Prevention of combination drug therapy-induced OM (stomatitis) This is the second clinical trial supported by Novartis in patients taking combination drug therapy (everolimus and exemestane).

This is the first and largest OM prevention study completed that combines therapeutic management with proactive patient engagement to reduce the incidence of OM in patients who are postmenopausal and receiving combination pill therapy(everolimus and exemestane) as treatment for hormone receptor-positive, HER2-negative metastatic breast cancer. Dexamethasone oral solution was used for two minutes, four times a day.

This is the second clinical trial performed by Novartis to eliminate dose interruption of everolimus tablets in combination therapy for women with hormone receptor-positive, HER2-negative metastatic breast cancer. The average age of the 92/86 female participants was 61 years.

This was a multi-center study in the U.S.

It was a single-arm phase 2 study

Stomatitis was graded with a composite score of CTCAE 4.0, visual analogue scale, and Normalcy of Diet Scale. 

The primary endpoint of the incidence of Grade 2 or worse OM was significantly reduced by proactive oral care use of alcohol-free dexamethasone oral solution (SWISH). At 8 weeks, incidence of Grade 2 mucositis was 2% (dexamethasone) versus 33% for historical controls.

The use of dexamethasone oral solution for two minutes, four times a day, will stop OM from occurring or reduce the severity. It is used for eight weeks or longer if results are positive.

The primary limitation is it is for only one targeted group and for one target drug. The clinical trial is high strength and high quality. There could not be a control group due to the fact that the investigators did not find it ethical for patients to suffer with OM. Novartis is the manufacture of dexamethasone oral rinse and gives free eight-week supplies. There were no long-term results.

The nursing implication is to teach an oral care protocol to all patients with cancer and ask for more clinical trials for patients with other types of cancer or receiving other treatments. The SWISH trial found that a commercially available, inexpensive, well tolerated dexamethasone oral rinse is an effective intervention in the prevention of OM in women with HER2-negative metastatic breast cancer treated with everolimus.

To investigate the clinical phenotype of CIPN and longitudinal patterns of CIPN over 24 month period in patients on the SWOG S0715 trial (double-blind RCT of stage I-III patients with breast cancer who received an adjuvant taxane-based regimen and compared CIPN between those in the treatment group - acetyl-L-carnitine (ALC) versus the placebo control group x 24 weeks)

• SWOG S0715 post-trial statistical analysis evaluating two-year trends for effect of ALC on peripheral neuropathy using baseline demographics factors and longitudinal data (24 months) of neurotoxicity scores (NTX) scores collected at study baseline, 12, 24, 36, 52, and 104 weeks (see SWOG S0715 trial below). Neurotoxicity scores were analyzed using linear mixed models. Linear regression analyzed individual time points. Baseline neurotoxicity scores and stratification factors were considered in the regression analysis.
• SWOG S0715 trial: A double-blind RCT of women older than age 18 years and with a diagnosis of stage I-III breast cancer receiving an adjuvant taxane-based chemotherapy regimen with a stratified random assignment (by taxane-based chemotherapy regimen and age younger than 60 or older than 60) to either the study drug group: Acetyl-L-carnitine (ALC) 3,000 mg per day divided into six tablets (1,000 mg three times a day) versus control group: matching placebo cellulose 3,600 mg per day divided into six tablets,(1,200 mg three times a day). Treatment with either ALC versus placebo control started at the beginning of chemotherapy and continued daily for a duration of 24 weeks. Peripheral neuropathy was measured at baseline and at 12, 24, 36, 52, and 104 weeks. 
• Taxane-based chemotherapy regimens: weekly paclitaxel 80 mg/m² for 12 cycles, biweekly paclitaxel 175 mg/m² for 4 or 6 cycles, every-three-week docetaxel 75 mg/m² for 4 or 6 cycles

• N = 409 at baseline; 327 at two years   
• MEAN AGE: Combined, 52.5 years; ALC, 53.3; placebo, 51.9
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage I-III breast cancer starting adjuvant treatment with a taxane-based regimen
• OTHER KEY SAMPLE CHARACTERISTICS: Age, race, ethnicity, weight, prior mastectomy, planned treatment regimen, performance status, and receipt of G-CSF; patients with diabetes, prior CIPN, and kidney disease, and those taking vitamin E, glutamine, gabapentin, nortriptyline, amitriptyline, duloxetine, or other potentially CIPN-treating supplements were excluded.

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

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care

Multi-site double-blind randomized-controlled trial

Peripheral neuropathy measured by the 11-item neurotoxicity section of the Functional Assessment of Cancer Therapy-Taxane (FACT-NTX). A lower score indicates worse CIPN and more than 10% (or 5 points) is considered clinically significant. Sensitivity analysis done to evaluate a 10-point decrease in the FACT-NTX scores from baseline; other measurements were secondary outcomes: FACT-Taxane Trial Outcome Index; fatigue measured by 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. All patient measurements taken at baseline and weeks 12, 24, 36, 52, and 104.

Linear mixed model results showed the average difference of NTX between the ALC group and placebo control group was statistically significant (p = 0.01) with worsened CIPN in the ALC group, at 24 weeks (p = 0.02); 36 weeks (p = 0.04); and 52 weeks (p = 0.02) compared to the placebo control group. Functional status (FACT TOI) scores worsened at weeks 24 (p = 0.04) and week 52 (p = 0.05), but was not significantly different at week 104 (p = 0.09). No difference between ALC group and placebo control group for FACIT-Fatigue. No differences observed between groups for medications taken to treat CIPN. At one year, women aged 60 or older had a higher risk of worsening peripheral neuropathy compared with women 60 years or younger at one year (OR = 1.74, p = 0.02) and at two years (OR = 1.67, p = 0.04).

In women receiving a taxane-based chemotherapy, 24 weeks of ALC therapy to reduce symptoms of CIPN caused a statistically significant worsening of short- and long-term CIPN over two years compared to placebo. Age was a risk factor for long-term CIPN. Women 60 years or older were 1.5 times more likely to have clinically significant long-term CIPN.

Exploratory statistical plots showed a non-linear relationship requiring statistical transformation procedures; no quantifiable neuro-diagnostic tests, such as balance/nerve conduction/TNS; no differentiation between sensory, motor, or autonomic neuropathy; no reports of comorbidities developing over course of study; no cumulative taxane dose or number of cycles received

Acetyl-L-carnitine (ALC) has previously been identified as a potential pharmacotherapeutic option for CIPN; however, based on the study results, ALC is not recommended as therapy for CIPN because it can cause harm in worsening CIPN. This study points to the necessity for further research into the mechanisms of CIPN, toxicities, and preventive interventions.

To explore the effects of aromatherapy hand/foot massage on chemotherapy-induced peripheral neuropathy (CIPN), pain incidence and severity, and fatigue severity, compared to standard care in GI cancer survivors who are actively receiving oxaliplatin

• Intervention: Aromatherapy hand/foot massage: ~40 minute sessions (10 minutes each hand/foot), 3 times per week, for 6 weeks (1-2 rest days between massages). Techniques included effleurage, light friction, and petrissage.
  •   Interventionist: the PI “qualified in massage therapy”
  •   Setting: Patients’ homes
  •   Essential oils: Chamomile, peppermint, and rosemary 1:1:1 blend in coconut oil made q72 hours ~2 ml applied to each hand/foot.
• Control condition: Standard care

• N = 46   
• AGE: 55.8 years (SD = 8.49) 
• MALES: 59%  
• FEMALES: 41%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Actively receiving FOLFOX6; primarily patients with colon cancer; stage of cancer unknown.
• OTHER KEY SAMPLE CHARACTERISTICS: Paresthesias rated ≥ 1 on NRS (range = 1-7); 2 (4%) patients had neuropathic pain at baseline per the DN4 cut-off; similar groups at baseline (including CIPN levels and dose/cycle of oxaliplatin received). Excluded patients with brain metastasis and preexisting neuropathy; whose oxaliplatin dose was reduced; and who were taking medication for neuropathy. 63% of eligible participants were recruited; 87% completed study. Two control group participants discontinued study due to fear of getting CIPN. 15% had received chemotherapy prior to their current FOLFOX regimen.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Ankara, Turkey: two university/research oncology hospitals

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care, palliative care

Pilot, open-label, repeated measures, non-randomized, standard care-controlled quasi-experiment.

• Douleur Neuropathique 4 Questions (DN4): assessed patient self-reported neuropathic pain degree and presence via interview of neuropathic pain characteristics and association of pain with numbness, tingling, and itching; and clinical examination of painful area (hypoesthesia, pinprick, and allodynia). 
• Patient-report surveys: “Patient Questionnaire” (CIPN symptom location, aggravating factors, timing of peak severity, demographic, and clinical characteristics); 0-10 NRS (Current painful paresthesia severity-no pain to worst possible pain); Piper Fatigue Scale (PFS)
  • Timepoints of measurement: 
    • Baseline (before starting intervention)
    • At chemotherapy visits
      • ~mid-study (at 2 and 4 weeks)
      • ~post-intervention (6 weeks)
      • ~2 weeks postintervention completion (8 weeks)
  • Assessor: PI

• DN4: significantly lower CIPN neuropathic pain incidence in the intervention group (IG) than the control group (CG) at 6 weeks (p = 0.046), and severity at 4 and 6 weeks (p range = 0.006-0.027). 
• 0-10 NRS: significantly lower painful paresthesia severity after just one week in the IG than the CG (p ≤ 0.016). Median NRS scores remained a 3-4 at each follow-up (weeks 2-8), which was lower than the baseline score of 4.3, in the IG; but the NRS scores steadily increased from 4 at baseline to 5.5 at 8 weeks in the CG.
  • These effects (DN4 and NRS) did not last up to the 8-week timepoint.
• Piper Fatigue Scale (PFS): significantly lower fatigue levels at the 8-week timepoint in the IG than the CG (p = 0.036).

Aromatherapy hand/foot massage, using chamomile, rosemary, and peppermint oil, given 3 times per week for 40 minutes (10 minutes each hand/foot) during FOLFOX treatment may: 

• Transiently reduce the incidence and severity of CIPN neuropathic pain after 6 weeks, compared to standard care
• Help to treat or prevent the worsening of CIPN pain, as early as after one week of intervention; and fatigue long-term (2 weeks post a 6-week period of aromatherapy/massage treatment)

However, more rigorous RCTs with blinded assessors, utilizing larger sample sizes, are needed to evaluate the preventative and treatment effectiveness, necessary dosage, physiological mechanisms, and long-term effects of aromatherapy hand/foot massage on FOLFOX-induced CIPN pain.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition) 
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Selective outcomes reporting
• Measurement validity/reliability questionable
• Intervention expensive, impractical, or training needs
• Other limitations/explanation: Participants were recommended for the study by the med-oncs (sample bias); named as randomized, but procedures described a stratified but not randomized approach. PI was the massage therapist (unclear certification for massage therapy) and assessor of the primary outcome. Therapeutic interaction during massage could have contributed toward the intervention efficacy. Unspecified baseline assessment timing relative to chemotherapy infusion. Missing values were filled-in using the last-observation-carried-forward method. Mentioned a “primary education program” on page 5 with a very low completion rate, but this program was not mentioned elsewhere. No report of “Patient Questionnaire” outcomes. Measures were highly subjective. Intervention requires a certified aromatherapy/massage therapist able to travel to give 3 home visits of 40 minutes each. No control for potential moderators, such as mood/psychological well-being/coping.

Aromatherapy hand/foot massage during oxaliplatin treatment may be a safe and promising nonpharmacologic therapy for CIPN pain and fatigue. Further investigation of this therapy is warranted.