Table 1 Characteristics of included studies

Alternative medical systems

Dupuis, L 2018 [25]

Acupressure bands for chemotherapy-induced nausea

RCT

Single-blind RCT

Medical centers in Canada

Compare CIN control in the acute phase provided by standard antiemetic agents combined with acupressure bands versus sham bands in children 4–18 yrs. of age receiving HEC***. Compare CIN⁺ control in the delayed phase compared to CIV^§ control in the acute and delayed phases

187

22

Children 4—18 yrs. old. n = 83 (acupressure bands) vs 82 (sham bands). Total: (n = 165)

Power calculation reported

Inclusion: English speaking patients aged 4–18 yrs. with non relapsed cancer and with and English speaking guardian Exclusion: Patients with prior history of acupressure use or who planned to received antiemetic agents other than ondansetron, granisetrin, dexamethasone, or aprepitant on a scheduled basis

Acupressure bands 30 min before chemo vs. Sham band

Bands did not improve CIN or CIV control in children

Six adverse events (four in the intervention group and 2 in the sham group). Bands being too tight. No serious adverse effects reported

National cancer institute

Ghezelbash, S 2017 [30]

Acupressure for nausea-vomiting and fatigue management in acute lymphoblastic leukemia in children

RCT

Single-blind RCT

Two pediatric hospitals in Iran

Examine the effectiveness of acupressure for controlling CINV^ and CRF (cancer related fatigue)

120

0

Children ages 8–12 yrs. old. Finger acupressure n = 60 vs. Sham acupressure n = 60. Total:(n = 120)

NR

Exclusion: Patients with low platelet count (< 50,000), a bleeding disorder, hemoglobin levels < 9 g/dl and hematocrit < 30, or were on active treatment for anemia

Finger acupressure (p6, st36) vs. sham acupressure (SI3,LI12)

Significant differences were observed between the two groups based on the fatigue and nausea intensity immediately and one hour post intervention (P ≤ 0.001)

NR

NR

Gottschling S, 2008 [7]

Acupuncture to alleviate chemotherapy-induced nausea and vomiting

RCT

Single-blind RCT crossover trial

5 pediatric oncology centers in Germany

Evaluate the efficacy and acceptance of acupuncture as an additive antiemetic treatment during highly emetogenic chemotherapy in pediatric cancer patients

23

0

Children 4- 18 yrs. old. n = 23 (intervention) vs 23 (standard care only). (Participants were their own controls). Total: (n = 23)

Power calculation reported

Exclusion: Patients with full control of CINV without need of antiemetic rescue mediation during 1st chemo course. Children under 6 or over 18, previous experience with acupuncture within the last 6 months

Acupuncture vs chemotherapy/antiemetic regime

Use of rescue antiemetic medication was lower among those using acupuncture (p = 0.001). Episodes of vomiting among those receiving acupuncture were lower (p = 0.01) in pediatric oncology patients

Four cases of pain from needling. Adverse effects were minor and transient

NR

Jones, PA 2008 [32]

Acupressure for CIVN in children with cancer

Pilot study

Prospective randomized crossover clinical trial (RCT)

Children's hospital USA

Assess feasibility, safety, and effectiveness of acupressure therapy for preventing or reducing CIVN in children receiving chemotherapy

21

3

Children ages 2–20 yrs. old. n = 18 (acupressure band) vs 18 (placebo band). Total: (n = 18) (Participants were their own controls)

NR

Exclusion: If patients were not expected to received at least 3 courses of chemotherapy, parents did not consent, were over 7 yrs. old and did not assent to participate, no English speaking

Acupressure wrist bands vs. sham wrist bands (wrist bands placed on wrist prior to starting chemo)

Acupressure bands did not offer significant benefits

NR

NR

Reindl, TK 2006 [8]

Acupuncture for CIVN in children with cancer

RCT, multicenter crossover trial

Randomized multicenter, prospective crossover trial

4 German pediatric oncology centers

Evaluate the efficacy and acceptance of acupuncture as a supportive antiemetic approached during highly emetogenic chemotherapy

11

0

Children 6–18 yrs. old (n = 11). n = 11 (needle acupuncture) vs 11 (standard care only). Total: (n = 11). Participants were their own controls

Did not reach power

Inclusion: Children who received several courses of highly melogenic chemotherapy as part of therapy protocols for Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma, including 5-HT3 antagonists as basic antiemetic medication

Antiemetic medication vs. Antiemetic medication plus acupuncture. Acupuncture was applied on day 1 and throughout the chemotherapy course

Acupuncture enable patients to experience higher levels of alertness during chemo and reduced nausea and vomiting

One case of needle pain

CD Foundation and Friedrich-Sicker Foundation

Varejão, C 2019 [29]

Laser acupuncture for relieving nausea and vomiting in pediatric patients undergoing chemotherapy

Single-blinded RCT

Single-blind randomized clinical trial

Oncology Hospital in Rio de Janeiro, Brazil

1.Apply laser acupuncture in children and adolescents undergoing chemo 2. Analyze the effects of laser acupuncture in terms of preventing and/or relieving nausea and vomiting 3. Propose a nursing care protocol using laser acupuncture to prevent and/or relieve nausea and vomiting

18

1

Children between 6–17 yrs. old. n = 7 (intervention) vs 10 (sham acupuncture). Total:( n = 17)

Power calculation reported and reached

Inclusion: Children 6–17 yrs. with solid tumors. Patients going chemo with cisplatin, methotrexate, doxorubicin, etoposide, infosfamide, and/or cyclophosphamide. Use of medium and/or highly emetogenic drugs Exclusion: previous history of gastrointestinal diseases or antiulcer treatment. Prior history of acupuncture treatment. Use of aprepitant

Laser acupuncture vs sham laser acupuncture. A total of 26 treatments in each group ( 1 day of chemo)

Significant relief from nausea in the intervention group ( p < .0005). Decrease in the number of vomiting episodes on the 2nd and 3rd day of chemotherapy (p = .0001)

NR

Provided by researchers. No funding from companies or public agencies

Yeh, CH 2012 [18]

Auricular acupuncture for nausea and vomiting

Pilot study crossover trial

Randomized single blinded crossover trial

Hospital in Taiwan

Determine if auricular acupressure point is more effective than sham acupressure point and standard care for chemotherapy induced nausea and vomiting

17

7

Children ages 5–18 yrs. old n = 10 auricular acupressure, n = 10 Sham acupressure intervention. Total: (n = 10). Participants were their own controls

Power calculation reported

Inclusion: Children diagnosed with cancer and that had at least one round of chemotherapy treatment who were prescribed chemotherapy drugs with high or moderate level of emetogenic agents; were prescribed standard antiemetics with their chemotherapy drugs and had not previously received any acupuncture or acupressure treatments in the previous 3 months

Auricular acupressure (AAP) vs. Sham acupressure intervention (SAP)

Patients in the auricular acupuncture point group had lower occurrence and severity of acute and delayed nausea (p = 0.0289) and shorter vomiting (p = .0024) duration than patients receiving sham acupuncture and standard care

NR

NR

Biological-based therapies

Consolo, Lzz 2013 [24]

Zinc supplement for weight gain and infectious episodes in children with acute leukemia

Double blinded RCT

Double blind placebo controlled study

Regional Hospital in Brazil

Evaluate the effects of oral zinc supplementation on weight gain and infectious episodes in children and adolescents with acute leukemia

38

0

Children 1–18 yrs. old, n = 20 (intervention, syrup with zinc) vs n = 18 (placebo, only syrup). Total (n = 38)

NR

Inclusion: Children with previously established clinical and laboratorial diagnoses either for lymphocytic or myeloid leukemia. Exclusion: acute infectious disease, renal failure, post surgery status or usage of zinc containing drug

Group A: Oral placebo syrup containing no zinc. Group B syrup containing zinc

Significant difference was found in favor of the intervention group regarding weight gain (p = 0.032) and the number of infections episodes ( P = 0.02). No significant differences in xerostomy, taste dysfunction nausea and vomiting between the two groups (P = 0.812)

NR

Brazilian agencies CNPq and FUNDECT-MS

El-Housseiny, AA 2007* [19]

Effectiveness of vitamin E to treat mucositis

RCT

Randomized controlled trial

Oncology department Alexandria University and El-Talaba hospital of Alexandria

To compare the effect of vitamin E topically and systematically in the treatment of chemotherapy induced oral mucositis

80

17

Children under 12 yrs. old n = 30 (Vitamin E topical), n = 33 (Vitamin E systemic).Total: (n = 63)

NR

Inclusion: Children with chemotherapy induced oral mucositis

Topical Vitamin E application vs. Systemic Vitamin E intake

Topical application of Vitamin E twice daily was significant more effective than systemic Vitamin E for chemotherapy-induced mucosis ( P > 0.001)

NR

NR

Evans, A 2018 [26]

The use of aromatherapy to reduce CIN in children with cancer

Double-blinded RCT, with three arms

double blind placebo controlled study

Infusion center for emetogenic chemo in So. California

To investigate the utility of ginger aromatherapy in relieving chemotherapy-induced nausea in children with cancer

49

0

Children 8 to 21 yrs. old, n = 10 (water gr), n = 19 (shampoo gr), n = 20 (ginger gr). Total: (n = 49)

Power calculation /Intent to treat reported

Inclusion: Diagnoses of cancer with any type and amount of prior therapy. Thirty minute infusion of moderately emetogenic chemotherapy. Exclusion: Patients with asthma on daily medication. Patients unable to complete the four point face scale

Aromatherapy (inhalation of ginger aroma oil) vs. no treatment (inhalation of water) vs. placebo (shampoo)

Ginger aromatherapy did not significantly decrease nausea. Fifty-nine percent (n = 29) reported no change while 29% (n = 14) reported improvement

NR

J. Patrick Barnes Grant from the DAISY foundation

Khurana, H 2013 [27]

An evaluation of Vitamin E and Pycnogenol (P) in children suffering from oral mucositis during cancer chemotherapy treatment

Single blinded RCT

Single-blind randomized controlled clinical trial

CSM Medical University, Lucknow. India

Evaluate P for its beneficial effects on oral mucositis in children and to compare with E

72

0

Children 16–15 yrs. old n = 24 (Pycnogenol); n = 24 (Vitamin E); n = 24 (Placebo (glycerine)). Total: (n = 72)

NR

Inclusion: Children receiving chemotherapeutic regime with signs of chemotherapy-induced mucositis and patients whose parent /guardian provided consent. Exclusion: Children who received chemotherapy in the head and neck region, on anti-platelet or anticoagulant therapy, having pre-existing oral disease

Preparations of Vitamin E vs Pycnogenol vs Glycerine

Both drugs Vitamin E and Pycnogenol were effective for treatment of oral mucositis compared to placebo (P < 0.001)

NR

NR

Ladas, EJ 2010 [22]

Milk thistle (Silybum marianum) for the treatment of hepatotoxicity in childhood ALL^^

A double-blind RCT

Randomized, controlled, double-blind study

Columbia University Medical Center

To evaluate the safety and feasibility of Milk thistle for the treatment of hepatotoxicity in children with ALL who are receiving maintenance-phase chemotherapy

50

1

Children between 1 -21 yrs. old, n = 23 (Milk Thistle), n = 26 (placebo). Total: (n = 49)

Power calculation reported

Inclusion: Children with ALL. Maintenance phase of therapy Hepatic toxicity of grade 2 or greater on ALT, AST, total bilirubin. Exclusion: Patients with extra hepatic biliary obstruction, or malabsorption syndromes

Milk thistle vs placebo for 28 days

Milk Thistle was associated with trend toward significant reductions in liver toxicity (AST* P = .05; ALT** P = .07)

Seven cases of adverse effects in the intervention group: Diarrhea (n = 2), flatulence (n = 1),irritability (n = 2) and stomach ache (n = 2). Six cases in the placebo group: Decreased appetite (n = 1), Diarrhea (n = 2), Stomach ache (n = 2), soft stools (n = 1). No significant differences in patient reported adverse effects

American Institute for Cancer Research. The Tamarind Foundation. Part of NCI grant

Pillai AK, 2011 [33]

Ginger powder vs. Placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy

Double-blind RCT

Prospective double-blind, randomized single institutional study

All India Institute of medical sciences,New Delhi, India

To evaluate the efficacy of ginger powder in reducing CINV

60

3

Children and young adults 8–21 yrs. old, n = 30 (Ginger gr), n = 27 (Placebo gr),Total: (n = 57)

NR

Inclusion: Children newly diagnosed bone sarcomas undergoing therapies with high emetogenic chemo. Exclusion: Children with weight < 20 kg or > 60 kg, those receiving radiotherapy and patients additionally receiving aprepitnat with the standard antiemetics were excluded

Ginger root powder capsules vs placebo

Ginger root powder significantly reduced the severity of both acute and delayed CINV (p = 0.003); Acute vomiting (p = 0.002); Delayed nausea (p =  < 0.001); Delayed vomiting (p = 0.022)

NR

NR

Rathe, M 2019 [21]

Bovine colostrum against chemotherapy-induced gastrointestinal toxicity in children with ALL

Double-blinded RCT

Double blind placebo controlled clinical trial

Hans Christian Andersen Children's Hospital, Odense University Hospital and Rigshopitalet. University Hospital of Copenhagen, Denmark

To investigate nutrition supplementation with bovine colostrum effect on fever, infectious morbidity, and mucosal toxicity during induction treatment for childhood ALL

62

0

Children 1–18 yrs. old, n = 30 (treatment), n = 32 (placebo), Total: (n = 62)

Power calculation and intention to treat analysis performed

Inclusion: Newly diagnosed with ALL. Exclusion: Children with known lactose intolerance or allergy to cow's milk protein

Received daily dietary supplement with either bovine colostrum or a placebo supplement from the first day of chemotherapy until day 29 or end of induction therapy

Peak severity of oral mucositis was significantly reduced by colostrum compared with placebo (p = 0.02). No difference was observed for days of fever, neutropenic fever, intravenous antibiotics, or incidence of bacteremia

No adverse effects of the supplement were reported

Danish Childhood Cancer Foundation, Odense University Hospital research fund, common research fund b/w Odense University Hospital and Rigshospitalet and University of Southern Denmark

Tomaževič T, 2013 [23]

Propolis (bee glue) for effectiveness in the treatment of severe oral mucositis in chemotherapy treated children

Single blinded RCT

Single-blind randomized controlled clinical trial

Slovenia University children's hospital

Assess the efficacy of propolis versus placebo for the treatment of chemotherapy induced oral mucositis

50

10

Children 1–19 yrs. old (n = 19 propolis) vs (n = 21, placebo). Total:( n = 40)

Power calculation reported

Inclusion: Pediatric patients who had been diagnosed with cancer and had started chemotherapy. Exclusion: Allergy to propopolis and pre-diagnosed oral disease or therapy for oral disease

Propolis vs placebo

No significant difference were found between the groups.Propolis cannot be recommended for severe oral mucositis

No adverse effects of the supplement were reported

Colgate Palmolive Adria

Wada M, 2010 [34]

Effects of the administration of Bifidobacterium breve (probiotic) on patients undergoing chemotherapy for pediatric malignancies

Single-blinded RCT

Single-blinded, placebo controlled trial

Juntendo University Hospital, Tokyo Japan

To evaluate the effects of probiotic, Bifidobacterium breve, and its ability to prevent infection, fecal micro flora, and intestinal environments in cancer patients on chemotherapy

40

2

Children ages 1–13 yrs. old, n = 17 (probiotic), n = 21 (placebo), total: (n = 38)

Power calculation reported

Exclusion: Presence of congenital immune deficiency and oral intake of the probiotic during 2 weeks prior to the trial

Probiotic vs. placebo

Frequency of fever (p = 0.02) and use of IV antibiotics were lower in the probiotic group (p = 0.04), suggesting that probiotic could be beneficial for immunocompromised hosts by improving intestinal environment

NR

NR

Ward E, 2009 [35]

The effect of high-dose enteral glutamine on the incidence and severity of mucositis in pediatric oncology patients

RCT cross-over trial

Randomized controlled

St. James's University Hospital, Leeks, UK Yorkshire Regional Center for Pediatric oncology

To determine if enteral glutamine daily for 7 days was effective in reducing the incidence an severity of mucositis in pediatric oncology patients

76

26

Children between 1–21 yrs., total: (n = 50). Patients were their own control

Power calculation reported

Inclusion: Patients who had two identical courses of chemo and were receiving chemotherapy likely to cause mucositis

Glutamine vs. placebo administered daily for 7 days

The study showed that high-dose enteral glutamine did not reduced the incidence and severity of oral mucositis as determined by subjective toxicity measurements, but did show a significant reduction in parenteral nutrition usage (p = .049)

NR

SHS International (provided glutamine)

Mind–body therapies

Abdulah, DM 2018 [31]

Investigated group art therapy on quality of life in pediatric patients with cancer

RCT

Randomized controlled trial

Heevi Pediatric Hospital in Duhok, Iraq

To evaluate the effectiveness of art therapy on the health related quality of life for children undergoing chemotherapy

61

1

Children ages 7–16 yrs. old, n = 30 (treatment), n = 30 ( control). Total: (n = 60)

Power calculation reported

Inclusion: Children previously diagnosed with cancer and had received chemotherapy for at least the last 6 months. Exclusion: Patients who attended fewer than six two hours painting and drawing sessions

Art therapy ( painting) vs control ( not explained)

Patients in the experimental group were more physically active and energetic (p < 0.001), were less depressed and had fewer stressful feelings (P = 0.004). They also had more opportunities to structure and enjoyed their social and leisure time and participation in social activities (P = 0.003), creates more social relationships (P = 0.043) and had better overall health (P < 0.001)

NR

NR

Jacknow, DS 1994 [20]

Hypnosis in the prevention of CINV in children

Single-blinded RCT

Randomized and controlled single-blind trial

Lucille Salter Packard Children's Hospital (Stanford Univ.) and Moffitt/Long Hospitals (Univ. Of California- San Francisco)

To study the effectiveness of hypnosis for decreasing antiemetic medication usage and treatment of CINV

20

1 loss to follow-up, data was used in the analysis

Children ages 6–18 yrs. old, n = 10 (treatment), n = 10 (control), Total: (n = 20)

NR

Inclusion: Newly diagnosed patients with no previous experience with chemotherapy. Exclusion: Evidence of central nervous system disease

Hypnosis and antiemetics vs standard anti-emetic regimen/conversation with therapist

The hypnosis group experienced less anticipatory nausea than the control group (p < .02) and used less antiemetic medication (p < .04)

NR

DHHS Maternal and child health bureau

Nguyen, TN 2010 [28]

Music therapy to reduce pain and anxiety in children with cancer undergoing lumbar puncture (LP)

Single-blinded RCT

Single blinded randomized clinical trial

National Hospital of pediatrics. Hanoi. Vietnam

To evaluate if music therapy influences pain and anxiety in children with cancer

40

0

Children 7–12 yrs. old, n = 20 (treatment), n = 20 (control). Total: (n = 40)

Power calculation reported

Inclusion: Patients that were due to undergo LP and had previously undergone LP at least once previously Exclusion: Children had any significant hearing or visual impairments or cognitive disorder

Music vs control (no music)

Lower pain (p < .003), respiratory rate (p < .003) and anxiety scores (p < .001) were significant lower in music group after the LP compared with the control group

NR

There was no financial support

Zeltzer, LK 1991 [36]

Behavioral intervention (hypnosis) for chemotherapy distress in children

RCT

Randomized controlled trial

Two pediatric oncology centers University of Texas Health Science Center in San Antonio and Children's Hospital of Los Angeles

To determine the relative efficacy of the two forms of behavioral intervention for reducing chemotherapy related distress

54

0

Children 5–17 yrs. old, n = 21 (hypnosis), n = 16 (support), n = 17 (control), Total: (n = 54)

Not reported

Inclusion: Children with cancer, reliable reporting of significant chemotherapy related nausea and /or vomiting during baseline assessment and were able to consistent independent self reports of their chemotherapy related distress. Exclusion: Patients that could not provide reliable consistent reporting

Hypnosis vs support (relaxation) vs control ( causal conversation)

Children in hypnosis group reported the greatest reduction of both vomiting (p =  < .005) and shorter duration of nausea (p =  < .001)

NR

Grant from the National Cancer Institute