Do You Want to Stay Single? Considerations on Single-Arm Trials in Drug Development and the Postregulatory Space.

Single-arm trials (SATs), while not preferred, remain in use throughout the drug development cycle. They may be accepted by regulators in particular contexts (e.g., in oncology or rare diseases) when the potential effects of new treatments are very large and placebo treatment is unethical. However, in the postregulatory space, SATs are common, and perhaps even more poorly suited to address the questions of interest. In this manuscript, we review regulatory and HTA positions on SATs; challenges posed by SATs to address research questions beyond regulators, evolving statistical methods to provide context for SATs, case studies where SATs could and could not address questions of interest, and communication strategies to influence decision making and optimize study design to address evidence needs.

Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study.

OBJECTIVES: To explore patient and disease factors, and reasons behind the physician's choice of platinum backbone for the first-line treatment of non-small cell lung cancer (NSCLC), as observed in a European prospective observational study of patients receiving platinum-based chemotherapy as first-line treatment for advanced or metastatic NSCLC (the FRAME study). Additionally, overall survival (OS) for patients who received cisplatin or carboplatin was evaluated. MATERIALS AND METHODS: A post-hoc analysis of the prospective study population was conducted. Baseline characteristics of patients receiving cisplatin versus carboplatin were compared and summarized by propensity score. Survival for matched patients was summarized using the Kaplan-Meier approach. RESULTS: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. Patients treated with carboplatin were older than patients receiving cisplatin (mean age 67 versus 61 years; p<0.001), had poorer performance status (p<0.001), and more comorbidities (p<0.001). Cisplatin was most frequently combined with pemetrexed (47%), and carboplatin most frequently with taxanes (31%). Unadjusted median OS estimates for patients from the total prospective study sample were 11.5 months (95% confidence interval [CI] 10.1-12.9) for cisplatin recipients and 9.0 months (95% CI 8.1-10.6) for carboplatin recipients. Median (95% CI) overall survival for the matched cohorts was 10.8 months (8.8-14.3) for cisplatin versus 9.5 months (8.2-11.3) for carboplatin; p=0.086. CONCLUSION: This post-hoc analysis illustrated real-life differences in patients with NSCLC prescribed platinum-based first-line treatment, and suggested that baseline patient and disease characteristics were associated with physician's choice of platinum agent, with cisplatin being more frequently prescribed to younger and fitter patients.

Outcomes and resource use of non-small cell lung cancer (NSCLC) patients treated with first-line platinum-based chemotherapy across Europe: FRAME prospective observational study.

INTRODUCTION: FRAME was a prospective observational study that captured real-world data on patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapies as first-line treatment (FLT) across Europe. As previously reported, most patients observed in the study had initiated FLT with either pemetrexed, gemcitabine, vinorelbine or taxanes in combination with a platinum. Baseline patient and disease characteristics including age, performance status, and histology varied (all p<0.01) across cohorts. METHODS: Consenting adult patients initiating FLT for advanced or metastatic NSCLC with platinum-based chemotherapy, with or without a targeted agent, entered the study between April 2009 and February 2011. The choice of FLT was left to physicians' discretion per routine clinical practice. The primary objective was to evaluate overall survival (OS) across platinum-based doublet chemotherapy cohorts and key secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented. RESULTS: Median OS in months was 10.3 across cohorts (n=1524), 10.7 for pemetrexed (n=569), 10.0 for gemcitabine (n=360), 9.1 for taxanes (n=295), and 10.7 for vinorelbine (n=300). For patients with non-squamous NSCLC who received cisplatin (n=616, 40% of total), median OS in months was 10.6 across the cohorts, 11.6 for pemetrexed, 8.4 for gemcitabine, 9.6 for taxanes, and 9.9 for vinorelbine. CONCLUSIONS: FRAME describes real-world treatment patterns and survival for patients initiating FLT for advanced or metastatic NSCLC between 2009 and 2011 across Europe.

Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study.

OBJECTIVES: We report on a post-hoc analysis of patients with brain metastases from a large prospective observational study of first-line treatment of non-small cell lung cancer (NSCLC). The aim was to describe baseline characteristics of NSCLC patients with brain metastases, understand their first-line treatment and report outcomes attained in real-world settings. MATERIALS AND METHODS: This post-hoc analysis included all patients in the European observational FRAME study who had brain metastases at initiation of first-line treatment. Descriptive statistics were used for continuous and categorical variables and survival outcomes were assessed using the Kaplan-Meier approach. RESULTS: Our data showed that 17% of patients (263/1564) had spread of the disease to the brain at initiation of first-line treatment. Patients with brain metastases were slightly younger, and more likely to have NSCLC of non-squamous histology than the overall study sample. 34% had received prior palliative radiotherapy to the brain. Our analysis showed a median overall survival (OS) of 7.2 months [95% confidence interval (CI) 6.1-8.2] for all patients with brain metastases treated with first-line platinum-based chemotherapy, ranging from 5.6 months for those treated with gemcitabine plus platinum up to 9.3 months for those treated with pemetrexed plus platinum. Further analysis showed that patients with brain metastases were more frequently treated with pemetrexed platinum-doublet therapy than with any other regimen. CONCLUSIONS: Our analysis provides a unique set of real-world data which adds to current understanding about treatment decisions and outcomes for NSCLC patients with brain metastases for whom there is little clinical trial data available.

Critical evaluation of mixed treatment comparison meta-analyses using examples assessing antidepressants and opioid detoxification treatments.

Comparing multiple treatment options using meta-analytical methods requires complex statistical methods called mixed treatment comparisons (MTCs). Such methods offer the possibility to summarize data from many clinical trials comparing the different available options. However, those methods are based on a number of assumptions and inherent difficulties that are discussed and illustrated with examples from the psychiatric literature to help readers to understand the strengths and weaknesses of these methods. This review will help enable readers to critically appraise the methodology and results of publications that use MTCs.

Influence of histology and biomarkers on first-line treatment of advanced non-small cell lung cancer in routine care setting: baseline results of an observational study (FRAME).

FRAME is a prospective observational study of first-line treatments for advanced non-small cell lung cancer (NSCLC). This interim analysis examines the influence of histology and biomarkers on therapeutic decisions. Baseline characteristic, treatment, and diagnostic procedure data were collected on European patients with stage IIIB/IV NSCLC who were treated with any first-line platinum-based doublet, with or without targeted agents, in routine clinical practice. A total of 1567 patients were observed in 11 countries between April 2009 and February 2011. Patients were mostly non-Asian (96.4%), male (71.5%), smokers (84.4%) with stage IV NSCLC (76.6%) and a performance status of 0-1 (82.2%). Median age was 64 years (range, 33-87). First-line treatments were platinum-based combinations with pemetrexed (36.3%), gemcitabine (23.0%), vinorelbine (19.2%), taxanes (18.9%), or other (2.6%), with concurrent targeted agents in 8.4% of patients (mainly bevacizumab, 7.3%). Diagnosis was based on histology in 70.6%, cytology in 20.3%, and both in 9.1% of patients. The final diagnosis was nonsquamous in 72.2% (including 'not otherwise specified [NOS]' in 11.0%), squamous in 24.4%, and other in 3.4% of patients, with the most common reasons for NOS diagnosis being 'subtyping not technically possible' (42.9%) and 'not important for treatment decision' (40.5%). Only 1.1% (6 patients) in the pemetrexed cohort and 0.9% (1 patient) of patients who received bevacizumab had squamous cell carcinoma. At least one immunohistochemical (IHC) marker was used in 53.5% of patients (thyroid transcription factor-1 [TTF-1]: 47.5%, cytokeratin 7 [CK7]: 38.6%, cytokeratin 5/6 [CK5/6]: 17.9%, p63: 8.8%, cluster of differentiation 56 [CD56]: 4.2%, cytokeratin 14 [CK14]: 1.9%, and other: 24.2%). Testing for additional biomarkers was less common, with the most common being for epidermal growth factor receptor (EGFR) mutation status (26.0%). Physician-reported key factors influencing treatment choice were 'histopathological/cytological diagnosis' (77.4%), 'performance status' (63.2%), and 'age' (52.8%). Similar factors were identified using logistic regression models. Frequent histological testing was observed, likely resulting in few NOS diagnoses. In addition, IHC and predictive biomarkers were routinely assessed. Histology, performance status, and age were key factors influencing first-line treatment choice in the routine care of patients with advanced NSCLC. Clinical Trials. gov registry identifier number: NCT01067794.

Patients' preference for olanzapine orodispersible tablet compared with conventional oral tablet in a multinational, randomized, crossover study.

OBJECTIVES: The aim of this study was to compare patients' preference for olanzapine orodispersible tablet (ODT) with oral conventional tablet (OCT). METHODS: A 12-week randomized, crossover, multinational, open-label study was conducted to estimate the proportion of patients preferring ODT or OCT. Outpatients with stable schizophrenia on OCT monotherapy were randomly assigned 1:1 to ODT or OCT. Compliance and drug attitude were measured using the Drug Attitude Inventory (DAI-10) and Medication Adherence Form (MAF) scales; tolerability and safety by Association for Methodology and Documentation in Psychiatry (AMDP-5) questionnaire and adverse event summary. RESULTS: A total of 175 patients answered a preference question: 106 (61%) preferred ODT and 48 (27%) preferred OCT (P<0.001 adjusted for treatment sequence); 21 (12%) expressed no preference. There was no significant change in DAI-10 with either formulation. MAF was above 75% in 94% vs. 93% of patients on ODC and OCT, respectively. Compliance as measured by tablet count was above 98% on both formulations. The adverse event profiles did not differ between formulations. Mean weight increase over 6 weeks on ODT was 0.8 kg and on OCT was 0.6 kg. CONCLUSIONS: Given the importance of patients' preference for treatment planning and success, the ODT formulation should be routinely considered as a treatment option.

Long-term, naturalistic treatment with olanzapine, risperidone, quetiapine, or haloperidol monotherapy: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

Objective. To compare the effectiveness of olanzapine, risperidone, quetiapine, or haloperidol monotherapy in patients with schizophrenia who were treated in routine clinical practice settings for a period of 2 years. The incidence and persistence of adverse events encountered during long-term therapy are also reported. Method. Outpatients with schizophrenia who entered this 3-year, prospective, observational study were classified according to their initially prescribed antipsychotic monotherapy: olanzapine (n=3222), risperidone (n=1116), quetiapine (n=189), or haloperidol (n=256). Patients were included in the analysis for as long as this treatment was maintained. Results. Over 2 years, olanzapine recipients had significantly (P≤0.001) greater reduction in overall CGI-S score (and the negative, depressive, and cognitive symptoms domains), lower incidence of sexual and motor dysfunction, and greater odds of response compared to risperidone or haloperidol-treated patients. However, olanzapine patients gained more weight than patients in other treatment groups. The incidence of motor dysfunction was significantly (P≤0.001) greater in haloperidol-treated patients, relative to the atypical treatment groups. Conclusion. The results of this observational study indicate that, in these patients with schizophrenia, long-term monotherapy with olanzapine may offer benefits over risperidone and haloperidol, but the potential for weight gain should be considered in the clinical management of these patients.

Antipsychotic prescription patterns in outpatient settings: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

This report describes antipsychotic prescription patterns for outpatients with schizophrenia prescribed olanzapine (n=3,222), clozapine (n=236), risperidone (n=1,117), quetiapine (n=189) or haloperidol (n=256) monotherapy at study entry and treated in a naturalistic, clinical practice setting over 24 months. Predictive factors associated with remaining on monotherapy were also identified. Olanzapine patients had significantly greater odds of remaining on their initial monotherapy compared to other treatment groups, while clozapine or risperidone recipients were more likely to remain on monotherapy, compared to haloperidol patients. Switching antipsychotic medication was more common than addition of another antipsychotic agent, and the most common reason for modifying treatment was lack of effectiveness. The odds of modifying antipsychotic prescription due to intolerability were lower for patients treated with olanzapine, compared to patients treated with risperidone or haloperidol (p

Treatment preferences in men with erectile dysfunction: an open label study in Korean men switching from sildenafil citrate to tadalafil.

AIM: To evaluate patient preferences for sildenafil citrate or tadalafil (PDE-5 inhibitors available for the treatment of erectile dysfunction [ED]) and assess potential reasons for these preferences. METHODS: This open-label study was conducted on Korean men taking sildenafil, at least 6 weeks prior to study entry, for ED. Following screening, patients continued sildenafil treatment for 4 weeks, then after a 1-week washout period, switched to tadalafil for 8 weeks. Patients then continued with their treatment of choice during an extension phase. Psychosocial factors (time concern, spontaneity, sexual self-confidence) were evaluated using Psychological and Interpersonal Relationship Scales (PAIRS), while timing of dose to sexual attempt patterns were assessed from patient diaries. RESULTS: The present study enrolled 160 Korean men (mean age 55 years) with prior median sildenafil use of 585 days. During the extension phase, 73.7% of patients elected to take tadalafil, whereas 26.3% chose sildenafil (P < 0.001). After switching from sildenafil to tadalafil, mean PAIRS time concern scores decreased from 2.54 to 2.42 (P = 0.002), with no statistically significant differences observed between the sildenafil and tadalafil assessment phases in sexual spontaneity and self-confidence scores. Sexual attempts made > 4 h to =/< 36 h post-dose occurred in 4.5% of patients during the sildenafil assessment phase compared with 17.5% during the tadalafil assessment phase. CONCLUSION: After experiencing both sildenafil and tadalafil, the majority of patients exhibited a preference for tadalafil. This preference might be influenced by psychosocial factors, such as decreased time concerns, and a broader window of opportunity available for sexual activity.

Treatment with olanzapine, risperidone or typical antipsychotic drugs in Asian patients with schizophrenia.

OBJECTIVE: To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings. METHOD: In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline. RESULTS: At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p < 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p < 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p < 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p < 0.001). CONCLUSIONS: The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.

Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

PURPOSE: Sexual dysfunction in patients with schizophrenia can reduce quality of life and treatment compliance. This report will compare the effects of selected atypical and typical antipsychotics on sexual function in a large, international population of outpatients with schizophrenia who were treated over 1 year. SUBJECTS AND METHODS: Outpatients with schizophrenia, who initiated or changed antipsychotic treatment, and entered this 3-year, prospective, observational study were classified according to the monotherapy prescribed at baseline: olanzapine (N=2638), risperidone (N=860), quetiapine (N=142) or haloperidol (N=188). RESULTS: Based on patient perception, the odds of experiencing sexual dysfunction during 1 year of therapy was significantly lower for patients treated with olanzapine and quetiapine when compared to patients who received risperidone or haloperidol (all P< or =0.001). Females on olanzapine (14%) or quetiapine (8%) experienced a lower rate of menstrual irregularities, compared to females on risperidone (23%) or haloperidol (29%). Significant discordance was evident between patient reports and psychiatrist perception of sexual dysfunction, with psychiatrists underestimating sexual dysfunction (P< or =0.001). CONCLUSION: These findings indicate clinically relevant differences exist in the sexual side effect profiles of these selected antipsychotics. These factors should be considered when selecting the most appropriate treatment for outpatients with schizophrenia.

Timing of dose relative to sexual intercourse attempt in previous sildenafil citrate users treated with tadalafil.

OBJECTIVES: Tadalafil, a phosphodiesterase type 5 inhibitor, has an extended period of effectiveness, up to 36 hours, for the treatment of erectile dysfunction (ED). Changes in behavior of long-term sildenafil users were evaluated by assessing time of dose relative to sexual intercourse attempts during treatment with sildenafil and tadalafil. MATERIALS AND METHODS: This open-label study was conducted in men with ED and a history of >or=6-week prior sildenafil use in Australia, New Zealand, Asia, Central and Eastern Europe, the Middle East, and Latin America. Patients continued sildenafil treatment for 4 weeks, then switched to tadalafil for 8 weeks. Timing of sexual intercourse attempt relative to dose was assessed through patient diaries for the final 4 weeks of each treatment period. Patients continued their treatment of choice in an extension period. RESULTS: A total of 2,760 men (mean age 54.4 years) with a median duration of prior sildenafil use of 474 days were enrolled. Significant increases in median time from dose to intercourse attempt were observed when changing treatment from sildenafil citrate (1.21 hours) to tadalafil (3.25 hours; P < 0.001). Fifty-nine percent of intercourse attempts were within 4 hours of dosing when patients were treated with tadalafil (88% with sildenafil). The proportion of intercourse attempts per patient made >4 hours after dose was considerably higher during the tadalafil than during the sildenafil assessment period. Similar daily cycles of frequency of dosing and intercourse attempts were observed in all study periods and were characterized by a small peak in the morning and a large peak in the evening. When changing treatment to tadalafil, patients administered the drug earlier in the day and over a broader period of time. CONCLUSION: Following the dosing instructions reflecting tadalafil's extended period of effectiveness, men with a history of established sildenafil use changed their dose-attempt behavior when treated with tadalafil.

Effectiveness and tolerability of schizophrenia treatment in Central and Eastern Europe: results after 1 year from a prospective, observational study (IC-SOHO).

Objective. The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study is intended to complement smaller, shorter-term observational studies and randomised controlled clinical trials in providing information on the treatment of schizophrenia in various geographies that have not been well studied previously. Methods. Interim results after 12 months are presented for a subset of patients from eight Central and Eastern European (CEE) countries initiating or switching to olanzapine, risperidone, or typical antipsychotic monotherapy at Baseline (n=1387). Results. Patients initially prescribed olanzapine and risperidone experienced significantly greater improvements in a broad range of schizophrenia symptom domains compared with patients prescribed typicals. Furthermore, patients in the olanzapine group showed significantly greater improvements in overall and negative symptom domains compared with the risperidone group (all P≤0.05). While patients in the olanzapine group gained more weight than the other two groups, they had significantly lower odds of developing extrapyramidal symptoms, loss of libido, and sexual dysfunction. Patients initially prescribed olanzapine were also significantly less likely to have changed or added antipsychotics during 12 months of treatment compared with the risperidone and typicals groups. Conclusion. In this CEE sample, schizophrenia treatment outcomes after 12 months varied between patients initially prescribed different antipsychotics.

[Functional status and quality of life in Latin American outpatients with schizophrenia treated with atypical or typical antipsychotics: outcomes of the 12 months schizophrenia outpatient health outcomes (IC-SOHO) Study]. / Estado funcional y calidad de vida en pacientes latinoamericanos con esquizofrenia tratados con un antipsicótico atípico o típico: resultado de 12 meses del estudio Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO).

OBJECTIVE: Functional status and quality of life outcomes in Latin American outpatients with schizophrenia were compared after 12 months of monotherapy treatment with olanzapine, risperidone or typical antipsychotics. METHOD: Both outcomes were assessed as part of a prospective, large (N= 7658), international (27 countries), observational study. RESULTS: from the Latin American subpopulation (N= 2671; 11 countries) are presented. Compared to typical antipsychotics, olanzapine and risperidone were associated with significantly (p < 0.05) greater odds of employment and social activity, and significantly greater improvements in quality of life. Olanzapine was also associated with significantly greater odds of living independently, compared to typical antipsychotics. CONCLUSION: This study indicates that functional status and quality of life outcomes are likely to be more favorable when Latin American outpatients with schizophrenia are treated with olanzapine or risperidone monotherapy, rather than typical antipsychotics.

Estado funcional y calidad de vida en pacientes latinoamericanos con esquizofrenia tratados con un antipsicótico atípico o típico: resultado de 12 meses del estudio Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO). / [Functional status and quality of life in Latin American outpatients with schizophrenia treated with atypical or typical antipsychotics: outcomes of the 12 months schizophrenia outpatient health outcomes (IC-SOHO) Study]

OBJECTIVE: Functional status and quality of life outcomes in Latin American outpatients with schizophrenia were compared after 12 months of monotherapy treatment with olanzapine, risperidone or typical antipsychotics. METHOD: Both outcomes were assessed as part of a prospective, large (N= 7658), international (27 countries), observational study. RESULTS: from the Latin American subpopulation (N= 2671; 11 countries) are presented. Compared to typical antipsychotics, olanzapine and risperidone were associated with significantly (p < 0.05) greater odds of employment and social activity, and significantly greater improvements in quality of life. Olanzapine was also associated with significantly greater odds of living independently, compared to typical antipsychotics. CONCLUSION: This study indicates that functional status and quality of life outcomes are likely to be more favorable when Latin American outpatients with schizophrenia are treated with olanzapine or risperidone monotherapy, rather than typical antipsychotics.

Estado funcional y calidad de vida en pacientes latinoamericanos con esquizofrenia tratados con un antipsicótico atípico o típico: resultado de 12 meses del estudio Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) / [Functional status and quality of life in Latin American outpatients with schizophrenia treated with atypical or typical antipsychotics: outcomes of the 12 months schizophrenia outpatient health outcomes (IC-SOHO) Study]

OBJECTIVE: Functional status and quality of life outcomes in Latin American outpatients with schizophrenia were compared after 12 months of monotherapy treatment with olanzapine, risperidone or typical antipsychotics. METHOD: Both outcomes were assessed as part of a prospective, large (N= 7658), international (27 countries), observational study. RESULTS: from the Latin American subpopulation (N= 2671; 11 countries) are presented. Compared to typical antipsychotics, olanzapine and risperidone were associated with significantly (p < 0.05) greater odds of employment and social activity, and significantly greater improvements in quality of life. Olanzapine was also associated with significantly greater odds of living independently, compared to typical antipsychotics. CONCLUSION: This study indicates that functional status and quality of life outcomes are likely to be more favorable when Latin American outpatients with schizophrenia are treated with olanzapine or risperidone monotherapy, rather than typical antipsychotics.

A randomized phase IIb trial of pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium.

PURPOSE: Preclinical studies suggest that inhaled budesonide may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of inhaled budesonide in smokers with bronchial dysplasia. EXPERIMENTAL DESIGN: A total of 112 smokers with more than or equal to one site of bronchial dysplasia > 1.2 mm in size identified by autofluorescence bronchoscopy-directed biopsy was randomly assigned to receive placebo or budesonide (Pulmicort Turbuhaler) 800 microg twice daily inhalation for 6 months. The primary end point was change in the histopathologic grade on repeat biopsy of the same sites at the end of 6 months. RESULTS: There were no significant differences in the regression or progression rates of bronchial dysplasia between the two groups. There was a statistically significant but modest decrease in p53 and BclII expression in the bronchial biopsies after 6 months of Pulmicort Turbuhaler versus placebo (P = 0.01 and P = 0.001, respectively). There was a small but statistically significant decrease in the proportion of computed tomography-detected lung nodules after Pulmicort Turbuhaler compared with placebo (P = 0.024). CONCLUSIONS: Our results suggest that in smokers, inhaled budesonide in the dose of 1600 microg daily for 6 months had no effect in regression of bronchial dysplastic lesions or prevention of new lesions. Budesonide treatment resulted in a modest decrease in p53 and BclII protein expression in bronchial biopsies and a slightly higher rate of resolution of computed tomography-detected lung nodules. Whether budesonide truly has an effect in preneoplastic lesions in the peripheral airways and alveoli requires additional investigation.

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia.

BACKGROUND: Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia. METHODS: One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided. RESULTS: One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication. CONCLUSION: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.