Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study.

PURPOSE: Febrile neutropenia (FN) is a major complication of chemotherapy. Antibiotics as well as granulocyte colony-stimulating factor (G-CSF) are effective in preventing FN. This multicenter randomized phase III trial determines whether the addition of G-CSF to antibiotic prophylaxis can further reduce the incidence of FN in patients with small-cell lung cancer (SCLC) at the risk of FN. PATIENTS AND METHODS: Patients (N = 175) were stratified for stage of disease, performance status, age, and prior chemotherapy treatment, and were randomly assigned for treatment with cyclophosphamide, doxorubicin, and etoposide (CDE), followed by prophylactic antibiotics alone (ciprofloxacin and roxithromycin) or by antibiotics in combination with G-CSF on days 4 to 13. RESULTS: In cycle 1, 20 patients (24%) in the antibiotics group developed FN compared with nine patients (10%) in the antibiotics plus G-CSF group (P = .01). In cycles 2 to 5, the incidences of FN were practically the same in both groups (17% v 11%). Only the treatment parameters (odds ratio, 0.33; 95% CI, 0.14 to 0.78) and age (1.067 per year; 95% CI, 1.013 to 1.0124) were related to the probability of FN in cycle 1. CONCLUSION: Primary G-CSF prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in SCLC patients at the risk of FN with the first cycle of CDE chemotherapy. For patients with similar risk of FN, the combined use of prophylactic antibiotics plus G-CSF can be considered, specifically in the first cycle of chemotherapy.

Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir.

BACKGROUND: The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity. METHODS: This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h. RESULTS: Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio - fasting/fed and 95% confidence interval (CI): 1.28 (1.08-1.52), P=0.01] and a trend to a shorter indinavir tmax (P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmax and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir. CONCLUSIONS: Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.

Preconception counseling improves folate status of women planning pregnancy.

OBJECTIVE: To assess whether counseling women planning pregnancy to start or continue folic acid supplementation improves folate status. METHODS: Women and their partners reported folic acid supplement intake in a preconceptional health questionnaire, and the women were categorized as reported "users" or "nonusers" of supplements before counseling. The use of periconceptional folic acid was addressed at a subsequent preconceptional consultation. Differences between reported supplement users and nonusers before counseling as well as between assumed users and nonusers of folic acid (with precounseling red cell and serum folate levels above and below 590 nmol/L and 20 nmol/L, respectively) were analyzed. RESULTS: A total of 111 (66%) of 168 eligible women participated. Estimated mean red cell folate levels of women who reported no use of folic acid supplements before counseling increased significantly after 4 months from 540 nmol/L to 680 nmol/L. Red cell folate levels of women who reported taking supplements (44%) remained stable up to 1 year after counseling. Women with low precounseling folate levels showed a highly significant mean increase in red cell folate from 475 nmol/L to 689 nmol/L 4 months after counseling. CONCLUSION: Addressing periconceptional folic acid use at a preconceptional consultation improves folate status among women planning to conceive.

Validation of clinical and image skin scoring systems for a single chronic discoid lupus erythematosus lesion.

OBJECTIVE: The purpose of this study was to achieve a validated clinical and image scoring system for a single chronic discoid lupus erythematosus (CDLE) lesion. METHODS: Fifteen patients with a CDLE lesion were scored twice by four observers and clinical photographs were taken. These pictures were assessed by the same four observers at two time points. Patients were scored using the DLE-Skin Score (DLE-SS). In addition, the DLE-Photo Score (DLE-PS) was calculated. Statistical analysis was carried out by measuring inter- and intra-observer agreement for both methods and by measuring the correlation between the DLE-SS and DLE-PS. RESULTS: Both the DLE-SS and DLE-PS proved reliable methods in the assessment of CDLE. The inter-observer variability of the DLE-SS and DLE-SS was low. The intra-observer variability was estimated to be 0 in both methods. The correlation coefficient between the DLE-SS and DLE-PS was high (0.81). CONCLUSION: Both the DLE-SS and the DLE-PS are reliable and easy-to-use methods to score disease activity in CDLE patients, and can be used in monitoring single target lesions in clinical trials.

Predicting outcome of TENS in chronic pain: a prospective, randomized, placebo controlled trial.

UNLABELLED: Transcutaneous electrical nerve stimulation (TENS) is an easy to use non-invasive analgesic intervention applied for diverse pain states. However, effects in man are still inconclusive, especially for chronic pain. Therefore, to explore the factors predicting result of TENS treatment in chronic pain we conducted a prospective, randomized, placebo-controlled trial (n=163), comparing high frequency TENS (n=81) with sham TENS (n=82). Patients' satisfaction (willingness to continue treatment; yes or no) and pain intensity (VAS) were used as outcome measures. The origin of pain and cognitive coping strategies were evaluated as possible predictors for result of TENS treatment. RESULTS: Fifty-eight percent of the patients in the TENS group and 42.7% of the sham-TENS group were satisfied with treatment result (chi square=3.8, p=0.05). No differences were found for pain intensity. Patients diagnosed with osteoarthritis and related disorders (especially of the vertebral column) or peripheral neuropathic pain were less satisfied with high frequency TENS (OR=0.12 (95% CI 0.04-0.43) and 0.06 (95% CI 0.006-0.67), respectively). Injury of bone and soft tissue (especially postsurgical pain disorder) provided the best results. Treatment modality or interactions with treatment modality did not predict intensity of pain as a result of treatment. We conclude, that predicting the effect of high frequency TENS in chronic pain depends on the choice of outcome measure. Predicting patients' satisfaction with treatment result is related to the origin of pain. Predicting pain intensity reflects mechanisms of pain behavior and perceived control of pain, independent of treatment modality. Pain catastrophizing did not predict TENS treatment outcome.

Outcome of transcutaneous electrical nerve stimulation in chronic pain: short-term results of a double-blind, randomised, placebo-controlled trial.

The aim of this study was to test the efficacy of shortterm transcutaneous electrical nerve stimulation (TENS) treatment in chronic pain with respect to pain intensity and patients' satisfaction with treatment results. We therefore performed a randomised controlled trial comparing TENS and sham TENS. Patients, researchers and therapists were blinded for treatment allocation. One hundred and sixty-three patients with chronic pain referred to the Pain Centre entered the study. Conventional TENS and sham TENS were applied in the segments of pain, for a period of ten days. Outcome measures were pain intensity (visual analogue scale) and patients' satisfaction with treatment result (yes or no). The proportions of patients satisfied with treatment result differed significantly for TENS compared to sham TENS (58 and 42.7% respectively, chi(2)=3.8, p=0.05). However, no differences in pain intensity were found for patients treated with TENS or sham TENS. Only for patients satisfied with treatment results pain intensity gradually decrease equally both for TENS and sham TENS with repeated treatment application.

Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer.

PURPOSE: Recently, a Dutch, randomized, phase III trial demonstrated that, in small-cell lung cancer patients at risk of chemotherapy-induced febrile neutropenia (FN), the addition of granulocyte colony-stimulating factor (GCSF) to prophylactic antibiotics significantly reduced the incidence of FN in cycle 1 (24% v 10%; P = .01). We hypothesized that selecting patients at risk of FN might increase the cost-effectiveness of GCSF prophylaxis. METHODS: Economic analysis was conducted alongside the clinical trial and was focused on the health care perspective. Primary outcome was the difference in mean total costs per patient in cycle 1 between both prophylactic strategies. Cost-effectiveness was expressed as costs per percent-FN-prevented. RESULTS: For the first cycle, the mean incremental costs of adding GCSF amounted to 681 euro (95% CI, -36 to 1,397 euro) per patient. For the entire treatment period, the mean incremental costs were substantial (5,123 euro; 95% CI, 3,908 to 6,337 euro), despite a significant reduction in the incidence of FN and related savings in medical care consumption. The incremental cost-effectiveness ratio was 50 euro per percent decrease of the probability of FN (95% CI, -2 to 433 euro) in cycle 1, and the acceptability for this willingness to pay was approximately 50%. CONCLUSION: Despite the selection of patients at risk of FN, the addition of GCSF to primary antibiotic prophylaxis did not result in cost savings. If policy makers are willing to pay 240 euro for each percent gain in effect (ie, 3,360 euro for a 14% reduction in FN), the addition of GCSF can be considered cost effective.

Minimization of sample size when comparing two small probabilities in a non-inferiority safety trial.

In clinical trials success rates of two treatments to be compared often range from 10 to 90 per cent. When the comparison probabilities are (much) smaller than 10 per cent, standard methods for sample size and power calculations may provide invalid results. This situation may occur when there is interest in safety rather than in efficacy. In such trials, no more patients should be included than strictly necessary. We compared the results of maximum likelihood methods for the computation of sample sizes in a non-inferiority trial, including exact procedures and considered unequal sample sizes for experimental and reference treatment. An exact, unequal sample size maximum likelihood procedure is advocated when the specified non-zero risk difference under the null hypothesis is not too large. Such a procedure is also indicated when the parameter of interest is the relative risk, rather than the risk difference.