Non-pharmacological interventions for side effects of antineoplastic chemotherapy prioritized by patients: systematic review.

Introduction

In 2020, Globocan reported 19,292,789 new cancer cases worldwide 1 . Specific treatment regimens have been studied for each type of disease, with chemotherapy being the main intervention 2 . The incidence of side effects is reported to be 70-80% due to the involvement of rapidly growing cells 3 . There is evidence ofside effects such as nausea, vomiting, alopecia, mucositis, fatigue, constipation, neutropenia, and mood changes, which affect a person's quality of life 4 , 5 . Treatment plans include medications to control these symptoms; however, these medications can trigger other secondary symptoms that further impact the quality of life 6 .

Integrative oncology, in coordination with evidence-based complementary therapies and conventional cancer care, improves patients' quality of life and clinical outcomes. This orientation empowers patients' participation in their treatment 7 . It has been reported that approximately 50% of cancer patients use complementary and alternative medicine (CAM), and in patients with advanced disease, the prevalence of CAM use can reach 100% 7 .

The evidence shows a wide varietyofnon-pharmacological interventions, which presentsa challenge to the caregiver when seeking symptom control. This process involves balancing pharmacological treatment, complementation with non-pharmacological interventions, and individual preferences 8 . This review aims to synthesize the existing evidence on non-pharmacological interventions to control the side effects of chemotherapy, as prioritized by patients and healthcare professionals.

Materials and Methods

The protocol was published in the International Prospective Register of Systematic Reviews (PROSPERO CRD4202017212) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA, 2009) 9 guidelines; the analysis database was stored in Mendeley Data 10 . We included randomized clinical trials (RCTs) and longitudinal analytic observational studies conducted in adults with cancer undergoing treatment that described non-pharmacological interventions to control chemotherapy-related side effects. Studies were only included in the review if the nonpharmacological interventions were delivered by trained personnel. Descriptive studies, cost-effectiveness studies, conference proceedings, systematic reviews, meta-analyses, clinical practice guidelines, letters to the editor, or studies with unanalyzable data or without reported measures of effect, animal studies, or studies in pregnant women were excluded.

Outcome selection and prioritization

The outcomes were prioritized according to the preferences of patients and health professionals at the time of making a decision about an intervention, including the list described in the literature 3 , 11 . Ten cancer experts and chemotherapy patients from a university hospital oncology department were independently asked to prioritize each side effect on a scale of 1 to 9, with 7 to 9 being critical, 4 to 6 being important, and 1 to 3 being of limited importance (according to the GRADE approach 12 ). For this review, outcomes with scores greater than 8 were included ( Figure 1 ).

Search strategy

The electronic databases PubMed/MEDLINE, Ovid Embase, LILACS/Bireme, The Cochrane Library, and Epistemonikos were searched from March 2021 to May 2023. University repositories and reference lists of included studies were also searched. Authors and clinical experts in cancer were also contacted to inquire about possible published studies in this area. The search algorithm was developed using free search terms and the Medical Subject Headings (MeSH) ( Table 1 ).

Figure 1 Prioritization of symptoms secondary to chemotherapy by healthcare professionals and cancer patients

Table 1 Search strategies used in PubMed, Embase, and LILACS Database Search strategy PubMed ((((carcinoma chemotherapy OR chemotherapy OR "Chemotherapy, Cancer, Regional Perfusion"[Mesh] OR "Chemotherapy, Adjuvant"[Mesh]) OR "Chemotherapy, Cancer, Regional Perfusion"[Mesh] OR "Chemotherapy, Adjuvant"[Mesh], carcinoma chemotherapy, carcinoma chemotherapy, antineoplastic drugs, "Antineoplastic Agents"[Mesh] OR "Antineoplastic Agents" [Pharmacological Action]) NOT (Child[Mesh] OR oncology pediatric OR pediatric OR child* OR children)) AND (("Oncology Nursing"[Mesh], OR nursing practices, cancer nursing, palliative care nurse, nursing care, nursing interventions, nursing intervention, "Oncology Service, Hospital"[Mesh] OR "Oncology Nursing"[Mesh], "Hospice and Palliative Care Nursing"[Mesh] OR "Oncology Nursing"[Mesh] OR "Nursing Care"[Mesh] OR "Patient Care Planning"[Mesh] OR home care) NOT ((non-pharmacological intervention) OR (non-pharmacological treatment) OR (non-pharmaco*)))) AND ((((((alopecia) OR (((Sleep Wake Disorders) AND (Sleep Disorders, Intrinsic)) AND (((neutropenia) AND ((nausea) AND (vomiting))) AND ((anorexia))))) OR (((neutropenia) AND ((nausea) AND (vomiting))) AND ((anorexia)))) OR ("Metabolic Side Effects of Drugs and Substances"[Mesh] OR "Drug-Related Side Effects and Adverse Reac-tions"[Mesh] OR secondary side effects)) OR (((Peripheral Nervous System Diseas-es) AND (Peripheral Neuropathies)) AND (pain))) OR ("Metabolic Side Effects of Drugs and Substances"[Mesh] OR "Drug-Related Side Effects "[Mesh] OR second-ary side effects)) Embase #11 AND (2020:py OR 2021:py OR 2022:py OR 2023:py) AND 'vomiting'/dm AND ('clinical article'/de OR 'clinical study'/de OR 'clinical trial'/de OR 'clinical trial topic'/de OR 'cohort analysis'/de OR 'controlled clinical trial'/de OR 'controlled study'/de OR 'cross sectional study'/de OR 'double blind procedure'/de OR 'evidence based medicine'/de OR 'evidence based practice'/de OR 'human'/de OR 'human ex-periment'/de OR 'intervention study'/de OR 'interview'/ de OR 'longitudinal study'/de OR 'major clinical study'/de OR 'multicenter study'/de OR 'normal human'/de OR 'observational study'/de OR 'open study'/de OR 'pilot study'/de OR 'prospective study'/de OR 'randomized controlled trial'/de OR 'randomized controlled trial top-ic'/de) AND ([adult]/lim OR [aged]/lim OR [middle aged]/lim OR [very elderly]/lim OR [young adult]/lim) AND ('article'/it OR 'article in press'/it) LILACS (tw:("palliative care nursing" OR "nursing interventions" OR "nursing care" OR "cancer nursing" OR "Enfermagem Oncológica" OR "Hospice and Palliative Care Nursing")) AND (tw:("Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos" OR "efeitos adversos" OR "side effect" OR "adverse effect" OR "adverse events" OR "drug side effect" AND "Tratamento Farmacológico" OR "Tratamento Farmacológico" OR "Antineoplásicos" OR "Tratamento Farmacológico" OR "Antineoplásicos" OR "Quimioterapia Adjuvante"))

Study selection and data extraction

Two groups of reviewers (Group 1 - MEG-N and ABP; Group 2 - LI/EP and OC) independently screened references found by title and abstract according to the RAYYAN eligibility criteria for systematic reviews 13 . Two reviewers read full texts for final inclusion. Disagreements were resolved with the assistance of a third reviewer (AB-L). A matrix was created in Microsoft Excel® in which two independent reviewers entered data including authors, year of publication, study’s country of origin, sex, cancer diagnosis, comorbidities, sample size, study population, non-pharmacological intervention used, and measure of the effect in both the experimental and control groups. The authors were contacted to request information on missing data.

Risk of bias assessment

Figures 2A , B , C , D , E , and F show the graphical visualization of the risk of bias for experimental studies assessed with the RoB-2 tool 14 . Figure 2G shows the risk of bias assessment for analytic observational cohort studies assessed with the Newcastle-Ottawa Scale (NOS) 15 ( Figure 2 ).

Figure 2A Risk of bias of articles with experimental study design included in the outcome nausea and vomiting

Figure 2B Risk of bias of articles with experimental study design included in the outcome alopecia

Figure 2C Risk of bias of articles with experimental study design included in the outcomes pain and neuropathy

Figure 2D Risk of bias of articles with experimental study design included in the outcome sleep disorder

Figure 2E Risk of bias of articles with experimental study design included in the outcome neutropenia

Figure 2F Risk of bias of articles with experimental study design included in the outcome anorexia

Figure 2G Risk of bias in observational analytical cohort studies

Synthesis of evidence

Study characteristics were described narratively by outcome. The heterogeneity of the studies was assessed by clinical observation of the population, outcomes and their measurement, and description of the intervention performed 10 .

Results

A total of 7,520 references were found, of which 237 were selected for full-text reading. Sixty-two references were included between 1988 and 2023 ( Figure 3 ). Nineteen interventions evaluating 6,613 participants were identified across all studies in the United States, and 4,577 women participated.

Nausea and vomiting

Twenty-nine references were included; 25(89.21%) are RCTs and 4(13.73%) are quasi-experiments with participants between 16 and 96 years of age. We reviewed 4(12.91%) care and counseling programs, 5(16.14%) muscle relaxation techniques, 4(12.95%) guided relaxation with music therapy and imagery, 2(6.44%) natural drinks, 2(6.43%) therapeutic touch and reflexology, 12(38.70%) acupressure at P6 point, and 2(6.41%) hologram bracelets. Studies on interventions such as acupressure were consistent in affirming that there was improvement before and after the intervention; however, they showed high heterogeneity regarding the types of interventions and scales used to measure nausea and vomiting ( Table 2 ).

Anorexia

One RCT conducted in Turkey 16 involving women aged 29 to 69 years with stage II or III gynecological cancer was included. The intervention involved a nursing program based on Jean Watson's theory. Nursing professionals visited and followed up with the participants via telephone for 60 to 120 minutes once a week. Information on symptom management was provided and compared with standard hospital management. The authors assessed changes in appetite using the Chemotherapy Symptom Assessment Scale (C-SAS). They found that the intervention group had a lower mean change in appetite of 1.00 SD (0.61) than the control group of 2.00 SD (1.08). This study had a high risk of bias due to the lack of randomization and blinding.

Alopecia

Eight studies evaluated non-pharmacological interventions to control alopecia, such as scalp cooling with hypothermic caps, and one study used videos on makeup and wigs. Five studies used WHO criteria to evaluate the effect of scalp cooling on reducing alopecia. The other studies used instruments such as the Dean scale, the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and the breast cancer stem cells (BC SCs) to assess the efficacy of the intervention on hair loss. In general, these studies have a high risk of bias, and scalp cooling shows a possible effect on reducing alopecia compared to placebo ( Table 3 ).

Pain and neuropathy

A total of 1,403 patients, aged 15 to 86 years, were observed in 14 studies. Interventions included educational programs, acupuncture, physical activity, psychological therapies, natural substance applications, massages, and foot baths. Pain and neuropathy were measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC), Numerical Pain Scale (NPS), the Dutch Language Version of the McGill Pain Questionnaire (MPQ-DLV), and Symptom Experience Scale. Of the total, 6 (42.81%) studies evaluated disease-related pain, and 8 (57.20%) studies evaluated platinum or taxane chemotherapy-related neuropathy ( Table 4 ). These studies have a high risk of bias due to selective reporting of outcomes, lack of concealment, and lack of blinding. Interventions such as home-based care nursing programs and acupuncture were demonstrated to reduce mean pain and neuropathy when comparing pre- and post-intervention measurements.

Sleep disorders

Nine studies evaluated non-pharmacological interventions to control sleep disorders. Acupressure, telephone follow-up programs, home exercises, relaxation therapies such as foot baths, mindfulness therapies, back massages, and Chinese practices like Chan-Chuang qigong have been studied for their effectiveness in improving sleep quality. However, it is observed that interventions such as acupressure and physical exercise improve sleep quality when comparing intervention groups with post-intervention control groups ( Table 5 ).

Neutropenia

Two studies analyzed 167 participants diagnosed with neutropenia, defined as a decrease in neutrophils following chemotherapy treatment, and administered Chan-Chuang qigong therapy for 21 minutes over 21 days. This technique includes mind and body relaxation, with white blood cell counts measured before and after the procedure. The studies have a high risk of bias due to the non randomization of participants, but the intervention showed an increase in white blood cell counts after the intervention ( Table 6 ).

Figure 3 PRISMA description of search findings and study selection

Table 2 Nonpharmacological interventions: Nausea and vomiting outcome Outcome Author, year Design Population and population size N Instrument Intervention Outcome Before After Intervention Control Intervention Control Nursing intervention programs Teskereci, 2022 16 Randomized clinical trial Gynecologic cancer N=52 Herth Hope Scale Nursing program based on Watson's Theory of Human Caring Nausea severity Mean (SD) 1.0 (0.84) 3.0 (0.75) Molassioti, 2009 17 Randomized clinical trial Colorectal and breast cancer N=164 Chemotherapy Symptom Assessment Scale (C-SAS) Home nursing care program for symptom management Nausea severity Mean (SD) 1.0 (0.84) 3.0 (0.75) Alboughobeish, 2017 18 Quasi experimental Different types of cancer Mobile care program designed by nurses Vomiting frequency. Mean (SD) 1.8 (1.77) 1.64 (1.84) 0.84 (1.37) 2.48(2.16) Kearney, 2007 19 Randomized clinical trial Lung, colorectal, and breast cancer N= 112 Advanced symptom management system (ASyMS©) Mobile care program designed by nurses Severity of vomiting distress. Mean (SD) Severity of nausea distress (SD) 0.51 (0,93) 1.23(1.19) 0.50 (0.81) 1.43 (1.08) Campos de Carvalho, 2007 20 Pretest -Posttest Different types of cancer N=30 Huskisson's visual analog scale Muscle relaxation therapy Level of nausea Median (IQR) Level of vomiting. Median (IQR) 6.00 (3.75-7.00) 4.00 (2.00-5.25) 4.50 (3.00-6.00) 2.00 (1.00-3.00) Molassioti, 2000 21 Randomized clinical trial Breast cancer. N= 8 Morrow assessment of nausea and vomiting (MANE) Muscle relaxation program Nausea duration. Hours Vomiting duration. Hours 7 hours 2.75 hours 1.5 hours 1.67 hours Lerman, 1990 22 Randomized clinical trial Different types of cancer N=96 Emesis Rating Scale Muscle relaxation techniques Nausea prevalence N (%) 5(46%) 3(27%) 6(54%) 8(73%) Sensory distraction techniques Ezzonne, 1998 23 Randomized clinical trial Bone marrow transplant N= 39 Thermometer shaped visual analog scale Music therapy Vomiting episodes. Mean (range) 0.69 (0-4) 1.73 (0-6) 0.94(0-2) 0.31 (0-2) Hosseini, 2016 24 Quasi experimental Breast cancer N=55 Morrow Assessment of Nausea and Vomiting Image illustration and audio CD Nausea severity. Mean (SD) Nausea frequency. Mean (SD) Vomiting severity. Mean (SD) Nausea frequency. Mean (SD) a. 1.91 (1.97) b. 1.67 (0.88) c. 0.48 (0.09) d. 1.10 (0.24) a. 2.07 (1.63) b. 1.91 (0.63) c. 0.62 (0.05) d. 0.42 (0.05) Karagozoglu, 2013 25 Randomized clinical trial Lung, gastric, and breast cancer N= 40 Visual Analog Scale (VAS) Music therapy and visual imagery Nausea severity. Hours Vomiting severity. Hours Nausea duration. Hours (1-4h) Vomiting duration. Hours (1- 4h) a. 5 (12.5%) b. 1 (2.5%) c. 5 (12.5%) d. 6 (15%) a. 4 (10%) b. 2 (5%) c. 8 (20%) d. 7(17.5%) a. 8 (20%) b. 9 (22.5%) c. 7 (17.5%) d. 8 (20%) a. 2 (5%) b. 0 c. 8 (20%) d. 9(22.5%) Moradian, 2015 26 Randomized clinical trial Breast cancer N=99 Rhodes Index of Nausea, Vomiting and Retching (INVR) Music therapy Nausea prevalence. Mean (SD) Vomiting prevalence. Mean (SD) a. 4.31 (4.31) b. 1.38 (2.70) a.3.0 (3.33) b.1.46 (3.29) Substances for oral administration Ingersoll, 2010 27 Randomized clinical trial Different types of cancer except for head and neck cancer N=77 Rhodes Index of Nausea, Vomiting and Retching (INVR) Flavonoid- rich adjunctive treatment (Concord grape juice) Nausea and vomiting frequency Mean (SD) 1.6 (CI 95%: 0.6-2.6) 1.7 (CI 95%: 0.6-2.8) 1.6 (CI 95%: 0.3 2.9) 2.0 (CI 95%: 0.6-3.5) Sanaati, 2016 28 Randomized clinical trial Breast cancer N= 65 Chemotherapy- induced nausea and vomiting (CINV) a. Ginger capsules b. Chamomile capsules a. Number of nausea. Mean difference (SD) b. Number of vomiting. Mean difference (SD) Nausea: Ginger 1.5845 (0.57) a. Nausea: Chamomile 0.0769 (0.58) Vomiting: Ginger 0.108 (0.24) b. Vomiting: Chamomile 0.8394 (0.28) Manual therapies and reflexology Vanaki, 2016 29 Randomized clinical trial Breast cancer N= 108 Visual Analog Scale (VAS) Therapeutic touch: Patterns of energy disturbance in the participant's body Nausea duration. Mean (SD) Nausea frequency. Median (IQR) a. 5.36 (2.17) b. 50.29 a. 10.81 (1.77) b. 31.44 Ozdelikara, 2017 30 Randomized clinical trial Breast cancer N= 60 Rhodes Index of Nausea, Vomiting and Retching (INVR) Reflexology a. Nausea and vomiting experience Mean (SD) b. Nausea and vomiting development. Mean (SD) c. Nausea and vomiting distress Mean (SD) a. Nausea: 2.53 (2.80) Vomiting: 0.83 (1.57) Nausea: 1.83 (2.05) Vomiting: 0.56 (1.07) Nausea: 0.70 (0.83) c. Vomiting: 0.26 (0.52) a. Nausea: 5.46(4.15) Vomiting: 3.83(4.29) b. Nausea: 3.70 (2.79) Vomiting: 2.40(2.82) c. Nausea: 1.76(1.38) Vomiting: 1.43(1.56) Nausea: 2.06 (3.33) a. Vomiting: 0.96 (2.39) Nausea: 1.43 (2.35) b. Vomiting: 0.63(1.56) c. Nausea: 0.63(0.99) Vomiting: 0.33(0.84) a. Nausea: 6.56(4.09) Vomiting: 4.0(3.29) b. Nausea: 4.40(2.82) Vomiting: 2.40(2.02) c. Nausea: 2.16(1.34) Vomiting: 1.60(1.35) Acupressure Avci, 2016 31 Randomized clinical trial Myeloblastic Leukemia N= 90 Visual Analog Scale (VAS) Acupressure, P6 point Nausea severity Vomiting severity Number of nausea episodes Number of vomiting episodes a. 3.3(0.8) b. 2.4(1.3) c. 5.5(0.8) d. 1.0(1.5) a. 6.4 (0.6) b. 4.6 (0.9) c. 5.3 (1.3) d. 1.9 (0.6) 2.8(0.6) 1.4(1.3) 5.4 (0,8) 0.6 (0,5) 6.5(0.6) 4.6 (0.8) c. 6.6 (1.9) d. 2.2 Dibble, 2000 32 Randomized clinical trial Breast cancer N=17 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Nausea experience 2.83 (1.6) 3.00 (0.58) Dibble, 2007 33 Randomized clinical trial Breast cancer N= 147 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Differences in the incidence of nausea between the experimental and control groups after the intervention. RIN: c2 = 1.19, p = 1.23, p = 0.55; NRS: c2 = 0.55 Eghbali, 2016 34 Randomized clinical trial Breast cancer N=48 Morrow Assessment of Nausea and Emesis (MANE) Auricular Acupressure Nausea intensity. Mean (SD) Nausea frequency. Mean (SD) Vomiting intensity. Mean (SD) d. Vomiting frequency. Mean (SD) a. 5.63 (3.98) b. 5.79 (6.4) c. 1.04 (1.71) d. 0.79 (1.33) a. 3.71 (4.05) b. 3.54 (5.31) c. 2.29 (4.71) d. 2.08 (5.29) 2.08 (3.3) 1.85 (3.1) 0.79 (2.15) 0.54 (1.49) 7.54 (4.14) 6.85 (7.25) 3.71 (3.24) 2.06 (2.06) Genç, 2013 35 Quasi experimental Lung, breast and cervical cancer N=64 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Nausea and vomiting experience. Z (P value) Z=-3,88 P:0.0001 Experimental vs. Placebo: P<0.05 Z=-3.15 P: 0.0001 Genç, 2015 36 Quasi experimental Breast cancer N=64 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Nausea experience Vomiting experience Nausea occurrence Vomiting occurrence 4.71 (3.53) 3.96 (3.18) 3.28 (2.45) 2.56 (2.28) a.5.57 (3.47) b.4.78 (2.85) c.3.84 (2.42) d.3.15(1.90) a. 1.87 (2.60) b. 0.46 (1.64) c. 1.25 (1.77) d. 0.34 (1.12) a. 4.75 (2.59) b. 0.31 (0.89) c. 3.12(1.73) d. 0.21 (0.60) Molassiotis, 2007 37 Randomized clinical trial Breast cancer N=50 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Nausea experience Vomiting experience c. Nausea occurrence Vomiting occurrence Nausea distress Vomiting distress a. 0.87 (2.2) b. 0.66 (2.6) c. 0.66 (1.6) d. 0.53 (2.1) e. 0.20 (0.6) f. 0.12 (0.5) a. 1.46 (3.1) b. 0.94 (2.7) c. 2.16 (2.4) d. 0.66 (1.9) e. 0.55 (1.0) f. 0.28 (0.8) a. 2.72 (3.1) b. 0.2 (0.5) c. 1.20 (2.6) d. 0.13 (0.5) e. 0.27 (0.6) f. 0.31 (0.4) a. 2.5 (3.4) b. 0.5 (1.5) c. 1.94 (2.3) d. 0.22 (0.6) e. 0.55 (1.1) f. 0.67 (0.9) Molassiotis, 2013 38 Randomized clinical trial Different types of cancer N=500 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Nausea and vomiting experience. Median (IQR) Nausea frequency N (%) Vomiting frequency. N (%) a.1.0 (0.0-7.50) b.79 (63%) c.109 (87%) a.1.43 (0.0-8.57) b.69 (59%) c.100 (85%) a. 0.00 (0.0-9.86) b. 70 (78%) c. 71 (88%) a. 1.14 (0.0-9.14) b. 50 (62%) Molassiotis, 2014 39 Randomized clinical trial Different types of cancer N=334 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point a. Nausea experience (range 0 to 12). Median (IQR) 1.0 (2.97 - 7.50) 1.43 (3.71 - 8.57) 0.00 (1.82 - 9.86) 1.14 (4.00- 9.14) Shen, 2019 40 Quasi experimental Lung cancer N=70 Morrow Assessment of Nausea and Emesis (MANE) Acupressure, P6 point Nausea severity. Mean (SD) Vomiting severity. Mean (SD) 2.94 (0.8) 0.4 (0.1) 2.94 (0.9) 1.06 (1.4) 0.46 (0.7) 0.03 (0.2) a.2.66 (0.8) b.0.8 (1.3) Shin, 2004 41 Randomized clinical trial Gastric cancer N=40 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point Severity. Mean (SD) Duration. Mean (SD) Frequency. Mean (SD) a. 1.55 (3.42) b. 0.45 (1.36) c. 0.10 (0.45) 3.85 (6.38) 0.65 (1.46) c. 0.10 (0.45) a. 6.05 (2.85) b. 1.70 (2.49) c. 0.30 (0.73) a.9.55 (5.47) b. 4.25 (3.27) c. 0.90 (1.33) Suh, 2012 42 Randomized clinical trial Breast cancer N=120 Rhodes Index of Nausea, Vomiting and Retching (INVR) Acupressure, P6 point a. Level of nausea and vomiting. Media (DE) 7.97 (5.1) 12.09(9.44) 3.12 (4.3) 9.17 (7.58) Akhu-Zaheya, 2017 43 Randomized clinical trial Different types of cancer N=224 Functional Living Index Emesis (FLIE), Chemotherapy- induced nausea and vomiting (CINV) Hologram bracelets Vomiting frequency. Mean (SD) Nausea severity. Mean (SD) Vomiting severity. Mean (SD) a. 0.26 (1.27) b. 1.00 (2.14) c. 0.44 (1.65) a. 0.46 (1.46) b.1.09 (2.17) c. 0.72 (1.97) a. 0.31(1.33) b. 1.82 (2.99) c. 0.59 (1.93) a.0.59 (1.45) b. 2.91 (2.97) c. 1.28 (2.75) Pearl, 1999 44 Randomized clinical trial Gynecologic cancer N=32 Not reported Transcutaneous stimulation bracelet Report of reduced vomiting intensity 71% 21%

Table 3 Non-pharmacological interventions: alopecia outcome Population and popula-tion Outcome Author, year Design size N Instrument Intervention Outcome Before After Intervention Control Intervention Control Betticher, 2013 45 Non-randomized controlled study Different types of cancer N= 167 WHO alopecia grading (I: slight and regular hair loss, II: moderate hair loss, III: complete but reversible hair loss, IV: complete and irreversible hair loss) Scalp cooling Paxman® PSC-2 machine (PAX) Reduction of alopecia grades III and IV % 80% 78% Giaccone, 1988 46 Randomized clinical trial Different types of cancer N= 39 Unclear. A 4-point grading scale is used: 0 no hair loss, 1 minimal hair loss (<25%), 2 moderate hair loss (25 50%), and 3 severe alopecia (>50%). Hypothermia Cap (commercially available as Spenco Hypothermia Cap- Spenco Medical Corporation, Texas) Hair loss (reduction of alopecia grade 3) Grade 0:5 Grade 1:2 Grade 2:1 Grade 3:11 Grade 0:0 Grade 1:0 Grade 2:1 Grade 3:15 Kargar, 2011 47 Non-randomized experiment Unspecified cancers. N=63 WHO alopecia scale Scalp cooling system Hair loss (reduction of alopecia grades 3-4) Grade 1-2: 24 (77.4%) Grade 3-4: 7 (22.6%) Grade 1-2: 12 (38.7%) Grade 3-4: 19 (61.3%) Grade 1-2: 15 (50%) Grade 3-4: 15 (50%) Grade 1-2: 8 (25%) Grade 3-4: 24 (75%) Macduff, 2003 48 Randomized clinical trial Breast cancer N=30 WHO alopecia scale Cool cap Hair loss (increase from grade 0 to 2) Grades 0 a 2: 73% Grades 0 a 2: 23% Grades 0 a 2: 25% Grades 0 a 2: 0% Nangía, 2016 49 Randomized clinical trial Breast cancer N=182 CTCAE v. 4.0 grade 0 (No hair loss), grade 1 (Hair loss of <50% of normal but it does not require wearing a wig). Failure was defined as CTCAE v4.0 grade 2 (Hair loss of >50% normal and it requires wearing a wig). Scalp cooling Efficacy: success in hair preservation N (%) N=95 Grade 0: 48 (50.5%) Grade 1: 5 (5.3%) Grade >2: 47 (49.5%) N=47 Grade 0: 0 (0%) Grade 1: 0 (0%) Grade >2: 47 (100%) Lemenage, 1997 50 Randomized clinical trial Different types of cancer N=98 WHO alopecia grading Grade 0: No hair loss Grade 1: Slight hair loss Grade 2: moderate hair loss Grade 3: complete but reversible hair loss Grade 4: complete and irreversible hair loss Cool cap Efficacy: Degree of alopecia less than 2 N (%) Grades 0-1: 83 (85.60%) Grades 2-4: 14 (14.4%) Nolte, 2006 51 Randomized clinical trial Gynecologic cancer N=187 Breast cancer stem cells (BC SCs) (Secord & Jourand, 1953). 45-minute video featuring makeup techniques and suggestions for women's hairstyles and headpieces. Body image perception 2.24 (0.61) 2.17 (0.53) Rugo, 2017 52 Randomized clinical trial Breast cancer N=182 Dean scale Scalp colling Efficacy: success in hair preservation N (%) 67 (66.3%) 0 (0%)

Table 4 Non-pharmacological interventions: pain and neuropathy outcome Author, year Design Popul Instrumen Interve Outcom Outcome ation t ntion e Before After and popula-tion size N Intervention Control Intervention Control Nursing intervention program Molassiotis, 2009 17 Randomized clinical trial Colorectal and breast cancer N=164 CTCAE Toxicity Rating Scale (NIH/ NCI) Home care nursing program Toxicity grading Mean NR NR 2.9 6.3 Rustoen, 2014 53 Randomized clinical trial Different types of cancer with bone metastasis N=179 Care Needs Assessment (CNA) Nursing program for pain management (PRO SELF) Pain Mean - 3.6 3.7 2.7 3.1 De Wit, 1997 54 Randomized clinical trial Different types of cancer N=313 McGill Pain Questionnaire (MPQ-DLV) Pain education program Pain % 58.4 55.9 39.4 16.9 Muscle exercises Aghabati, 20 08 55 Randomized clinical trial Cancer patients N=90 Care Needs Assessment (CNA) Therapeutic touch Pain Mean 1.9 0.02 1 0 Miladinia, 2017 56 Randomized clinical trial Acute Leukemia N=64 Care Needs Assessment (CNA) Slow-Stroke Back Massage (SSBM) Pain Mean 6.5 6 4.8 6.3 Dhawan, 2020 57 Randomized clinical trial Different types of cancer N=45 Chemotherapy- induced peripheral neuropathy (CIPN) Muscle strengthening exercises Neuropathy Mean 132.5 129.3 83.1 140.8 Self-affirmation Yildirim, 20 1 7 58 Randomized clinical trial Different types of cancer N=140 Edmonton Symptom Assessment System (ESAS) Self-affirmation Pain Mean 0.66 1.31 0.09 2.03 Given, 2015 59 Randomized clinical trial Different types of cancer N=113 Symptom experience scale Supportive care Pain n (%)/mean 29(69)/7.3 30(63)/6.8 19(54)/3.3 25(58)/4.4 Foot bath Park, 2015 60 Quasi experimental Colorectal and gastric cancer N=48 CTCAE Toxicity Rating Scale (NIH/ NCI) Foot bath Neurotoxicity grades 2 and 3 n (%) 24(100) 24(100) 20(83) 21(87.5) Neural gliding Andersen, 2020 61 Randomized clinical trial Breast cancer N=61 Disability of the Arm, Shoulder and Hand (DASH) questionnaire Nerve gliding exercises Neuropathy. Mean 44.1 44.8 40.6 45.9 Acupuncture Zhi, 2022 62 Randomized clinical trial Different types of cancer N=63 Quantitative Sensory Testing (QST) Acupuncture Thermal neuropathy n/mean 21/46.31 19/46.31 17/47.12 16/46.96 Arslan, 2020 63 Randomized clinical trial Colorectal and gastric cancer. N=60 CTCAE Toxicity Rating Scale (NIH/ NCI) Henna application Neuropathy Mean 65 67.9 40.9 68.4 Greenlee, 2016 64 Randomized clinical trial Breast cancer N=63 Net Promoter Score de 4 (NPS-4 score) Acupuncture Neuropathy Mean 16.8 35.2 7.9 18

Table 5 Non-pharmacological Interventions: Sleep Disorders Author, year Design Population and popula-tion Instrument Intervention Outcome Outcome size N Before After Intervention Control Intervention Control Acupressure Tsao, 2019 65 Quasi experimental Ovarian cancer N=60 PSQI- Pittsburgh Sleep Quality Index Acupressure Sleep quality Mean 2.5 2.24 2.4 4.05 Kuo, 2018 66 Randomized clinical trial Ovarian cancer N=40 PSQI- Pittsburgh Sleep Quality Index Acupressure Sleep quality Mean 13.2 12.25 4.21 12.75 Telephone follow-up programs Barsevick, 2010 11 Randomized clinical trial Different types of cancer N=276 PSQI- Pittsburgh Sleep Quality Index Telephone follow ups and education Sleep quality Mean 8.01 7.83 7.96 8.24 Physical exercise programs Coleman, 2012 67 Randomized clinical trial Multiple myeloma N=187 Actigraphy* Physical exercise program Sleep quality Mean 79.7 81.39 77.79 76,57 Foot bathing Yang, 2010 68 Randomized clinical trial Gynecologic cancers N=50 Verran y Snyder-Halpern Sleep Scale Warm-water footbath Sleep quality Mean 805.5 743 944.9 763.2 Movement and relaxation practices Chuang, 2017 69 Randomized clinical trial Non-Hodgkin lymphoma N=96 Verran y Snyder-Halpern Sleep Scale Practice of Chan- Chuang qigong Sleep quality Mean 657 79.7 922.9 77.19 Yang, 2021 70 Cohort Ovarian cancer N=389 PSQI- Pittsburgh Sleep Quality Index Exercise and cognitive behavioral therapy Sleep quality Mean 13.94 14.76 14.29 14.37 Reich, 2015 71 Randomized clinical trial Breast cancer N=79 PSQI- Pittsburgh Sleep Quality Index Mindfulness Sleep quality Mean 7.97 8.39 6.91 6.91 Baraz, 2017 56 Randomized clinical trial Acute leukemia N=64 PSQI- Pittsburgh Sleep Quality Index Slow-Stroke Back Massage on Symptom (SSBM) Sleep quality Mean 12.23 9.7 12.1 12.37 *Actigraphy: An instrument used to monitor sleep and wakefulness patterns.

Table 6 Non-pharmacological Interventions: Neutropenia Author, year Design Population and Instrument Intervention Outcome Outcome Before After population size N Intervention Control Intervention Control Mei Ling Yeh, Quasi- Breast cancer SYSMEX9000 Chan-Chuang qi-gong WBC count 1.955 |Æ 1.955 |Æ > 416.25 |Æ > 810.57 |1L 2006 72 experimental N: 67 automatic blood therapy Hemoglobin 11.42 g/dL 11.32 g/dL < 0.27 g/dL < 0.43g/dL analyzer Platelets 189,500 |Æ 194,523 |Æ > 92,531.25|1L > 67,057.14 |1L Chuang TY, Randomized Non- Beckman Chan-Chuang qi-gong WBC count 4,731.46 |Æ (SD 2,074.34 |1L) 5,482.29 |Æ (SD 3,460.63 |1L) 6,478.33 |1L (SD 4,222.05 |1L) 4,150.42 |1L (SD 2,142.67 |1L) 2017 69 clinical trial Hodgkin lymphoma N:100 automatic blood analyzer therapy Hemoglobin Platelets 11.64 g/dl (SD 2.03 g/dL) 173,479.17(SD 96,707.49 |1L) 11.39 g/dL(SD 2.03 g/dL) 200,645.83 |1L (94,867.32 |1L) 11.97 g/dL (SD 2.06 g/dL) 177,395.83 |1L (SD 80,056.29 |1L) 11.07 g/dL (SD 2.15 g/dL) 179,250.00 |1L (SD 80,795.38 |1L)

Discussion

This review described non-pharmacological interventions for controlling the primary side effects of chemotherapy with a high degree of heterogeneity and internal validity among the studies. This is consistent with some studies stating that non-pharmacological interventions are complementary to medical treatments; however, they emphasize the lack of valid evidence to present the effect of these interventions as complementary to pharmacological treatments 73 , 74 .

The review described several types of non-pharmacological interventions to address the side effects of chemotherapy. These interventions include education and exercise programs, hypothermia devices, acupressure techniques, music therapy, traditional Chinese medicine techniques, relaxation techniques, foot baths, and transcutaneous electrical nerve stimulation 75 , 76 .

Nurse-led home-based patient education programs are designed to manage symptoms. These non- pharmacological interventions have shown measurable differences in pain levels before and after the intervention 54 , 59 . A need was identified to standardize educational programs and to know the content and indicators for pain assessment 26 , 76 , 79 . However, for patients with multiple symptoms, these processes should be accompanied by psychological support and strengthening of mental health to ensure beneficial application and results in the control of the symptoms.

Holistic medical systems such as acupressure have been studied extensively. This review found that acupressure consistently reduced nausea and vomiting compared to standard care in all measurements 36 . This result is consistent with the study by Lee A et al. 78 , who conducted a review and found that acupressure at the P6 point has a moderate effect compared to placebo, although the studies have limitations in terms of variation in effects and methodological quality. However, when comparing acupressure with antiemetics, no difference in the incidence of nausea and vomiting was observed. Therefore, it can be concluded that the available evidence may support a combined therapy of P6 point stimulation and antiemetic drugs rather than drug prophylaxis alone and that further high-quality trials are needed 76 , 79 ).

Manipulative and body-based practices, such as muscle relaxation therapies, reflexology, and therapeutic touch, along with sensory intervention techniques like music therapy and guided imagery, have been described and evaluated with positive effects 80 , 81 ; however, the reported studies record wide variability of populations, techniques, and study periods regarding outcomes such as pain, nausea and vomiting 76 , 81 . The main limitation of these studies was the lack of control for confounding factors, such as the use of medications and other therapies and individual perception of the symptom.

It is important to consider that these types of studies are valuable in building the body of evidence that will later support evidence-based recommendations 82 . The literature consistently states that acupressure is a complementary technique and does not replace traditional treatment 79 . The reported studies agree that environmental factors and the use of patients' unreported therapies limit the evaluation of interventions; hence, there is a need to identify what type of interventions patients are conducting.

The immune system's vulnerability to opportunistic infections and the extended duration of treatment make neutropenia a priority in evaluating non-pharmacological interventions. Chan-Chuang qigong therapy has been evaluated in people diagnosed with cancer 69 , 72 and showed an increase in white blood cell count before and after the intervention. However, variables such as time, comorbidities, and treatments must be controlled to estimate the true effect of this intervention.

Alopecia is one of the secondary symptoms that compromise biological, psychological, emotional, and social aspects, affecting the health status of people who suffer from it and is increasingly becoming a priority outcome for the well-being of patients 83 , 84 . Video tutorials for makeup, wig styling, and scalp cooling are techniques that have been increasingly reported in recent years to mitigate these effects and improve the quality of life for patients. There is a need to further clarify alopecia measurement strategies with validated scales for different populations.

This review included observational and experimental studies, giving a broad overview of the interventions reviewed. These results suggest some implications for clinical practice and future research. First, each of these interventions and their results should be considered with caution since the representativeness of the populations and the standardization of the techniques used can only be generalized to patients with characteristics similar to those studied in the included studies. Secondly, for research purposes, it is highly recommended that future reviews focus on interventions by symptom clusters 85 . The search strategies used in this review enabled us to capture the broadest selection of relevant literature according to the side effects of chemotherapy using distinct search terms. The included studies showed low methodological quality and evidence that interventions could have a real effect on controlling various symptoms, as evidenced by acupressure on symptoms such as nausea and vomiting, sleep disorders, pain, and neuropathy. The findings of this review highlight the gaps in the available literature and emphasize the importance of further documenting the effect of non-pharmacological interventions on chemotherapy side effects.

Conclusion

Prioritizing side effects for patients guides care plans for individuals. Non-pharmacological interventions such as acupressure, Chinese therapies such as Chan-Chuang qigong, muscle relaxation therapies, and nursing intervention programs have been evaluated and described with evidence for nausea and vomiting, pain and neuropathy, sleep disorders, alopecia, neutropenia, and anorexia. However, there is still high variability in the type of intervention, outcomes measuring, and lack of statistical power, making it difficult to estimate the effects of these interventions. Research with methodological rigor and standardization of these interventions is needed to validate their effects on these outcomes.

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