Efficacy and side-effects of three relatively low gabapentin doses in comparison to placebo.

Randomized to:

• Placebo for 28 days, or
• Gabapentin 300 mg at bedtime for 28 days, or
• Gabapentin 300 mg at bedtime for 7 days then 300 mg twice a day for 7 days then 300 mg three times a day for 14 days

• Men undergoing androgen deprivation therapy for prostate cancer with at least 14 hot flashes per week.
• N = 223; 214 completed the study.
• Mean age: 70 years old
• Inclusion: Men with a history of prostate cancer on a program of androgen ablation hormone therapy four weeks prior study and planning continuation of therapy during study; bothersome hot flashes of at least 14 times per week with hot flashes present at least 1 month prior study entry; Antidepressant use at least one month prior study with continuation during study trial.
• Exclusion: Renal insufficiency; concurrent therapies, including antineoplastic chemotherapy, androgens, estrogens, or progestational agents; previous therapy with gabapentin

Outpatient oncology centers

Double-blind, placebo-controlled.

Hot flash frequencies and severities were recorded daily for a baseline week and for four weeks while taking the study medication; symptom experience diaries were completed weekly for five weeks; 30-item Profile of Mood States–Brief was completed at the end of the baseline week and the end of four weeks of treatment.

By the fourth treatment week, mean hot flash scores decreased from baseline in the placebo group by 4.1 units. They also decreased in the three increasing dose gabapentin groups by 3.2, 4.6, and 7.0 units. No significant difference was reported in the three combined gabapentin arms versus placebo: Wilcoxon rank-sum p values for change in hot flash scores and frequencies after four weeks of treatment were 0.10 and 0.02 comparing the highest dose gabapentin arm to the placebo arm, respectively.

Short follow-up period

To determine the effectiveness of Gabapentin in combination with an antidepressant for the treatment of hot flashes.

Women must have been on a stable dose of antidepressant for the tx of hot flashes. In week one, patients completed a hot flash diary. In the second week, patients took 300 mg gabapentin at bedtime for 3 days, then twice daily for 3 days, then 3 times a day for 22 days. In one arm of the study patients remained on their previous dose of antidepressant and in the other arm patients weaned off antidepressants over 7-10 days and physician discretion was allowed. Patients completed a daily hot flash diary for 4 week and a weekly symptom assessment.

SITE  Single site    SETTING TYPE  Outpatient    LOCATION USA

PHASE OF CARE Late effects and survivorship

RCT

Both groups experienced a reduction in hot flashes: gabapentin = 60% reduction (95% CI, 33%-73%) and gabapentin plus antidepressant = 56% reduction (95% CI, 26%-71%)No difference between groups in hot flash scores or frequency from baseline to 4 weeks in either arm. No difference in toxicities reported by either arm. No difference in QOL in either arm.

This trial failed to demonstrate that the combination of gabapentin with antidepressants is more effective to reduce the number of hot flashes experienced by breast cancer survivors.

Risk of bias (no control group)

Risk of bias (no blinding)

Risk of bias(sample characteristics)

Other limitations/*explanation  All breast cancer patients, no placebo arm

The combination of gabapentin plus antidepressant does not appear to be an effective regimen to decrease hot flashes in breast cancer survivors

The study sought to assess the efficacy of fluoxetine for treatment of hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen because of a breast cancer risk.

Patients received four weeks of fluoxetine (20 mg/day orally) versus an identical-appearing placebo. For the next four weeks, patients were crossed over to the alternative arm.

The study enrolled 81 women with a history of breast cancer or a perceived increased risk of breast cancer. Sevent-two patients completed the study. Their mean age was older than 50 years.

• Inclusion criteria:
  • Women with a history of breast cancer or a perceived increased risk of breast cancer 
  • Patients without current evidence of malignant disease 
  • History of bothersome hot flashes (at least 14 per week) that were severe enough for patients to desire intervention; hot flashes present for at least one month
  • Concomitant therapy with tamoxifen or raloxifene was permitted if patient wason  therapy for at least one month and was planning continuation of therapy during study.
• Exclusion criteria:
  • Concomitant therapy with antineoplastic chemotherapy, androgens, estrogens, progestational drugs, or warfarin use
  • Previous use of fluoxetine antidepressant use for two years prior to study entry

This was a placebo-controlled, double-blind, cross-over clinical trial.

Assessments included:

• Daily hot flash diary for nine weeks
• Toxicity questionnaire weekly
• Beck Depression Inventory
• Uniscale global QOL instrument at study entry and study completion

At the end of the first treatment period (four weeks), hot flash scores (frequency x average severity) decreased 50% inthe  fluoxetine arm versus 36% in the placebo arm. Cross-over analysis showed a significantly greater improvement in hot flash scores with fluoxetine than placebo (p = .02). More than half (54%) of the patients reported depressive symptoms of at least mild severity at baseline compared with only 30% of patients after the first treatment period and 21% after the second treatment period. After five weeks of treatment, QOL did not differ between groups. After cross-over, QOL showed a relative improvement trend for fluoxetine compared to placebo.

Age and tamoxifen use were not adjusted for as potential confounding factors.

STUDY PURPOSE: To review evidence regarding the use of opioids for dyspnea and associated risks of respiratory depression

• DATABASES USED: MEDLINE, TRIP database, Cochrane Collaboration 
• KEYWORDS: MESH terms for morphine; respiratory insufficiency or respiratory function; and opioid. Search terms provided in the article
• EXCLUSION CRITERIA: Studies in pediatric patients

TOTAL REFERENCES RETRIEVED: 47

• FINAL NUMBER STUDIES INCLUDED = 8 
• TOTAL PATIENTS INCLUDED IN REVIEW = 118
• SAMPLE RANGE ACROSS STUDIES: 9–31 patients
• KEY SAMPLE CHARACTERISTICS: Various disease types, including cancer

PHASE OF CARE: End-of-life care
 
APPLICATIONS: Palliative care

In studies measuring dyspnea, opioids were consistently shown to significantly reduce dyspnea and respiratory effort. A few studies described minor changes in respiratory rate and PaCO₂, but they were not clinically significant.

Findings support the safety and effectiveness of opioids for the management of dyspnea in patients with advanced disease.

• Limited number of studies
• Small samples

This review provides additional support for the effectiveness of opioids to reduce dyspnea, and provides some evidence that this does not cause significant respiratory depression.

To assess the efficacy and safety of megestrol acetate in improving appetite, weight gain, and health-related quality of life in patients with anorexia-cachexia syndrome who had advanced cancer, AIDS, or other underlying pathologies. Other aims were to evaluate the efficacy of different doses and the safety of megestrol acetate.

The following databases were searched: Cochrane Collaboration, Cochrane Controlled Trials Register, MEDLINE, and Embase. A hand search of reference lists was completed. The keywords used were randomized controlled clinical trial, double-blind, single-blind, megestrol acetate, terminally ill, terminal care, and wasting syndrome. Variants of megestrol acetate were also keywords. There was no language restriction. Data were extracted by two reviewers who used the Jadad scale to assess quality. A third reviewer participated if needed.

Of the 296 studies identified, 26 published between 1980 and 2002 met the inclusion criteria. Of these, 19 compared megestrol acetate to a placebo, 6 compared megestrol acetate to other drugs, and 6 studied the effectiveness of different dose levels. The quality of the studies was rated on the Jadad scale: 10 were high-quality, 7 were medium-quality, and 9 were low-quality.

• A total of 3,887 patients had cancer or AIDS and had a clinical diagnosis of anorexia-cachexia syndrome or indicative symptoms (e.g., loss of appetite, decrease in muscle mass).
• Of these patients, 86% (3,368) had cancer, 11% (427) had AIDS, and 2% (81) had other diagnoses.
• Of the patients with cancer, 40% had lung cancer, 23% had gastrointestinal cancer, 7% had head and neck cancer, 2% had pancreatic cancer, 2% had gynecologic cancer, and 26% had other cancers.
• Mean age in the megestrol acetate group was 57 years. Thirty-one percent were women.
• Mean age in the placebo group was 59 years. Thirty-two percent were women.
• There was no difference in sociodemographic characteristics between the megestrol acetate and placebo groups. 
• Megestrol acetate doses ranged from 160 to 1,600 mg/day. The most frequently used dose was 480 mg/day.
• Ten of the 26 studies administered a dose of 800 mg/day.

A meta-analysis of the studies assessing appetite had homogeneous results, showing statistically significant improvement with megestrol acetate over the placebo (RR = 2.33, 95% CI 1.52–3.59)

For weight gain, results were homogeneous and in favor of megestrol acetate, but not statistically significant (RR = 1.88, 95% CI 1.43–2.47).

For quality of life, there was significant heterogeneity because of the variety of instruments used. When the results using only the Karnofsky Performance Status Scale were analyzed, heterogeneity was not observed, and the results were positive in favor of megestrol acetate (RR = 1.64, 95% CI 1.06–2.55). Subgroup analysis in patients with cancer showed positive results in favor of megestrol acetate over placebo on appetite (RR = 2.33, 95% CI 1.52–3.59), weight gain (RR = 2.16, 95% CI 1.45–3.21), and quality of life (RR = 1.81, 95% CI 1.13–2.89).

In comparing megestrol acetate to other drugs, it showed benefit in terms of weight gain. No difference was noted between megestrol acetate and other drugs in terms of quality of life. For appetite, megestrol acetate was superior to dronabinol, but showed no advantage to other drugs studied.

In comparing the efficacy of different megestrol acetate doses, the only statistically significant result was observed in patients with cancer, for whom higher doses were associated with greater weight gain (RR = 1.65, 95% CI 1.00–2.73). There were no statistically significant differences between treatment and placebo groups in terms of adverse events, excepting edema, which was greater in the megestrol acetate group (RR = 1.67, 95% CI 1.22–2.28).

When compared with a placebo, there were significant improvements in appetite and weight gain in patients with cancer who were treated with megestrol acetate. This meta-analysis confirms the results of earlier systematic reviews that demonstrated megestrol acetate's advantages over placebo in terms of weight gain and improved appetite. This review did not define the optimal dose of megestrol acete.

Given the adverse events profile, megestrol acetate is a safe treatment option.

Investigate Rhodiola algida on healthy human lymphocytes in vitro and on the healing time of oral ulcers in breast cancer

Secondary aim: Animal study portion

In the test group, the patients consumed 200 mL boiled Rhodiola algida at a concentration of 50 mg/ml for seven consecutive days after receiving chemotherapy. Control patients were given honey bee water. All patients were given 0.2% chlorhexidine mouthwash. Rhodiola algida is a Tibetan plant used in traditional Chinese medicine, believed to affect the immune system by nourishing Chi.

The study was comprised of 130 patients, age 24-58, with a mean age of 48.5 years.

Females: 100%

Diagnosis information: Invasive ductal carcinoma

Single site: University of Hong Kong

Control trial- not clear if it was random nor blind.

Oral Mucositis Assessment Scale (OMAS) Numeric Rating Scale for pain

There were three ulcers in the treatment group and five in the control group. The diameter of ulcers in the treatment group was smaller than those in the control group. The treatment group had less pain, shorter duration of ulceration, and better body weight maintenance than the control group, all of these parameters had statistical significance (p < 0.05). Findings related to measures of immune function are provided. The WBC count in the treatment group was 5.3 (±1.02) compared to 3.2 (±0.82) in the control group. This effect may have implications for other symptoms in addition to mucositis.

Although this study showed some improvement in oral healing and pain, this group of patients does not typically experience severe mucositis.

Breast cancer only, very few episodes of mucositis to measure effectiveness; nausea and vomiting in this population may affect weight loss.

Many other potential effects of this agent. Further research with this agent would be useful.

To evaluate the efficacy of a regimen of three-day aprepitant, a single dose of palonosetron, and three-day dexamethasone in patients receiving cisplatin-based, highly emetogenic chemotherapy (HEC)

Patients were given the following regimen. On day 1, patients were given 0.25 mg IV palonosetron, 20 mg IV dexamethasone, and 125 mg oral aprepitant before chemotherapy; on day 2, they received 80 mg oral aprepitant and 4 mg oral or intramuscular dexamethasone; and on day 3, they were given 80 mg oral aprepitant and 4 mg oral or intramuscular dexamethasone.

Rescue therapy was 10 mg metoclopramide and 4 mg dexamethasone. Patient diaries were used to record emesis, use of rescue medication, and severity of nausea for 5 days after chemotherapy.

• The study consisted of 222 participants.
• Median age was 62 years, with a range of 22–82 years.
• The sample was 23.4% female and 76.6% male.
• The most frequent diagnoses were lung, head and neck, stomach, and bladder cancers.
• Patients with stage IV disease represented 77.5% of the sample.
• All patients were chemotherapy naïve and receiving HEC.

The study was conducted in multiple outpatient settings in Italy.

All patients were in active treatment.

This was a prospective trial.

• Patients rated nausea severity on a 4-point Likert-type scale.
• The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ30) was used.
• Complete response was defined as no emetic episodes and no use of rescue medication.

• The majority of patients (70.3%) had complete response, and 92.8% did not have vomiting but did use rescue medication.
• More than half of patients (59.9%) did not experience any nausea, and 31.1% experienced mild nausea.
• Nausea was the main reason for use of rescue medication.
• No major adverse events with antiemetics were seen.
• Patients reporting constipation represented 39% of participants, and headache was reported by 5%.

Palonosetron in combination with aprepitant and dexamethasone was found to be effective in preventing acute and delayed nausea and vomiting with HEC.

• The study did not have an appropriate control group.
• Data for complete response were analyzed only for the overall phase with no subgroup analysis for acute and delayed symptoms.

The findings confirmed the efficacy of palonosetron as part of an antiemetic drug regimen for patients receiving HEC.

To evaluate whether the antiemetic efficacy of triple combination aprepitant, palonosetron, and dexamethasone could be sustained for up to six cycles of highly emetogenic chemotherapy (HEC) (cisplatin ≥ 50 mg/m²)

To be eligible, patients had to be chemotherapy-naïve adults with lung cancer, have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2, and be receiving 4–6 cycles platinum-based therapy (cisplatin ≥ 50 mg/m²).

All eligible patients received 125 mg oral aprepitant, 0.25 mg IV palonosetron, and 20 mg IV dexamethasone before chemotherapy on day 1, and 80 mg oral aprepitant and 4 mg oral or intramuscular dexamethasone on days 2 and 3. Patients recorded all vomiting episodes, any use of rescue medication, and the severity of nausea on 4-point Likert-type scale in diaries for 5 days (0–120 hours) after chemotherapy during all planned cycles.

• The study began with 156 patients, and 118 completed the study.
• The median age of participants was 64 with a range of 33–81.
• The sample was 77% male and 23% female.
• Cancer staging was 74% stage IV and 12% stage IIIb.
• Cisplatin dosing was 46% 75 mg/m² and 41% 80 mg/m².  Patients receiving cisplatin combined with two other drugs represented 87% of the sample.
• Number of chemotherapy cycles planned was 6 cycles (80%) and 4 cycles (18%). The majority (84%) completed their planned cycles.
• Patients were excluded if they had
  • Emesis within 24 hours before starting chemotherapy
  • Noncontrolled metastasis in the brain
  • Previous radiation to the brain, abdomen, or pelvis
  • Concomitant medication with antiemetic activity or known to induce cytochrome P450 enzymes.

The study was conducted at multiple outpatient sites in Italy.

All patients were in active antitumor treatment.

This was a prospective observational study.

• Patients maintained study-specific diaries for 5 days (120 hours) post chemotherapy (up to 6 cycles) using a 4-point Likert-type scale and reporting adverse events. 
• Complete response (CR) was defined as no emetic episodes and no use of rescue therapy during the overall phase of all planned chemotherapy.
• Complete control (CC) was defined as no emesis, no rescue therapy, and no more than mild nausea.
• No grade 3-4 adverse events reported.

• CR rates ranged rom 74.4%-82.0% per cycle, and CC ranged from 74.4%-82.0% per cycle (CI 95%).
• More than 90% of patients were emesis free during all cycles (CI 95%).
• No severe nausea was detected. More than 60% of patients were nausea free during all chemotherapy cycles.
• The authors did not report on acute versus delayed chemotherapy-induced nausea and vomiting (CINV).

The triple combination of aprepitant, palonosetron, and dexamethasone enhanced antiemetic protection during the first cycle and the efficacy was sustained for up to six cycles of cisplatin-based highly emeotgenic chemotherapy (HEC) in patients with lung cancer. The majority (84%) of patients were able to complete their planned number of chemotherapy treatment cycles.

• Study limitations include the risk of bias because the study had no control group, no blinding, and no random assignment.
• The measurement and methods were not well described.
• The measurement validity and reliability was questionable.
• Forty patients were lost to attrition by cycle 6.

Patients with advanced stage lung cancer treated with HEC who are given CINV prophylaxis according to accepted guidelines prior to each cycle maintain the benefit from the CINV prophylaxis through all cycles of treatment. Managing the distress caused by CINV may increase overall quality of life and is an important consideration when treating patients with palliative chemotherapy.

To compare Bepanthen cream with no topical ointment

Patients used Bepanthen on one side of the treatment field and used no topical treatment on the other side. Patients were instructed to not inform the physician of which region or field received the application of the cream, and they randomized their own application. Bepanthen twice a day began on day 1 of radiation therapy. Skin assessments were performed weekly during treatment and two weeks following treatment.
 

• The study sample (N = 79) was comprised of patients with breast (n = 63) and T1 and T2 N0, M0 laryngeal (n = 16) cancer.
• Median age of patients with breast cancer was 55 years, with a range of 31–78 years. Median age of patients with laryngeal cancer was 69 years, with a range of 51–85 years.
• Patients with laryngeal cancer received definitive radiation therapy at 2 Gy/fraction and total dose of 70 Gy.
• Twenty-one patients with breast cancer received low-dose cyclophosphamide, methotrexate, and 5-fluorouracil during radiation therapy at cobalt-60 and total dose of 50 Gy.

The study used a quasi-experimental blinded trial design.

• The European Oncology Radiation Therapy Consortium and Radiation Therapy Oncology Group acute skin reaction scoring was recorded weekly, two, and six to eight weeks following treatment.
• Erythema was chosen as the primary efficacy variable.
• Wilcoxan-Signed Rank-Test was used for the primary and secondary efficacy variables.
• Logistic regression analysis was performed to examine the effect of concomitant chemotherapy, skin type, gender, age, and upper verses lower area (for patients with breast cancer only).

For both cancers, all skin reactions were more severe at completion of six weeks of radiation treatments, which was chosen as a reference point to standardize assessment data. No significant difference was observed in erythema, most desquamation, itch, or pain. No significant effect of any of the variables was found in regression analysis regarding erythema and desquamation.
 

Bepanthen did not provide any significant benefit.

• In patients with breast cancer, there were many different techniques of radiation therapy administration and use of bolus.
• No information about patient adherence to the protocol was provided.
• The two groups of cancers treated received different accumulative doses of irradiation.
• Data was not separated for those who also received chemotherapy, which would affect skin toxicity.

Tissue toxicity is associated with 60-cobalt.

The purpose of the study was to examine the superiority in reducing grade 4 leucopenia of pegfilgrastim given on day 4 over giving pegfilgrastim on day 2.

Patients were randomized to receive pegfilgrastim subcutaneously (6 mg) on day 2 or on day 4 in a 1:1 ratio. All sub study patients received intense dose-dense (IDD) chemotherapy consisting of epirubicin 150 mg/m² every two weeks for three cycles, paclitaxel 225 mg/m² every two weeks for three cycles, and cyclophosphomide 2,000 mg/m² every two weeks for three cycles. All received prophylactic oral quinolone antibiotics.

• 355 patients were randomized to receive pegfilgrastim on day 2 (n = 177) or day 4 (n = 178).  
• The median age was 45 years with a range of 24–69 years.
• 100% of the participants were female.
• Female patients biologically younger than 65 years with histologic confirmed, unilateral, or bilateral node-positive breast carcinoma.   
• Patients were required to have adequate surgical treatment with histologic complete resection (R0) of the tumor and greater or equal 10 axillary nodes with primary wound healing and no signs of infection.
   

A single-site setting in Germany

• The phase of care was active treatment.
• The application was for late effects and survivorship.
   

Randomized two-group trial

GAIN (German Adjuvant Intergroup Node Positive) study toxicity grading

The study failed to demonstrate that pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia. For patients receiving epirubicin overall, 11% of patients receiving day 2 dosing had an episode of grade 4 leucopenia during the first three cycles of chemotherapy, compared to 4% of those receiving CSF on day 4 (p = 0.015). There were no significant differences between groups in chemotherapy dose reductions or delays. During cyclophosphamide, significantly more infections occurred in the day 2 administration group (p = 0.035). Across the entire treatment, there were no differences between groups in febrile neutropenia, infections, and treatment alterations.

This study failed to demonstrate that administering pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections.

No blinding
 

The data does not support a change in the current standard dosing schedule; however, it does suggest that administration of colony-stimulating factor on day 4 might be an appropriate alternative to day 2 dosing.