19):1444–1453.

17.

MacPherson

Vertosick

Lewith

, et al. Influence of control group on effect size in trials of acupuncture for chronic pain: a secondary analysis of an individual patient data meta-analysis. PLoS One. 2014; 9(4):e93739.

18.

Witt

Reinhold

Brinkhaus

Roll

Jena

Willich

SN.

Acupuncture in patients with dysmenorrhea: a randomized study on clinical effectiveness and cost-effectiveness in usual care.

Am J Obstet Gynecol. 2008; 198(2):166.e1–166.e8.

19.

Witt

Jena

Brinkhaus

Liecker

Wegscheider

Willich

SN.

Acupuncture for patients with chronic neck pain.

Pain. 2006; 125(1–2):98–106.

20.

Melchart

Streng

Hoppe

, et al. Acupuncture in patients with tension-type headache: randomised controlled trial. BMJ. 2005; 331(7513):376–382.

21.

Linde

Streng

Jurgens

, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA. 2005; 293(17):2118–2125.

22.

Jena

Witt

Brinkhaus

Wegscheider

Willich

SN.

Acupuncture in patients with headache.

Cephalalgia. 2008; 28(9):969–979.

23.

Lee

Done

ML.

The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis.

Anesth Analg. 1999; 88(6):1362–1369.

24.

Chao

Zhang

Liu

Cheng

Lam

SK.

The efficacy of acupoint stimulation for the management of therapy-related adverse events in patients with breast cancer: a systematic review.

Breast Cancer Res Treat. 2009; 118(2):255–267.

25.

Choo

Kong

Lim

Gao

Chua

Leong

SS.

Electroacupuncture for refractory acute emesis caused by chemotherapy.

J Altern Complement Med. 2006; 12(10):963–969.

26.

Dibble

Luce

Cooper

, et al. Acupressure for chemotherapy-induced nausea and vomiting: a randomized clinical trial. Oncol Nurs Forum. 2007; 34(4):813–820.

27.

Dundee

Ghaly

Fitzpatrick

Abram

Lynch

GA.

Acupuncture prophylaxis of cancer chemotherapy-induced sickness.

J R Soc Med. 1989; 82(5):268–271.

28.

Roscoe

Morrow

Hickok

, et al. The efficacy of acupressure and acustimulation wrist bands for the relief of chemotherapy-induced nausea and vomiting. A University of Rochester Cancer Center Community Clinical Oncology Program multicenter study. J Pain Symptom Manage. 2003; 26(2):731–742.

29.

Ezzo

Streitberger

Schneider

Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting.

J Altern Complement Med. 2006; 12(5):489–495.

30.

Ezzo

Richardson

Vickers

, et al. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev. 2010; 11:CD002285.

31.

Gardani

Cerrone

Biella

, et al. A progress study of 100 cancer patients treated by acupressure for chemotherapy-induced vomiting after failure with the pharmacological approach. Minerva Med. 2007; 98(6):665–668.

32.

Genc

Tan

The effect of acupressure application on chemotherapy-induced nausea, vomiting, and anxiety in patients with breast cancer.

Palliat Support Care. 2015; 13(2):275–284.

33.

Lee

Dodd

Dibble

Abrams

Review of acupressure studies for chemotherapy-induced nausea and vomiting control.

J Pain Symptom Manage. 2008; 36(5):529–544.

34.

Shen

Wenger

Glaspy

, et al. Electroacupuncture for control of myeloablative chemotherapy-induced emesis: a randomized controlled trial. JAMA. 2000; 284(21):2755–2761.

35.

Treish

Shord

Valgus

, et al. Randomized double-blind study of the Reliefband as an adjunct to standard antiemetics in patients receiving moderately-high to highly emetogenic chemotherapy. Support Care Cancer. 2003; 11(8):516–521.

36.

Alimi

Rubino

Pichard-Leandri

Fermand-Brule

Dubreuil-Lemaire

Hill

Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial.

J Clin Oncol. 2003; 21(22):4120–4126.

37.

Beikmoradi

Najafi

Roshanaei

Pour Esmaeil

Khatibian

Ahmadi

Acupressure and anxiety in cancer patients.

Iran Red Crescent Med J. 2015; 17(3):e25919.

38.

Molassiotis

Bardy

Finnegan-John

, et al. Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial. J Clin Oncol. 2012; 30(36):4470–4476.

39.

Vickers

Straus

Fearon

Cassileth

BR.

Acupuncture for postchemotherapy fatigue: a phase II study.

J Clin Oncol. 2004; 22(9):1731–1735.

40.

NIH Consensus Conference. Acupuncture. JAMA. 1998; 280(17):1518–1524.

41.

Lee

Fan

LT.

Stimulation of the wrist acupuncture point P6 for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2009;(2):CD003281.

42.

Yang

Hao

Zhang

Guo

Efficacy and safety of acupuncture in children: an overview of systematic reviews.

Pediatr Res. 2015; 78(2):112–119.

43.

Jones

Isom

Kemper

McLean

TW.

Acupressure for chemotherapy-associated nausea and vomiting in children. J Soc Integr Oncol. 2008; 6(4):141–145.

44.

Effect of acupressure on acute and delayed nausea and vomiting in children receiving chemotherapy. Cleveland, OH: School of Nursing, Case Western Reserve University; 1998.

45.

Dupuis

Kelly

Krischer

, et al. Acupressure bands do not improve chemotherapy-induced nausea control in pediatric patients receiving highly emetogenic chemotherapy: a single-blinded, randomized controlled trial. Cancer. 2018; 124(6):1188–1196.

46.

Liodden

Sandvik

Valeberg

Borud

Norheim

AJ.

Acupuncture versus usual care for postoperative nausea and vomiting in children after tonsillectomy/adenoidectomy: a pragmatic, multicentre, double-blinded, randomised trial.

Acupunct Med. 2015; 33(3):196–203.

47.

Lewis

Pryn

Reynolds

Pandit

Wilton

NC.

Effect of P6 acupressure on postoperative vomiting in children undergoing outpatient strabismus correction.

Br J Anaesth. 1991; 67(1):73–78.

48.

Gottschling

Reindl

Meyer

, et al. Acupuncture to alleviate chemotherapy-induced nausea and vomiting in pediatric oncology – a randomized multicenter crossover pilot trial. Klin Padiatr. 2008; 220(6):365–370.

49.

Yeh

Chien

Chiang

Lin

Huang

Ren

Reduction in nausea and vomiting in children undergoing cancer chemotherapy by either appropriate or sham auricular acupuncture points with standard care.

J Altern Complement Med. 2012; 18(4):334–340.

50.

Reindl

Geilen

Hartmann

, et al. Acupuncture against chemotherapy-induced nausea and vomiting in pediatric oncology. Interim results of a multicenter crossover study. Support Care Cancer. 2006; 14(2):172–176.

51.

Bastani

Khosravi

Borimnejad

Arbabi

The effect of acupressure on cancer-related fatigue among school-aged children with acute lymphoblastic leukemia.

Iran J Nurs Midwifery Res. 2015; 20(5):545–551.

52.

Lee

Chan

Fan

LT.

Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2015;November(11):CD003281.

53.

Adams

Cheng

Jou

Aung

Yasui

Vohra

The safety of pediatric acupuncture: a systematic review.

Pediatrics. 2011; 128(6):e1575–e1587.

54.

Children’s Oncology Group. COG Supportive Care Endorsed Guidelines. https://childrensoncologygroup.org/downloads/COG_SC_Guideline_Document.pdf. Published 2015. Accessed February 23, 2016.

55.

Gold

Nicolaou

Belmont

Katz

Benaron

Pediatric acupuncture: a review of clinical research.

Evid Based Complement Alternat Med. 2009; 6(4):429–439.

56.

Dune

Shiao

SY.

Metaanalysis of acustimulation effects on postoperative nausea and vomiting in children.

Explore (NY). 2006; 2(4):314–320.

57.

Hunt

Ernst

The evidence-base for complementary medicine in children: a critical overview of systematic reviews.

Arch Dis Child. 2011; 96(8):769–776.

58.

Kemper

Sarah

Silver-Highfield

Xiarhos

Barnes

Berde

On pins and needles? Pediatric pain patients’ experience with acupuncture. Pediatrics. 2000; 105(4 Pt 2):941–947.

59.

Kundu

Berman

Acupuncture for pediatric pain and symptom management.

Pediatr Clin North Am. 2007; 54(6):885–889.

60.

Golianu

Yeh

Brooks

Acupuncture for Pediatric Pain.

Children. 2014; 1:134–148.

61.

Sapru

Steward

, et al. Using acupunture for acute pain in hospitalized children. Pediatr Crit Care Med. 2009; 10(3):291–296.

62.

Chan

Tetzlaff

Altman

, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013; 158(3):200–207.

63.

Dai

Cheng

Tian

, et al. Standard protocol items for clinical trials with traditional Chinese medicine 2018: recommendations, explanation and elaboration (SPIRIT-TCM extension 2018). Chin J Integr Med. 2019; 25(1):71–79.

64.

MacPherson

Altman

Hammerschlag

, et al. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. PLoS Med. 2010; 7(6):e1000261.

65.

Schulz

Altman

Moher

Group

CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials.

BMJ. 2010; 340:c332.

66.

Boutron

Moher

Altman

Schulz

Ravaud

Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration.

Ann Intern Med. 2008; 148(4):295–309.

67.

Dodd

Miaskowski

Paul

SM.

Symptom clusters and their effect on the functional status of patients with cancer.

Oncol Nurs Forum. 2001; 28(3):465–470.

68.

Miaskowski

Aouizerat

Dodd

Cooper

Conceptual issues in symptom clusters research and their implications for quality-of-life assessment in patients with cancer.

J Natl Cancer Inst Monogr. 2007(37):39–46.

69.

Dean-Clower

Doherty-Gilman

Rosenthal

DS.

The value of acupuncture in cancer care.

Hematol/Oncol Clin N Am. 2008; 22(4):631–648, viii.

70.

Zijlstra

van den Berg-de Lange

Huygen

Klein

Anti-inflammatory actions of acupuncture.

Mediat Inflamm. 2003; 12(2):59–69.

71.

Song

Halbreich

Han

Leonard

Luo

Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment.

Pharmacopsychiatry. 2009; 42(5):182–188.

72.

Moon

Jeong

Kim

, et al. Use of electroacupuncture at ST36 to inhibit anaphylactic and inflammatory reaction in mice. Neuroimmunomodulation. 2007; 14(1):24–31.

73.

Lin

Yeh

Chien

Morone

Glick

Albers

KM.

The anti-inflammatory actions of auricular point acupressure for chronic low back pain.

Evid Based Complement Alternat Med. 2015; 2015:103570.

74.

Kavoussi

Ross

BE.

The neuroimmune basis of anti-inflammatory acupuncture.

Integr Cancer Ther. 2007; 6(3):251–257.

75.

Jeong

Hong

Nam

, et al. The effect of acupuncture on proinflammatory cytokine production in patients with chronic headache: a preliminary report. Am J Chin Med. 2003; 31(6):945–954.

76.

Maciocia

The Practice of Chinese Medicine: The Treatment of Diseases With Acupuncture and Chinese Herbs, Second Edition. Edinburgh, England: Elsevier Churchill Livingstone; 2008.

77.

Xinnong

CE.

Chinese Acupuncture and Moxibustion. Beijing, China: Foreign Languages Press; 1998.

78.

Butkovic

Toljan

Matolic

Kralik

Radesic

Comparison of laser acupuncture and metoclopramide in PONV prevention in children.

Paediatr Anaesth. 2005; 15(1):37–40.

79.

Chu

Lin

Hsieh

, et al. Effect of BL-10 (tianzhu), BL-11 (dazhu) and GB-34 (yanglinquan) acuplaster for prevention of vomiting after strabismus surgery in children. Acta Anaesthesiol Sin. 1998; 36(1):11–16.

80.

Molassiotis

Helin

Dabbour

Hummerston

The effects of P6 acupressure in the prophylaxis of chemotherapy-related nausea and vomiting in breast cancer patients.

Complement Ther Med. 2007; 15(1):3–12.

81.

Rusy

Hoffman

Weisman

SJ.

Electroacupuncture prophylaxis of postoperative nausea and vomiting following pediatric tonsillectomy with or without adenoidectomy.

Anesthesiology. 2002; 96(2):300–305.

82.

Schlager

Boehler

Puhringer

Korean hand acupressure reduces postoperative vomiting in children after strabismus surgery.

Br J Anaesth. 2000; 85(2):267–270.

83.

Wang

Kain

ZN.

P6 acupoint injections are as effective as droperidol in controlling early postoperative nausea and vomiting in children.

Anesthesiology. 2002; 97(2):359–366.

84.

Bao

Goloubeva

Pelser

, et al. A pilot study of acupuncture in treating bortezomib-induced peripheral neuropathy in patients with multiple myeloma. Integr Cancer Ther. 2014; 13(5):396–404.

85.

Dean-Clower

Doherty-Gilman

Keshaviah

, et al. Acupuncture as palliative therapy for physical symptoms and quality of life for advanced cancer patients. Integr Cancer Ther. 2010; 9(2):158–167.

86.

Garcia

Driver

Haddad

, et al. Acupuncture for treatment of uncontrolled pain in cancer patients: a pragmatic pilot study. Integr Cancer Ther. 2014; 13(2):133–140.

87.

Garcia

Cohen

Guo

, et al. Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study. J Hematol Oncol. 2014; 7:41.

88.

Kotani

Hashimoto

Sato

, et al. Preoperative intradermal acupuncture reduces postoperative pain, nausea and vomiting, analgesic requirement, and sympathoadrenal responses. Anesthesiology. 2001; 95(2):349–356.

89.

Mao

Farrar

Bruner

, et al. Electroacupuncture for fatigue, sleep, and psychological distress in breast cancer patients with aromatase inhibitor-related arthralgia: a randomized trial. Cancer. 2014; 120(23):3744–3751.

90.

Lown

Mehling

Dvorak

, et al. Hematopoietic cell transplant and use of massage for improved symptom management: results from a pilot randomized control trial. Evid Based Complement Alternat Med. 2012;2012:1–9.

91.

Balk

Day

Rosenzweig

Beriwal

Pilot, randomized, modified, double-blind, placebo-controlled trial of acupuncture for cancer-related fatigue. J Soc Integr Oncol. 2009; 7(1):4–11.

92.

Deng

Chan

Sjoberg

, et al. Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial. Support Care Cancer. 2013; 21(6):1735–1741.

93.

Molassiotis

Sylt

Diggins

The management of cancer-related fatigue after chemotherapy with acupuncture and acupressure: a randomised controlled trial.

Complement Ther Med. 2007; 15(4):228–237.

94.

Lee

Shim

Lee

Yang

Hahm

DH.

Effects of acupuncture on chronic corticosterone-induced depression-like behavior and expression of neuropeptide Y in the rats.

Neurosci Lett. 2009; 453(3):151–156.

95.

Kasymjanova

Grossman

Tran

, et al. The potential role for acupuncture in treating symptoms in patients with lung cancer: an observational longitudinal study. Curr Oncol. 2013; 20(3):152–157.

96.

Dupuis

Boodhan

Holdsworth

, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer. 2013; 60(7):1073–1082.

97.

Dupuis

Roscoe

Olver

Aapro

Molassiotis

2016 updated MASCC/ESMO consensus recommendations: anticipatory nausea and vomiting in children and adults receiving chemotherapy.

Support Care Cancer. 2017; 25(1):317–321.

98.

Dupuis

Sung

Molassiotis

Orsey

Tissing

van de Wetering

2016 updated MASCC/ESMO consensus recommendations: prevention of acute chemotherapy-induced nausea and vomiting in children.

Support Care Cancer. 2017; 25(1):323–331.

99.

Flank

Robinson

Holdsworth

, et al. Guideline for the treatment of breakthrough and the prevention of refractory chemotherapy-induced nausea and vomiting in children with cancer. Pediatr Blood Cancer. 2016; 63(7):1144–1151.

100.

Patel

Robinson

Thackray

, et al. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: a focused update. Pediatr Blood Cancer. 2017; 64(10):2148–2162.

101.

World Health Organization. Cancer Pain Relief and Palliative Care in Children. Geneva, Switzerland: World Health Organization; 1998.

102.

Robinson

Oberoi

Tomlinson

, et al. Management of fatigue in children and adolescents with cancer and in paediatric recipients of haemopoietic stem-cell transplants: a clinical practice guideline. Lancet Child Adolesc Health. 2018; 2(5):371–378.

103.

Varni

Thissen

Stucky

, et al. PROMIS(R) Parent Proxy Report Scales: an item response theory analysis of the parent proxy report item banks. Qual Life Res. 2012; 21(7):1223–1240.

104.

Garcia

Cella

Clauser

, et al. Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative. J Clin Oncol. 2007; 25(32):5106–5112.

105.

Forrest

Bevans

Tucker

, et al. Commentary: the patient-reported outcome measurement information system (PROMIS(R)) for children and youth: application to pediatric psychology. J Pediatr Psychol. 2012; 37(6):614–621.

106.

DeWitt

Stucky

Thissen

, et al. Construction of the eight-item patient-reported outcomes measurement information system pediatric physical function scales: built using item response theory. J Clin Epidemiol. 2011; 64(7):794–804.

107.

Irwin

Stucky

Langer

, et al. An item response analysis of the pediatric PROMIS anxiety and depressive symptoms scales. Qual Life Res. 2010; 19(4):595–607.

108.

Varni

Stucky

Thissen

, et al. PROMIS pediatric pain interference scale: an item response theory analysis of the pediatric pain item bank. J Pain. 2010; 11(11):1109–1119.

109.

Kashikar-Zuck

Carle

Barnett

, et al. Longitudinal evaluation of patient-reported outcomes measurement information systems measures in pediatric chronic pain. Pain. 2016; 157(2):339–347.

110.

Yost

Eton

Garcia

Cella

Minimally important differences were estimated for six PROMIS-Cancer scales in advanced-stage cancer patients.

J Clin Epidemiol. 2011; 64(5):507–516.

111.

DeWalt

Gross

Gipson

, et al. PROMIS((R)) pediatric self-report scales distinguish subgroups of children within and across six common pediatric chronic health conditions. Qual Life Res. 2015; 24(9):2195–2208.

112.

Irwin

Gross

Stucky

, et al. Development of six PROMIS pediatrics proxy-report item banks. Health Qual Life Outcomes. 2012; 10:22.

113.

Hung

Stuart

Higgins

Saltzman

Kubiak

EN.

Computerized adaptive testing using the PROMIS physical function item bank reduces test burden with less ceiling effects compared with the short musculoskeletal function assessment in orthopaedic trauma patients.

J Orthop Trauma. 2014; 28(8):439–443.

114.

Stukenborg

Blackhall

Harrison

, et al. Cancer patient-reported outcomes assessment using wireless touch screen tablet computers. Qual Life Res. 2014; 23(5):1603–1607.

115.

Klassen

Dix

Papsdorf

Klaassen

Yanofsky

Sung

Impact of caring for a child with cancer on single parents compared with parents from two-parent families.

Pediatr Blood Cancer. 2012; 58(1):74–79.

116.

Dupuis

Taddio

Kerr

Kelly

MacKeigan

Development and validation of the pediatric nausea assessment tool for use in children receiving antineoplastic agents.

Pharmacotherapy. 2006; 26(9):1221–1231.

117.

Champion

Goodenough

von Baeyer

Thomas

Measure of pain by self-report. In: GA

Finley

McGrath

, eds. Measurement of pain in infants and children; Progress in pain research and management. Vol 10. Seattle, WA: IASP Press; 1998:123–160.

118.

Vol

Flank

Lavoratore

, et al. Poor chemotherapy-induced nausea and vomiting control in children receiving intermediate or high dose methotrexate. Support Care Cancer. 2016; 24(3):1365–1371.

119.

Hesketh

Gralla

du Bois

Tonato

Methodology of antiemetic trials: response assessment, evaluation of new agents and definition of chemotherapy emetogenicity.

Support Care Cancer. 1998; 6(3):221–227.

120.

Molassiotis

Coventry

Stricker

, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom Manage. 2007; 34(2):148–159. www.assessmentcenter.net/documents/PROMIS%20Pediatric%20Profile%20Scoring%20Manual.pdf

121.

PROMIS, System PROMI. PROMIS Pediatric Profile Scoring Manual; 2015.

122.

International Association for the Study of Pain. FACES Pain Scale-Revised home. https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1519&navItemNumber=577. Published 2017. Accessed October 16, 2017.

123.

Bieri

Reeve

Champion

Addicoat

Ziegler

JB.

The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties.

Pain. 1990; 41(2):139–150.

124.

Hicks

von Baeyer

Spafford

van Korlaar

Goodenough

The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement.

Pain. 2001; 93(2):173–183.

125.

Stinson

Kavanagh

Yamada

Gill

Stevens

Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents.

Pain. 2006; 125(1–2):143–157.

126.

Tomlinson

von Baeyer

Stinson

Sung

A systematic review of faces scales for the self-report of pain intensity in children.

Pediatrics. 2010; 126(5):e1168–e1198.

127.

Tsze

Hirschfeld

von Baeyer

Bulloch

Dayan

PS.

Clinically significant differences in acute pain measured on self-report pain scales in children.

Acad Emerg Med. 2015; 22(4):415–422.

128.

Lai

Stucky

Thissen

, et al. Development and psychometric properties of the PROMIS((R)) pediatric fatigue item banks. Qual Life Res. 2013; 22(9):2417–2427.

129.

Forrest

Ravens-Sieberer

Devine

, et al. Development and evaluation of the PROMIS® pediatric positive affect item bank, child-report and parent-proxy editions. J Happiness Stud. 19(3):699–718.

130.

Ravens-Sieberer

Devine

Bevans

, et al. Subjective well-being measures for children were developed within the PROMIS project: presentation of first results. J Clin Epidemiol. 2014; 67(2):207–218.

131.

O'Sullivan

Dupuis

Gibson

, et al. Refinement of the symptom screening in pediatrics tool (SSPedi). Br J Cancer. 2014; 111(7):1262–1268.

132.

Tomlinson

Dupuis

Gibson

, et al. Initial development of the Symptom Screening in Pediatrics Tool (SSPedi). Support Care Cancer. 2014; 22(1):71–75.

133.

Dupuis

Johnston

Baggott

, et al. Validation of the symptom screening in pediatrics tool in children receiving cancer treatments. J Natl Cancer Inst. 2018; 110(6):661–668.

134.

Hyslop

Dupuis

Baggott

, et al. Validation of the proxy version of symptom screening in pediatrics tool in children receiving cancer treatments. J Pain Symptom Manage. 2018; 56(1):107–112.

135.

Kong

Kaptchuk

Polich

, et al. An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment. Neuroimage. 2009; 47(3):1066–1076.

136.

Garcia

McQuade

Lee

Haddad

Spano

Cohen

Acupuncture for symptom management in cancer care: an update.

Curr Oncol Rep. 2014; 16(12):418.

137.

Mao

Xie

Bowman

MA.

Uncovering the expectancy effect: the validation of the acupuncture expectancy scale. Altern Ther Health Med. 2010; 16(6):22–27.

138.

PROMIS. PROMIS Pediatric and parent proxy profile instruments. http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Pediatric_and_Proxy_Profile_Scoring_Manual.pdf. Published 2017. Accessed December 14, 2017.

139.

Pilkonis

Choi

Reise

, et al. Item banks for measuring emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS(R)): depression, anxiety, and anger. Assessment. 2011; 18(3):263–283.

140.

Thompson

ER.

Development and validation of an internationally reliable short-form of the positive and negative affect schedule (PANAS).

J Cross-Cult Psychol. 2007; 38(2):227–242.

141.

Sandin

Escalas panas de afecto positivo y negativo para niños y adolescentes (PANASN) [PANAS scales of positive and negative affect for children and adolescents (PANASN)]. Revista de Psicopatología y Psicología CUnica. 2003; 8(2):173–182.

142.

Vera-Villarroel

Urzua

Jaime

, et al. Positive and Negative Affect Schedule (PANAS): psychometric properties and discriminative capacity in several Chilean samples. Eval Health Prof. 2017;January:1–25.

143.

Blevins

Weathers

Davis

Witte

Domino

JL.

The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): development and initial psychometric evaluation.

J Trauma Stress. 2015; 28(6):489–498.

144.

Barlow

Powell

Gilchrist

Fotiadou

The effectiveness of the Training and Support Program for parents of children with disabilities: a randomized controlled trial.

J Psychosom Res. 2008; 64(1):55–62.

145.

Bandura

Adams

Beyer

Cognitive processes mediating behavioral change.

J Pers Soc Psychol. 1977; 35(3):125–139.

146.

Lorig

Chastain

Ung

Shoor

Holman

HR.

Development and evaluation of a scale to measure perceived self-efficacy in peoplke with arthritis.

Arthritis Rheum. 1989; 32:37–44.

147.

Barlow

Shaw

Wright

CC.

Development and preliminary validation of a self-efficacy measure for use among parents of children with juvenile idiopathic arthritis.

Arthritis Care Res. 2000; 13(4):227–236.

148.

Barlow

Powell

Gilchrist

The influence of the training and support programme on the self-efficacy and psychological well-being of parents of children with disabilities: a controlled trial.

Complement Ther Clin Pract. 2006; 12(1):55–63.

149.

Mehling

Jacobs

Acree

, et al. Symptom management with massage and acupuncture in postoperative cancer patients: a randomized controlled trial. J Pain Symptom Manage. 2007; 33(3):258–266.

150.

Press Ganey. Patient Satisfaction Surveys. http://www.pressganey.com/cs/inpatient. Published 2010. Accessed August 2, 2019.

151.

Molassiotis

Russell

Hughes

, et al. The effectiveness and cost-effectiveness of acupressure for the control and management of chemotherapy-related acute and delayed nausea: Assessment of Nausea in Chemotherapy Research (ANCHoR), a randomised controlled trial. Health Technol Assess. 2013; 17(26):1–114.

152.

Multinational Association of Supportive Care in Cancer (MASCC). Acute AINV Guideline, Guideline for the Prevention of Acute Nausea and Vomiting due to Antineoplastic Medication. http://www.pogo.ca/healthcare/practiceguidelines/acuteainvguideline/. Published 2016. Accessed September 28, 2016.

153.

Carr

Johnson

Kenaan

Welton

JM.

Effects of P6 stimulation on postoperative nausea and vomiting in laparoscopic cholecystectomy patients.

J Perianesth Nurs. 2015; 30(2):143–150.

154.

Efird

Blocked randomization with randomly selected block sizes.

Int J Environ Res Public Health. 2011; 8(1):15–20.

155.

Laird

NM.

Missing data in longitudinal studies.

Statistics in medicine. 1988; 7(1–2):305–315.

156.

Witt

Schutzler

Ludtke

Wegscheider

Willich

SN.

Patient characteristics and variation in treatment outcomes: which patients benefit most from acupuncture for chronic pain?

Clin J Pain. 2011; 27(6):550–555.

157.

NIH State-of-the-Science Statement on symptom management in cancer: pain, depression, and fatigue. NIH Consens State Sci Statements. 2002; 19(4):1–29.

158.

Patrick

Ferketich

Frame

, et al. National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 2002. J Natl Cancer Inst. 2003; 95(15):1110–1117.

Acupressure to Reduce Treatment-Related Symptoms for Children With Cancer and Recipients of Hematopoietic Stem Cell Transplant: Protocol for a Randomized Controlled Trial

Abstract

Background

Objective

Design

Setting

Patients

Intervention

Main Outcome

Secondary Outcomes

Parent Outcomes

Discussion

Keywords

Introduction

Background and Rationale

Trial Objectives/Aims

Trial Design

Stakeholder Involvement

Methods: Participants, Intervention, and Outcomes

Study Setting

Participants’ Eligibility Criteria

Intervention

Acupoint treatment order

Delivery of Intervention for Each Group

Intervention precautions

Parent acupressure intervention

Usual care for symptom management applied to both groups

Discontinuation of Intervention

Intervention Fidelity

Outcomes

Participant Timeline

Sample size

MDEs in context

Recruitment

Methods: Assignment of Interventions for Controlled Trials

Randomization, Allocation Concealment Mechanism, and Blinding

Methods: Data Collection, Management, and Analysis

Data Collection

Data Management

Statistical Analysis

Aim 1: Child Outcomes

Summary of proposed modeling approach

Technical description of analysis approach

Assumptions and sensitivity analyses

Dose–response analysis using marginal structural models (Aim 1)

Aim 2: Parent Outcomes

Exploratory analysis of heterogeneity of treatment effects

Missing Data Approaches

Definition of populations

Methods: Monitoring

Data Safety Monitoring and Audits

Interim Analyses and Stopping Rules

Adverse Events

Ethics and Dissemination

Confidentiality

Access to Data

Discussion

Trail Status

Footnotes

Appendix 1

Author Contributions

Declaration of Conflicting Interests

Funding

References