Imaging in Cancer: A National Cancer Institute "Extraordinary Opportunity"Imaging the patient with cancer has become an essential aspect of patient care. As recently as 25 years ago, when the practicing physician suspected a malignancy, the patient would have few options for diagnosis and staging other than exploratory surgery or limited radiological evaluations. Over the past 20 years, advancements and refinements in imaging technology have substantially broadened the range of imaging procedures. Current techniques provide improved resolution and much clearer and more detailed images of organs and tissues than were previously possible. With the advent of CT, ultrasound, and MRI, it became possible to provide important structural and anatomic information. These techniques, in some instances, allow the radiologist to differentiate malignant from benign lesions, rule out the possibility of metastatic spread, and assist in accurately staging the patient. CT and ultrasound have become important in assisting with localization for biopsy, thus eliminating the need for complex and costly open surgical procedures to obtain tissue for pathology. The impact that CT imaging has had on the practice of oncology has been immense. Currently, therapeutic response criteria are often based on tumor measurements made from the CT scan. The anatomic information obtained from a CT or MRI scan helps to plan the surgical approach, defines the extent of tumor, and assists in localizing important normal structures such as vessels and nerves. It is now possible to image at less than millimeter resolution. Newer imaging procedures have already had a lifesaving effect in detecting some early cancers. For example, X-ray mammography has saved the lives of many women by revealing the presence of very small cancers before they could be detected by physical examination or other techniques.
During the past decade there has been a revolution in our basic understanding of human disease. This has been made possible from the rapid development of basic molecular techniques. These advancements have allowed scientists to explore and sequence human genes, elucidate molecular pathways, automate DNA sequencing, determine protein specific causes of disease, develop transgenic animal models, and use cell lines to rapidly test drugs and therapies. Associated with the developments in basic molecular biology, the imaging sciences have made remarkable advances in technologies and methodologies.
Molecular and functional imaging allows the imaging clinician or scientist to visualize physiology and cellular or molecular processes in living tissue. These newly developed techniques allow visualization and quantitation of clinically relevant physiologic variables such as blood flow, oxygen consumption, glucose metabolism, proliferative activity, and tissue hypoxia as they take place in living cells and tissues. As basic scientists gain a better understanding of the fundamental molecular nature of cancer, molecular, cellular and metabolic imaging will be an important adjunct in translating this knowledge into clinical practice. Molecular imaging can potentially identify important and key molecular structures and receptors that cover the surface of tumors. This important information may elucidate how the tumor behaves and will respond to certain drugs, treatments, and therapies. The development of contrast agents, specific ligands and imaging probes has allowed for the in vivo elucidation of metabolic pathways and specific cell cycle functions. These developments have occurred across all of the conventional disciplines of imaging including CT, MRI, nuclear medicine, and ultrasound. Newer techniques such as optical imaging hold promise for the detection and elucidation of disease and pathogenisis at the microscopic level, potentially even in situ. With continued evolution of technology it will be possible to visualize and quantitate intracellularly the changes as the cell transforms from normal to cancerous. It will become possible to evaluate at-risk populations of patients earlier in the cancer process, perhaps before a tumor has even had the chance to become malignant. Eventually it is anticipated that with molecular imaging techniques, the actual molecular signatures of cancer will be visualized in vivo. The molecular imaging specialist will be able to visualize and determine which genes are being expressed in specific cancers and be able to translate this information directly into better clinical management of the patient. In other words, the ability to detect, through imaging, the molecular changes associated with a tumor cell will vastly improve our ability to detect and stage tumors, select appropriate treatments, monitor the effectiveness of a treatment, and determine prognosis.
To facilitate the development of molecular imaging technologies there have been associated developments in image enhancement agents, imaging probes, and imaging ligands. These developments are improving our ability to capture changes in the biochemical makeup of cells and other living structures. Imaging agents, including contrast agents, probes, and ligands contribute to improved image formation in one of three ways: (1) they localize in certain body organs or structures (anatomic localization); (2)they attach to specific molecules in the body (receptor localization); or (3) they become activated by certain biochemical or physical conditions, such as the presence of a specific enzyme or low oxygen concentration in the cell (activatable agents). It is anticipated that contrast agents, imaging probes, and ligands of the future will be able to reveal the functional and molecular characteristics of tumors that determine clinical behavior and response to therapy. In imaging, as elsewhere in cancer research, animal models of cancer are making it possible to perform certain kinds of studies that are difficult, if not impossible, to perform in humans. In addition to learning more about cancer, research with animal models will facilitate imaging technology improvements that then can be eventually applied to the care of patients with cancer. The advantage of non-invasive imaging in animal models of cancer is the ability to perform repetitive observations of the biological processes underlying cancer growth and development. Furthermore, the level of resolution with some small animal imaging modalities is now approaching the size of individual cells. Imaging in animals can also help assess the effectiveness of new instruments and therapeutic technologies such as radiation therapy and directed drug therapies.
Imaging in Cancer: The Goals
Over the past several years the National Cancer Institute (NCI) has been keenly aware of the potential power of imaging techniques and molecular imaging in particular. Imaging has been identified as an area of "Extraordinary Opportunity" in the past several "NCI Bypass Budgets". The "NCI Bypass Budget" is a public document produced annually by NCI to identify for the Administration and Congress those scientific priorities on which the budget appropriation will be spent. Several program announcements have occurred to provide funding for molecular imaging. These have included specific announcements for Molecular and Cellular Imaging Centers, Small Animal Imaging Resource Programs, and a significant increase in funding to improve imaging technologies including probe and ligand development. The goals of the NCI include: (1) develop and validate imaging technologies and agents (e.g., probes, radiocontrast agents) that have the sensitivity to detect precancerous abnormalities or very small cancers; (2) develop imaging techniques that identify the biological properties of precancerous of cancerous cells that will predict clinical course and response to interventions; (3) develop minimally invasive imaging technologies that can be used in interventions and in assessing treatment outcomes; (4) foster interaction and collaboration among imaging scientists and basic biologists, chemists, and physicists to help advance imaging research and; (5) create infrastructures to advance research in developing, assessing, and validating new imaging tools, techniques, and assessment methodologies.
The NCI has already made progress in the last several years toward reaching these goals with the introduction of various programs and initiatives.
NCI will award two to three grants in the coming year to support In-Vivo Cellular and Molecular Imaging Centers (ICMICs). ICMICs will facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on cellular and molecular imaging. Because the integration of this breadth of expertise is still in its early stages, the NCI will also award six pre-ICMIC planning grants. The pre-ICMIC planning grants will provide time and funds for investigators and institutions to prepare themselves, organizationally and scientifically to establish an ICMIC.
Small animal models, particularly genetically engineered mice, are powerful discovery tools, but we have yet to capitalize fully on their potential in cancer research. NCI has funded five Small Animal Imaging Resource Programs. This initiative will support activities to develop and apply a wide variety of imaging modalities that focus on functional, quantitative imaging. Quantitating image data for small animals will lead the way to quantitative methods that can be applied in humans.
Before new or refined imaging tools can be used as cancer diagnostic instruments, they must be evaluated for their safety and effectiveness. In March 1999, NCI funded the Diagnostic Imaging Network (ACRIN) to bring together imaging experts from around the nation to perform a broad spectrum of multi-institutional clinical trials on diagnostic imaging related to cancer. ACRIN will establish collaborations with NCI Cooperative Groups to expedite the integration of diagnostic imaging technologies into clinical trials aimed at assessing new therapies.
Improved imaging techniques can enable clinicians treating prostate cancer to accurately localize and stage a tumor, information that can be useful for choosing treatments. NCI has set aside funding to launch a new initiative aimed at developing non-invasive imaging technologies for the localization, biopsy, and minimally invasive treatment of prostate cancer. New drug discovery programs are producing an ever-increasing number of molecules for investigation, in turn stimulating a need for research that integrates imaging techniques into preclinical and clinical studies to assess newly developed therapeutic agents. NCI has set aside funding for the development and application of labeled therapeutic agents as compounds for imaging studies and imaging agents that serve as metabolic markers of response to newly developed therapeutic agents.
NCI, the National Electrical Manufacturers Association, the FDA, and the Health Care Financing Administration (HCFA) are collaborating to facilitate the development, clinical testing, regulatory approval, and clinical implementation of imaging technology.
Imaging in Cancer: Meeting the Goals
To assure that the initially defined goals are met and completed in future years, the NCI has set forth in the 2001 Bypass Budget specific priorities and initiatives. These include:
Accelerate development of clinically useful technologies for detecting malignant and precancerous cells and for visualizing their functional characteristics.
Expand the number of In-Vivo Cellular and Molecular Imaging Centers.
Expand the Small Animal Imaging Resources Program to improve access to researchers testing new approaches to diagnosis, treatment, and prevention in animal models of cancer. NCI will foster collaborations between this program and the Mouse Models of Human Cancers Consortium.
Support multidisciplinary centers of expertise to develop optical technologies and perform clinical feasibility tests of instruments able to visualize epithelial tissue at risk for common cancers and recognize the optical signatures of precancerous abnormalities.
Develop, synthesize, validate, and distribute to the research community novel imaging agents. Create a program similar to NCI's Rapid Access to Intervention Development (RAID) initiative (which is designed to accelerate the movement of novel intervention from the laboratory to the clinic) for imaging agents. NCI will, on a competitive basis, synthesize, test, and distribute probes that image the physiological and functional status of tumor tissue in the human body.
Establish a publicly available database of agents available to the research community, together with information on their properties.
Expand and improve clinical studies of imaging modalities and image-guided interventions.
Establish centers for developing and clinical feasibility testing of technologies enabling minimally invasive, image-guided therapy for localized malignancies (e.g., brain, breast, prostate).
Enable collaborations between the clinical cooperative groups and the Diagnostic Imaging Network (ACRIN) for definitive testing of minimally invasive, image-guided interventions that appear promising in early feasibility studies.
Expand the Diagnostic Imaging Network (ACRIN)to permit it to develop a full menu of clinical trials relating to all major cancers.
Develop methodologies to assess the medical value of diagnostic tests in clinical trials. Support the full development of outcomes research as applied to the evaluation of imaging diagnostics.
Integrate molecular and functional imaging technologies into drug development and early clinical trials.
Support the development of in vivo and clinical imaging research tools for assessing the biologic effect of cancer drugs on their intended target or pathway.
Establish information archives and repositories needed by the research community.
Establish data banks of standardized digital images associated with known clinical outcomes.Provide resources to develop and test image processing and analysis algorithms on these standardized data sets.
Imaging in Cancer: The State of the Art
This introduction is intended to provide an overview of the National Cancer Institute's goals for imaging of cancer in the future. This current edition of Neoplasia presents eleven review articles that clearly outline and review the current state of the art in molecular imaging. Various modalities including MRI, MRS, CT, PET and optical technologies are discussed. The authors provide insight into the current applications of these imaging techniques and the potential for their use in the future. Many of the authors included in this issue have received or are currently receiving NCI funding to continue their impressive scientific research. With the continued support of the NCI and the intellectual capabilities of these and other investigators throughout the world currently involved in imaging research, it is likely that the NCI goals and visions of imaging in cancer research and patient care will be met. It is gratifying to note that the power of molecular imaging with MR spectroscopy, positron emission tomography (PET), ultrasound, CT, optical imaging, and numerous other techniques is being recognized and these techniques are becoming available in routine clinical practice. These modalities will allow for the functional, biochemical, and physiologic assessment of important aspects of malignancy. They are already beginning to show their potential power in the management of the patient with cancer. With the continued advancements that are going to occur, imaging will assume a critical and essential role in the basic scientific understanding, diagnosis, staging, and monitoring of cancer.
John M. Hoffman, M.D.
Chief: Molecular Imaging Branch
Biomedical Imaging Program
National Cancer Institute