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Meeting Reports |
National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA
Correspondence: Gregory A. Curt, M.D., Clinical Director, Oncology Program, National Cancer Institute/National Institutes of Health, 9000 Rockville Pike, Building 10, Room 12N214, Bethesda, Maryland 20892-0001, USA. Telephone: 301-496-4251; Fax: 314-496-9962; e-mail: curtg{at}pbmac.nci.nih.gov
Scientific meetings, like living organisms, tend to evolve over time. For example, the yearly ASCO meeting, which began as a small American academic oncology gathering emphasizing clinical research, has grown into a large, international forum which increasingly emphasizes best standard of care and reimbursement issues [Editor's note: see ASCO review by Chabner, Friedberg in this issue, 263].
One meeting which has remained true to its initial mission is the NCI-EORTC Symposium on New Drugs in Cancer Therapy which occurs every two years in Amsterdam. Originally organized to help coordinate phase I cancer drug development between the United States and Europe, the meeting fills an important scientific niche. Largely because of the clinical trials standards which have been shared in this forum, phase I data from Europe are now used to launch phase II cancer trials in the United States. Today, the meeting focus—really, the meeting's challenge—remains cancer drug development in Europe and the United States.
In an era when the FDA, industry, and academia are working to make drug development a seamless, international process with a common vocabulary and shared informatics based on the promise of basic research, the NCI-EORTC meeting is a place both to take the pulse and sense the future of cancer drug development. The meeting has other qualities to recommend it. It is held every two years, so that incremental progress is easier to appreciate. The presentations, carefully selected by the organizers, occur in a single amphitheater and are punctuated by poster sessions and workshops with adequate time for dialogue. Perhaps most important, the attendance has been purposely limited so that there is every opportunity to discuss accomplishments, plans, and areas of mutual interest.
The sessions themselves represented the areas of highest scientific opportunity in today's world of cancer drug development: anti-angiogenesis and anti-metastatic agents, apoptosis, topoisomerase inhibitors, cancer chemoprevention, tumor vaccines, DNA-interactive agents, signal transduction, tubulin inhibitors, novel delivery systems and prodrugs, the tumor microenvironment, and gene therapy—all discussed by internationally recognized leaders in their fields. An impressive agenda for a four-day meeting! And yet, it works, because the meeting is so well-planned and organized by the Symposium President, Dr. H.M. Pinedo.
In this issue of The Oncologist, Dr. Mace Rothenberg reviews the meeting's scientific presentations in one specific topic: the emerging area of metalloprotease inhibitors [Editor's note: see 271]. This was one of several highlights at the EORTC meeting. I am delighted that this summary is the first installation of a regular column, "New Drugs on the Horizon," which Dr. Rothenberg will edit for The Oncologist.
One of the important messages of the meeting was that the design and implementation of phase I trials in cancer medicine may need to be changed dramatically to meet the challenge of interpreting today's biologic science into the next generation of translational clinical research. The old paradigms of maximum tolerated dose (MTD), complete response (CR), partial response (PR) and progressive disease (PD) may no longer be so relevant.
In the Opening Ceremony, Dr. Elizabeth Eisenhauer of the NCI-Canada (NCIC) Clinical Trials Group raised questions which resonated at the subsequent scientific sessions. New therapeutics may be cytostatic rather than cytotoxic. If so, then what endpoints can replace tumor regression as an assessment of efficacy for design of phase II studies? What can or should replace simple toxicity as a means of defining dose recommendations? Most important, can these new clinical endpoints be shown to be relevant in terms of their relationship to survival?
Is stable disease a meaningful clinical endpoint in the emerging era of cancer medicine? Dr. Eisenhauer presented mature data from NCIC studies in lung cancer which showed convincingly that in this disease patients with stable disease do as well as those with a PR. Louise Grochow of Johns Hopkins also presented new information which strongly suggested that time on study, as a surrogate for stable disease, could successfully predict agents with clinical utility—but not necessarily clinical activity as it is currently defined.
Indeed, several of the scientific presentations indicated that the old paradigms may need to change—and quickly. Dr. Isaiah Fidler and others showed preclinical data which clearly demonstrated that, where biologicals are concerned, more is not necessarily better. Effective therapy, when pushed to toxicity, can be worse than no therapy at all. Dr. Judah Folkman presented anecdotal clinical data which demonstrated that a patient who would eventually respond dramatically to interferon therapy could initially demonstrate progressive disease which would have terminated treatment prematurely in studies as currently designed.
Future cancer clinical trials will need new endpoints, not simply response, if we are to capture the next generation of active drugs. Among those discussed at the meeting were tumor markers, immune response (for vaccines), PET/magnetic resonance spectroscopy (for metabolic profiling), and tumor blood flow (for anti-angiogenesis agents).
It was also clear that the clinical trials infrastructure is already adapting to meet these challenges. Dr. Michael Friedman, Acting Commissioner of the U.S. FDA, reviewed how this regulatory agency, alternatively perceived as an irresistible force or an immovable object, is changing to meet the future challenges of cancer drug development. Electronic filing, uniform marketing applications, fast-track review of therapies for life-threatening disease, and development of a common dictionary for clinical trials are all indicative of an appreciation that drug development and regulation is an international activity. Actions in one nation will have a growing impact on others, an appropriate theme for the Symposium.
As already mentioned, a common dictionary for cancer protocols will be vital for sharing information internationally. Such a resource is essential for the health of cancer trials and the benefit of our patients. Dr. Percy Ivy, of the NCI, reviewed the considerable progress that has been made in this area as well. The new Common Toxicity Criteria for cancer clinical trials actually made sense, no doubt because of the considerable work and input of investigators from EORTC, NCI, NCIC, the Cooperative Groups (including the Children's and Radiation Groups), FDA, Japan, and Industry. In a sign of the times, you can visit highlights and tools at: http://ctep.info.nih.gov
These are exciting times in cancer medicine. New targets for drug development attack the essential properties that make a cell malignant: uncontrolled growth, metastasis, new blood vessel formation, drug resistance, and dedifferentiation. Clinical trial design will need to keep pace with the emerging biological opportunities. The NCI-EORTC Symposium on New Drugs in Cancer Therapy manages to place these realities in context in a user-friendly meeting. It was time well spent. See you in two years, Dr. Pinedo!
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