The progression of a new drug or biological agent, whether for cancer prevention or treatment, from laboratory discovery to clinical testing occurs through an integrated series of steps. These span: preparing the new agent for administration to people; testing it in people to establish safety and assess benefit; and comparing it to standard approaches to see whether it really represents an advance. As described below, our Prostate Cancer Research Plan will enable us to circumvent barriers that currently exist at each of these steps. The Plan will expedite the several pre-clinical steps that develop new molecules into innovative drug candidates (see our section on Translational Research). It will accelerate and amplify our early clinical trials program and reorient it to provide scientific and clinical validation of new approaches; this will pave the way for more informative clinical testing and more effective discovery. And finally, it will broaden and speed our approach to the large randomized trials involving many centers, so that the most promising findings in early trials are subjected quickly and efficiently to definitive tests of efficacy.
In addition to strengthening clinical trials and drug discovery capabilities, the NCI has begun to explore an increasingly visible area of treatment - complementary and alternative medicine (CAM). Americans are turning in record numbers to complementary and alternative therapies for cancer and other diseases and conditions. In response, the NCI has established the Office of Cancer Complementary and Alternative Medicine (OCCAM). This office seeks to promote and support research in the various disciplines and modalities associated with the field of complementary and alternative medicine as they relate to the diagnosis, prevention and treatment of cancer and the management of cancer patients. We anticipate that that this Office will be actively involved in efforts to evaluate strategies proposed by the CAM community that are relevant to prostate cancer.
Our Prostate Cancer Research Plan for clinical sciences can be separated into two distinct parts. The first three Strategies will help us develop the infrastructure we need to speed new ideas from the laboratory to the clinic; expand our nation's clinical trials system so that all who would benefit can easily participate; and develop a sophisticated informatics system linking centers, physicians, researchers, and patients. While these Strategies are not prostate-specific, they lay a "foundation for discovery" that will facilitate enhanced research capability in prostate cancer as well as all other types of cancer. In the second set of strategies, our expanded infrastructure will help us to answer key scientific questions, such as whether early detection of prostate cancer really does lead to decreased mortality, and the potential morbidities associated with prostate cancer screening; test exciting new treatments, such as image-guided therapy; and conduct much needed clinical trials in prostate cancer prevention.
Strategies & Plans: Early Clinical Trials
Goals:
Develop the infrastructure and processes needed to quickly assess and validate treatment interventions.
Test new agents that have not been used against prostate cancer.
Test agents and approaches directed at novel and specific targets relevant to prostate cancer.
Initiatives:
"QuickTrials" Program for the Rapid Approval of Early Clinical Trials
This would be a new grants program to provide a rapid and efficient way to move new ideas for therapeutic interventions into Phase I and II clinical trials for prostate cancer. This program would be set up in recognition of the urgent need for new types of interventions that are effective at different stages of prostate cancer, as well as the growing number of intervention ideas that are ready to be tested in patients.
This program would also be developed in response to the unsuitability of conventional application and review procedures, which have lengthy review cycles more suitable for larger scale or more protracted projects, and in which evaluation of untested leads tends not to fare well because of the absence of preliminary data. The NCI's goals would be to increase the number of patients participating in early clinical trials by two- to three-fold and to initiate 10 to15 new trials.
Cancer Therapy Evaluation Trials
There is a changing emphasis in cancer research to use molecular-target based drug discovery and to create research tools for discovery and development. These changes provide the research tools needed to conduct clinical trials that can answer the questions about why a particular therapeutic intervention does, or does not, lead to a beneficial response. There is likely to be a high volume and continuously increasing stream of compounds and research approaches in the pipeline that would need to be brought rapidly into clinical testing.
This year, through NCI's Cancer Therapy Evaluation Program in Prostate Cancer, we will initiate approximately 35 new Phase I/II trials with agents directed against a number of particularly promising molecular targets and mechanisms. The targets include:
angiogenesis and metastasis, the processes by which cancers induce new blood-vessel formation, invade these blood vessels, and spread throughout the body;
growth factors and their receptors, which mediate growth signals to cancer cells; and
the expression of tissue-specific genes expressed selectively in prostate or prostate cancer cells, thus allowing for the targeting of tumor-killing substances to these cells.
Compared to the 1998 level of effort, NCI plans to more than double the number of early clinical trials in prostate cancer in the first year.
Strategies & Plans: Multi-center Clinical Trials Program
Goals:
Enrich scientific input into clinical trials conception and design, streamline operations, and broaden access to trials participation among both patients and physicians across the country.
Target critical, pressing clinical questions facing patients with prostate cancer.
Restructure the clinical trials system to be as effective, efficient, and accessible as possible.
Initiatives:
Treatment Trials in Prostate Cancer
In large clinical trials we compare promising new therapies to standard treatment approaches. These studies are designed to show definitively what works and what doesn't, and to provide the evidence base for determining the standard of cancer care.
We expect several new Phase III trials to be initiated this year that will attempt to optimize hormonal and chemotherapeutic approaches for the most common clinical presentations. These include:
after prostatectomy: adjuvant therapy with androgen deprivation, with and without mitoxantrone and prednisone;
after prostatic irradiation: adjuvant therapy with androgen deprivation, with and without estramustine + etoposide + paclitaxel;
before radiation, comparison of the now-standard 8 weeks of androgen deprivation with more prolonged (28 weeks) androgen deprivation;
after initial hormone failure: secondary hormonal therapy with ketoconazole / hydrocortisone versus chemotherapy with estramustine/paclitaxel versus biological therapy with vitamin D2;
for androgen-independent disease (including rising Prostate Specific Antigen only): estramustine + docetaxel versus mitoxantrone + prednisone.
We described above the new multi-center trials that will be activated in the next few months. In subsequent years the choice of which new trials to activate will depend on the outcome of current planning efforts, as well as on the small pilot studies of novel approaches that are currently in early stages. It seems likely that our future clinical trials agenda will focus on the following questions:
for patients with androgen-independent disease (including rising PSA): studies of chemotherapy with and without bisphosphonates;
for asymptomatic patients with androgen-independent disease manifested only by a rising PSA: studies of matrix metalloproteinase inhibitors, antiangiogenesis agents, bisphosphonates, vaccines, molecules that interfere with cell signaling, interactions with growth factors, or other cancer-relevant pathways;
for patients with rising PSA after primary therapy with prostatectomy or radiation: Trials of high-priority agents in which the agents (alone or combined with standard therapy) are compared to standard therapy or to each other;
for patients with newly diagnosed, high-risk presentations (high grade or bulky disease) receiving radiation as primary therapy: (a) large-scale evaluations of brachytherapy or three-dimensional conformal radiation; (b) radiotherapy with sensitization using gene transfer;
for patients with newly diagnosed localized tumors of "normal" risk: (a) definitive study of prostatectomy versus brachytherapy; (b) adjuvant trials combining anti-angiogenesis agents with current hormonal strategies.
Restructuring the NCI Clinical Trials Program
NCI and many of the clinical researchers the Institute supports are fundamentally re-engineering the Institute's clinical trials program. The aim is to enrich the scientific input into clinical trials conception and design, streamline operations, and broaden access to trials participation among both patients and physicians across the country. Pilot implementation steps are planned that will test new systems for identifying the best trials, improving trial planning, speeding trial activation, and improving availability of trials to patients throughout the country.
Prostate and lung cancers will be the two major tumor categories that will serve as the primary testing grounds for these new planning and expanded access efforts. NCI has already begun coordinating development of a common methodology for the conduct and analysis of prostate cancer trials, including common endpoints. In addition, during the next year NCI expects to begin a series of State of the Science meetings to define the key areas for emphasis in clinical research on prostate cancer.
Strategies & Plans: Informatics and Clinical Trials
Goals:
Enable the linkage, transfer, and analysis of biomedical information relating to cancer.
Use informatics to make clinical trials more efficient and more accessible.
Initiatives:
National Cancer Informatics Infrastructure for Prostate Cancer Clinical Trials
As part of its clinical trials restructuring initiative, and in close collaboration with outside experts in academia and industry, NCI is developing a national Cancer Informatics Infrastructure to enable the linkage, transfer, and analysis of biomedical information relating to cancer. The initial emphasis of this project is on systems to support clinical trials. NCI is currently collaborating with CapCure, a private, national prostate cancer organization, in the development of a consensus terminology for prostate cancer and common standards for form design.
Strategies & Plans: Clinical Early Detection Markers
Goals:
Determine whether early detection impacts mortality and whether routine screening of asymptomatic men carries a net benefit.
Identify the effects of early detection on morbidity, mortality, and quality of life.
Initiative:
Enhancements to the Prostate, Lung, Colorectal and Ovarian Screening Trial
The ongoing PLCO Cancer Screening Trial is designed to determine whether yearly screening for prostate cancer using the Prostate Specific Antigen (PSA) blood test and Digital Rectal Examination (DRE) will decrease mortality from prostate cancer. The PLCO Trial will enroll 75,000 men, who will be randomized into a screened group (37,500 men) and a "usual care" group (37,500 men). The screened group will be screened at yearly intervals for four years for prostate cancer. The "usual care" arm has been asked to continue their usual medical care with their physician. Both groups will be followed up with respect to cancer occurrence, morbidity and/or mortality for ten years after entry into the PLCO Trial.
Planned enhancements to the PLCO Trial would include two additional years of screening for the screened group and an additional three years of follow-up in both groups for a total of thirteen years of follow-up. These enhancements would increase the ability to detect possible beneficial effects of screening, such as decreased morbidity or mortality. The two additional PSA screenings would also provide for two additional specimens to be collected from every screened participant. These additional specimens would be placed in the PLCO Biorepository. The PLCO Biorepository would provide a important resource for doing future studies, including: evaluation of emerging candidate early detection or prognostic markers; studies of risk factors; and investigations into nutrients or lifestyle factors that reduce risk of prostate cancer.
Strategies & Plans: Image-Guided Therapy
Goals:
For localized tumors that require therapy, imaging has benefits that are getting closer to realization. The combination of using precise imaging techniques with therapeutic sources of radiation and high-performance computing has greatly improved our ability to target radiation treatments to a tumor's three-dimensional contours. In principle, imaging techniques can be interfaced with other tumor-destroying modalities as well, so that tissue destruction can be more precisely guided and is therefore less likely to harm normal surrounding tissue. In addition, medical therapies such as gene therapy vectors or toxic chemicals can also be delivered directly to tumor tissue using image-guided therapy in conjunction with catheter delivery systems.
These minimally invasive approaches to local treatment all depend on precise delineation of the treatment volume and accurate means of delivering the energy/agent to tissues and monitoring its effects. These methods hold great potential for minimizing surgical trauma, shortening recovery time, and reducing health costs. These methods are all potentially applicable to prostate cancer; however, difficulties in accurately delivering the therapy to the target tissue, sparing normal tissue, and monitoring the tissue damage created by the therapy have all posed serious limitations to wider clinical testing and usage.
Assess and validate technologies to facilitate image-guided therapy.
Develop and refine technologies for image-guided therapy and make them available for clinical application.
Integrate imaging technologies into the design of therapeutic interventions and in following the outcomes of treatment.
Initiative:
Technology Development and Testing in the Diagnostic Imaging Program
The Diagnostic Imaging Program would develop an initiative using a variety of support mechanisms to stimulate further technical development of these minimally invasive local therapies. This would require creating multidisciplinary research groups including biologists, clinicians, engineers, physicists, and computer scientists. When techniques are developed that are suitable for clinical testing, these would be carried out within the institutions and networks that NCI already supports under existing grant mechanisms. An example is the newly funded American College of Radiology Imaging Network, which will conduct imaging clinical trials relating to cancer diagnosis and therapy.
Strategies & Plans: Prevention Trials
Goal:
Progress and opportunities in prostate cancer chemoprevention are closely tied to the integration of promising chemopreventive agents, the identification of intermediate endpoint biomarkers, and development of new trial cohorts and more efficient clinical trial designs.
Evaluate promising preventive agents in clinical trials.
Initiatives:
Developmental Clinical Prevention Trials (Proof of Principle)
The time is ripe for evaluating a growing list of promising chemopreventive agents through the identification of several new high-risk study populations, including:
Approximately one million newly identified subjects per year with biochemical abnormalities (elevated PSA and negative biopsy) and
First degree relatives of prostate cancer patients (probands) with familial or hereditary prostate cancer syndromes.
These early chemoprevention trials would use intermediate endpoint biomarkers as primary endpoints. Incorporation of new genetic and chip technology would enhance the identification of select panels of prostate specific genes and proteins as surrogate endpoints.
Several types of agents and approaches are of particular interest and include: proapoptotics, signal transducers, antiangiogenics, isoflavones, differentiating agents, rational combinations (antiandrogens with selenium), and gene therapy. New pilot trials of novel agents and micronutrients (selenium, lycopene, vitamin E, vitamin D analogs and soy isoflavones) are planned and would be submitted for review.
Intermediate Clinical Prevention Trials (Proof of Efficacy)
The time is right for conducting several prevention trials of intermediate size (500 to 1000 subjects) using cancer incidence as the measured endpoint in two specific study populations:
High-risk subjects and
Subjects with prostatic intraepithelial neoplasia.
These trials would efficiently establish the role of chemoprevention for prostate cancer in selected high-risk populations.
Large-Scale Prostate Cancer Prevention Trials in the General Population
Several agents, including selenium and vitamin E, are ready to be tested in a large prostate cancer chemoprevention trial. These primary prevention trials would be completed in study subjects with risks similar to the general population and therefore require larger numbers of subjects in order to observe an effect of the chemopreventive agents. These trials would definitively establish the benefit (efficacy and safety) of select antioxidant micronutients for prevention of prostate cancer in the general population.
Strategies & Plans: Investigator-Initiated Research
Goal:
Maintain excellence and accelerate progress in investigator-initiated research by increasing the pool of researchers and clinicians and the number of grants funded in clinical science.
Initiatives:
Research Project Grants in Clinical Science
A principal support mechanism used by the NCI to foster enhanced investigator-initiated research into prostate cancer is the Research Project Grant. This mechanism permits both basic investigations into cellular and molecular questions, and research into creating interventions that translate our knowledge into improvements in treatment, prevention, and care. NCI fully expects the research community to respond with research proposals applicable to prostate cancer. NCI will pay particular attention to applications that address those aspects of prostate cancer research identified by the Prostate Cancer Progress Review Group. It is anticipated that during the course of this Five-Year Plan, approximately 215 additional investigator-initiated research grants focused on prostate cancer would be supported. Of these, approximately 55 would specifically address clinical science questions in prostate cancer.
Additional Investigator-Initiated Research Grants in Prostate Cancer: Funding Grants as Exceptions to the Payline
NCI expects to use a portion of its grant funds to support high-priority applications relevant to prostate cancer. We expect to give special attention to applications that fall within the defined areas of extraordinary opportunity in the Bypass Budget but fail to meet the established payline. The NCI would pay particular attention to applications addressing aspects of prostate-cancer research that are described as high-priority and important gap areas by the Prostate Cancer Progress Review Group.