Development of clinical trials in a cooperative group setting: the eastern cooperative oncology group.

PURPOSE: We examine the processes and document the calendar time required to activate phase II and III clinical trials by an oncology group: the Eastern Cooperative Oncology Group (ECOG). Methods: Setup steps were documented by (a) interviewing ECOG headquarters and statistical center staff, and committee chairs, (b) reviewing standard operating procedure manuals, and (c) inspecting study records, documents, and e-mails to identify additional steps. Calendar time was collected for each major process for each study in this set. RESULTS: Twenty-eight phase III studies were activated by ECOG during the January 2000 to July 2006 study period. We examined a sample from 16 of those studies in detail. More than 481 distinct processes were required for study activation: 420 working steps, 61 major decision points, 26 processing loops, and 13 stopping points. Median calendar days to activate a trial in the phase III subset was 783 days (range, 285-1,542 days) from executive approval and 808 days (range, 435-1,604 days) from initial conception of the study. Data were collected for all phase II and phase III trials activated and completed during this time period (n = 52) for which development time represented 43.9% and 54.1% of the total trial time, respectively. CONCLUSION: The steps required to develop and activate a clinical trial may require as much or more time than the actual completion of a trial. The data shows that to improve the activation process, research should to be directed toward streamlining both internal and external groups and processes.     

Ongoing US cooperative group trials using taxanes in the adjuvant setting

The use of systemic adjuvant therapy in women with early-stage breast cancer has been demonstrated to have a profound impact on survival. The role of paclitaxel and docetaxel in the adjuvant setting has attracted a great deal of attention. Both of these agents are highly active in patients with advanced breast cancer. In addition, they can be utilized in combination with anthracyclines, which have been shown to provide a slightly better outcome in patients with early-stage breast cancer compared to non-anthracycline-containing regimens. Randomized trials have demonstrated a potential role for paclitaxel in adjuvant chemotherapy. In the Cancer and Leukemia Group B 9344 trial, which explored the use of doxorubicin and cyclophosphamide with or without paclitaxel, the initial analysis demonstrated a 22% reduction in the relative risk of relapse and a 26% reduction in the relative risk of death in the paclitaxel group. However, a clear role for the use of paclitaxel in adjuvant therapy remains to be defined. The Breast Cancer International Research Group trial 001 compared the combination of docetaxel/doxorubicin/cyclophosphamide to 5-fluorouracil/doxorubicin/cyclophosphamide. This trial demonstrated a promising reduction in the relative risk of recurrence of 32% for the docetaxel/doxorubicin/cyclophosphamide group. Ongoing trials will help to further define the role of taxanes in the adjuvant setting for patients with operable breast cancer.     

Current and future trials of the EORTC brain tumor group

The EORTC Brain Tumor Group (BTG) is dedicated to clinical research of neoplasms of the brain. In the past years the BTG has carried out phase II and phase III trials on glial tumors, brain metastases and primary CNS lymphomas. Future studies will investigate novel drugs in combination with chemo-radiotherapy in glioblastoma multiforme, radiotherapy in meningioma, and chemotherapy in medulloblastoma. The BTG will also start a new phase III trial on newly diagnosed low-grade glioma comparing radiotherapy to temozolomide. In all our trials translational research is getting more and more important, often this is one of the most important ways to get useful conclusions from clinical trials. The wide recognition of the importance of translational research for clinical trials and in particular with targeted therapies implies that this type of research will become a mandatory element in many of our future trials.     

Implementation of the group sequential methodology in a randomized trial in metastatic colorectal carcinoma

A prospective randomized trial using the group sequential statistical method with frequent planned interim analyses was initiated in patients with metastatic colorectal adenocarcinoma comparing methotrexate and 5 fluorouracil (MTX-FU) to methyl CCNU, vincristine, FU, and streptozotocin (MOF-Strep). As a requirement of the group sequential design, a p value of 0.0125 was necessary to stop the trial at the first analysis. The first analysis was done after 17 patients were entered in each study arm and revealed six partial responses to MOF-Strep (35%) and one partial response to MTX-FU (6%) (p = 0.017). As a result, patient accrual continued. Problems encountered with the implementation of the group sequential methodology and the importance of stratification for prognostic variables are discussed.     

Sample size estimation in phase III cancer clinical trials.

This paper deals with the basic principles involved in sample size calculation of phase III cancer clinical trials. It illustrates the concepts and factors determining the sample size. Various examples of phase III cancer clinical trials are provided and the sample size is calculated taking into account the assumptions made. The examples provided include sample sizes for comparing proportions and sample sizes for comparing survival times. Several special topics are also discussed including choice of endpoint, number of treatment groups, factorial designs and equivalence trials.     

Impact of a dosimetry review program on radiotherapy in group trials

The impact of a quality assurance program on protocol compliance has been explored. A sample of 2258 patients, who received radiation therapy on 18 different NCI funded protocols, was selected for this study from the more than 6200 cases reviewed by the Quality Assurance Review Center (QARC) from 1974 to 1983. Analysis of this sample reveals a significant decrease in the protocol non-compliance rate as a function of QA participation time (35% down to 5%). The educational impact of the QA program is demonstrated by the drop in the protocol dose deviation rate from 11.4% (before QARC feedback) to 3.6% (after feedback, p less than .001). The corresponding drop in protocol deviations in treatment volume is from 21.5% to 10.5% (p less than .001). The effect of the "on-treatment" review process is studied; it is demonstrated that this process cuts the rate of major deviations in half. The technical discrepancies in dose are also analyzed and discussed.     

Sample size calculation for clinical trials: the impact of clinician beliefs

The UK Medical Research Council (MRC) randomized trial of gastric surgery, ST01, compared conventional (D1) with radical (D2) surgery. Sample size estimation was based upon the consensus opinion of the surgical members of the design team, which suggested that a change in 5-year survival from 20% (D1) to 34% (D2) could be realistic and medically important. On the basis of these survival rates, the sample size for the trial was 400 patients. However, this trial was exceptional in the way that a survey of surgeons' opinions was made at the start of the trial, in 1986, and again before results were analysed but after termination of the trial in 1994. At the initial survey, the three surgeons from the trial steering committee and 23 other surgeons experienced in treating gastric carcinoma were given detailed questionnaires. They were asked about the expected survival rate in the D1 group, anticipated difference in survival from D2 surgery, and what difference would be medically important and influence future treatment of patients. The consensus opinion of those surveyed was that there might be a survival improvement of 9.4%. In 1994, prior to closure of the trial, and before any survival information was disclosed, the survey was repeated with 21 of the original 26 surgeons. At this second survey, the opinion of the trial steering committee was that 9.5% difference was more realistic. This was in accord with the opinion of the larger group, which remained little changed since 1986. The baseline 5-year D1 survival was thought likely to be about 32%, which corresponded closely to the actual survival of recruited patients. Revised sample size calculations suggested that, on the basis of these more recent opinions, between 800 and 1200 patients would have been required. Both surveys assessed the level of treatment benefit that was deemed to be sufficient for causing surgeons to change their practice. This showed that the 13% difference in survival used as the study target was clinically relevant, but also indicated that many clinicians would remain unwilling to change their practice if the difference is only 9.5%. The experience of this carefully designed trial illustrates the problems of designing long-term, randomized trials. It raises interesting questions about the common practice of basing sample size estimates upon the beliefs of a trial design committee that may include a number of enthusiasts for the trial treatment. If their opinion of anticipated effect sizes drives the design of the trial, rather than the opinion of a larger community of experts that includes sceptics as well as enthusiasts, there is likely to be a serious miscalculation of sample size requirements.     

Pancreas cancer trials for early stage disease: Surgeons leading therapeutic cooperative group trials

Surgeon-led clinical trials have defined the standard of care for locoregional pancreatic cancer to date. The infrastructure and collaborative nature of cooperative oncology groups offer many advantages, such as providing an ideal mechanism through which multidisciplinary pancreatic cancer trials are performed. As key members of the treatment team, surgeons bring experience and expertise to the design of surgical and multidisciplinary trials and are uniquely poised to be leaders of future pancreatic cancer trials.     

A simulated sequential analysis based on data from two MRC trials.

The motivation for proposing sequential methods for cancer clinical trials is presented, and the methodology examined by re-analysing two completed phase III cancer trials of the Lung Cancer Working Party of the British Medical Research Council. The reanalysis proceeds as if the trials had been designed with a planned series of interim analyses governing stopping. Specifically, the triangular and double-triangular tests were applied. The sequential reanalysis gave a substantial reduction in the number of patient required, and deaths observed, for conclusions to be reached in comparison with the completed studies. In each case, the sequential analysis was stratified for baseline prognostic factors which were seen to be important at the first interim analysis.     

Feasibility and safety of sequential research‐related tumor core biopsies in clinical trials

BACKGROUND:

There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed.

METHODS:

This institutional review board‐approved, retrospective study included chart and interventional radiology case review from 6 phase 1/2 studies at the National Cancer Institute.

RESULTS:

One hundred forty‐two of 150 protocol patients who were approached gave consent for research biopsies. Patients' median age was 56 years (range, 27‐78 years), their median body mass index was 25.8 kg/m² (range, 14.4‐46.2 kg/m²), they had an Eastern Cooperative Oncology Group performance status of 0 or 1, and they had normal end‐organ function. Baseline biopsies were collected from 138 of 142 patients (97%), and paired specimens were collected from 96 (70%). Most patients had metastatic gynecologic cancers (85%), and 78% had target disease below the diaphragm with a median size of 2.7 cm (range, 1‐14.5 cm). Protocol therapies included kinase inhibitors (35%), angiogenesis inhibitors (54%), and olaparib/carboplatin (11%); therapy was not interrupted for biopsies. All adverse events were uncomplicated and were observed in 4 patients (liver subcapsular hematoma in 1 patient, vasovagal syncope in 2 patients, and pneumothorax in 1 patient). The complication rate in obese patients was similar to that in nonobese patients (3 of 108 patients vs 1 of 34 patients, respectively). Sixty‐seven patients (48%) were receiving bevacizumab at the time of subsequent biopsies. The complication rate was not different between patients who were and were not receiving bevacizumab (3 of 67 patients vs 1 of 71 patients, respectively). Ninety‐five percent of biopsies yielded useable material.

CONCLUSIONS:

Serial percutaneous core‐needle biopsies can be obtained safely and yield material applicable for multiple translational applications. Obesity and/or concomitant antiangiogenic therapy and depth of disease did not increase the risk or preclude the successful acquisition of useful tissue. Cancer 2013. © 2012 American Cancer Society.     

Statistical controversies in cancer research: using standardized effect size graphs to enhance interpretability of cancer-related clinical trials with patient-reported outcomes

Patient reported outcomes (PROs) are becoming increasingly important in cancer studies, particularly with the emphasis on patient centered outcome research. However, multiple PROs, using different scales, with different directions of favorability are often used within a trial, making interpretation difficult. To enhance interpretability, we propose the use of a standardized effect size graph, which shows all PROs from a study on the same figure, on the same scale. Plotting standardized effects with their 95% confidence intervals (CIs) on a single graph clearly showing the null value conveys a comprehensive picture of trial results. We demonstrate how to create such a graph using data from a randomized controlled trial that measured 12 PROs at two time points. The 24 effect sizes and CIs are shown on one graph and clearly indicate that the intervention is effective and sustained.     

Gynecologic oncology group trials in uterine corpus malignancies: recent progress

The Gynecologic Oncology Group (GOG) has conducted multiple trials related to malignancies of the uterine corpus. Recently, several of these trials have been presented and/or published. Areas of focus included the feasibility of laparoscopic staging for endometrial cancer, the adjuvant management of locally advanced endometrial cancer, whole abdominal irradiation in maximally resected advanced endometrial carcinoma, and combination chemotherapy regimens for stage I and II carcinosarcoma after primary surgery and for advanced or recurrent carcinosarcoma. This article will discuss the background and details of each of these important advances.     

Quality assurance of dosimetry and the impact on sample size in randomized clinical trials.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the impact of appropriate dosimetry quality assurance (QA) on patient number required in radiotherapy randomized control trials (RCT). MATERIALS AND METHODS: The steepness of clinical dose-response curves, gamma(clin.), was calculated by a convoluting a biological dose-response distribution and the distribution of technical and dosimetrical factors. Population size calculation was performed taking into account gamma(clin.) and expected difference in outcome between two arms of an RCT, for different levels of variation in dose to the patient population. RESULTS: Uncertainties in dose reduces gamma(clin.) to the largest extent when the initial gamma-value is high and less so for low gamma-value. Reduced uncertainty in dose led to a significant reduction in the number of patients required in an RCT if the expected difference between the experimental and conventional arm is small. The reduction in patient numbers is less when the differences between the conventional and experimental arm is larger. CONCLUSION: The number of patients required in an RCT may be reduced by introducing appropriate dosimetry QA as the risk of under-powering the study is minimized. Dosimetry QA in clinical studies is therefore cost-effective.     

Methodological and ethical quality in phase III cancer trials: role of the cooperative group

Phase III clinical trials (CT) are carried out more and more often in a multicentric way, under the aegis of one or more cooperative groups (CG). The goal of this study was to analyze the influence of the GC on ethical quality (EQ) and methodological quality (MQ) in phase III cancer CT. EQ (Berdeu-score) and MQ (Jadad scale) were assessed for all CTs (n=231) published between 1999 and 2001 in 10 international journals. The impact of CG on EQ and MQ was evaluated with an univariate analysis. 140 ECR (60.6%) were carried out under the aegis of a CG. There was no improvement of the MQ and EQ for the trials carried out under the aegis of a CG. The methodological score (Jadad) was of 9.9 +/- 1.15 for the CT-CG (+) and of 9.8 +/- 1.28 for the CT-GC (-) (p=0.7). The ethical score (Berdeu) was of 0.43 +/- 0.14 for the CT-CG (+) and of 0.40 +/- 0.11 for the CT-CG (-) (p=0.08). Interim analysis, defined stopping rules and independent monitoring were more frequent for the CT-CG (+) and were respectively 37.8% vs 15.4%, 20.7% vs 8.8%, 19.3 vs 6.6%. 31.9% of the CT-CG (-) and 19.3% of the CT-CG (+) were financed by industry (p=0.03). The CG have a major role to play in the protection of the patient in CT, because they monitored trials from the conception to the publication and communication of results.     

Trial sequential analysis of randomized controlled trials on neoadjuvant therapy for resectable pancreatic cancer

IntroductionMeta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence but can suffer from type I (false-positive) and II (false-negative) errors, which can be estimated through trial sequential analysis (TSA) demonstrating eventual credibility of results. Aim of the study was to establish through TSA which strategy between neoadjuvant approach or upfront surgery provides best results when treating potentially resectable pancreatic adenocarcinoma.Materials and methodsRCTs were searched until September 2021. Intention-to-treat (ITT) overall survival, resection rate, ITT R0 and N0 rates and per-protocol R0 and N0 rates were the outcomes considered. Fixed-effect model was applied. TSA assumed an alpha = 5% and a power = 80%.ResultsFour RCTs were identified accruing 325 patients for the ITT analyses and 242 for the per-protocol analyses. Neoadjuvant did not improve survival (p = 0.167) and TSA supported that this result was underpowered, requiring additional 1514 patients to prove credibility. Neoadjuvant reduced resection rate (p = 0.044) but type I error was not avoided. Neoadjuvant credibly increased per-protocol R0 and N0 rates (p = 0.003 and p < 0.001), and TSA showed that these were true-positive findings. Neoadjuvant did not increase ITT R0 rate since randomization (p = 0.169) but TSA showed lack of power. Neoadjuvant credibly increased the ITT N0 rate (p < 0.001) and TSA supported that this was a true positive finding.ConclusionsNeoadjuvant strategy credibly demonstrated superiority over upfront surgery in determine per-protocol R0 resection and N0 rates, as well as ITT N0 rate. For the remaining outcomes, TSA suggested the need of larger samples to exclude type I and II errors.