To test the potential benefit of psychostimulants in managing fatigue in men with prostate cancer.

Patients were randomly assigned to receive methylphenidate or placebo for up to six weeks. Methylphenidate was started at 5 mg once daily and titrated upward by 5 mg every two to three days to a maximum of 30 mg/day. The physician or research nurse was in contact with each patient at least twice weekly for dosage and patient safety evaluation. Study data were collected at the time of study entry and at the end of the six-week study period.

• The study was comprised of 39 men with advanced prostate cancer receiving either chemotherapy or hormonal therapy.
• Mean age was 70 years (standard deviation = 9 years). 
• Of the patients, 90% were Caucasian, 71% were married, and 70% had a college education.
• Patients were eligible if they rated an average level of fatigue of 4 or greater on a 10-point scale over the past two weeks.
• Patients were excluded if they had cognitive impairment, major depression, or medical conditions or were taking medications that contraindicated use of a psychostimulant. 

• Single site
• Outpatient 
• Memorial Sloan Kettering

This was a randomized, double-blind, placebo-controlled, intervention study.

• Brief Fatigue Inventory (BFI)
• Fatigue Severity Scale (FSS)
• Hospital Anxiety and Depression Scale (HADS)
• Beck Depression Inventory (BDI)
• Functional Assessment of Cancer Therapy–Prostate (FACT-P)
• Systematic Assessment for Treatment of Emergent Events (SAFTEE) questionnaire

Of the eligible patients screened, 54% declined to participate. Of the patients in the methylphenidate group, 31% were discontinued due to increased blood pressure, and another 16% were removed due to tachycardia. The methylphenidate group showed significant reduction in BFI fatigue scores from 5.13 to 2.19 (p = 0.01). The placebo group also showed significant reduction in scores (p = 0.02). There was a difference between groups in the changes in fatigue during the study, with those in the methylphenidate group showing greater reduction in fatigue (p = 0.07; d = .80). There were no significant differences between groups in depression, anxiety, quality of life, or measures of cognitive function. The separation of study drug and placebo effects emerged at weeks 3 and 6.

The results suggested that methylphenidate was associated with a decline in fatigue; however, it was also associated with substantial cardiovascular side effects in almost half of the patients. A significant placebo effect was also observed.

• The study had a small sample size, with less than 100 patients. 
• There was substantial difficulty accruing patients for the study, and the sample was not sufficiently powered.

Psychostimulants may be helpful to some patients in managing fatigue, but their use should be accompanied by close monitoring of potential side effects.

The purpose of this study was to evaluate the dosage, effectiveness, and tolerability of an isopropanolic extract of black cohosh (Cimicifuga racemosa) in patients with breast cancer taking tamoxifen and reporting menopausal symptoms.   

The study drug, Remifenin, was dosed at 2 tablets by mouth per day (40 mg black cohosh total) for 4 weeks but then participants could self-escalate the dose per patient preference (20, 40, 60, or 80 mg) and continue daily tablets for up to 6 months (mean 134 days). Participants were assessed at baseline and again 3- and 6-months later (90 and 180 days later). A subset of 4 patients also took St. John’s Wort.

• 50 participants completed baseline, 47 completed first assessment, 40 secondassessment, and 35 final assessment. All available participants were used in the analyses.
• AGE:  Mean age of 56 years (range 43-77), no age SD reported.
• MALES (%)  0%    FEMALES (%)  100%
• KEY DISEASE CHARACTERISTICS:  All stages of breast cancer, estrogen receptor positive (n=44, 94%), metastases (n=4, 9%)
• OTHER KEY SAMPLE CHARACTERISTICS:  Mean of 8.6 months post diagnosis, 74% postmenopausal, 100% taking tamoxifen

• SITE: Single site   
• LOCATION: Germany
   

• PHASE OF CARE: Transition phase after initial treatment
• APPLICATIONS: Late effects & survivorship

Prospective, longitudinal, non-randomized study

• Menopause rating scale - self-assessment, profile and intensity of 11 menopausal symptoms, subscores for symptom domains of vegetative-somatic, psychic, and urogenital symptoms
• Physician documentation of tumor characteristics

There was a significant reduction in menopause rating scale scores, total scores, and subscales of vegetative-somatic and psychic symptoms at 1, 3, and 6 months of treatment. The overall MRS II score significantly decreased from 17.6 to 13.6 between baseline and last observation (p<0.001).   Two of the three symptom subscales also decreased significantly (vegetative-somatic and psychic both p<0.01).  However, the was no evidence of effectiveness for urogenital symptoms.  Symptoms that were initially most intense such as hot flashes, sweating, and sleep disturbances improved most during the observation period.

The effectiveness of black cohosh extract for treatment of menopausal symptoms among women taking adjuvant tamoxifen is still unclear.  Daily use over at least 4 weeks may result in reduced hot flashes and sleep disturbances.  The drug was well tolerated in the small sample; however, it is unclear what the ideal dosing is for therapeutic benefit.

Limitations of the study included:

• No appropriate control group
• Small, non-randomized study  
• 30% drop out rate over 6 months 
• Dosage varied
• Use of St. John’s Wort known to interfere with CYP450 isoenzymes and could have affected tamoxifen metabolism and the resulting side effects 
• Did not study possible impact on hormones
   

Black cohosh could be studied in a randomized trial but this study does not provide any efficacy information in relation to placebo. 

To evaluate the effectiveness of oral pyridoxine as prophylactic therapy for Palmar-Plantar Erythrodysesthesia (PPE)

The first 15 patients were treated without prophylaxis with oral pyridoxine. The following 20 patients were given oral pyridoxine 300 mg per day for 56 days.

• N = 35
• KEY DISEASE CHARACTERISTICS: Patients with locally advanced breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Receiving pegylated liposomal doxorubicin (PLD) (15 mg/m² biweekly for four administrations) and paclitaxel (80 mg/m² weekly for eight administrations) as neoadjuvant chemotherapy

• LOCATION: Oncology unit at S. Salvatore Hospital in Pesaro, Italy

• Phase II study
  • Started in 2004

• Article discussed grade 1, grade 2, and grade 3 PPE

In group 1, 33% developed PPE—one patient developed grade 3, and four patients developed grade 2 PPE. In group 2, 40% developed PPE—three patients developed grade 3, and five patients developed grade 2 PPE.

Prophylactic use of vitamin B₆ may not be useful with biweekly administrations at low dose (15–20 mg/m²) because of low frequency of PPE documented with this particular schedule.

• Small sample size
• No randomization of patients
• Low doses of PLD
• Inadequate description of measurement tool/method to grade PPE symptoms; reliability and validity unclear

GMCSF subcutaneously
(4 mcg/kg) from days 6-10 during cycle following the cycle Grade ≥ 2 mucositis was reported.

Also received “standard” anti-mucositis treatment

The study was comprised of 31 patients, age 39-77 years with a median age of 68.
Three stage phase II trial
Colorectal cancer treated with 5FU plus leucovorin and reporting mucositis ≥ Grade 2.
 

Chen design
WHO Mucositis – 3x/wk:

Grade 0 = none

I = painless ulcers, erythema, or mild soreness
2 = painful erythema, edema, or ulcers
3 = can’t eat solids
4 = TPN or enteral support
 

77 GM-CSF cycles were administered (median/pt = 3).

Success claimed based on reduction of at least one grade of mucositis.

9 of 20 responders mucositis disappeared – 64.5%

45% with mucositis responded, 12.9% failure, 3.2% stopped treatment
3.2 % (1 patient) with mucositis plus diarrhea responded, 3.2% treatment failure, 3.2% stopped treatment

Toxicity in 7 of 20 patients

 

Claim results are rationale for well-designed trial

No control group
Small N
No P values stated percentages hard to follow.

To evaluate the effectiveness of gabapentin for cancer-related neuropathic pain

Gabapentin was administered at a dose of 300 mg/day up to 1.8 g/day over 15 days. Final doses were taken in three divided doses. Two parallel groups were recruited with either treatment-related (n = 25) or tumor-related (n = 37) neuropathic pain. Gabapentin was dose-escalated from 300 mg/day to 1.8 g/day. Median dose was 1,200 mg/day. Patient selection was nonrandomized.

• The study reported on 62 patients: 16 males and 46 females, 21 of whom had had breast cancer.
• A total of 41 patients completed to day 15.
• Patients were excluded from the study if they had started treatment that was likely to affect their neuropathic pain, such as anticonvulsants (< one month), antidepressants or steroids (< seven days), and anesthetic interventions, such as nerve blocks (< two weeks).

Patients were selected from inpatient and outpatient settings in a U.K. tertiary referral center.

Prospective, open-label studies of inpatients and outpatients

Patients completed pain and side-effect scores and were evaluated by a clinician on days 0, 8, and 15. In addition, pain scores were obtained on day 4. Pain was assessed using the modified Brief Pain Inventory (BPI) to measure pain on a 0–10 scale. Patient descriptors of pain and scores of activities of daily living (0–10 scale) were collated together with demographic data. Toxicity scores ranged from “not at all” to “a little,” “quite a bit,” or “very much.”

Baseline and final pain scores were not significantly different between the tumor-related and treatment-related groups. In addition, ANOVA did not show etiology to be a significant predictor of response to gabapentin. Data from both groups were pooled into the primary analysis. A total of 41 patients completed the study, with the median-range dose of gabapentin to be 1,200 mg/day. A total of 28 of 62 patients achieved at least a one-third reduction in their pain score (95% CI); the number needed to treat to obtain this benefit was 2.2. There was a significant reduction in all scores measuring the impact of pain on daily living (p < 0.003). ANOVA suggested that gender and cancer diagnosis, but not etiology of neuropathic pain or type of neuropathic pain, were independent predictors of change in average pain score. There was suggestion that beneficial effect was only in women, not men; men with bowel or lung cancer showed no benefit. This may be a chance subgroup finding. There was significant reduction in worst, average, and current pain scores (p < 0.002), but not in least pain scores. The tumor group described pain as shooting, pins and needles, and the treatment group described pain as hot, burning sensations. There was no significant difference in pain scores on day 8 compared to day 15. No further pain relief was reported from day 8 to day 15—if improvement is not seen in one week, this suggests that an alternative drug should be started. Six patients (10%) discontinued study because of probable drug-related side effects, 14% reported mild/moderate side effects, and 45% were already taking steroids or antidepressants, although doses did not change during the study.

Gabapentin is an effective treatment for cancer-related neuropathic pain from both tumor and treatment.

• The study time period was short and therefore may not have given enough time for patients to gain confidence and reduce the amount of opioid use. Further, patients were not randomized, so the placebo effect is not clear.
• Breakthrough medications were available, but their use was not documented.
• Women had a better response, which may be a chance subgroup finding or related to diagnosis (21 of 46 female patients had breast cancer).
• Gabapentin was not used prophylactically.
• Dose escalation was limited by side effects. Side effects were not clear; 10% left study due to side effects, and 14% had mild/moderate side effects.
• Of 62 patients, 41 completed study to day 15.
• Patients in the tumor group were more likely to be on steroids, and patients in the treatment group were more likely to be on antidepressants.
• This was a single-site study; there was no comparison between methods employed at different radiation centers.

Side effects included drowsiness, unsteadiness, dizziness, nausea, headache, and others. There was no change in opioids during study—one might question whether there could there be a synergistic effect between gabapentin and opioids. Studies need to be performed to determine if the escalation of a dose greater than 1,800 mg/day is beneficial between men and women and different cancer diagnoses.

To compare the efficacy of two dose levels of octreotide long-acting release (LAR) in preventing chemotherapy-induced diarrhea (CID) in patients with active or prior CID

A sample of 124 evaluable patients were assigned randomly to either the 30-mg or 40-mg octreotide dose group. The first dose of ocreotide was given intramuscularly 7–14 days prior to day 1 of the patient's next chemotherapy cycle. The second dose coincided with the chemotherapy cycle. Subsequent cycles were given every 28 days up to a total of 6 doses on a schedule independent of the chemotherapy cycles. Prior to initiation of octreotide LAR, patients were given a 100-mcg test dose of octreotide subcutaneously to determine potential intolerance.

• The two treatment groups were similar in current chemotherapy regimens, severity of most recent diarrhea episode, body weight, primary tumor type, and proportion of patients with colostomy prior to study entry.
• More than half (57%) of patients were receiving regimens with 5-fluorouracil (5-FU) with or without irinotecan, leucovoran, or oxaliplatin; 25% were receiving irinotecan regimens with or without 5-FU, leucovoran, or oxaliplatin.
• Primary tumor types were colorectal (75%), breast (7%), lung (6%), hematologic (1%), other (10%).

This was an open label, randomized, multicenter study with a parallel-group design.

• Patient diaries were collected on a monthly basis to obtain data for diarrhea assessment, concomitant medications, adverse events, and use of healthcare resources.
• Health-related quality of life (QOL) was assessed at baseline and at the end of each study visit using a modified Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT_D) scale.
• Investigators collected data from the Treatment Satisfaction Questionnare for Medication for Chemotherapy Induced Diarrhea (TSQM-CID), a version of the previously validated TSQM, at baseline for loperamide and diphenoxylate and at the end of study visit for octreotide LAR.
• The primary study endpoint was the proportion of patients experiencing severe diarrhea (National Cancer Institute [NCI] grade 3 or 4).
• Secondary study endpoints were the proportion of patients requiring IV fluids, unscheduled provider visits, and changes in primary therapy because of diarrhea as well as treatment satisfaction and QOL.

• The proportion of patients who experienced severe diarrhea (grade 3 or 4) during the study was 61.7% in the 30-mg group and 48.4% in the 40-mg group (p = 0.14).
• Fewer patients in the 40-mg group experienced severe diarrhea, required IV fluid (p = 0.11), or had unscheduled diarrhea-related healthcare visits (p = 0.11).
• The percentage of patients in the 30-mg group who had changes in their primary therapy as a result of diarrhea was 61.7%, and the percentage in the 40-mg group was 64.1% (p = 0.78).

• No comparison was made between daily and three times per day octreotide and octreotide LAR.
• The 30-mg group contained a significantly greater proportion of females because sensitivity analysis showed no need to adjust for gender.

No specific recommendations regarding the superiority of 30 mg or 40 mg octreotide in the management of CID can be made based on this study.

To evaluate the effects of yoga, massage, and Reiki therapies on stress, pain, anxiety, mood, overall health, and quality of life (QOL)

Data were collected from patients who self-enrolled in yoga, Reiki, and massage services during a six-month period. Patients completed study questionnaires before and after participating in one of these services, within one to three minutes before and after participation.

• N = 150   
• AGE = Not provided
• MALES: 9%, FEMALES: 91%
• CURRENT TREATMENT: Chemotherapy, radiation therapy, other
• KEY DISEASE CHARACTERISTICS: Patients involved were at varied points in the care trajectory, and 75% were either newly diagnosed or had completed initial treatment. Disease types were not reported.

• SITE: Single site   
• SETTING TYPE: Other    
• LOCATION: Community center in Illinois

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care 

• Quasi-experimental

• 10-point rating scales for all outcome measures

The time patients had been participating in the service ranges from one month to more than three years. Significant changes in pain levels pre- and postservice provision were reported (p < 0.001). Individuals receiving Reiki had higher preservice pain levels. Center staff encouraged patients with pain to enroll in Reiki. No significant postservice differences in pain across the intervention types were reported. All patients reported lower anxiety scores after receiving the service (p < 0.001) with no differences between groups.

Integrative therapies such as Reiki, massage, and yoga may be helpful for management of symptoms such as pain and anxiety.

• 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
• Measurement validity/reliability questionable
• Author states that this was a repeated measures design and used repeated measures ANOVA, but description of methods looks as if each patient completed study assessment only immediately pre and post a single service. 
• Measurements were at a time point immediately before and after a service—it is unclear how meaningful this timing is in terms of looking at ongoing symptom management.
• Validity of the instrument for measurement and interpretation of anxiety and mood is questionable.
• Pain levels overall were low,suggesting potential floor effects in measurement in non-Reiki patients.
• No information is provided about chronicity, type, etc., for pain, or any other interventions being used for pain.

This study has numerous limitations and high risk of bias, so no firm conclusions can be drawn about the actual efficacy of the interventions being evaluated.

Palifermin was administered at 40 mcg/kg IV for three consecutive days before each of two chemotherapy cycles with fluorouracil (5-FU) or leucovorin (LV).

The study reported on patients with metastatic colorectal cancer receiving 5-FU or LV. The group receiving palifermin had 28 patients, and the group receiving placebo had 36 patients.

This was a phase I and II randomized double-blind, placebo-controlled study.

• The World Health Organization (WHO) Oral Toxicity scale was used.
• Patients were assessed on days 1, 4, 8,12, 15, and at the end of both cycles on day 28.
• Patients also were assessed with the Oral Mucositis Daily Questionnaire, which consists of 10 questions on overall health, mouth and throat soreness, and diarrhea.
• Incidence and severity of mucositis and diarrhea were recorded.

• Statistically significant differences in grade 2 or higher mucositis were observed during the first cycle (p = 0.002).
• Lower incidence of mucositis was observed during the second cycle (still statistically significant for palifermin group) (p = 0.003).
• Fewer patients receiving palifermin required a chemotherapy dose reduction of 10% or more.
• Disease outcomes were similar for the two groups; the authors concluded that palifermin had no effect on the disease in this clinical setting.

• A researcher had relationships with Amgen.
• The study involved the IV formulation.
• Expense was not addressed.
• Palifermin currently is not U.S. Food and Drug Administration (FDA) approved for nonhematologic malignancies.

To evaluate whether cognitive behavioral therapy for insomnia (CBT-I) in combination with a wakefulness-promoting agent, armodafinil, results in better insomnia outcomes in cancer survivors compared to CBTI-I alone

• N = 73  
• MEAN AGE = 56 years
• MALES: 12.5%, FEMALES: 87.5%
• KEY DISEASE CHARACTERISTICS: Self-reported insomnia for at least three months that was caused or worsened by any cancer and its treatment; chemotherapy or radiation therapy completed greater than one month prior and no measurable disease; no sleep aids one week before baseline and throughout 11-week study
• OTHER KEY SAMPLE CHARACTERISTICS: 68% breast cancer; original protocol called for only breast cancer but was broadened to include any cancers

• SITE: Multi-site    
• SETTING TYPE: Outpatient  
• LOCATION: Two northeastern cities in the United States

• PHASE OF CARE: Late effects, survivorship

Randomized, placebo-controlled trial

• Insomnia Severity Index (ISI)
• Pittsburgh Sleep Quality Index (PSQI)
• Demographics, clinical information, and sleep history

Analyses controlling for baseline differences showed that both the CBT-I plus armodafinil (p = 0.001) and CBT-I plus placebo (p = 0.010) groups experienced significantly greater reductions in insomnia severity postintervention than the placebo group with effect sizes of 1.31 and 1.02, respectively. Similar improvements were seen for sleep quality. Gains on both measures persisted three months later. CBT-I plus armodafinil was not significantly different from CBT-I plus a placebo (p = 0.421), and armodafinil alone was not significantly different from a placebo alone (p = 0.584).

• Small sample (< 100)
• Baseline sample/group differences of import
• Questionable protocol fidelity
• Subject withdrawals ≥ 10%
• Other limitations/explanation: Patients were told of their random assignment to CBT-I (or another group) after the completion of the two-week baseline period. All study personnel and patients were blinded to medications (armodafinil or the placebo) but not to CBT-I assignment.

Considering the prevalence of insomnia in patients with cancer and survivors, the potential for poorer outcomes if insomnia remains untreated, and the efficacy of CBT-I in treating chronic insomnia, it is desirable that providers and patients obtain increased access to evidence-based nonpharmacologic sleep interventions as an integral part of comprehensive cancer care. The findings of this study demonstrated that the addition of armodafinil to CBT-I treatment did not improve results for sleep.

The intervention involved polarity therapy for a 60- to 70-minute session. A trained therapist used anatomical hand positions (connectors) to examine energy flow, discover trigger points, and restore homeostatic energy flow. Polarity therapy promotes healing, relaxation, and well-being by unblocking and balancing energy flow and reestablishing homeostasis within the human energy field.

• The sample included 15 women older than 18 years in the third week of radiotherapy for breast cancer with a fatigue level greater than 2.
• Average age was 52.5 years (range 35–72).
• Fourteen of 15 patients were Caucasian.

Single radiotherapy center

Patients were undergoing the active treatment phase of care.

This was a pilot study with three arms:

• Arm 1:  standard care
• Arm 2:  one polarity therapy treatment
• Arm 3:  two polarity therapy treatments one week apart.

• Brief Fatigue Inventory (BFI)
• Functional Assessment of Cancer Therapy–Fatigue (FACIT-F)

A statistically significant improvement was observed in fatigue and health-related quality of life in 10 patients who received polarity therapy versus five who did not. There may have been a dose effect. Eight of 10 patients reported improvement.

• The study had a very small sample.
• Certification was required.