To document the use of methadone as part of an opioid-rotation strategy for the treatment of uncontrolled pain in patients with delirium at the end of life

Ten patients rotated from morphine, five from fentanyl, two from hydromorphone, and three from fentanyl-morphine or morphine- hydromorphone combinations. Authors were purposefully conservative in calculating the starting methadone dose. Within the first week four patients expired, one changed to IV methadone, and two rotated back to morphine because of worsening delirium and inadequate analgesia. At two weeks, 10 patients had expired. Of the remaining 10, seven stayed on methadone. The average dose was 1.1 mg/hour. Two patients returned to morphine, and one was rotated to Percocet.

• The sample was composed of 20 patients with cancer who were experiencing severe pain and delirium at the end of life and whose delirium did not resolve 24 hours after administration of a neuroleptic.
• The age range of patients was 47–77 years.
• Ten males and 10 females participated in the study.
• The study included patients with a variety of cancer diagnoses.

United States

Nonrandomized open-label prospective study

• Numeric analog scale (NAS), to measure pain
• Scale, 0–3, to measure sedation
• Memorial Delirium Assessment Scale (MDAS)
• Opioid dose

Pain control was significant in 15 of 20 patients; average analgesia was good to excellent. Sedation rating decreased from 1.65 to 0.55 on 1–3 scale. Cognitive status improved for nine patients. Six patients achieved moderate improvement in cognitive status; two, partial improvement; and three, no improvement. Three days after the switch from an opiod, average MDAS score improved from 23.6 to 10.6. Decreased alertness on methadone was devoid of agitation.

Methadone can be an acceptable alternative to an opioid in the treatment of refractory pain and terminal delirium. The use of methadone can minimize the need for sedation to treat delirium.

• The study had a small sample. Sample size decreased as patients expired.
• Authors did not specify the process of converting from an opioid to methadone.
• Many patients must be rotated to a different drug.

To evaluate the effectiveness of oral pyridoxine for preventing and treating palmar plantar erythrodysesthesia (PPE) associated with capecitabine

Of the patients receiving oral pyridoxine, 73 patients (74%) received it as prophylaxis, and the remainder (26%) received it as acute hand-foot syndrome (HFS) treatment. The median dose of pyridoxine was 200 mg/m².

• N = 198–99 patients who were receiving capecitabine and pyridoxine and 99 patients who were receiving capecitabine and no pyridoxine

• SITE: Multi-site
• SETTING TYPE: Outpatient centers
• LOCATION: Sentara Cancer Institute in Norfolk, VA

• Retrospective review of 198 charts

• National Cancer Institute Common Toxicity Criteria version 2.0

The data did not support that vitamin B₆ prophylaxis prevented overall PPE incidence in a greater proportion of patients compared with those who did not receive prophylaxis (60% versus 53%). However, when used as treatment, a greater proportion of patients receiving vitamin B₆ reported symptom improvement (65% versus 12%, p < 0.001).

Pyridoxine is not recommended for prophylaxis but may provide some relief for patients with acute HFS.

• The data was obtained from chart review, which is subject to documentation bias and patient selection.
• This was not a controlled trial.
• A controlled trial of Xeloda^® with and without vitamin B₆ seems warranted.

Patients were given oral paroxetine 20 mg orally daily or placebo for eight weeks.

• In total, 479 patients (paroxetine, n = 244; placebo, n = 235) were included.
• Mean age was 56.5 years (standard deviation = 12.6 years) (range 27–87).
• Most of the patients were female, 90% were Caucasian, 57% had breast cancer, and 14% had lung cancer.
• All patients were receiving cyclic chemotherapy (but not concurrent with radiotherapy or interferon).

18 Community Clinical Oncology Program (CCOP) outpatient centers

Patients were undergoing the active treatment phase of care.

The study was a randomized, double-blind, placebo-controlled trial.

• Fatigue Symptom Checklist (FSCL)
• Multidimensional Assessment of Fatigue (MAF) (Question 1 only)
• Monopolar Profile of Mood States (POMS) Short Form Fatigue/Inertia subscale

The paroxetine group and the placebo control had comparable levels of fatigue and depression at study inception. Paroxetine had neither beneficial nor detrimental effects on fatigue. There was a significantly lower mean level of depression in the paroxetine group compared with the placebo group. Treatment with paroxetine also favorably affected patients’ general moods. There were no differences in the effect of paroxetine on fatigue by gender, age, indication for treatment (adjuvant treatment versus treatment for metastatic disease), or by whether patients were more or less fatigued at baseline.

• Whether the paroxetine group and the placebo control group had comparable hemoglobin levels at study inception is unknown.
• Less than .01% (n = 2) of the patients in the paroxetine arm experienced adverse events (skin rash and pulmonary embolus) that were possibly related to the study medication.

No special training is required to deliver the intervention. There are costs related to drug acquisition.

To compare the efficacy and safety of palonosetron with older 5HT3 receptor antagonists (RAs) in preventing chemotherapy-induced nausea

• N = 1,132 (MEC), 1,781 (HEC)
• MEAN AGE = 54.9 years (study 1), 54.4 years (study 2), 55.5 years (study 3), and 56 years (study 4)
• MALES: 22.8% (study 1); 23.1% (study 2); 44.7% (study 3); 44% (study 4), FEMALES: 77.2% (study 1); 76.9% (study 2); 55.3% (study 3), 56% (study 4)
• KEY DISEASE CHARACTERISTICS: Breast, lung, colorectal, ovarian, and gastric cancers and Hodgkin disease; included naïve and not naïve patients 
• OTHER KEY SAMPLE CHARACTERISTICS: Steroids were allowed. Alcohol and tobacco use were tracked.

• SITE: Multi-site
• SETTING TYPE: Multiple settings
• LOCATION: Studies that occurred in Europe or North America

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

Data were pooled from four studies that were multicenter, randomized, double-blinded clinical trials comparing palonosetron, ondansetron, dolasetron, or granisetron.

• Nausea (complete control, nausea-free rates, nausea severity, and use of rescue medication over five days following chemotherapy)
• Nausea and vomiting assessments were done by phone or during clinic visits. Patients were to document all episodes of emesis and nausea, the severity of nausea, and the use of rescue medication in their dairies for five days following chemotherapy.
• A nausea severity four-point categorical scale was used.

The patients treated with palonosetron experienced less nausea each day then the other 5HT3 RAs, and fewer patients receiving palonosetron had moderate to severe nausea. The use of rescue medication was less frequent among patients in the palonosetron arm. The complete control rates for palonosetron versus older 5HT3 RAs were 66% versus 63% during the acute acute phase, 52% versus 42% in the delayed phase, and 46% versus 37% in the overall phase. No safety differences or concerns were noted.

Palonosetron was more effective in treating and preventing nausea than ondansetron, dolasetron, and granisetron. All four agents tolerated equally well.

• Per the authors, the analysis included summarized data but was not powered for statistical comparisons between the agents.
• Nausea is subjective. The reliability may be influenced by the data collector.  
• NK1, which is a standard practice medication, was not used for HEC.

Nurses are aware that palonosetron has a longer half-life and is the medication of choice for outpatient treatment. This study reinforces palonosetron use by noting that more patients receiving it had nausea-free days, lower nausea ratings, and less rescue medication use. Nausea is very subjective, but nurses are aware that it is more of a problem in the delayed phase than actual vomiting. Nausea affects quality of life, and this study can help nurses choose the correct 5HT3 RA.

To describe the use of microsurgical lymphatic venous anastomosis (LVA) to prevent lower limb lymphedema (LLL) in patients with vulvar cancer undergoing inguinofemoral lymph node dissection (ILND)

The intervention group underwent the LVA procedure. Before incision of the skin in the inguinal region, blue dye was injected in the thigh muscles to identify the lymphatic vessels draining the leg. Lymphatic venous anastomosis was performed by inserting the blue lymphatics coming from the lower limb into one of the collateral branches of the femoral vein (telescopic end-to-end anastomosis). For the intervention group, circumferential measurements were assessed at preoperation, at drain removal, at eight weeks and four months postsurgery, and during routinely follow-up examinations. A lymphoscintigraphy was performed one month postsurgery. For the control group, circumferential measurements were taken at routine cancer surveillance examinations. Lymphoscintigraphies were performed at variable intervals of time from the surgery.

• N  = 15  
• AGE RANGE = 54–87 years
• MALES: 0%, FEMALES: 100% 
• KEY DISEASE CHARACTERISTICS: Patients with histologically confirmed invasive carcinoma of the vulva, requiring either unilateral or bilateral ILND, entered the study from November 2009 to June 2011.
• OTHER KEY SAMPLE CHARACTERISTICS: 1 mm or greater stromal invasion, stage IB–III (according to International Federation of Gynecology and Obstetrics classification), and performance status of less than 2 according to the World Health Organization.

• SITE: Single site 
• SETTING TYPE: Not specified 
• LOCATION: University of Genoa, Italy

• PHASE OF CARE:  Mutliple phases of care

• Quasi-experimental design

• Circumferential measurement of the ankle, midcalf, and midthigh
•  Lymphoscintigraphy: Transport index

In the study group, four patients underwent bilateral ILND, and four patients underwent unilateral ILND. Blue-dyed lymphatics and nodes were identified in all patients. It was possible to perform LVA in all the patients. The mean time required to perform a monolateral LVA was 23.1 minutes (SD = 3.6; range, 17–32 minutes). The mean follow-up was 16.7 months (SD = 6.2); there was only one case of grade 1 lymphedema of the right leg. Lymphoscintigraphic results showed total mean transport index were 9.08 and 14.54 in the study and the control groups, respectively (p = 0.092).

This study shows, for the first time, the feasibility of LVA in patients with vulvar cancer undergoing ILND. Although no significant difference noticed in lymphoscintigraphy at one month postsurgery, a trend toward a smaller mean of transport index was noted in the study group. Future studies with larger samples sizes are needed.

• Small sample (< 30)
• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: Different follow-up schedule between the two study groups; short follow-up; single-site study

The study provides nurses with updated information about potential feasibility and early clinical outcome of LVA in patients with vulvar cancer undergoing ILND. However, the small sample size, non-randomized, controlled trial design, as well as short follow-up do not allow the researchers to draw definitive conclusions on the effectiveness of LVA technique in this population. Future large, long-term follow-up randomized, controlled trials are warranted.

To determine efficacy of an icy mouth rinse during the administration of cytarabine

Patients were instructed to rinse the mouth with ice-cold water every 10 minutes during the two-hour cytarabine infusion and for one hour after completion of cytarabine infusion. At each time, patients were instructed to rinse the mouth three times. Oral mucositis grading was evaluated daily from the day treatment began to day 28 post-transplant or until complete resolution of mucositis. Maximum grades were used in analysis.

• The study reported on 15 patients. These patients were compared to 35 historical controls.
• Median age of patients was 50 years, with a range of 31–57 years. In the historical control group, the median age of patients was 40 years, with a range of 20–56.
• The sample was 46% female and 54% male.
• All were patients undergoing allogeneic stem cell transplant with a conditioning regimen of total body irradiation and high-dose cytarabine.

The study was conducted at a single-site inpatient setting in Tokyo, Japan.

This was a prospective trial with comparison to historical controls.

The National Cancer Institute common toxicity criteria grading for mucositis was used.

Incidence of grade 2 mucositis  (p = 0.009) and grade 3 mucositis (p = 0.02) was significantly lower in patients who used the mouth rinse compared to the historical controls.

Findings suggest that the cytarabine excreted into saliva contributes to high-dose, cytarabine-induced oral mucositis. Approaches such as mouth rinsing may remove this from the oral cavity and help in the prevention of severe mucositis. How the temperature of the rinse may influence effects is not known.

• The sample size was small with fewer than 30 patients.
• This was not a prospective study.
• No appropriate control or comparison group was included.

Use of ice water rinses during chemotherapy infusion is a simple intervention that might be helpful for prevention of oral mucositis. Well-designed research in this area is warranted, and application and timing of use with other chemotherapeutic agents needs to be examined.

To determine if shorter duration of cryotherapy would minimize side effects without affecting efficacy

Patients were instructed to use cryotherapy 15 minutes before, for 15 minutes during, and for an additional 30 minutes after receiving high-dose melphalan infusion (140 mg/m²). The cryotherapy consisted of continuously swirling ice chips in the mouth and gargling with and swallowing ice-cold water every 10-20 minutes throughout a total of 60 minutes. These patients were compared to 18 historical controls who used cryotherapy for 120 minutes. The 17 patients in the study received fludarabine 25 mg/m² daily for five days and melphalan 70 mg/m² per day over 15 minutes for two days, two days prior to hematopoietic stem cell transplantation (HSCT). Some patients received additional chemotherapy or radiation therapy.

The National Cancer Institute (NCI) common toxicity criteria (CTC) were used to evaluate stomatitis.

Two of the 17 patients in the study (11.1%) developed grades 2–3 oral mucositis, compared to two out of 18 historical controls (11%) who used cryotherapy for a longer time period. Although this is not a statistically significant difference, patients in the study group did report significantly lower incidence of unpleasant symptoms compared to those in the historical control group (p < 0.001).

This article provided an interesting discussion and rationale for adjusting the length of oral cryotherapy to relieve patient discomfort.

The sample size was small, and this was not a controlled study.

Two grams of powdered NaHCO₃ diluted in 250 ml water was sipped during the days of irinotecan administration, starting in the morning. Other fluids were taken ad lib.

• N = 24
• KEY DISEASE CHARACTERISTICS: Patients with gastrointestinal carcinoma 
• OTHER KEY SAMPLE CHARACTERISTICS: Patients receiving varying irinotecan-based regimens 

• SITE: Multi-site
• LOCATION: Four Spanish community practice settings

• Experimental, interventional, prospective study
  • No control

• Diarrhea grade, although no mention of which grading scale was used

Four of 24 patients (16%) had grade III–IV diarrhea (8 had prior pelvic radiation therapy, a risk factor associated with diarrhea). Comparison was made to incidence of grade II–IV diarrhea in previous colorectal cancer studies. The researchers’ conclusion was that intestinal alkalization may be effective in preventing diarrhea with patients with gastrointestinal cancer receiving irinotecan.

• Uncontrolled trial
• Small numbers

To determine if pre- and postmastectomy treatment with memantine can prevent neuropathic pain, impaired cognition, and decreased quality of life (QOL)

Memantine 5–20 mg or placebo was given daily for four weeks starting two weeks prior to mastectomy, with increasing doses during the first two weeks prior to mastectomy and maintained at 20 mg during two weeks after surgery. The control received placebo daily for four weeks starting two weeks prior to mastectomy. Assessment was baseline, two weeks prior to surgery, two weeks after surgery, and three and six months postop.

• N = 40   
• AGE = 18 years and older
• FEMALES: 100%
• CURRENT TREATMENT: Immunotherapy
• KEY DISEASE CHARACTERISTICS: Woman diagnosed with breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Participants were aged 18 years or older, planned for mastectomy with or without axillary dissection, and were able to understand and follow protocol. Exclusions: contraindications for memantine and hypertension, severe cardiac insufficiency and/or diabetes, alcohol addiction, treatment with certain drugs, childbearing age, no use of effective contraceptive, pregnancy or lactation, involvement in another trial, inability to comply with protocol requirements

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: University Oncology Hospital, Clermont-Ferrand, France

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

• Randomized, single-blind, placebo controlled trial

• Numerical rating scale
• Brief Pain Inventory (BPI)
• McGill Pain Questionnaire (MPQ)
• Neuropathic Pain Diagnostic Questionnaire (DN4)
• Neuropathic Pain Symptom Inventory
• Trail Making Test (TMT)
• Digit symbol substitution test (DSST)
• Leeds Sleep Evaluation Questionnaire (LSEQ)
• Quality of life by the SF-36
• Surgical- and chemotherapy-induced neuropathic pain were differentiated.

A significant reduction in pain at three months postoperatively was noted (p = 0.017) and better ability to cope with pain was demonstrated (p = 0.032). No significant difference was noted at six months. Secondary outcomes for pain intensity showed no significant difference. A significant difference existed in use of antiepileptics for pain at M3 which was maintained up to M6 (M3, p = 0.04; M6, p = 0.04) with overall significant time difference (p = 0.041). Pain was significantly less for those receiving chemotherapy at M3 (p = 0.04) and M6 (p = 0.009). In addition, chemotherapy-induced paresthesias/dysesthsias was significantly reduced at M3 compared to the day of inclusion (p = 0.01). No significant difference was noted in cognitive function or QOL. No significant difference was noted in regards to LSEQ; however, significance was noted for behavior following wakefulness at M6 (p = 0.038).

Memantine can potentially reduce post-mastectomy and chemotherapy-induced nerve pain while limiting polypharmacy and comorbidity associated with the current treatment approach. This approach would need to be demonstrated in a larger population, with a longer term follow-up and potential dosing change.

• Small sample (< 100)
• Findings not generalizable
• Not generalizable to all chemotherapy patients nor surgical patients for treating neuropathic pain

Nurses would need to be educated on use of memantine for pain control and the potential side effects. Patient education would be required to help the patients understand the use of this medication for treatment of pain. Results of the effects of this approach may be limited.

• FINAL NUMBER STUDIES INCLUDED = 12
• TOTAL PATIENTS INCLUDED IN REVIEW = 442
• SAMPLE RANGE ACROSS STUDIES = 12–107 patients
• KEY SAMPLE CHARACTERISTICS: Although education status may influence neuropsychological test results, only half of the studies provided this information. Likewise, menopausal status may affect cognition, and this was only reported by two thirds of the studies.

PHASE OF CARE: Late effects and survivorship

Studies of pharmacologic interventions were not found to be effective in improving cognitive function. Medications reviewed included d-methylphenidate (n = 1), epoetin alfa (n = 2), and ginkgo biloba (n = 1). Evidence for nonpharmacologic interventions was mixed. No improvements in cognitive function were found with Tibetan sound meditation (n = 1). Natural restorative therapy (n = 1) improved attention only when comparing the baseline with the final 90-day evaluation (p = 0.01). Exercise (n = 1) improved attention (p = 0.019) and verbal memory (p = 0.048) but not working memory. Cognitive rehabilitation (n = 1) improved four out of six measures of information processing speed (p < 0.05) but not attention, verbal memory, or executive function. Cognitive behavioral training (n = 2) improved verbal memory (p < 0.05) in both studies and was effective in improving in information processing speed when compared to baseline scores in one study (p ≤ 0.01) but not the other. Computerized cognitive training was effective in one study in improving processing speed (p = 0.009), executive function (p = 0.008), and a measure of executive function and language (p = 0.003) but not verbal memory. However, in another study, there was no difference in verbal memory or information processing speed between the intervention and control groups.

Nonpharmacologic interventions, especially cognitive training, may have a role for improving attention, information processing speed, and verbal memory. Exercise and computerized cognitive training may be effective for improving executive function. However, additional research validating these findings with larger sample sizes and evaluating other cognitive domains is needed. In addition, studies determining the dose or duration of interventions is required for a durable response.

• A small number of studies (n = 12) were included in the review for multiple types of interventions.
• Only one study had a sample size greater than 100 (range = 12–107).
• Studies of low quality were included. 

These findings suggest that nonpharmacologic, not pharmacologic, interventions may be helpful in managing chemotherapy-induced cognitive impairment in patients with breast cancer. However, these findings were based on a small number of studies per intervention. Additional research validating which interventions might be useful in improving cognitive impairments in women receiving chemotherapy for breast cancer is needed.