Peter M. Ellis

Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer

PURPOSE Etoposide and cisplatin (EP) has been a standard treatment for extensive-disease small-cell lung cancer (SCLC). An earlier phase III trial reported improved survival for patients receiving irinotecan plus cisplatin (IP) versus EP. Our trial was designed to determine if a modified weekly regimen of IP would provide superior survival with less toxicity than EP. PATIENTS AND METHODS The primary objective was to compare overall survival in extensive-disease SCLC patients randomly assigned to receive IP (n = 221) or EP (n = 110). Patients were randomly assigned in 2:1 ratio to cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days, or cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until progressive disease, or until intolerable toxicity resulted. RESULTS Selected grade 3/4 toxicities for IP/EP were: neutropenia (36.2% v 86.5%; P < .01), febrile neutropenia (3.7% v 10.4%; P = .06), anemia (4.8% v 11.5%; P = .02), thrombocytopenia (4.3% v 19.2%; P < .01), vomiting (12.5% v 3.8%; P = .04), and diarrhea (21.3% v 0%; P < .01). There was no significant difference in response rates (48% v 43.6%), median time to progression (4.1 v 4.6 months), or overall survival (median survival time, 9.3 months v 10.2 months; P = .74). CONCLUSION Treatment with this dose and schedule of IP did not result in improved survival when compared with EP. Fewer patients receiving IP had grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia compared with patients receiving EP, but more had grade 3/4 diarrhea and vomiting.

Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction

Abstract 5-(2′-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRATM), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.

Communicating With Realism and Hope: Incurable Cancer Patients' Views on the Disclosure of Prognosis

PURPOSE To identify preferences for the process of prognostic discussion among patients with incurable metastatic cancer and variables associated with those preferences. PATIENTS AND METHODS One hundred twenty-six (58%) of 218 patients invited onto the study participated. Eligible patients were the consecutive metastatic cancer patients of 30 oncologists, who were diagnosed within 6 weeks to 6 months before recruitment, over 18 years of age, and without known mental illness. Patients completed a postal survey measuring patient preferences for the manner of delivery of prognostic information, including how doctors might instill hope. RESULTS Ninety-eight percent of patients wanted their doctor to be realistic, provide an opportunity to ask questions, and acknowledge them as an individual when discussing prognosis. Doctor behaviors rated the most hope giving included offering the most up to date treatment (90%), appearing to know all there is to know about the patients cancer (87%), and saying that pain will be controlled (87%). The majority of patients indicated that the doctor appearing to be nervous or uncomfortable (91%), giving the prognosis to the family first (87%), or using euphemisms (82%) would not facilitate hope. Factor analysis revealed six general styles and three hope factors; the most strongly endorsed styles were realism and individualized care and the expert/positive/collaborative approach. A range of demographic, psychological, and disease factors were associated with preferred general and hope-giving styles, including anxiety, information-seeking behavior, expected survival, and age. CONCLUSION The majority of patients preferred a realistic and individualized approach from the cancer specialist and detailed information when discussing prognosis.

Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors.

BACKGROUND Enrolling participants onto clinical trials of cancer presents an important challenge. We aimed to identify the concerns of patients with cancer about, and the barriers to, participation in clinical trials. METHODS We did a systematic review to assess studies of barriers to participation in experimental trials and randomised trials for validity and content. We estimated the frequency with which patients identified particular issues by pooling across studies that presented data for barriers to participation in clinical trials as proportions. FINDINGS We analysed 12 qualitative studies (n=722) and 21 quantitative studies (n=5452). Two qualitative studies inquired of patients who were currently enrolled onto clinical trials, and ten inquired of patients who were eligible for enrolment onto various clinical trials. Barriers to participation in clinical trials were protocol-related, patient-related, or physician-related. The most common reasons cited as barriers included: concerns with the trial setting; a dislike of randomisation; general discomfort with the research process; complexity and stringency of the protocol; presence of a placebo or no-treatment group; potential side-effects; being unaware of trial opportunities; the idea that clinical trials are not appropriate for serious diseases; fear that trial involvement would have a negative effect on the relationship with their physician; and their physicians attitudes towards the trial. Meta-analysis confirmed the findings of our systematic review. INTERPRETATION The identification of such barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.

Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non–Small-Cell Lung Cancer Guideline

PURPOSE To determine the role of adjuvant chemotherapy and radiation therapy in patients with completely resected stage IA-IIIA non-small-cell lung cancer (NSCLC). METHODS The Cancer Care Ontario Program in Evidence-Based Care and the American Society of Clinical Oncology convened a Joint Expert Panel in August 2006 to review the evidence and draft recommendations for these therapies. RESULTS Available data support the use of adjuvant cisplatin-based chemotherapy in completely resected NSCLC; however, the strength of the data and consequent recommendations vary by disease stage. Adjuvant radiation therapy appears detrimental to survival in stages IB and II, with a possible modest benefit in stage IIIA. CONCLUSION Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases. Evidence from RCTs demonstrates a survival detriment for adjuvant radiotherapy with limited evidence for a reduction in local recurrence. Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA.

Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update

PURPOSE To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non-small-cell lung cancer (NSCLC). METHODS An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014. RESULTS This guideline update reflects changes in evidence since the previous guideline. RECOMMENDATIONS There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki.

Randomized Clinical Trials in Oncology: Understanding and Attitudes Predict Willingness to Participate

PURPOSE To explore the association at different time points in the trajectory of breast cancer care, between anxiety, knowledge, and attitudes, on womens willingness to participate in randomized clinical trials. MATERIALS AND METHODS A cross-sectional survey was undertaken among women attending a breast clinic for screening mammography or diagnostic assessment plus women with newly diagnosed breast cancer to assess attitudes toward and willingness to participate in randomized clinical trials of breast cancer treatment. RESULTS Five hundred forty-five women completed questionnaires assessing knowledge of and attitudes toward randomized clinical trials. The mean age of respondents was 48.9 years (SD, 11.3 years). Thirty-three percent of women would consider participating in a clinical trial if they had breast cancer. Women with breast cancer (31%) were significantly more likely to decline to participate than women attending for screening mammography (15%) or diagnostic assessment (15%, P =.0002). Women who might consider participating in a randomized clinical trial were more knowledgeable about randomized trials (mean difference, 0.7; 95% confidence interval [CI], 0.2 to 1.2; P =.003). In a multivariate analysis, women who would consider participating in a randomized trial were younger (odds ratio [OR], 0.96; 95% CI, 0.93 to 0.99), more likely to want an active role in decision-making (OR, 3.2; 95% CI, 1.3 to 7.6), and reported a greater impact from the positive aspects of clinical trials (OR, 2.2; 95% CI, 1.3 to 3.8) and less impact from the negative aspects of clinical trials (OR, 2.2; 95% CI, 1.3 to 3.2). CONCLUSION These findings suggest that women who have a better understanding of issues about clinical trials have more favorable attitudes toward randomized trials and are more willing to consider participation in a clinical trial.

Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study

PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2)) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial

BACKGROUND Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING Merck KGaA (Darmstadt, Germany).

Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer

Purpose To evaluate the efficacy of cetuximab added to first-line gemcitabine/platinum in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods In this noncomparative, randomized trial, chemotherapy-naive patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) were eligible. Patients received cisplatin (75 mg/m2 IV, every 3 weeks) or carboplatin (area under the concentration-versus-time curve of 5 intravenously [IV], every 3 weeks), and gemcitabine (1,250 or 1,000 mg/m2 IV, days 1 and 8) plus cetuximab (400 mg/m2 IV day 1, followed by 250 mg/m2 weekly), in arm A, or chemotherapy alone, in arm B. Response rate was the primary end point; safety, progression-free survival, and overall survival were secondary end points. Results Sixty-five patients were randomly assigned to arm A and 66 to arm B. Partial responses were observed in 18 patients (27.7%; 95% CI, 17.3 to 40.2) in arm A and 12 (18.2%; 95% CI, 9.8 to 29.6) in arm ...