Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.

PURPOSE: To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS: Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS: A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.     

Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial.

PURPOSE: We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m(2) over a 15-minute infusion period before oxaliplatin) or normal saline solution. Clinical neurologic evaluation and electrophysiologic investigations were performed at baseline and after four (oxaliplatin dose, 400 mg/m(2)), eight (oxaliplatin dose, 800 mg/m(2)), and 12 (oxaliplatin dose, 1,200 mg/m(2)) cycles of treatment. RESULTS: At the fourth cycle, seven patients showed clinically evident neuropathy in the GSH arm, whereas 11 patients in the placebo arm did. After the eighth cycle, nine of 21 assessable patients in the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo arm. With regard to grade 2 to 4 National Cancer Institute common toxicity criteria, 11 patients experienced neuropathy in the placebo arm compared with only two patients in the GSH arm (P =.003). After 12 cycles, grade 2 to 4 neurotoxicity was observed in three patients in the GSH arm and in eight patients in the placebo arm (P =.004). The neurophysiologic investigations (sural sensory nerve conduction) showed a statistically significant reduction of the values in the placebo arm but not in the GSH arm. The response rate was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction in activity of oxaliplatin. CONCLUSION: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.     

Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized,double-blind,placebo-controlled study

BackgroundFentanyl buccal soluble film (FBSF) has been developed as a treatment of breakthrough pain in opioid-tolerant patients with cancer. The objective of this study was to evaluate the efficacy of FBSF at doses of 200–1200 μg in the management of breakthrough pain in patients with cancer receiving ongoing opioid therapy.Patients and methodsThis was a multicenter, randomized, double-blind, placebo-controlled, multiple-crossover study that included opioid-tolerant adult patients with chronic cancer pain who experienced one to four daily episodes of breakthrough pain. The primary efficacy assessment was the sum of pain intensity differences at 30 min (SPID30) postdose.ResultsThe intent-to-treat population consisted of 80 patients with ≥1 post-baseline efficacy assessment. The least-squares mean (LSM ± SEM) of the SPID30 was significantly greater for FBSF-treated episodes of breakthrough pain than for placebo-treated episodes (47.9 ± 3.9 versus 38.1 ± 4.3; P = 0.004). There was statistical separation from placebo starting at 15 min up through 60 min (last time point assessed). There were no unexpected adverse events (AEs) or clinically significant safety findings.ConclusionsFBSF is an effective option for control of breakthrough pain in patients receiving ongoing opioid therapy. In this study, FBSF was well tolerated in the oral cavity, with no reports of treatment-related oral AEs.     

Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study

Purpose: To determine the efficacy of sildenafil citrate (Viagra) in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy (3D-CRT) for prostate cancer.

Methods and Materials: 406 patients with complaints of erectile dysfunction and who completed radiation at least 6 months before the study were approached by mail. 3D-CRT had been delivered (mean dose 68 Gy). Sixty patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received during 2 weeks 50 mg of sildenafil or placebo; at Week 2 the dose was increased to 100 mg in case of unsatisfactory erectile response. At Week 6, patients crossed over to the alternative treatment. Data were collected using the International Index of Erectile Function (IIEF) questionnaire, and side effects were recorded.

Results: Mean age was 68 years. All patients completed the study. For most questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with sildenafil, but not with placebo. Ninety percent of the patients needed a dose adjustment to 100 mg sildenafil. Side effects were mild or moderate.

Conclusion: Sildenafil is well tolerated and effective in improving erectile function of patients with ED after 3D-CRT for prostate cancer.     

Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer.

PURPOSE: Children surviving acute lymphoblastic leukemia (ALL) and malignant brain tumors (BTs) have a higher incidence of attention and learning problems in school than do their healthy peers. The present study tests the hypothesis that the psychostimulant methylphenidate (MPH) improves cognitive and social functioning among these patients. PATIENTS AND METHODS: We report on 83 long-term survivors of ALL and BT identified as having attentional deficits on behavioral testing and parent or teacher report, and problems with academic achievement. The 47 male and 36 female patients ranged from 0.6 to 14.3 years (median, 5.4 years) of age at diagnosis and 6.7 to 17.9 years (median, 11.9 years) of age at participation. The patients (40 ALL, 43 BT) participated in a randomized, double-blind, 3-week home cross-over trial of placebo (bid), low-dose MPH (0.3 mg/kg; maximum dose, 10 mg bid), and moderate-dose MPH (0.6 mg/kg; maximum dose, 20 mg bid). The primary end points were weekly teacher and parent reports on the Conners' Rating Scales and Social Skills Rating System. RESULTS: Compared to placebo, significant improvement with MPH was reported by teachers and parents on the Conners' Rating Scales and by teachers on the Social Skills Rating System. However, no consistent advantage of moderate dose over low dose was observed. Of those participating, 66 (79.5%) of the 83 patients continued on best clinical management. CONCLUSION: Treatment with MPH can at least temporarily reduce some attentional and social deficits among survivors of childhood ALL and BT. Long-term follow-up will reveal those subsets of patients who are more likely to benefit from MPH.     

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized,double-blind,placebo-controlled trial

Background

To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT).

Methods

Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed.

Results

Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62–0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks.

Conclusions

Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT.RTOG 0614, ClinicalTrials.gov number CT00566852.     

A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results

The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.     

Helicobacter pylori eradication and gastric preneoplastic conditions: a randomized, double-blind, placebo-controlled trial.

Helicobacter pylori causes gastric adenocarcinoma; whether treatment of H. pylori infection prevents this cancer remains unknown. In a randomized, double-blind, placebo-controlled trial of H. pylori eradication, we determined whether treatment for H. pylori decreases gastric cancer risk, using preneoplastic conditions as surrogate markers. A total of 248 healthy volunteers (age >40 years) randomly received H. pylori treatment (omeprazole, amoxicillin, clarythromycin; n = 122) or matched placebo (n = 126) for 1 week. Endoscopy was performed at baseline and at 6 weeks and 1 year. Seven biopsies from each endoscopy were reviewed by two pathologists using the revised Sydney classification. Outcome measures were both a consensus "worst biopsy" diagnosis and a weighted index score that incorporated degrees of severity of preneoplasia from all biopsies. We compared change in these outcomes over time between the two treatment groups. H. pylori cure rates for compliant subjects in the treatment arm were 79.2% and 75.7% at 6 weeks and 1 year, respectively. No statistically significant change in the worst biopsy diagnosis was observed from 6 weeks to 1 year between placebo and treated subjects (for improvement/worsening, placebo, 19.4%/10.5%; treatment, 22.5%/8.3%; P = 0.74). Change in index score was favorably greater in treatment compared with placebo subjects (intention-to-treat analysis, P = 0.03); this finding was particularly evident in the antrum. H. pylori eradication gave more favorable gastric histopathologies over 1 year than no treatment. Such incomplete regression suggests but does not prove that eradication of H. pylori decreases cancer risk.     

Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.

PURPOSE: This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Adult patients with hemoglobin < or = 14.5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles. RESULTS: The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12.8 g/dL and 13.0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, -6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, -9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10.5 and 10.4 months, respectively) and overall mortality (91.7% and 87.8%, respectively; hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion. CONCLUSION: These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.     

Inhalation aromatherapy during radiotherapy: results of a placebo-controlled double-blind randomized trial.

PURPOSE: To determine whether the inhalation of aromatherapy during radiotherapy reduces anxiety. PATIENTS AND METHODS: Three hundred thirteen patients undergoing radiotherapy were randomly assigned to receive either carrier oil with fractionated oils, carrier oil only, or pure essential oils of lavender, bergamot, and cedarwood administered by inhalation concurrently with radiation treatment. Patients underwent assessment by the Hospital Anxiety and Depression Scale (HADS) and the Somatic and Psychological Health Report (SPHERE) at baseline and at treatment completion. RESULTS: There were no significant differences in HADS depression or SPHERE scores between the randomly assigned groups. However, HADS anxiety scores were significantly lower at treatment completion in the carrier oil only group compared with either of the fragrant arms (P =.04). CONCLUSION: Aromatherapy, as administered in this study, is not beneficial.     

Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled,double-blind crossover study

AIMS AND BACKGROUND: Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain. METHODS: Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded. RESULTS: No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P < 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P < 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects. CONCLUSIONS: In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned.     

Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.

PURPOSE: This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival. PATIENTS AND METHODS: Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels < or = 10.5 g/dL, or greater than 10.5 g/dL but < or = 12.0 g/dL after a hemoglobin decrease of > or = 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study. RESULTS: Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P =.0057) and increased hemoglobin (P <.001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P <.01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P =.13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P =.052) favoring epoetin alfa. Adverse events were comparable between groups. CONCLUSION: Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.     

Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II,double-blind,placebo-controlled,randomized trial

A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20–29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10–19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated.