To evaluate the use of plain ice, flavored ice, and standard care in the management of oral mucositis

Patients receiving 5-fluorouracil (5-FU) were randomized to receive standard care plus plain ice, standard care plus flavored ice, or standard care alone. Standard care alone consisted of mouthwashes of plain or salty water four times daily plus use of a soft toothbrush and nonabrasive toothpaste. Patients who were assigned to one of the cryotherapy arms were instructed to swirl the ice around the mouth for five minutes prior to, five minutes during, and 20 minutes after the injection. Patients who used plain ice were instructed to do so three times daily. Flavored ice was in the form of a purchased product called \"icy poles.\" Nurses assessed mucositis prior to each chemotherapy cycle and 15 days after each intervention. The sequencing of the interventions was random.

• The study reported on 79 patients across three cycles of chemotherapy.
• The majority of patients were male (67%) and had colorectal cancer (92%).

The study was conducted in an outpatient, chemotherapy, acute care setting at a teaching hospital in Australia.

This was a randomized, controlled, crossover trial.

• Investigators used an Oral Assessment Guide (OAG) and the Western Consortium Cancer Nursing Research (WCCNR) scale to assess mucositis.
• A patient questionnaire was used to gather information regarding comfort, satisfaction, and factors affecting compliance.

• Data analysis of 67 patients were provided as 12 patients were unable to complete the first intervention.
• The reported odds ratio (odds of symptoms increasing versus not increasing) were as follows.
  • Standard care versus ice: OAG 3.26, p = 0.002; WCCNR 3.23, p = 0.021
  • Standard care versus flavored ice: OAG 3.50, p = 0.003; WCCNR 4.00, p = 0.012
  • Ice versus flavored ice OAG 1.07, p = 0.872; WCCNR 1.20, p = 0.774
  • Leucovorin versus no leucovorin: 4.46, p = 0.050
• Pain scores were only available for analysis on 28 data sets because of incomplete data. Ice chips were found to be more effective than standard care in reducing pain (p = 0.009). Flavored ice did not differ from either of the other two treatments (p = 0.152, p = 0.581).
• The taste of the flavored ice and the time required to complete either form of oral cryotherapy were the two main concerns.

• Both forms of cryotherapy were effective in reducing the severity of oral mucositis after each cycle.
• The use of leucovorin appeared to increase the odds of patients experiencing mucositis at least fourfold.
• Use of crossover design is a strength of this study.

• The sample size was small.
• Only conducting oral assessment prior to chemotherapy initiation and on day 15 may not have provided a complete picture of the differences across groups.
• The study was not able to be blinded because of the nature of the intervention.

The study explored the effects of daily use of isoflavonoids on climacteric symptoms and QOL in postmenopausal women who had been treated for breast cancer.

Phytoestrogen tablets and similar-looking placebo tablets (six tablets per day) were taken every 12 hours with a glass of water. The participants were seen at the research center before and after each treatment period. Sixty-two postmenopausal, symptomatic women were randomized to use either phytoestrogen (tablets containing 114 mg of isoflavonoids) or a placebo for three months; the treatment regimens were reversed after a 2-month washout period.

Six women discontinued the trial for various reasons during the first phase. Thus, 56 women completed the study. The mean age pf participants was 54 (± 6 years).

• Inclusion criteria: breast cancer survivors (none using tamoxifen) who reported incapacitating hot flashes and other climacteric symptoms after the onset of spontaneous menopause, as seen from their high circulating levels of FSH and LH. 
• Exclusion criteria: Use of sex steroids (including tamoxifen); use of natural products with possible estrogenic activity; use of drugs possibly affecting climacteric symptoms, metabolism, or absorption of phytoestrogens (e.g., antibiotics during the previous three months); and history of any thromboembolic or hepatic event.

This was a randomized placebo-controlled crossover trial of phytoestrogens in treatment of menopause in breast cancer participants.

At each visit, the participants were interviewed about hot flashes and other typical climacteric symptoms using the Kupperman index and Menopausal Visual Analogue scale. Blood levels of phytoestrogens, FSH, LH, estradiol, and sex hormone-binding globulin, liver enzymes, and creatinine levels were followed. Compliance with treatment was confirmed by diary records and by measurement of serum phytoestrogen levels.

The use of phytoestrogens led to significant rises in the levels of phytoestrogens, whereas the placebo regimen had no effect. Kupperman indexes at the end of treatment with phytoestrogen or placebo did not differ. Hot flashes and the other components of the Kupperman index were not relieved by the phytoestrogen regimen when evaluated separately.

Pure isoflavonoids at a dose of 114 mg for three months did not relieve hot flashes or other menopausal symptoms in participants with breast cancer

Potential limitations of the trial included:

1. Study period was of short duration (three months). 
2. Possibility that phytoestrogens may trigger changes in target organs in processes requiring more than three months. It would be valuable to have long-term data on the effects of phytoestrogens.
3. Were doses physiologically suitable? Doses appeared sufficiently large, given the elevations in phytoestrogen levels in participants.

To clarify the effect of music interventions on anxiety for adult patients with cancer from rigorously conducted studies
 

TYPE OF STUDY: Meta-analysis and systematic review

• Databases searched were PubMed, PsycINFO, CINAHL, Web of Science, and the WorldCat dissertation database.
• Search keywords were music, music therapy, music intervention and cancer, neoplasm, and malignancy.
• Studies were included in the review if they
  • Were a randomized controlled trial
  • Tested a music intervention
  • Studied an adult population
  • Reported measurable anxiety outcomes
  • Used validated measures
  • Were accessible in full text
  • Scored at least 5 on the PEDro scale, indicating a high-quality study.
• Exclusion criteria were not specified.

• A total of 606 references were retrieved.
• The PEDro scale was used to evaluate quality, applied independently by two people.

• A final number of 13 studies were reviewed, with 4 included in meta-analysis.
• A total of 709 patients were included in the review, with a sample range across studies of 20–98.
• The sample had various tumor types. Most studies were done during active treatment. One study was done related to a bone marrow biopsy procedure.

Patients were undergoing active antitumor treatment.

Length of the intervention varied substantially from 5 minutes to 4 hours. There was high variability in the number of sessions delivered. Most studies examined a single intervention with immediate pre and post anxiety measurement. Three delivered live music, 1 involved a music therapist, and 11 involved listening to music via headphones. Meta-analysis showed no significant difference between the music intervention and controls (SMD = -0.003 (95% CI -0.51, 0.52).

Meta-analysis showed no significant effect of music interventions on anxiety in adults with cancer.

• A low number of studies were included in meta-analysis.
• There was high heterogeneity among the studies.
• There was variability in the type, duration, and timing of the music interventions used.

Results of this analysis do not support an effect of music interventions on anxiety in adults with cancer.

To evaluate the effects of budesonide on cabazitaxel-induced diarrhea during two treatment cycles

Patients were randomized to receiver cabazitaxel plus prednisone or cabazitaxel plus prednisone with 9 mg budesonidedaily for 44 days. Budesonide was given for the first two courses and was begun two days before chemotherapy administration. Loperamide was used for diarrhea.

• N = 227   
• MEDIAN AGE = 68 years
• AGE RANGE = 49–85 years
• MALES: 100%  
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Ninety-one percent had prior chemotherapy, and 52% had prior radiation therapy.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Netherlands

PHASE OF CARE: Active antitumor treatment

• Randomized, open-label, phase II trial

• Common Terminology Criteria for Adverse Events (CTCAE)

Among those receiving budesonide, 18% had grade 2 or 3 diarrhea, compared to 12% in the comparison group. Seven patients were hospitalized for diarrhea during treatment. No difference in diarrhea grade or prevalence existed between study groups.

Budesonide had no significant effect on the incidence or severity of diarrhea.

• Risk of bias (no blinding)
• Unintended interventions or applicable interventions not described that would influence results
• Use of loperamide was not reported

Budesonide was not shown to be effective to reduce the prevalence or severity of diarrhea among patients receiving cabazitaxel.

To investigate the dose-response relationship of topical morphine and pain in pediatric cancer patients with oral mucositis; to investigate, after topical morphine administration, the plasma levels of morphine and metabolites
 

The sample included 12 children receiving treatment for chemotherapy-induced oral mucositis. Seven patients were in the dose-response study and five were in the absorption group.

Both groups received oral morphine for pain relief. All children in the study received an oral solution containing morphine hydrochloride, 1 or 2 mg/ml, administered as a spray by means of an atomizer. The child was then to retain the solution in the mouth for 10 seconds before spitting out the solution. All children in the study also received 10‐15 mg/kg acetaminophen every 6 hours. Supplemental analgesics were allowed in the study either by patient-controlled analgesia pump or intravenously.
 

• The sample was composed of 12 patients.                         
• Mean patient age was 9 years (SD = 7 years). In the dose-relationship study, the age range of participants was 6‐15 years, with the mean age being 8 years. In the absorption study, the age range of participants was 2‐17 years, with mean age being 10.4 years.
• Of all participants, 66.6% were male and 33.3% were female.
• Diagnoses in both groups were varied and included non-Hodgkin lymphoma (NHL); neuroblastoma (NBL); hematopoietic stem cell transplantation (HSCT), including concomitant radiation therapy; and acute lymphoblastic leukemia (ALL). ALL was the most common diagnosis. The list that follows specifies diagnosis by percentage of all patients.
  • 50% (n = 6) ALL.
  • 16.6% (n = 2) NHL.
  • 25% (n = 3) NBL.
  • 8.3% (n = 1) HSCT, including concomitant radiation therapy.

• Single site
• Inpatient
• Department of Pediatrics, Copenhagen University Hospital, Sweden

• Phase of care: active treatment
• Clinical application: pediatrics

Prospective observational sequential study

• Age-appropriate 11-point pain scale, to assess pain intensity, with 0 = no pain and 10 = worst pain
• Visual analog scale (VAS), 0–10, for children older than age 8
• Wong-Baker FACES Pain Rating Scale, a VAS consisting of six faces, to assess the pain of children ages 6–8
• Face, Legs, Activity, Cry, Consolability (FLACC) Scale, composed of five behavioral components to access the pain of preverbal children age 5 and younger
• World Health Organization (WHO) Oral Mucositis Scale, on which 0 = no oral mucositis and 4 = severe oral mucositis
• Analysis of plasma and metabolites to show morphine level

In the dose-response group, the morphine mouthwash was associated with a decrease of at least 36% in the oral pain score of six of seven patients. Thirty minutes after topical doses of 0.25–0.4 mg/kg morphine, pain decreased by approximately 36%. The absorption study reported concentrations of morphine and metabolites well below effective analgesic levels; authors reported no increase in plasma concentration of morphine.

The extremely small sample size prevents applying study results to the pediatric population of patients diagnosed with oral mucositis. Further research should investigate the reliability of these findings.
 

• The study had a small sample size, with fewer than 30 patients.
• The use of a systemic opiod as a rescue medication may have caused inconsistent results.

The evidence from this study is insufficient to allow researchers to draw conclusions about the effect of topical morphine on the pain associated with oral mucositis. However, oral analgesics such as morphine could be effective supplements, causing few side effects, to established treatments. More research is needed.
 

To determine the effectiveness of laser liposuction in combination with a lymph node flap transfer on moderate upper limb lymphedema in patients with breast cancer

Patients first received a lymph node flap transfer. The lymph node flap was placed in the wrist. Laser liposuction was scheduled one to three months following the flap procedure to debulk the affected limb. Measurements were taken preoperatively and at three and six months following the procedure.

• N = 10
• MEAN AGE = 54.6 years (SD = 9.3 years, range = 35–67 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer-related upper limb lymphedema (moderate)
• OTHER KEY SAMPLE CHARACTERISTICS: Breast cancer survivors who received modified radical mastectomies, axillary lymphadenectomy, and chemoradiotherapy

• SITE: Single site    
• SETTING TYPE: Multiple settings    
• LOCATION: Plastic and Reconstructive Surgery Department of the China Medical University Hospital in Taichung, Taiwan

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Palliative care 

Prospective clinical study with pre- and post-test measures

• Photography
• Serial arm measurements 
• DermaLab^® Combo device (skin tonicity) 

Six months after treatment, patients showed a reduction in arm circumference (mean = 30.5 cm, SD = 1.6 cm), which was a 90% improvement from baseline measurements. In addition, forearm circumference was reduced (mean = 27.5 cm, SD = 2.4 cm). This was a 93% improvement from baseline measurements. There was a significant reduction in arm volume from pre- to post-treatment (p > 0.01).

Combining laser liposuction with lymph node flap transfer is a novel procedure. In this study, the intervention appeared safe and reliable, and it was an effective way to significantly reduce limb volume in patients with breast cancer experiencing upper limb lymphedema.

• Small sample (< 30)
• Baseline sample/group differences of import
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Measurement/methods not well described
• Findings not generalizable
• Intervention expensive, impractical, or training needs

Free lymph node flap transfer and laser-assisted liposuction is very new for lymphedema treatment. This study's results were confusing, and nurses should continue observing this method. The small sample size makes it difficult to determine the extent to which this intervention would be effective for the majority of patients with upper limb lymphedema.

PURPOSE: Systematically review literature and define updated clinical practice guidelines regarding use of anti-inflammatory agents

TYPES OF PATIENTS ADDRESSED: Patients receiving chemotherapy or radiation therapy

RESOURCE TYPE: Evidence-based guideline

PROCESS OF DEVELOPMENT: Studies evaluated using Hadorn criteria and assigned levels of evidence on Somerfield criteria by independent reviewers. Findings were integrated into guidelines based on overall level of evidence for each intervention.

DATABASES USED: MEDLINE (1966–December 31, 2010)

KEYWORDS: aminosalicylic acid, amifostine, amlexanox, anti-inflammatory, anti-TNF, anti-tumor necrosis factor, aspirin, Benadryl^®, benzydamine, betamethasone, celecoxib, corticosteroid, dexamethasone, diphenhydramine, Ethyol^®, flurbiprofen, histamine, hydrocortisone, ibuprofen, indomethacin, infliximab, irsogladine, lactoferrin, mesalazine, misoprostol, N-acetylcysteine, non-steroidal anti-inflammatory agents, NSAIDS, orgotein, prednisone, prostaglandin, RK-02-02, salicylic acid, steroid, thalidomide, TNF antibody, TNF inhibitor, and tumor necrosis factor/TNF

INCLUSION CRITERIA: Articles involving anti-inflammatory agents for prevention or treatment of oral mucositis

PHASE OF CARE: Active antitumor treatment

Forty-one studies were included in the review involving use of multiple anti-inflammatory agents.

• Benzydamine mouthwash is recommended for prevention in patients with head and neck cancer receiving moderate-dose radiation therapy without concomitant chemotherapy.
• Misoprostol is not recommended for use of prevention of radiation-induced oral mucositis.
• For all other anti-inflammatory agents, no guidelines were deemed possible due to insufficient evidence.

• Most evidence reported was from studies of patients with head and neck cancer.
• Very few studies per individual agent were reviewed, and the level of evidence was low for all but benzydamine.

Two new guidelines were identified by this systemic review. The panel suggests that misoprostol mouthwash should not be used for the prevention of radiation-induced oral mucositis in patients with head and neck cancer. The other new guideline the panel recommends is benzydamine mouthwash for the prevention of oral mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy (up to 50 Gy) without concomitant chemotherapy. In addition to this, the lack of clear evidence supporting the use of any anti-inflammatory agent other than benzydamine, the use of anti-inflammatory agents continues to be a promising strategy for the prevention and treatment of oral mucositis. More well-designed studies are needed to examine the use of anti-inflammatory agents for oral mucositis in various cancer care settings.

Patients were given a mouthwash of 400 mcg granulocyte-macrophage colony-stimulating factor (GM-CSF) dissolved in 1 mL sterile water, added to 200 mL drinking water, to treat grade II–IV mucositis. Patients were instructed to use the mouthwash once a day after the end of the second week of therapy. They were instructed to use as a mouthwash and then swallow in fragments within one hour.

• GM-CSF was given to 46 patients with radiation-induced ulcers.
• All patients were receiving radiation therapy (RT) for head and neck cancer. Some patients also received chemotherapy.

Physicians used the following grading system.

• 0 - None
• I - Diffuse erythema
• II - Erythema, small foci of ulcers
• III - Ulcers covered by pseudomembranes in more than half of mucosa
• IV - Necrotic ulcers and hemorrhage

Patients used the following grading system.

• 0 - none
• I - Mild soreness, solid diet
• II - Mild to moderate pain, soft diet
• III - Severe pain and dysphagia, liquids only
• IV - Severe pain, liquids only, and/or parenteral support

The authors stated that because 20 out of 46 patients with initial mucositis of grade II and III completed RT with grade I mucositis, the mouthwash was beneficial. However, additional research is needed.

• Mucositis grade 1 was NOT treated.
• The article did not include statistical evidence.
• The article assumes that the oral mucositis resolved as a result of the mouthwash and not spontaneously; however, no control group was included to validate that conclusion.
• The article focused on infection.

STUDY PURPOSE: To review available literature from 1966 to December 31, 2010 to define clinical practice guidelines for the use of amifostine for prevention and treatment of oral mucositis in patients with cancer

TYPE OF STUDY: Systematic review

DATABASES USED: MEDLINE

KEYWORDS: Extensive list provided (anti-inflammatory agents) including amifostine, antitumor necrosis factor (TNF), non-steroidal anti-inflammatory drugs, TNF inhibitor, etc.

INCLUSION CRITERIA: Detailed information is provided in a different section of the journal. Studies relevant to the management of radiation and/or chemotherapy-induced oral mucositis using anti-inflammatory interventions including amifostine

EXCLUSION CRITERIA: Articles that did not report on intervention and mucositis outcomes, animal or in vitro studies, non-English articles, methodologic quality, and anti-inflammatory agents other than amifostine

TOTAL REFERENCES RETRIEVED: 908

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Only articles that investigated amifostine specifically were selected. Levels of evidence were based on the Somerfield criteria, and study methodology was evaluated on the Hadorn criteria. These were integrated into guideline categories—recommendation, suggestion, or no guideline possible.

• FINAL NUMBER STUDIES INCLUDED = 30
• SAMPLE RANGE ACROSS STUDIES, TOTAL PATIENTS INCLUDED IN REVIEW: Not indicated
• KEY SAMPLE CHARACTERISTICS: Head and neck, high-dose chemotherapy, chemotherapy and radiation

PHASE OF CARE: Active antitumor treatment

No guideline, suggestion, or recommendation for mucositis prevention with amifostine was possible in any of the following groupings.

• Head and neck radiotherapy
• Head and neck chemotherapy/radiation
• High-dose chemotherapy
• Standard-dose chemotherapy
• Radiotherapy alone
• Chemotherapy/radiation prevention

Conflicting results, insufficient data, and major Hadorn flaws did not allow any guideline related to the use of amifostine for oral mucositis prevention. New well-designed trials are necessary that include timing of amifostine infusion prior to radiotherapy, consistent dose of amifostine, and cancer therapy intensity and modality.

Too many studies may have been eliminated up front.

Because no guidelines are recommended by this review, nurses who continue to administer amifostine for mucositis prevention carefully should document the results and look for ways to participate in well-designed trials. Nurses may consider advocating against the use of amifostine outside of research until guidelines can be established for its use.

To determine the effectiveness and safety of methadone analgesia in patients with cancer pain; to assess the adverse effects associated with methadone analgesia for the treatment of cancer pain

Databases searched were Cochrane Pain, Palliative & Supportive Care Group Trials Register; The Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CancerLIT; CINAHL; National Research Register; CenterWatch clinical trials listing service; Current Controlled Trials; National Institutes of Health Clinical Trials Databases; BioMed; Glaxo Wellcome Clinical Trials Register; National electronic Library for Health (NeLH); System for Information on Grey Literature in Europe (SIGLE); Dissertation Abstracts OnDisc; Index to Theses (ASLIB Index); Proquest Digital Dissertations; Cochrane Database of Systematic Reviews (CDSR); and Database of Abstracts of Reviews of Effects (DARE).

• Studies were included if they
  • Involved patients of any age and gender with cancer pain that was chronic and of any intensity and any pain with a malignant etiology. (Etiology could be primary or secondary malignancy, solid or hematologic).
  • Involved patients in a home, outpatient, or inpatient setting.
• Studies were excluded if they involved patients who took methadone for the suppression of cough or patients taking or who had taken methadone for rehabilitation from opioid dependence.
• Of studies retrieved, author analyzed only randomized, controlled trials that assessed symptom control of cancer pain. The control group could be a placebo or an active control. Active controls included any opioid other than methadone, another analgesic, or an adjuvant analgesic. Author accepted published and unpublished trials and, in determining eligibility, established no size restriction.
• Six of the analyzed studies used only the oral route.
  • Three studies compared methadone to morphine.
  • One study compared methadone to a methadone-ibuprofen combination.
  • One study compared methadone to dextromoramide or pethidine.
  • One study compared methadone to diamorphine with cocaine.
• Two of the analyzed studies compared oral and parenteral routes of administration.
  • One study compared IM morphine with IM methadone with oral methadone
  • One study compared methadone with morphine administered intravenously and orally.
• The final study the author analyzed compared methadone with morphine analgesia delivered by a patient-controlled IV infusion system.
• Starting doses, titration schedules, and pain scoring varied widely among analyzed studies.

• The sample included patients, of any age and gender, with cancer pain that was chronic and with a malignant etiology. (Etiology could be a primary or secondary malignancy, solid or hematologic). The pain could be of any intensity. Patients could have been at home or in an outpatient or inpatient setting.
• Patients were excluded from the study if they were taking methadone for suppression of cough or if they were taking or had taken methadone for rehabilitation from opioid dependence.
• Of the trials retrieved, the author analyzed nine randomized controlled trials (six double-blinded trials and two crossovers).
• The sample was composed of 459 recruits, of whom 392 completed the trials.
• All studies involved an active placebo (five morphine, one dextromoramide or pethidine, one diamorphine-cocaine mixture). In each study the starting dose was different, as was each titration regimen and each pain scale.
• Six trials were inpatient studies. Two were outpatient studies. Author added one outpatient study after the last review, to make a total of three outpatient studies analyzed.

Evidence suggests that methadone is an analgesic with an efficacy similar to that of morphine and with side effects that are similar to those of morphine. Although methadone is similar to morphine, the pharmacokinetics and pharmacodynamics of methadone make dose titration difficult. Methadone presents the risk of drug accumulation to toxic levels. There is a significant danger that the effect of methadone accumulation leading to delayed onset of adverse effects has not been represented. The majority of studies involved were single-dose comparisons or pertained to short-term use. Such comparisons fail to reproduce clinical practice; such studies do not reveal delayed adverse effects. One study, which compared methadone to morphine over 28 days, reported an increased rate of withdrawal from the methadone group. Withdrawal was due to side effects. Author drew no conclusion regarding the relative merits, in the management of various pain syndromes, of methadone compared to those of other opioids. The additional study found methadone to be as effective as morphine in the treatment of neuropathic pain, but not superior to morphine.

Few studies presented complete data sets regarding pain. No meta-analysis was possible.