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Challenges to National Cancer Institute-Supported Cooperative Group Clinical Trial Participation: An ASCO Survey of Cooperative Group Sites
Abstract
Anecdotal information regarding clinical research sites limiting participation in NCI-funded cooperative group studies prompted ASCO to collect data on and investigate the reasons behind this trend.
... As noted, quicker trial development times can leave trials open longer to accrual. Moreover, membership in trials networks or consortiums can provide access to experienced staff and trial-eligible patients, 70 Yet, with shrinking research budgets and when cost recovery in federally funded clinical research may be only 40%-50% of total costs, 71 industry can be a pragmatic partner in trials research. Industry can contribute resources-like new biological agents, finances, and trained personnel-to support trial operations. 1 Recent studies also show that industry can run efficient trials, 17,72 although its promptness may be motivated by the desire to market a successful therapy. ...
... 31,[73][74][75] Moreover, because these collectives are inherently integrated, they may be well-positioned to consolidate infrastructure and improve patients' access to trials across communities. 22,75 It is worth noting, however, that networked groups are not de facto efficient entities, 42,65 are underfunded, 70 and have little, if any, control over their share of an institution's operating budget or the complex regulatory environment in which they function. ...
Background:
A significant barrier to conducting clinical trials is their high cost, which is driven primarily by the time and resources required to activate trials and reach accrual targets. The high cost of running trials has a substantial impact on their long-term feasibility and the type of clinical research undertaken.
Methods:
A scoping review of the empirical literature on the costs associated with conducting clinical trials was undertaken for the years 2001-2015. Five reference databases were consulted to elicit how trials costs are presented in the literature. A review instrument was developed to extract the content of in-scope papers. Findings were characterized by date and place of publication, clinical disease area, and network/cooperative group designation, when specified. Costs were captured and grouped by patient accrual and management, infrastructure, and the opportunity costs associated with industry funding for trials research. Cost impacts on translational research and health systems were also captured, as were recommendations to reduce trial expenditures. Since articles often cited multiple costs, multiple cost coding was used during data extraction to capture the range and frequency of costs.
Results:
A total of 288 empirical articles were included. The distribution of reported costs was: patient management and accrual costs (132 articles), infrastructure costs (118 articles) and the opportunity costs of industry sponsorship (72 articles). 221 articles reported on the impact of undertaking costly trials on translational research and health systems; of these, the most frequently reported consequences were to research integrity (52% of articles), research capacity (36% of articles) and running low-value trials (34% of articles). 254 articles provided recommendations to reduce trial costs; of these, the most frequently reported recommendations related to improvements in: operational efficiencies (33% of articles); patient accrual (24% of articles); funding for trials and transparency in trials reporting (18% of articles, each).
Conclusion:
Key findings from the review are: 1) delayed trial activation has costs to budgets and research; 2) poor accrual leads to low-value trials and wasted resources; 3) the pharmaceutical industry can be a pragmatic, if problematic, partner in clinical research; 4) organizational know-how and successful research collaboration are benefits of network/cooperative groups; and 5) there are spillover benefits of clinical trials to healthcare systems, including better health outcomes, enhanced research capacity, and drug cost avoidance. There is a need for more economic evaluations of the benefits of clinical research, such as health system use (or avoidance) and health outcomes in cities and health authorities with institutions that conduct clinical research, to demonstrate the affordability of clinical trials, despite their high cost.
... We found that the number of patients having difficulty understanding these concepts were more prevalent in older age groups. Difficulty with the concept of randomisation is a recognised factor affecting accrual to CCTs [15,[24][25][26][27]. Understanding and acceptability of clinical equipoise is important in determining whether patients consent to randomisation and accept the treatment allocation assigned to them [28]. ...
Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p < 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics; older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups.
... Although our estimate of costs for NCTN trials also included those supporting early-stage (phases 1 and 2) trials, these trials are not often as closely tied to the eventual phase 3 trial and are not as numerous. Further, federal dollars invested in network group clinical trials frequently do not cover all of the capitation and institutional costs related to trial participation.54 For these reasons, network groups sometimes explicitly collaborate with industry to conduct trials, providing the design, conduct, and analysis of clinical trials, whereas industry may provide support for per-case costs atJAMA Network Open | OncologyAssociation of NCTN Group Studies With Guideline Care and New Drug Indications ...
Importance
National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying effective new antineoplastic regimens. However, the downstream clinical effect of their trials has not been systematically examined.
Objective
To examine the association of NCTN trials with guideline care and new drug indications.
Design, Setting, and Participants
This retrospective cohort study evaluated phase 3 SWOG Cancer Research Network clinical trials from January 1, 1980, through June 30, 2017. Only completed trials with published results were included. To be considered practice influential (PI), a trial must have been associated with guideline care through its inclusion in National Comprehensive Cancer Network (NCCN) clinical guidelines or US Food and Drug Administration (FDA) new drug approvals in favor of a recommended treatment. Data were analyzed from June 15, 2018, through March 29, 2019.
Main Outcomes and Measures
Estimated overall rate of PI trials, as well as trends over time. The total federal investment supporting the set of trials was also determined.
Results
In total, 182 trials consisting of 148 028 patients were studied. Eighty-two studies (45.1%; 95% CI, 37.7%-52.6%) were PI, of which 70 (38.5%) influenced NCCN guidelines, 6 (3.3%) influenced FDA new drug approvals, and 6 (3.3%) influenced both. The number of PI trials was 47 of 65 (72.3%) among those with positive findings and 35 of 117 (29.9%) among those with negative findings. Thus, 35 of 82 PI trials (42.7%) were based on studies with negative findings, with nearly half of these studies (17 of 35 [48.6%]) reaffirming standard of care compared with experimental therapy. The total federal investment spent in conducting the trials was $1.36 billion (2017 US dollars), a rate of $7.5 million per study or $16.6 million per PI trial.
Conclusions and Relevance
Nearly half of all phase 3 trials by one of the NCTN’s largest groups were associated with guideline care or new drug indications, including those with positive and negative findings. Compared with the costs of a new drug approval in pharmaceutical companies, typically estimated at more than $1 billion, the amount of federal funds invested to provide this valuable evidence was modest. These results suggest that the NCTN program contributes clinically meaningful, cost-efficient evidence to guide patient care.
... According to the data of international cancer-registers of different countries, during last 50 years the improvement of cancer patients treatment results took place that was manifested by the increase of general relapse-free survival rate at the main cancer localizations [1]. It became possible not only due to the early diagnostics and realizations of the programs of populational screening but also at the expanse of intensification of antitumor therapy methods [2]. ...
The necessity of long-term venous access in cancer patients appears at frequent and long-term courses of cytotoxic therapy. Peripheral veins of forearms are most often used for these aims. The conditions of peripheral venous channel in 32 cancer patients, who underwent the long-term treatment with antitumor preparations were analyzed in the article on own investigatory material.
The methods of dopplerography, morphological and immunohystochemical studies were used.
The qualitative and quantitative dopplerographic changes in forearm veins in different terms after chemotherapy start were revealed in most patients.
The conclusion was made about unsuitability of forearm peripheral veins for the long term administration of cytostatics and the necessity to create the alternative vascular access that would correspond to the criteria of safety, reliability and long-term exploitation.
... It was also offered to funding institutions to help establish feasible lump-sums. For the future this might promote participation of investigators in non commercial trials, where underfunding has been identified as a problem [17], lowering clinician acceptance [18,19]. Third, it has been proposed to make trial fees transparent to the patient during informed consent process [5,20]. ...
Conducting clinical trials is costly and time consuming. Trial sites usually do not calculate site costs. Underestimating required resources slows enrollment and lowers data quality but it is currently unclear how to reliably estimate trial site costs. A group of trial staff designed and validated a tool for compiling trial tasks and calculating required expenditures prior to initiating a clinical trial. The tool was validated in two steps. Round-robin tests for accuracy compared case payments for the same trial calculated by different participants. A narrow CI was reached (22.95–715.69) demonstrating significantly similar estimates of the test participants (p = 0.039). To confirm the predictive value, the predicted and actual hours were compared and a correlation coefficient of 0.952 (p = 0.003) was found. A web-based tool, the Study Site Budgeting Tool, was developed, which allows trial sites to estimate staff costs at the site and determine the budget needed to conduct a clinical trial.
... 37 In a 2010 ASCO survey of more than 500 research sites, 33% planned to limit participation in cooperative group trials. 38 Seventy-five percent cited inadequate funding as a factor. Industry sponsors are a crucial source of innovation, but there are disadvantages to concentrating research conduct within a modest number of companies, including studying agents that cannot be patented, combining therapeutics from different companies, directly comparing existing therapies and/or investigational therapies, developing treatments for rare diseases, and exploring higher risk strategies. ...
This article is one in a series of articles published in the 2014 Journal of Oncology Practice celebrating the 50th anniversary of ASCO and reflecting on cancer care and research over that time period. Key events enabled research to be integrated into many community oncology practices. We recount milestones affecting community-based research, focusing primarily on the period that begins in 1964, the year ASCO was established. The past provides rationale for the community structures we have today, although our primary goal is to discuss the current transition and future challenges. These challenges—advances in science and technology, changes in practice environment, demonstrating quality and value-based performance, decreasing research funding, integration of rapid learning systems, and patient perceptions of research—present unique opportunities and risks. In the face of transformation, however, the historical strengths of community-based research and dedication to improving our patients' outcomes and cancer care experience provide the perseverance to face these uncertainties.
... 4 One result of this is that one third of 509 sites surveyed by the American Society of Clinical Oncology in 2010 reported that they would limit enrollment to cooperative group trials. 2 Recently it was reported that the NCI intends to develop a plan to increase reimbursement to $4,000 for high performance academic and community sites that enroll a large number of patients to help offset the additional costs that result from increased accruals and large patient follow-up burden. 5 This would be an excellent step in the right direction but ultimately requires either an increase in the NCI budget or a reallocation of scarce, existing NCI resources. ...
... The recent online poll conducted by ASCO and published in this issue of Journal of Oncology Practice documents that inadequate NCI per-case reimbursement negatively affects cooperative group trial participation, despite the fact that investigators prefer government-sponsored trials. 1 If research programs have been directing their participants-their most valuable resource for clinical trials-away from cooperative group studies, is the ASCO survey relevant today? Is the information embodied in the survey timely and important? ...
Multicenter clinical trial designs offer a unique opportunity to leverage the diversity of patient populations in multiple geographic locations, share the burden of resource acquisition, and collaborate in the development of research questions and approaches. In a time of increasing globalization and rapid technological advancement, investigators are better able to conduct such projects seamlessly, benefiting investigators, sponsors, and patient populations. Regulatory agencies have embraced this shift towards the use of multicenter clinical trials in product development and have issued statements and guidance documents promoting their utility and offering best practices. Some governmental health agencies have even formed clinical trial networks to facilitate the use of multicenter clinical trials to answer a broad range of clinical questions related to a disease or disease area. This chapter will cover design considerations, data coordination, regulatory requirements, and study monitoring of multicenter clinical trials as well as how they can be conducted with a clinical trial network.
Background:
Accrual to cancer clinical trials is suboptimal. Few data exist regarding whether financial reimbursement might increase accruals.
Objective:
The objective of this study was to assess perceptions about reimbursement to overcome barriers to trial accrual.
Research design:
This was a cross-sectional survey.
Subjects:
Oncologists identified from the American Medical Association Physician Masterfile.
Measures:
We report descriptive statistics, associations of physician characteristics with perceptions of reimbursement, domains, and subthemes of free-text comments.
Results:
Respondents (n=1030) were mostly medical oncologists (59.4%), ages 35-54 (67%), and male (75%). Overall, 30% reported discussing trials with >25% of patients. Barriers perceived were administrative/regulatory, physician/staff time, and eligibility criteria. National Cancer Institute cooperative group participants and practice owners were more likely to endorse higher reimbursement. Respondents indicated targeted reimbursement would help improve infrastructure, but also noted potential ethical problems with reimbursement for discussion (40.7%) and accrual (85.9%). Free-text comments addressed reimbursement sources, recipients, and concerns about the real and apparent conflict of interest.
Conclusions:
Though concerns about a potential conflict of interest remain paramount and must be addressed in any new system of reimbursement, oncologists believe reimbursement to enhance infrastructure could help overcome barriers to trial accrual.
Over the last 40 years the National Cancer Institute (NCI) has created a vibrant public-private partnership for the implementation of NCI-sponsored cooperative group (Network) clinical trials throughout the United States and Canada. Over these four decades, the cancer clinical trials process has become more complex more precise and more resource intensive. During this same time period, financial resources to support the NCI community research initiative have become more constrained. The newest manifestation of NCI-sponsored community based cancer clinical trial research, known as the National Community Oncology Research Program (NCORP) began initial operation August 1, 2014. We describe several key strategies that community sites may use to not only be successful but to thrive in this new financially austere research environment.
Clinical trial costs may be reduced by identifying enriched subpopulations of patients with favorable risk profiles for the events of interest. However, increased selectivity affects accrual rates, with uncertain impact on clinical trial cost.
We conducted a secondary analysis of Southwest Oncology Group (SWOG) 8794 randomized trial of adjuvant radiotherapy for high-risk prostate cancer. The primary endpoint was metastasis-free survival (MFS), defined as time to metastasis or death from any cause (competing mortality). We used competing risks regression models to identify an enriched subgroup at high risk for metastasis and low risk for competing mortality. We applied a cost model to estimate the impact of enrichment on trial cost and duration.
The treatment effect on metastasis was similar in the enriched subgroup (HR, 0.42; 95% CI, 0.23-0.76) compared to the whole cohort (HR, 0.50; 95% CI, 0.30-0.81) while the effect on competing mortality was not significant in the subgroup or the whole cohort (HR 0.70; 95% CI 0.39-1.23, vs. HR 0.94; 95% CI, 0.68-1.31). Due to the higher incidence of metastasis relative to competing mortality in the enriched subgroup, the treatment effect on MFS was greater in the subgroup compared to the whole cohort (HR 0.55; 95% CI 0.36-0.82, vs. HR 0.77; 95% CI, 0.58-1.01). Trial cost was 75% less in the subgroup compared to the whole cohort ($1.7million vs. $6.8million), and the trial duration was 30% shorter (8.4 vs. 12.0years).
Competing event enrichment can reduce clinical trial cost and duration, without sacrificing generalizability.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Clinical trials are critical vehicles for evaluating novel therapeutics and biomarkers that
emerge from basic biomedical research and vital in the quest to translate knowledge into clinical
practice and public health policies. In February 2010 the Canadian Cancer Research Alliance
(CCRA) established the CCRA Clinical Trials Working Group to examine the trends in clinical
cancer research in Canada, to report on the issues identified and to examine models of
international clinical trials support. Most important, the CCRA Clinical Trials Working Group
was to develop recommendations to ensure that Canada remains a global leader in the discovery of
new, personalized cancer therapies and the opportunities for cancer patients to be enrolled in
clinical trials are increased.
Canada has an outstanding international reputation for its contributions to cancer
therapeutics development, from first-in-human studies to randomized controlled trials that have
resulted in improved patient outcomes, the identification of new biomarkers for individualizing
therapeutic decisions, changed clinical practice and new international collaborations. Indeed, many
have argued that Canada has had an impact far outstripping the size of its research community and
the funding for clinical research. This reputation for leadership is largely, but not exclusively,
related to the studies conducted by academically based cooperative clinical trials groups, such as the
NCIC Clinical Trials Group (core funding from the Canadian Cancer Society), the Ontario
Clinical Oncology Group (funding from Cancer Care Ontario and Hamilton Health Sciences), and
the Princess Margaret Hospital Phase II Consortium (core funding from the National Cancer
Institute (U.S.)).
In 2009, however, the CCRA consulted with researchers, patients, policy makers, and
funders across Canada as part of the development of the Pan-Canadian Cancer Research Strategy
and found that the ability to conduct cancer clinical trials in Canada was under growing threat.
This was particularly the case for trials based on ideas developed by the academic sector (i.e., those
from cooperative groups). It was also observed that pharmaceutical trials are increasingly moving to
Eastern Europe or Asia, where rapid accrual at lower costs is possible. At the same time, it is clear
that there is now an unprecedented opportunity to take the fruit of decades of molecular biology
research into the clinic in the form of new agents and for the development of new biomarkers.
Clinical trials developed and conducted by Canadian academic investigators are likely to answer the
clinical and translational questions that are based on the most promising discoveries from
Canadian laboratory researchers and that address the greatest concerns to the health and wellbeing
of Canadians in a manner most relevant to the our health care systems.
This research is of profound importance to patients, clinicians, researchers, those who
deliver health care and those who promote innovation. Without clinical trials, the outcomes of
cancer patients will not continue to improve. In response, the CCRA formed a working group of
experts led by representatives of the CCRA Secretariat and the Canadian Cancer Society, to review
the state of cancer clinical trials in Canada and to make recommendations based on its findings.
This article discusses the growth and infrastructure of a clinical trials program in a large community hospital. An association between increased patient accrual and establishment of site-specific tumor boards and patient care navigators is also discussed. Strong hospital administrative support and clinical research staff are crucial for success.
Oncology has become one of the most active areas of drug discovery, with >800 cancer therapeutics in development. This not only presents an unprecedented opportunity to improve the outcome for patients with cancer but also requires an effective and efficient clinical trials network to generate the evidence necessary for regulatory approval and optimal integration of new treatments into clinical care. The Clinical Trials Cooperative Group Program supported by the National Cancer Institute has been instrumental in establishing standards of care in oncology over the last 50 years, but it currently faces numerous challenges that threaten its ability to undertake the large-scale, multi-institutional trials that advance patient care. The Institute of Medicine recently appointed a consensus study committee to assess the organization and operation of the Cooperative Group Program and recommend ways to improve the quality of cancer clinical trials conducted by the Groups and others. The committee developed a set of recommendations, summarized here, that aim to improve the speed and efficiency of trials; incorporate innovative science and trial design; improve prioritization, selection, and support of trials; and increase participation by patients and physicians.
The Institute of Medicine report on cooperative groups and the National Cancer Institute (NCI) report from the Operational Efficiency Working Group both recommend changes to the processes for opening a clinical trial. This article provides evidence for the need for such changes by completing the first comprehensive review of all the time and steps required to open a phase III oncology clinical trial and discusses the effect of time to protocol activation on subject accrual.
The Dilts and Sandler method was used at four cancer centers, two cooperative groups, and the NCI Cancer Therapy Evaluation Program. Accrual data were also collected.
Opening a phase III cooperative group therapeutic trial requires 769 steps, 36 approvals, and a median of approximately 2.5 years from formal concept review to study opening. Time to activation at one group ranged from 435 to 1,604 days, and time to open at one cancer center ranged from 21 to 836 days. At centers, group trials are significantly more likely to have zero accruals (38.8%) than nongroup trials (20.6%; P < 0.0001). Of the closed NCI Cancer Therapy Evaluation Program-approved phase III clinical trials from 2000 to 2007, 39.1% resulted in <21 accruals.
The length, variability, and low accrual results demonstrate the need for the NCI clinical trials system to be reengineered. Improvements will be of only limited effectiveness if done in isolation; there is a need to return to the collaborative spirit with all parties creating an efficient and effective system. Recommendations put forth by the Institute of Medicine and Operational Efficiency Working Group reports, if implemented, will aid this renewal.
Like many health professionals who care for people with cancer, I entered the field because of specific patients who touched my heart. They still do. In an effort to weave together my personal view of what the American Society of Clinical Oncology (ASCO) stands for and the purpose the organization serves, my presidential theme this year is "Patients. Pathways. Progress." Patients come first. Caring for patients is the most important, rewarding aspect of being an oncology professional. At its best, the relationship between doctor and patient is compassionate and honest-and a relationship of mutual respect. Many professional organizations have an interest in cancer, but no other society is so focused on the entire spectrum of cancer care, education, and research. Nor is any other society as particularly interested in bringing new treatments to our patients through clinical trials as ASCO is. Clinical trials are the crux for improving treatments for people with cancer and are critical for continued progress against the disease. "Pathways" has several meanings. Some pathways are molecular-like the cancer cell's machinery of destruction, which we have only begun to understand in recent years. But there are other equally important pathways, including the pathways new therapies follow as they move from bench to bedside and the pathways patients follow during the course of their diseases. Improved understanding of these pathways will lead to new approaches in cancer care, allowing doctors to provide targeted therapies that deliver improved, personalized treatment. The best pathway for patients to gain access to new therapies is through clinical trials. Trials conducted by the National Cancer Institute's Cooperative Group Program, a nationwide network of cancer centers and physicians, represent the United States' most important pathway for accelerating progress against cancer. This year, the Institute of Medicine released a report on major challenges facing the Cooperative Group Program. Chief among them is the fact that funding for the program has been nearly flat since 2002. ASCO has called for a doubling of funding for cooperative group research within five years and supports the full implementation of the Institute of Medicine recommendations to revitalize the program. ASCO harnesses the expertise and resources of its 28,000 members to bring all of these pathways together for the greater good of patients. Progress against cancer is being made every day-measurable both in our improved understanding of the disease and in our ability to treat it. A report issued in December 2009 by the National Cancer Institute, the Centers for Disease Control and Prevention, the American Cancer Society, and the North American Association of Central Cancer Registries found that rates of new diagnoses and rates of death resulting from all cancers combined have declined significantly in recent years for men and women overall and for most racial and ethnic populations in the United States. The pace of progress can be and needs to be hastened. Much remains to be done. Sustained national investment in cancer research is needed to bring better, more effective, less toxic treatments to people living with cancer. Pathways to progress continue in the clinic as doctors strive to find the right treatments for the right patients, to understand what represents the right treatments, and to partner with patients and caregivers for access to those treatments. This report demonstrates that significant progress is being made on the front lines of clinical cancer research. But although our nation's investment in this research is paying off, we must never forget the magnitude of what lies ahead. Cancer remains the number two killer of Americans. Future progress depends on continued commitment, from both ASCO and the larger medical community. George W. Sledge Jr, MD President American Society of Clinical Oncology.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy.
Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life.
The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.
The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel.
By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831.
Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)
Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis.
To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes.
The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005.
Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years.
Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events.
There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death.
Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs.
clinicaltrials.gov Identifier: NCT00003906.
Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss.
Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization.
Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P < or = .001); longer progression-free survival was most apparent in this subset.
For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.
Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour.
We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197.
All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group.
Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.
US National Institutes of Health and Novartis Pharmaceuticals.
Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide.
The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)).
The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens.
As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.
Physicians frequently receive payment for enrolling subjects onto clinical trials. Some view these payments as conflicts of interest. Others contend that these payments are necessary reimbursements for conducting clinical research. We evaluated the clinical and nonclinical hours and costs associated with conducting a mock phase III clinical research trial.
We collected data from representatives of 21 clinical sites, on the numbers of hours associated with 13 activities necessary to the conduct of clinical research. The hours were based on enrolling 20 patients in a 12-month randomized placebo-controlled trial of a new chemotherapeutic agent. The outcome measures were disease progression and quality-of-life reports. These costs were evaluated for both government and pharmaceutical industry-sponsored trials.
On average, 4,012 hours (range, 1,512 to 13,319 hours) were required for a government-sponsored trial, and 3,998 hours (range: 1735 to 15,699) were required for a pharmaceutical industry-sponsored trial involving 20 subjects with 17 office visits, or approximately 200 hours per subject. Thirty-two percent of the hours were devoted to nonclinical activities, such as institutional review board submission and completion of clinical reporting forms. On average, excluding overhead expenses, it cost slightly more than 6,094 dollars (range, 2,098 dollars to 19,285 dollars) per enrolled subject for an industry-sponsored trial, including 1,999 dollars devoted to nonclinical costs.
Based on the results of our mock trial, the time required for nontreatment trial activities is considerable, and the associated costs are substantial.
Improving the quality of cancer clinical trials. Presented at the Institute of Medicine National Cancer Policy Forum
- Rl Comis
Comis RL: Improving the quality of cancer clinical trials. Presented at the Institute
of Medicine National Cancer Policy Forum, Washington, DC, October 4 –5, 2007
A Guidance Document for Implementing Effective Cancer Clinical Trials Executive Summary: Version 1.2. http://www.c-changetogether.org/pubs/ reports/GuidanceDocument_ES.pdf 15. National Cancer Institute: Cooperative Group Accrual Patterns
C-Change: A Guidance Document for Implementing Effective Cancer Clinical
Trials Executive Summary: Version 1.2. http://www.c-changetogether.org/pubs/
reports/GuidanceDocument_ES.pdf
15. National Cancer Institute: Cooperative Group Accrual Patterns. Bethesda,
MD, National Institutes of Health, 2009
Herceptin: Joint Analysis of NSABP B-31 and NCCTG. http:// www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp 5. National Cancer Institute: Cancer Drug Decreases Recurrence of Gastrointestinal Stromal Tumors
- Genentech
Genentech: Herceptin: Joint Analysis of NSABP B-31 and NCCTG. http://
www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp
5. National Cancer Institute: Cancer Drug Decreases Recurrence of Gastrointestinal Stromal Tumors. http://www.cancer.gov/aboutnci/servingpeople/gist