To perform an integrative review of four electronic databases to determine the effectiveness of complementary and alternative medical (CAM) interventions, either alone or as an adjunct to pharmacologic therapy, in alleviating procedure-related pain, anxiety, and distress in children and adolescents with cancer

Databases searched were MEDLINE, CINAHL, PsycINFO, and Cochrane Database.

Search keywords were procedure, pain, anxiety, distress, childhood cancer, pediatric oncology, CAM, and complementary therapies.

Studies were included in the review if

• The studies were case reports or reports of a clinical series or reports of clinical trials that included at least one CAM intervention aimed at reducing procedure-related pain, anxiety, or distress
• The studies reported on a CAM intervention in one of the following: bone marrow aspiration or biopsy, lumbar puncture, injection, venipuncture for the purpose of blood sampling or starting an IV, or percutaneous access (excluding surgical procedure) to an implanted vascular device
• The sample included at least some children and adolescents (that is, young people between the ages of 2 and 18 years) with cancer
• The studies were published in English

Excluded from the review were studies that reported on surgical procedures (except percutaneous access to an implanted vascular device) and on the anxiety and distress of a parent.

• Investigators retrieved a total of 195 references.
• Reviewers read each paper and extracted information, including names of authors, publication year, study design, medical procedure performed, CAM modalities studied, description of study sample, level of evidence, and summary of  results.
• Results were analyzed for themes.

• Thirty-two studies—two meta-analyses, 18 experimental studies, 9 quasi-experimental studies, one nonexperimental study, and two case studies—were included in the review.
• The total sample size was 1,760, with a range across studies of 3–514 participants.
• Eleven studies included children with leukemia only; 13 included children with various cancer diagnoses other than leukemia; and 8 included children with a range of pediatric illnesses, including cancer.
• Seven studies reported on children younger than 10 years, 3 studies reported on older children (10–17 years), and 22 studies included both age groups.

• Phase of care: diagnostic
• Clinical applications: pediatrics, procedure-related

Results suggest that mind-body intervention may be effective, alone or as an adjunct to pharmacologic interventions, in managing procedure-related pain, anxiety, and distress in pediatric patients with cancer. In this population the three most commonly studied mind-body modalities were distraction, hypnosis, and imagery.

Although multiple studies demonstrated the value of CAM interventions, many of the studies were small and incorporated multiple CAM therapies as a single intervention. These types of interventions may be useful, particularly when used in combination with pharmacologic agents, but further research is needed to identify which interventions were valuable.

To investigate whether the addition of a neutral, supersaturated, calcium phosphate (CP) mouth rinse benefits the severity and duration of acute mucositis in patients with head and neck cancer treated with (chemo)radiation

Patients in group A were instructed to use caphosol mouth rinse twice daily with 15 ml solution for one minute plus standard care. Patients in group B were instructed to use standard care consisting of gargling with 15 ml of “magic mouth wash” (hydrocortisone, lidocaine, nystatin, propylene glycol, sodium carboxymethylcellulose, aqua admixture) up to six times per day, swallowing one time out of two. Two experienced physicians conducted visual inspection of the oral cavity and visualized oropharyns weekly until two to seven weeks after completion or until mucositis grade 1 or 0.

• N = 58
• MALES: 84.4%, FEMALES: 15.5%
• Patients had all histological subtypes of head and neck cancer.
• Patients were receiving curative radiation (intensity-modulated radiation therapy of 60–72 Gy over six to seven weeks), primary or postoperative oral mucosa or part of oral mucosa in radiation field, concurrent chemotherapy consisting of 100mg/m² cisplatin at weeks one and four, and induction chemotherapy with docetaxel, cisplatin, fluorouracil, or epidermal growth factor receptor monoclonal antibody.
• Patients were excluded from the study if they had received prior head and neck cancer radiation therapy.

• Single site
• Outpatient radiotherapy department at the University Hospital of Leuven, Belgium

PHASE OF CARE: Active antitumor treatment

• Single center
• Prospective randomized controlled (no placebo) study

• The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3 (NCI CTCAE 3.0)
• Oral pain was scored with a visual analog scale.

No significant differences were found in grade, time of onset, or duration of peak mucositis between groups. Fewer patients in the study arm experienced grade 3 or higher mucositis (59% versus 71%). Mean time to development  of mucositis was 28.6 days in the study group versus 28.7 days in the control group (p = .96). Duration of mucositis was 22.7 days in the study group versus 24.6 days in the control group (p = .62). No significant reduction in the need for analgesics was found.

An oral solution of neutral CP mouth rinse does not reduce frequency, duration, or severity of oral mucositis or pain in patients treated with (chemo)radiation for head and neck cancer. No evidence supports its standard use.

• Small sample (< 100)
• Key sample group differences that could influence results
• Other limitations include the heterogeneity of the patient population and treatment sample and no assessment of patient characteristics that could influence mucositis (poor oral health, alteration salivary production, alcohol use, or existing mucosal damage).

Mucosal damage continues to be an important and debilitating side effect that warrants continued research.

• Six studies looking at the incidence of bone pain associated with GCSFs in cancer patients evaluating diagnosis, dosing, and incidence
• Five studies looking at incidence of bone pain associated with GCSFs in healthy people evaluating dose and incidence
• Three studies involving elderly patients with lymphoma who received GCSFs evaluating chemotherapy regimens with or without GCSFs and incidence
• Six studies evaluating the prevention and treatment of bone pain with GCSFs in varying forms of interventions with a maximum of two studies looking at opioids, one with no reported relief of pain

There was no real difference between pegfilgrastim and daily GCSFs in terms of incidence of bone pain, and most patients will benefit from the use of NSAIDs to control pain. The authors suggest that patients who do not respond to NSAIDs should consider second-line treatment with antihistamines. The study cites a series of four patients and one case study in which this was effective.

Only one study was cited that evaluated the efficacy of antihistamines in relieving or decreasing bone pain associated with GCSFs from 2005. Main evidence is case reports only.

More studies are needed to evaluate the efficacy of antihistamines versus NSAIDs or acetaminophen in relieving bone pain.

The purpose of this study was to determine if a misoprostol oral rinse would reduce the severity of mucositis in patients receiving high-dose chemotherapy for autologous stem cell transplant.

This multi-center study employed a randomized, double blind, placebo controlled, parallel-group design. Participants were assigned to the misoprostol arm or placebo arm. Subjects swished and gargled the misoprostol or placebo solution (in 15 ml of water), held it in their mouths for 60 seconds, and then swallowed. Administration began 45 min. to 2 hours before the initiation of the conditioning regimen and then every 8 hours until 24 hours after the conditioning regimen was complete. All subjects also received instructions on standard care and instructed not to use other oral care for 1 hour after the misoprostol or placebo solution. The Oral Mucositis Index was used to grade mucositis every 2 to 3 days.

The study was comprised of 48 patients, 22 in treatment arm and 26 in placebo group, with an age greater than or equal to 18 years.
MALES 30%, FEMALES 70%
KEY DISEASE CHARACTERISTICS: Lymphoma, multiple myeloma, or solid tumor patient undergoing autologous stem cell transplant.
OTHER KEY SAMPLE CHARACTERISTICS: Patients could not have been receiving cisplantin/carboplatin conditioning regimens or total body irradiation.

SITE: Multi-site

SETTING TYPE: Inpatient

LOCATION: Six participating sites in the United States

PHASE OF CARE: Active antitumor treatment
APPLICATIONS: Palliative care

Randomized, double-blind, placebo-controlled, parallel group design

• Modified Oral Mucositis Index
• Clinical examination by calibrated examiners
• Photographs
• Visual Analog Scale
• Pain Affect Faces Scale
• Length of hospital stay
• Days of parental nutrition

No statistically significant differences in Oral Mucositis Index scores. No statistically significant differences in the peak mucositis severity scores. No statistically significant differences in pain ratings, length of hospital stay, or days of total parenteral nutrition. There were no serious adverse events.

There was not a statistically significant benefit to using a misoprostol rinse in deterring the development or the severity of oral mucositis in patients undergoing autologous stem cell transplant. There was also no decrease in the length of stay or the use of total parenteral nutrition.

Small sample (<100)

Findings not generalizable

Other limitations/*explanation: The patient population was limited to only those cancer patients undergoing autologous stem cell transplant.

This study provides no evidence to support using a misoprostol mouth rinse to prevent the development of mucositis, decrease the severity of mucositis, decrease the length of stay, or decrease the use of total parenteral nutrition in patients undergoing a non-TBI based or non-cisplatin/carboplatin-based conditioning regimen for autologous stem cell transplant.

570 articles were included in this literature review. Literature contained prevention and/or treatment methods for mucositis. Interventions for treatment of mucositis were given, recommendations against an intervention were provided, suggestions in favor of an intervention were supplied, and suggestions against an intervention were given.

Recommendations included a combination of teeth brushing, flossing, mouth rinsing, and use of growth factors and cytokines in treatment of mucositis. The use of anti-inflammatory agents was also recommended. Low level laser therapy was recommended in prevention of mucositis with specific types of cancer treatment. Cryotherapy was also recommended for patients receiving chemotherapy. A list of natural and miscellaneous agents was recommended for treatment and prevention of mucositis.

Limitations of this study include clinical situations that were not seen in the literature review or that are rare in clinical settings. These limitations occur because of conflicting evidence or not enough evidence provided.

Nurses should be assessing patients' pain control, nutritional support, ability to eat, and oral hygiene practices, and should be teaching on the use of oral care products that are essential for prevention.

To investigate the effects of cyclooxygenase-2 (COX-2) inhibition on the severity and morbidity or oral mucositis in patients with head and neck cancer undergoing radiation based on the role of inflammatory pathways in oral mucositis pathogenesis

Patients were randomized using a one-to-one ratio in blocks of 10 to receive either celecoxib or a placebo. The celecoxib and placebo capsules were identical. The first four patients took 200 mg of celecoxib twice per day beginning five days prior to the first day of radiation therapy and continuing for three days after the conclusion of radiation therapy. Dosing was modified for all subsequent patients to 200 mg of oral celecoxib once per day only on the days of radiation therapy from the first to the last day of therapy. Subsequent patients assigned to the control arm took the placebo once per day for the same duration. Data were collected two to three times per week for the six to seven weeks during which radiation occurred.

• N = 40  
• AVERAGE AGE = 54.6 years 
• MALES: 32 (80%), FEMALES: 8 (20%)
• KEY DISEASE CHARACTERISTICS: Head and neck cancer

• SITE: Multi-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Hartford Hospital (outpatient setting)

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care

Prospective, randomized, double-blinded, placebo-controlled, parallel-arm trial

• Oral Mucositis Assessment Scale (OMAS)
• World Health Organization (WHO) oral mucositis scale
• National Cancer Institute's Common Toxicity Criteria (NCI-CTC) Scale version 2
• Brief Pain Inventory (BPI)
• Performance Status Scale (PSS)
• Advanced opioid converter

There was no difference in oral mucositis severity between the celecoxib and placebo groups (p = .67).

The use of a COX-2 inhibitor during radiation in patients with head and neck cancer did not reduce the severity of clinical oral mucositis, mouth pain, dietary compromise, or use of opioid analgesics. This study’s power calculation seems to be weak. The dropout and missing data rate (usually 20%) should be added to satisfy the original power calculation. This increases the significant risk of type II error. Without a study with a larger sample size, this practice cannot be recommended.

• Small sample (< 100)
• Risk of bias (sample characteristics): This study has a significant discrepancy for gender distribution. The study was predominantly male patients.
• Other limitations/explanation: The researchers note that because most of the subjects were on high doses of opioids, the small analgesic effect of 200 mg celecoxib daily may not have been enough of a dose to appreciate a response. They do mention that the four subjects that were on higher-dose therapy (celecoxib 200 mg BID) did not discern any effect on oral mucositis.

This is not an effective option for treating radiation-induced mucositis.

The study focused on the secondary prevention of febrile neutropenia with G-CSF and antibiotics.

G-CSF (5 mcg/kg subcutaneous) or G-CSF with antibiotics (ciprofloxacin 500 mg by mouth every eight hours and amoxicillin 500 mg by mouth or clavulanate 125 mg by mouth every eight hours) daily starting 48 hours after chemotherapy and continuing until the absolute neutrophil count is greater than 2,000 cells/mm³. Patients were included in the study for one treatment cycle.
 

• The 48 eligible patients were adults who received chemotherapy for solid tumors and had experienced a prior episode of febrile neutropenia.
• Patients were scheduled to continue on the same regimen without dose reduction.
• Most patients were receiving treatment for breast, ovarian, or lung cancer.

Two sites in Europe.

Prospective, randomized pilot trial.

Patients were evaluated with:

• Regular complete blood counts
• Temperature monitoring once daily
• Observation for adverse effects of the prophylactic antibiotics.

In the event of a fever, the antibiotic prophylaxis was discontinued and a complete clinical evaluation for infection was completed.

No episodes of febrile neutropenia occurred in the G-CSF group, and only one incident of febrile neutropenia was reported in the combined group (p = 1). Reported side effects were similar and mild.

G-CSF reduced the risk of febrile neutropenia recurrence. Antibiotics did not provide any additional benefit in terms of prophylaxis.

• Not placebo controlled, not blinded.
• Patients were not stratified, and the groups were not balanced, particularly by disease and the number of prior chemotherapy cycles.
• The study was inadequately powered, since the frequency of the outcome measure was close to none (febrile neutropenia episodes).
• Cost implications were discussed but not in detail.

To evaluate the effect of omitting day 2 administration of granisetron in the treatment of chemotherapy-induced nausea and vomiting (CINV)

• All patients received 16 mg IV ondansetron, 20 mg dexamethasone, and 50 mg ranitidine before highly or moderately emetogenic chemotherapy on day 1.
• On day 2, all patients received 10 mg metoclopramide, every 8 hours on days 2, 3, and 4; 8 mg dexamethasone daily on days 2 and 3; and 150 mg ranitidine every 12 hours.
• Patients were randomly assigned to receive either 0.5 mg granisetron on days 2 and 3 or placebo instead of granisetron on day 2 and 0.5 mg granisetron on days 3 and 4.
• Patients recorded emetic episodes and side effects of antiemetic medications in self-report diaries, which were evaluated on day 6.

• The study consisted of 73 participants.
• Mean age was 51.4 years.
• The majority (94%) of patients were female.
• The majority (95%) of patients had breast cancer.
• The majority were receiving chemotherapy containing 60 mg/m² doxorubicin.
• Nearly half (49%) of patients had previously experienced complete protection in the first cycle of chemotherapy at baseline.

The study was conducted at a single outpatient setting in Brazil.

All patients were in active treatment.

This was a randomized, placebo-controlled, double-blind trial.

• Emesis was measured using the Functional Living Index-Emesis (FLIE).
• Complete protection was defined as absence of any episode of nausea or vomiting.

• A higher proportion of patients in the experimental group experienced complete protection from nausea and vomiting (p = 0.046) in the acute phase.
• No significant differences were found between groups in FLIE scores or proportions of patients who achieved complete protection from nausea and vomiting in other treatment phases.
• No differences were found between groups in adverse events.

Differences in rates of complete protection from nausea and vomiting in this study were unclear and difficult to interpret because different groups experienced better CINV control at different time points.

• The sample had fewer than 100 participants.
• Although the authors concluded that elimination of one dose of granisetron resulted in better control, the actual results reported did not appear to support that conclusion.
• It was also unclear how the two groups truly differed, other than the timing of the medication, because the “control” group received granisetron on the same number of days in the treatment cycle.
• Measurement depended on patient diaries; however, overall compliance rate with diaries was not reported.
• Statistical significance was not seen, despite power analysis that demonstrated a sufficient sample size to demonstrate a 35% difference in complete protection rates.
• Because the study sample was predominantly female, the ability to generalize is questionable.

No clear conclusions can be drawn from this study.

To evaluate whether skipping day 2 antiemetic medications may improve delayed chemotherapy-induced nausea and vomiting (CINV), based on the hypothesis that repeated consecutive doses of antiemetics may lead to increased accumulation of 5-HT₃ at the presynaptic level in the gastrointestinal (GI) tract, decreasing the activity of the next dose of a 5-HT₃ receptor antagonist (tachyphylaxis)

Patients were given day 1 antiemetics according to American Society of Clinical Oncology (ASCO) guidelines. Patients in Study 1 received 10 mg metochlopramide by mouth every eight hours, 0.05 mg granisetron by mouth four times per day, and 8 mg dexamethasone four times per day on days 2 and 3. In Study 2, patients received the same medications except that no drugs were given on day 2. Patients recorded emetic episodes in diaries and responded to a quality-of-life (QOL) questionnaire at baseline and on day 6.

• The study consisted of 42 chemotherapy-naïve patients over age 18 who were receiving moderately to highly emetogenic chemotherapy (MEC to HEC).
• Patients were excluded from the study if they had abnormally high serum creatinine, bilirubin, or SGPT; if they were pregnant; if they reported vomiting or use of antiemetics 24 hours before the administration of chemotherapy; or if they were receiving radiation therapy. Patients with brain metastasis, GI obstruction, or regular use of corticosteroids or benzodiazepines before the initiation of chemotherapy also were excluded.

The studies were conducted in the hematology and oncology department of a School of Medicine in Brazil.

This research consisted of two pilot studies.

The Functional Living Index of Vomiting (FLIE) was used.

• Each study consisted of 21 patients. No significant differences were found between the two populations in terms of clinical characteristics or chemotherapy emetogenicity.
• Patients who received no antiemetic medications on day 2 had statistically significant complete control of their nausea and vomiting.

Skipping day 2 antiemetic medications does not seem to worsen delayed CINV and may reduce CINV.

Study limitations include the use of a nonrandomized design and the small sample size.

The objective of the study was to investigate the effect of guided imagery with theta music on dyspnea in patients with advanced cancer.

The intervention consisted of four periods.

• Three minutes resting quietly with no stimulation
• Four minutes of “control” (non-theta) music listening
• Guided imagery segment, consisting of three minutes of theta music only, followed by four minutes of theta music plus imagery instruction, followed by three minutes of theta music only
• Three minutes resting quietly with no stimulation.

Theta music was provided by a recording designed to stimulate brain waves in the theta range of 4–8 Hz. Music was provided by a standard audio CD with headphones. Dyspnea rating was done in the first and last periods of the intervention, while resting quietly. Physiologic parameters of respiratory rate, heart rate, end tidal CO₂, and pulse oxygen saturation were collected at each of the four segments of the intervention. Physiologic parameters were continuously measured using a Tidal Wave 715 capnograph/pulse oximeter, using a finger probe. Patients were interviewed at the end of the session via open-ended questions to elicit how they felt.

• The study reported on a sample of 53 participants.
• The mean age was 58 years (SD = 16.2 years).
• Of the sample, 58.5% were males and 41.5% were females.    
• Of the sample, 37.7% had lung cancer and the rest had other types of cancers.
• All had Borg scale scores greater than or equal to 5. 
• Of the sample, 54.7% were on oxygen therapy and 32.1% were on medication for dyspnea.
• Medications used are not described.
• Of the sample, 58.5% had secondary or higher-level education.
   

The study was conducted in a multi-site, inpatient setting in Taiwan.

• Patients were undergoing end-of-life care.
• The study has clinical applicability for late effects and survivorship and end-of-life and palliative care.
   

Single group repeated measures

• Modified Borg scale    
• Physiologic parameters via continuous pulse capnograph/eximeter
   

• The mean modified Borg scale score improved significantly with the intervention, with a baseline mean score of 5.9 and post-intervention score of 3.2 (p = .000). 
• Ninety percent of subjects said they felt that the intervention had benefited them, indicating they felt “refreshed\" or “comfortable and peaceful,\" and 57% fell asleep during the intervention. 
• Statistically significant declines were seen in heart rate (pre: 96.3 bt/min, post: 94.9 bt/min, p = .005) and respiratory rate (pre: 20.4/min, post: 18.9/min, p = .000). 
• No significant difference was seen in oxygen saturation. 
• End tidal CO₂  increased significantly from 28.5 pre-intervention to 29.1 post-intervention.
• Post hoc testing showed that CO₂ increased most with the combined guided imagery and theta music. 
• Subjects showed decline in heart and respiratory rates throughout all parts of the session.

Findings support the hypothesis that subjects who receive the guided imagery and theta music intervention experience reduction in heart and respiratory rate and subjective intensity of dyspnea.

• The study had a small sample size of less than 100.
• Although no control group was used for comparison, the repeated measures design did allow for comparison of physiologic parameters at various time points. 
• No analysis was done of differences between those on oxygen and those not, in terms of physiologic response. 
• Although changes in heart and respiratory rates were statistically significant, the level of the change does not suggest clinical significance of these changes. 
• Of an initial sample of 69 patients, 16 said they could not concentrate to complete the guided imagery. Analysis showed that these patients had significantly less formal education than others, suggesting that such factors may influence results. 
• The measures were short-term, so any more lasting effects on symptoms are not known. 
• Because the intervention was combined, what effects imagery versus the theta music itself had is not clear.
   

• Findings suggest that guided imagery and listening to theta music can be beneficial for patients with dyspnea.
• This appears to be a practical intervention. 
• Further research in this area is warranted to determine most effective “dosing” and timing of such an intervention and to further explore the relevance of education level to ability to participate fully in guided imagery. 
• Because most patients fell asleep during this intervention, the effect of this type of intervention to manage sleep disturbance may be useful as well.