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1.  Designing phase II trials in cancer: a systematic review and guidance 
British Journal of Cancer  2011;105(2):194-199.
Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design.
A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration.
A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design.
The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.
PMCID: PMC3142813  PMID: 21712822
phase II; methodology; systematic review; trial design; guidance manual
2.  Two or Three Year Disease Free Survival (DFS) as a Primary Endpoint in Stage III Adjuvant Colon Cancer Trials with fluoropyrimidines with or without Oxaliplatin or Irinotecan: Data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07, and C89803 
The ACCENT group previously established disease-free survival (DFS) with 2 or 3 years median follow-up to predict 5 year overall survival (5yr OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7 years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between endpoints in trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown.
Associations between the treatment effect hazard ratios (HRs) on 2 and 3yr DFS, and 5 and 6yr OS were examined in 6 phase III trials not included in prior analyses from 1997-2002. Individual data for 12,676 patients were analyzed; two trials each tested oxaliplatin, irinotecan, and oral treatment vs 5-FU/LV.
Overall association between 2/3 yr DFS and 5/6 yr OS HRs was modest to poor (simple R2 measures: 0.58 to 0.76, model-based R2: 0.17 to 0.49). In stage III patients, the association increased (model-based R2≥0.79). Observed treatment effects on 2 yr DFS accurately 5/6 yr OS effects overall and in stage III patients.
In recent trials of cytotoxic chemotherapy, 2 or 3yr DFS HRs are highly predictive of 5 and 6yr OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6yr OS, thus at least 6 year follow-up is recommended to assess OS benefit. These data support DFS as the primary endpoint for stage III colon cancer trials testing cytotoxic agents.
Funded by NCI Grant CA-25224 to the Mayo Clinic to support the North Central Cancer Treatment Group.
PMCID: PMC3073413  PMID: 21257306
3.  Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective 
Current Oncology  2011;18(Suppl 2):S20-S27.
Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.
Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.
PMCID: PMC3176906  PMID: 21969808
Ovarian cancer; clinical trials; progression-free survival; overall survival
4.  Progression-free survival as a primary endpoint in clinical trials of metastatic colorectal cancer 
Current Oncology  2011;18(Suppl 2):S5-S10.
In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the “gold standard”—the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer.
PMCID: PMC3176908  PMID: 21969810
Progression-free survival; metastatic colorectal cancer; surrogate endpoints; targeted therapies; randomized clinical trials
6.  Leptin secretion and leptin receptor in the human stomach 
Gut  2000;47(2):178-183.
BACKGROUND AND AIM—The circulating peptide leptin produced by fat cells acts on central receptors to control food intake and body weight homeostasis. Contrary to initial reports, leptin expression has also been detected in the human placenta, muscles, and recently, in rat gastric chief cells. Here we investigate the possible presence of leptin and leptin receptor in the human stomach.
METHODS—Leptin and leptin receptor expression were assessed by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot analysis on biopsy samples from 24 normal individuals. Fourteen (10 healthy volunteers and four patients with non-ulcer dyspepsia and normal gastric mucosa histology) were analysed for gastric secretions. Plasma and fundic mucosa leptin content was determined by radioimmunoassay.
RESULTS—In fundic biopsies from normal individuals, immunoreactive leptin cells were found in the lower half of the fundic glands. mRNA encoding ob protein was detected in the corpus of the human stomach. The amount of fundic leptin was 10.4 (3.7) ng leptin/g mucosa, as determined by radioimmunoassay. Intravenous infusions of pentagastrin or secretin caused an increase in circulating leptin levels and leptin release into the gastric juice. The leptin receptor was present in the basolateral membranes of fundic and antral gastric cells. mRNA encoding Ob-RL was detected in both the corpus and antrum, consistent with a protein of ~120 kDa detected by immunoblotting.
CONCLUSION—These data provide the first evidence of the presence of leptin and leptin receptor proteins in the human stomach and suggest that gastric epithelial cells may be direct targets for leptin. Therefore, we conclude that leptin may have a physiological role in the human stomach, although much work is required to establish this.

Keywords: leptin; leptin receptor; human stomach; gastrin; secretin
PMCID: PMC1727985  PMID: 10896907
7.  Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. 
British Journal of Cancer  1998;78(11):1479-1487.
The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.
PMCID: PMC2063202  PMID: 9836481

Results 1-7 (7)