Table 1.
Characteristics of included studies
| Study ID | Objectives | Method | Design | Setting | Aim (s) | Sample size | Drop-out | Participant(s) intervention/control | Intention to treat & power calculation | Inclusion/exclusion criteria | Intervention treatment vs control | Results | Adverse effects due to the use of CAM | Funding |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 |
^^ ALL: Acute lymphoblastic leukemia *AST: Aspartate amino transferase**ALT: Amino alanine transferase***HEC: Highly melogenic chemotherapy: §CIV:chemotherapy induced vomiting: + CIN:chemotherapy induced nausea:CINV^: chemotherapy induced nausea-vomiting: NR: Not reported in publication *excluded from further analysis due to low quality