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Worth More than a Thousand Wordsby Sunni Hosemann At one time, oncologists were taught to gauge the size of palpable tumors by practicing with wooden balls under a sheet and using calipers to measure them. This training was intended to help answer a very important question when monitoring cancer in the clinic: had the tumor changed? Of course, wooden balls and calipers have long since given way to modern diagnostic imaging, which allows oncologists not only to “see” neoplasms and calculate their volume but also to determine whether a tumor is metabolically active. The latter is important because in some kinds of cancer, such as lymphoma, the tissue mass that may remain after treatment can look the same as it did before but, in fact, no longer be an active cancer. One of the most important recent advances in imaging has been the fusion of positron emission tomography (PET) and computed tomography (CT) scanning. Fusing the images provides more sophisticated information than simply doing the scans separately and comparing the results. CT scans yield sharp anatomic images but don’t show physiologic activity; PET scans have relatively lower spatial resolution but do show metabolic activity. Over the past few years, fused PET/CT scans have proven invaluable in helping oncologists make more accurate diagnosis and staging assessments, choose the most appropriate therapies, and determine whether a therapy is effective against a cancer. Experts at The University of Texas M. D. Anderson Cancer Center are working far beyond that, however. “We want images to show what is happening not just at the cellular level, but much deeper,” said Donald Podoloff, M.D., a professor of nuclear medicine and head of M. D. Anderson’s Division of Diagnostic Imaging. “We want to see whether the signal pathways within cells have shut off after a course of chemotherapy. We want to see whether receptor sites on cell surfaces are open or blocked. “We want to see molecules.” PET/CT: How it works Both PET and CT have been staples of imaging in oncology for years, but the fusion of the two yields more information than do the two separately. During a PET/CT procedure, the same machine does both scans and shows each separately plus a third set of co-registered (or fused) images. The yield is an image showing an anatomically localized area (CT) of metabolic activity (PET).
The metabolic imaging component of the technology is actually based on a long-understood concept in cancer biology. Scientists have known since the 1930s that cancer cells are metabolically more active than normal cells: they grow, divide, and consume sugars more aggressively. So, the current generation of PET scans uses fluorodeoxyglucose, which is 2-deoxy-D-glucose labeled with fluorine-18, a positron emitter. The resulting substance “goes where glucose goes, which is into metabolically active cells,” said Homer Macapinlac, M.D., professor in and chair of M. D. Anderson’s Department of Nuclear Medicine. Once cancer cells take up the substance, he explains, the trapped fluorodeoxyglucose gives off gamma rays that the PET camera can “see”—and the information is translated on the screen into an accurate image of the tumor’s glucose uptake. There are practical advantages of PET/CT as well. “Our PET/CT scans are faster than conventional PET scans because the CT is used for attenuation correction of the image, which takes seconds, while traditional correction methods took as long as the PET scan itself—about 20 minutes,” said Dr. Macapinlac. “Also, the total radiation exposure to the patient is less than that of standard diagnostic CT scans, so PET/CT scans can be safely performed on infants and the elderly.” Benefits of PET/CT The benefits of PET/CT images in the entire spectrum of cancer care—from diagnosis and treatment planning to evaluation of treatment response—have come into focus in recent years as the technology has become a standard practice at M. D. Anderson. “This is a great help to patients,” said Dr. Macapinlac. “They want to know if they have cancer, and if they do, they want to know how bad it is. They also want to know if, when we give a treatment, it’s working. PET/CT can tell us that better and faster than X-ray or CT or PET alone.” Diagnosis PET/CT has proven particularly valuable in diagnostic applications for cancers that are not easily reached for biopsy, such as lung cancer. An experienced evaluator can easily distinguish between a benign lung mass and a malignancy. For tumor masses that are not homogeneous—where biopsy results might differ depending on the location within the tumor that was sampled—PET/CT can pinpoint areas of increased activity within a tumor that should be targeted for biopsy, as they will be the most aggressive parts of the tumor. And in the best cases, “We get to tell patients they don’t even have cancer,” said Dr. Macapinlac. Dr. Macapinlac likes a challenge, and if he could be said to have a favorite kind of case, it would be cancer of unknown primary site. These cases involve patients who present with metastatic lesions whose origin is a mystery. Sometimes an oncologic pathologist can provide clues, but sometimes the primary tumor is never found. “Using PET/CT, we’ve been able to find 10% to 15% of them,” he said. It may not sound like a lot, but for those patients, finding the primary site can mean the difference between receiving successful, targeted treatment or a potentially less successful, best-guess regimen. In one recent case, a young patient presented with a cancer-involved lymph node in his neck. The primary tumor was found buried in the mucosa under his tongue, invisible to other imaging modalities. Staging Cancer staging is a major determinant of treatment choice, and lymph node status is an important aspect of staging for most cancers. Cancer-involved lymph nodes are not necessarily enlarged, so a patient staged with conventional modalities might appear to have only localized disease when, in fact, it has spread to the lymph nodes. PET/CT can be used to determine whether any nodes are involved. It can also be used to find distant metastatic disease that used to be considered occult—that is, no symptoms or clinical signs, no abnormal results in key laboratory studies (such as alkaline phosphatase testing), and no masses visible by conventional imaging. Because the discovery of involved lymph nodes or distant metastases changes the disease stage and therefore treatment, PET/CT studies are becoming an integral tool in the staging of many cancers at M. D. Anderson. Response to treatment “Sometimes after chemotherapy,” said Dr. Macapinlac, “a tissue mass will continue to look the same for months with conventional images.” This can leave the clinician uncertain that the treatment worked; for the patient, such uncertainty can be anguishing. Lymphomas represent a case in point: it can be difficult to differentiate the tumor tissue from normal tissue with conventional imaging or, in the case of disseminated disease, even with multiple biopsies. PET/CT can help guide further therapy by either confirming response or signaling the need for a change. This information can also be prognostic: lymphoma patients with a negative scan after two or three cycles of chemotherapy have better rates of progression-free and overall survival. “So we’re able to tell them right away that it’s working and that they will likely be disease-free for a long time,” said Dr. Macapinlac. For patients who are undergoing aggressive and often expensive courses of treatment, such as high-dose chemotherapy and bone marrow transplants, the images provided by PET/CT are considered so valuable that the scans have become part of the lymphoma practice guidelines at M. D. Anderson. Although PET/CT is expensive, it has been shown to reduce costs in the long run and so is eligible for coverage by Medicare and most insurance plans.
The next generation The experience with PET/CT using fluorodeoxyglucose provides a paradigm for the future in which radiopharmaceutical agents will be used in combination with imaging modalities to look ever deeper into the body. Needed next: novel tracer substances that can show processes other than glucose metabolism and even more sophisticated imaging instrumentation to yield further insight into the behavior, growth, and treatment of tumors. Enter Juri Gelovani, M.D., Ph.D., professor in and chair of M. D. Anderson’s Department of Experimental Diagnostic Imaging. A pioneer in molecular imaging, Dr. Gelovani has been tapped to head M. D. Anderson’s Center for Advanced Biomedical Imaging Research, a research collaborative that will bring together the many specialties necessary to advance these technologies and move them from research labs to clinical use. “Some therapies have been difficult to translate to the clinic, in part because they are so difficult to evaluate,” said Dr. Gelovani. Gene therapy is an example. The location, magnitude, and duration of gene expression cannot be assessed by biopsy alone, and evaluation of therapeutic gene expression in the whole body would require biopsies of multiple sites—an unfavorable option. Even for therapies whose effects can be assessed by biopsy, the procedure’s invasive nature makes it impractical to do frequently. Next-generation imaging procedures being developed in the Center for Advanced Biomedical Imaging Research will show therapeutic processes as they take place. Tracers One of the key elements of this research will be the development of radiopharmaceuticals (or tracers) that, combined with advanced imaging modalities, show processes within cells that conventional and newer molecular therapies are meant to target. For example, if a drug’s mechanism is to disrupt a specific cell-signaling pathway, such a tracer would show whether, in fact, the pathway was disrupted or the receptor was adequately inhibited. Molecular tracing compounds can be designed to detect the presence or absence of specific cell-surface receptors or to determine whether certain cell signals are turned on or off, and such tracers can be employed before and after particular therapies. For example, tracers that home in on growth factors or on cell-surface receptors specific to new blood vessels can monitor the success of anti-angiogenesis agents non-invasively and can reveal vessels beginning to sprout in a tumor while the tumor is still too small to image conventionally. Reporter genes Another class of agents—reporter genes—can be attached to therapeutic agents, including gene therapy. “These substances do not perturb the process,” said Dr. Gelovani. “They simply trace it.” The role of reporter genes is to take up radioactive substances so they can be imaged—where they are active, so is the therapy. Dr. Gelovani invented the process for imaging the PET reporter gene HSVTK (herpes simplex viral thymidine kinase), and today, he and colleagues are working on adding it to an immunotherapy for leukemia in which T cells are given to initiate a graft-versus-leukemia response. When the T cells are genetically modified with HSVTK, clinicians will be able to observe the graft-versus-leukemia response with PET/CT and quickly detect and treat any undesirable graft-versus-host response before clinical symptoms develop. Stem cells labeled with PET reporter genes and those cells’ progeny can continue to report for months or years, enabling researchers to know where they go, whether they multiply, if and how they differentiate, and when they die. Dr. Gelovani refers to this as “theragnostics” or “imageable therapy.” He is developing one such application to repair cardiovascular damage with colleagues in the Department of Veterinary Medicine and Surgery, the Department of Stem Cell Transplantation and Cellular Therapy, and Texas Heart Institute. Repairing tissue damage
The team is targeting tissue that has been damaged by an infarct or chemotherapy—as Dr. Gelovani points out, the development of regenerative therapy for cardiovascular damage is increasingly important as cancer survivors live longer. The experimental therapy, which is moving toward trials in humans, is done with a minimally invasive procedure: a catheter is inserted into a major vessel and threaded to the heart. From inside the organ, a portal needle injects gene-labeled stem cells directly into the myocardium. PET/CT can then be used to visualize where and how well the cells have grafted to the original tissue; repeated imaging indicates the viability of the stem cell–derived tissue and its contribution to the heart’s contractile function. “Because the stem cells are labeled genetically, it should be possible to monitor the fate of the stem cell–derived tissue over the course of several years or as long as the tissue persists,” said Dr. Gelovani. Imaging is crucial to assessing the therapy because the heart cannot tolerate repeated biopsies. Predicting therapy response Another new imaging technology that will soon be moving into human trials can detect whether a tumor will respond to therapy with epidermal growth factor receptor (EGFR) inhibitors—before the therapy is given. This technology uses a receptor-site imaging agent that can show through PET/CT the presence of overexpressed EGFR, which is thought to cause many lung and brain cancers. “The presence of such receptors has been associated with a dramatic response to therapy with specific EGFR inhibitors, such as erlotinib,” said Dr. Gelovani, who is developing the imaging agent with Roy Herbst, M.D., professor and section chief of Thoracic Medical Oncology, and Waun Ki Hong, M.D., professor and head of the Division of Cancer Medicine. However, EGFR is present in only a small segment of the patient population—about 8–10% of lung cancer patients, for example. Thus, using imaging to identify those patients who would benefit from EGFR-inhibitor therapy would allow for greater customization of effective therapy, without the need for biopsy. The imaging agent also can show which parts of a heterogeneous tumor have activated EGFR, which would provide a treatment path when multiple tumors—some that may overexpress EGFR and others that may not—are present. Better outcomes ahead This arsenal of new and upcoming imaging therapies has taken plenty of imagination to develop, but it takes little imagination to see the potential. As has happened with PET/CT, technologies such as tracer compounds and reporter genes promise earlier and more accurate diagnoses, more targeted treatments, and, ultimately, better outcomes. “This work points to a day when patients could have a cancer or tissue damage imaged and treated—non-invasively—within a matter of hours or days, and we would be able to evaluate the effectiveness of the therapy just as quickly,” said Dr. Macapinlac. “We need to prove this happens at the tissue level so that molecular imaging becomes a surrogate marker for these processes. This is the future of diagnostic imaging.”For more information, contact Dr. Macapinlac at 713-792-7126 or Dr. Gelovani at 713-563-4875, or visit www.mdanderson.org/departments/physrelations. Other articles in OncoLog, December 2007 issue:
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