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EDITORIAL |
Dr. Yates is National Vice President, Research, American Cancer Society, Atlanta, GA.
There is substantial agreement among community and academic physicians that much of the improvement in their therapeutic and preventive armamentarium over the past half-century would not be possible without clinical trials. Although cardiologists have led the way with numerous large trials of treatment for hypertension and cardiovascular disease, oncology trials have contributed to clinical trial methodology, and to advances in treatment particularly for pediatric and young adult patients with cancer.
The importance of clinical trials extends beyond their influence as research studies. Clinical trial protocols are specialized management guidelines that enable physicians to provide high-quality cancer care. Patients participating in clinical trials can be assured they will receive the best available treatment and follow-up care. Individual participation guarantees access to optimal management advice incorporated in the protocols from leading cancer experts. The course of clinical trial protocol development and the subsequent approval process requires a thorough review of all current activity in a particular disease area, critical discussion among the experts responsible for the protocol, and pre-approval reviews designed to optimize safe and effective application of the best and most promising treatments.
These protocols not only enhance health insurance payers’ understanding of "state of the art" and new treatments, they also focus attention on important outcomes that go beyond a particular episode of care. Although the benefit is somewhat indirect, physician reviewers of these protocols gain a useful opportunity for continuing education.
Unfortunately, a disconnect exists between the collective desire for progress and professional and public acceptance of participation in clinical trials. Both the general public and the medical community consider the development of effective cancer treatment to be one of the highest public health priorities, but generally fail to recognize that the rate of progress toward this goal is directly linked to adequate patient participation in innovative clinical trials designed to examine new and promising approaches.
Both providers and patients are concerned about yielding their individual autonomy to a predetermined protocol of care. Patients are often reluctant to have their medical decisions made "at random," and may lack an understanding of potential benefits from study participation.1 Physicians may consider the introduction of patient management protocols as a territorial restriction of their practice rights. The physician’s obligation to collect information and the patient’s unwillingness to accept the uncertainties of randomization of care may further diminish or entirely eliminate interest in study participation.
Payers and purchasers of health insurance often express concern over cost issues as a reason for excluding coverage for certain costs associated with clinical trials from their benefit plans. However, available evidence suggests that these concerns are unwarranted. At least three studies have shown that protocol participation does not result in increased costs and may even be less costly than conventional care for some protocols.2–5
Results of clinical trials involving cancer patients over the past 50 years have provided us with steady improvements in cancer management; while progress has been incremental for most cancers, there has been spectacular progress in others. Despite steady progress against many cancers, the magnitude of each successive increment in response rate or survival rate has generally been small.
One of the most outstanding achievements of clinical trials is in the treatment of childhood acute lymphocytic leukemia over the past three decades. Outcomes have gone from approximately 20 percent long-term survival to 80-plus percent in recent years. In addition, morbidities have been reduced, and many pediatric oncologists have been educated through their participation. This was accomplished through incremental improvements in chemotherapy and adjuvant therapies to sanctuary sites, such as central nervous system disease. Progress made in the treatment of many other childhood cancers is also remarkable, but in all of these cancers, progress required multiple trials over many years.
Our rapidly expanding knowledge of molecular abnormalities occurring in chromosomes, genes, and protein products of neoplastic cells has led to identification of molecular targets and agents with which to attack those targets. Recently, we have seen a spectacular result in the application of imatinib mesylate (Gleevec) treatment in chronic myelocytic leukemia (CML) and gastrointestinal stromal tumors (GIST). Because the patients in these trials who were resistant to standard treatments were responding dramatically to this treatment, physicians who normally would not have referred patients into experimental protocol studies were clamoring to get their patients entered at participating institutions. Patients with CML and GIST and their families were using the Internet to identify participating investigators and institutions. Patient accrual to these studies was rapid; and dramatic trial results led to a rapid approval of imatinib mesylate (Gleevec) by the Food and Drug Administration.
Unfortunately, for most clinical trials, improvements in response rates to promising new treatments are usually much less dramatic, often falling in the 10-to-30 percent response range. These kinds of incremental gains require many more studies, representing stepwise improvements, and many more patients to demonstrate increasing efficacy. And often, there is less enthusiasm for participation because of the small potential benefit of the treatment.
When most patients and clinicians think of clinical trials, treatment trials are usually what they think of first. But with our increased understanding of cancer biology, we’ve learned that prevention and early detection trials are equally important. Few would argue about the importance of the proverbial "ounce of prevention" in reducing cancer mortality, but there is considerable and heated debate regarding which interventions should comprise those "ounces." Debates are often fueled by a lack of solid scientific evidence supporting or refuting inferential laboratory or pilot-study findings that suggest an intervention is beneficial, because most credible clinical trials require a large number of participants who are followed for months or even years for specific outcomes.
Convincing physicians and patients to participate in long-term studies is often difficult because of the desire for certainty and for immediate answers. Particularly in prevention trials, improvements in our understanding of the molecular cascade of events as normal cells progress toward malignancy should accelerate the growth of our knowledge about using intermediate molecular markers as early indicators of efficacy. The potential value to patients should be readily apparent, and thus make it attractive for physicians to accrue patients to these trials. Yet, unfortunately, the majority of clinicians, particularly those practicing in rural environments, are often unaware of the existence of clinical trials or may not appreciate which of their patients may be eligible.1
Without a commitment from patients, providers, and insurance payers to encourage participation in well-designed prevention, early detection, and treatment trials, the medical community would still be entirely dependent on anecdotal reports which often suffer from biases associated with patient selection. Premature celebration of early beneficial results brought on by investigator enthusiasm has led some cynics to comment that the first patients entered on a trial always seem to have the best response rates. For example, early enthusiasm for the widespread application of prophylactic tonsillectomies to prevent recurrent infections in children prevailed as standard treatment for decades before the indications were put to the test through a clinical trial. Likewise, anecdotal reports of benefit to patients with poor circulation in the lower extremities from sympathectomies led to acceptance of this treatment by less discerning physicians. Research evaluation through well-controlled clinical trials has allowed us to limit the indications for both these procedures.
Two articles in this issue of CA address clinical trials for treatment and the early detection and prevention of cancer. The article by Ford, et al.6 describes two ongoing prevention and two ongoing early detection clinical trials open to enrollment, each focused on leading cancers affecting men and women. Opportunities to enroll in these trials exist in hundreds of communities across the United States, and the questions these studies will attempt to answer are profoundly important to the large majority of adult men and women. Thus, they are ideal studies to highlight as examples of current opportunities for greater engagement by the primary care community to play their important enabling role vis-à-vis patient enrollment. The faster enrollment is completed, the faster these studies are on their path to completion; but more importantly, the faster results of these investigations will be made available to inform clinical practitioners. Ford and colleagues also highlight barriers to enrollment in clinical trials that affect both health care professionals and their patients.6
In the article by Cohen, he points out that only 10 percent of physicians enter 80 percent of the patients who participate in cancer clinical trials.7 These facts not only reflect inadequate provider education, but also, possibly, a lack of incentives, presence of disincentives, and low interest. Interestingly enough, many insurance payers are supportive of clinical trials and have not been reluctant to support their subscribers’ participation in clinical trials, except in some controversial high-cost trials (e.g., bone marrow transplants for metastatic breast cancer). Inadequate public knowledge of benefits derived from participating in clinical trials needs improvement as does physician awareness, interest, and, importantly, logistical support.
Slow progress in enrollment in clinical trials is not a new problem; its persistence, however, indicates that concerted, targeted efforts are needed to increase the participation of health care professionals. Several cancer initiatives, including the National Dialogue on Cancer and the Summit Series on Clinical Trials, have pursued efforts to dissect this problem and develop strategies designed to increase participation in clinical trials (http://www.ndoc.org and http://www.cancersummit.com/). Now a considerable effort is underway to increase public awareness and interest in clinical trials by working through patient advocacy organizations, voluntary health agencies, and professional organizations. Payer and media attention can also play an important role by leading patients to initiate discussions with physicians about participating in clinical trials. A common message from a variety of organizations could do much to dispel public concerns about "experimentation." Physicians’ enthusiasm and promotion of clinical trials for patients within their practices could greatly improve clinical research opportunities for all involved.
The American Cancer Society enthusiastically endorses the premise that clinical trials are the cornerstone for progressive evolution and improvement in modern cancer medicine. By publishing these two articles, we are trying to increase clinician awareness and appreciation of trials in prevention and early detection as well as in treatment. Information exchange about available clinical trials among the public, patients, providers, and payers can only enhance the research landscape. The American Cancer Society is simultaneously reaching out to the public by providing a clinical trials matching tool through our Web site (visit http://clinicaltrials.cancer.org/) and our clinical trial helpline (1-800-303-5691). Both of these sources can identify relevant clinical trials for patients based on information patients provide. The American Cancer Society data-base includes all of the open trials listed in the National Cancer Institute’s PDQ system (http://cancernet.nci.nih.gov/pdq.htm), plus some additional clinical and pharmaceutical trials not listed in the NCI system. With this information and with their physicians’ help, patients can assess their eligibility and learn which physicians and institutions are participating in a particular study. In this way, patients and their families can take some control of their situations and gain access to appropriate clinical trials.
These sources are not intended to replace the advice of a patient’s primary care physician or oncologist. Rather they are meant to help patients in their search for new and highly relevant information they can discuss with their physicians and also to spare both patients and physicians the unproductive and frustrating task of sifting through large stacks of irrelevant Internet documents and newspaper clippings.
Physicians who present their patients with opportunities to participate in clinical trials, and patients who apply to participate in clinical trials, contribute to the advancement of the world’s efforts to reduce the burden of cancer. The endorsement of clinical trials by providers and payers can do much to educate the public about the value of participation and dispel inhibitory misconceptions. New efforts will also require enhanced communication between patients and their physicians to ensure greater participation in clinical trials.
With greater commitment to removing barriers to enrollment in clinical trials and increasing awareness not only of opportunities but also of the importance of participation, we can expect to see faster completion of studies and thus, faster application of best practices that reduce the burden of cancer.
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Footnotes |
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