The goal is simple in concept if impossible in practice: to irradiate every cancer cell but no normal tissue. Newer imaging methods and application of enormous computing power are bringing that goal closer to reality.
Basic Planning Tool: Computed tomography
In a recent review, Hopper and associates from Penn State University noted that “CT plays a pivotal role in oncology” for both diagnosis and treatment planning. [1] Several technical developments have secured CT’s position as the modality of choice: the availability of the 512 x 512 matrix for higher resolution, faster and better reconstruction algorithms, and virtual-reality endoscopy. Spiral CT offers even better image quality and faster scan times, reducing the amount of contrast medium needed. The multidetector-array scanners will further improve image quality and scan time.
Radiation planning has different goals, depending on whether the desire is to cure the patient or provide palliation. In the former setting, the fields are designed to encompass, not only the tumor, but areas at risk for recurrence while making certain that critical structures such as the spinal cord are not irradiated beyond their tolerance. On the other hand, palliative therapy is aimed at controlling pain, maintaining the patency of the ureters or other passages, preventing pathologic fractures, and restoring organ function. Thus, irradiation of the entire tumor mass is not planned or, in most cases, even feasible.
In many radiation therapy centers, the standard procedure today is three-dimensional planning with spiral CT for fractionated radiotherapy. Cross-sectional 4-mm images are obtained through the region of the tumor in the immobilized patient with table movements of 3 mm. The radiation oncologist outlines areas of tumor and the normal structures on each section, and the slices are loaded in the planning computer, which selects a center target point for the radiation beam. The resulting anterior and lateral entry points for the beam are then marked on the patient, who can then leave the scanner while the computer creates a three-dimensional reconstruction and digital radiographs on which the tumor volume and normal tissues are superimposed.
The computer then simulates treatment plans, first displaying the patient’s anatomy and the tumor from the point of view of the radiation beam. Beam directions that minimize morbidity and maximize tumor exposure are then selected. Field-shaping devices can be designed, and dose-volume histograms can be constructed to confirm the doses to the tumor and the normal tissues. Various treatment fields can be examined in order to select the optimal plan.
Plan refinements
Even the refinements in targeting delivered by spiral CT are not entirely satisfactory.
Two other approaches are conformal and intensity-modulated therapy.
For conformal therapy, three-dimensional computer reconstructions of the tumor’s shape are used to mold (conform) the radiation beam. The procedure is even more complex than this description suggests, as accommodation must be made for all sources of variation in the target’s shape and position. Among the confounding factors are not only lung and heart motion but intestinal and ureteral peristalsis and filling of the bladder during irradiation. Prostate cancer has been a popular target for conformal radiation. Although conformal therapy entails more planning time, a recent study by Carlos A. Perez, MD, et al at Barnes-Jewish Hospital in St Louis suggested that it is more cost effective than standard radiotherapy in prostate cancer because it is more effective in controlling local disease and preventing metastases.
Intensity-modulated radiation therapy (IMRT) is an advanced type of conformal therapy in which the radiation beam is broken down into thousands of rays (pencil beams) of different intensities. As the gantry revolves around the patient with the radiation beam on, the pencil beams are turned on and off by moving the leaves of a collimator in and out of the beam. Cancers being treated with IMRT at present are those of the lung, head and neck, prostate, and pancreas, as well as primary and metastatic tumors of the liver or brain. The images used in treatment planning can be obtained by CT or MRI.
Despite its promise, IMRT presents many challenges to organizations, necessitating collaboration of departments that traditionally have not interacted and imposing needs for additional training and equipment.
Seeing Metabolism
The drawback of all of these methods of defining tumor size and shape is that they assume that all of an abnormal mass is cancerous.
“A mass does not always consist entirely of cancer,” notes Richard L. Wahl, MD, professor of radiology and director of the General Nuclear Medicine Section at the University of Michigan Medical School, Ann Arbor. “For example, uninvolved lung may collapse distal to a cancer, and on CT, it can be hard to tell the cancer from normal tissue. Yet it is important to make this distinction, because that collapsed lung has great potential for recovery, and you want to avoid it when you aim your therapy beam.”
Cancers differ metabolically from normal tissues, a fact that is increasingly being exploited to identify them, define their boundaries, and select treatment. Of particular note, most tumors have high rates of glycolytic metabolism, enabling them to be imaged by positron emission tomography after administration of fluorine 18-labeled deoxyglucose (FDG-PET). Receptor expression, DNA synthesis, and amino acid metabolism are also amenable to examination by PET as means of locating and characterizing tumors.
“A PET study helps you see how much of a mass is cancer,” Wahl reports. “It also is better than CT and MRI in showing whether the disease is in one place or several. For example, PET can detect some smaller lymph node metastases that are overlooked by CT, and these are lesions you would want to include in the therapy port. Sometimes, too, an enlarged lymph node that you might assume contains cancer has no tracer uptake. That node is most likely benign, so you would not include it in the field. Thus, PET studies can help you minimize treatment toxicity.” Wahl is the principal investigator on a multicenter project investigating another specialized use of PET: to detect tumor in the axillary lymph nodes of women with breast cancer. “We are looking prospectively at whether PET can replace lymph node dissection,” he says. “We hope to have the answer in a few months.”
At Memorial Sloan-Kettering Cancer Center in New York, PET is being applied to characterize endocrine-responsive tumors: thyroid, prostate, and breast cancers. With its help, the size as well as the metabolic status of the tumor can be determined. PET also is being used to image drugs, antibodies, and peptides as they seek their targets on cancer cells. Experimentally, PET is being used to study gene action.
Patient Care
A PET study not only helps define the size and shape of a tumor but also provides information that can help direct treatment for individual patients.
“There is some evidence that PET can detect hypoxia,” according to Wahl. Killing by radiation requires aerobic metabolism in tumor cells, so “hypoxic tumors need more aggressive therapy, such as hyperfractionation or radiosensitizers.” One biotechnology company is beginning trials of a drug that increases the release of oxygen from hemoglobin into tissues to improve radiation efficacy by relieving hypoxia.
In April, a research team from UCLA described a study of 12 patients with head and neck cancer who underwent quantitative FDG-PET before and 6 weeks after radiation therapy. Tumors with metabolic rates higher than that of the cerebellum were associated with significantly better local control, as were tumors having a drop of greater than 50% in their metabolic rate after radiation therapy. The team concluded that PET may help identify patients who would benefit from more aggressive therapy. [2]
Chemotherapy produces rapid changes in the metabolism of drug-sensitive tumor cells, and changes can be detected by PET within a few days instead of the 2 or 3 months needed to measure the response by conventional means. If the drugs are not killing the tumor, others can be substituted or radiation can be considered. There are fewer data on the use of PET to monitor radiation, but there is a suggestion that it will prove useful.
“However, you cannot look too early,” Wahl cautions. “Soon after radiation is completed, you will see tracer uptake that is attributable to residual viable (but dying) tumor or inflammation.”
“Metabolic imaging, especially PET, will dominate diagnostic oncology in the next decade,” in the opinion of Steven Larson, MD, chief of Nuclear Medicine Services and director of the Laurence and Alberta Gershel PET Center at Sloan-Kettering and professor of radiology at Weil Medical School, Cornell University, in New York City. “For certain cancers, such as lung, colorectal, and head and neck, PET is already a part of optimal care. With a little more experience, lymphoma, melanoma, and esophageal cancers will be added to this list. Eventually, virtually all tumors will be evaluated with this imaging tool.”
Another method of radiation planning exploits the original medical imaging modality: the human eye. For this treatment, which has been applied especially for soft-tissue sarcomas, the surgeon examines the operative field visually and by palpation after tumor debulking and decides how much tumor remains and where to place the radiation sources. Both high- and low-dose-rate radiation has been applied, often in combination with external-beam radiotherapy. In early trials, local control rates have been good and the morbidity acceptable.[3, 4]
Calling in the Targeting Experts
The most efficient way to get a job done often is to hire an expert to do it for you. That is the principle underlying the use of monoclonal antibodies that target a cancer-specific antigen and carry therapeutic radioactive isotopes. Radiotagged antibodies have a particular appeal in lymphoma and other disseminated cancers, as they can scurry around the body seeking out every vestige of the tumor, even microscopic lesions or free-floating cells in the bloodstream.
Tositumomab, developed at the University of Michigan, targets the CD20 antigen, which is expressed on B lymphocytes but not on other cells. Importantly, it is not expressed on B-lymphocyte precursors, so that the collateral destruction of normal B cells by the treatment has only a short-term effect on the patient’s immune system. A complex of this monoclonal antibody with Iodine 131, tositumomab I 131, is in clinical trials for non-Hodgkin’s lymphoma.
In order to determine the dose of antibody appropriate for a patient’s tumor burden and metabolism, an infusion of unlabeled anti-CD20 antibody and of trace-labeled antibody are given. A series of gamma camera studies over the next week yields data for calculating the whole-body half-life of the antibody and the total amount needed to deliver the maximum tolerated radiation dose.
Kaminski et al recently described the long-term multicenter follow-up of 59 patients with non-Hodgkin’s lymphoma who were treated with 131I-tositumomab. The response rate was approximately 80%, with half of the responses being complete. [5] Importantly, it was possible to obtain a second response in some patients by readministration of the antibody. An earlier study showed that tumor metabolism, as measured by FDG-PET, declined sharply within 1 to 2 months of 131I-tositumomab administration in patients whose cancers responded, suggesting that it may be possible to forecast the effectiveness of the antibody soon after treatment. [6]
At Duke University in Durham, NC, Edward Coleman, MD, professor and vice chair of radiology, director of the Division of Nuclear Medicine, and director of the PET facility, and his associates are conducting phase I/II trials of radiolabeled monoclonal antibodies to treat brain tumors.
“Initially, we tried to deliver the antibody intravenously, but we could not get a therapeutic amount into the brain,” he reports. “Now, we use direct administration. In one approach, the goal is to sterilize the surgical bed, so the surgeon installs a reservoir after the tumor is resected. We let the wound heal for a few days and then inject a radiopharmaceutical to be certain there is a cavity at the surgical site and that it does not leak. If the findings are satisfactory, we instill an antitenascin antibody into the reservoir. Initially, we used 13II, a beta emitter, to deliver the radiation, but recently, we have been using astatine 211, an alpha emitter. In the other approach, we inject the antibody directly into the primary or recurrent tumor using stereotactic guidance.”
Tenascin, an extracellular adhesive glycoprotein prominent in embryonic tissues, is ubiquitous in brain tumors but is not expressed on normal brain tissue. Astatine (atomic number 85) is a rare naturally radioactive halogen. The 211 isotope (t1/2 7.2 hours) can be created artificially by bombarding bismuth with alpha particles. Michael Zilutski, PhD, a Duke University radiochemist, is a leading expert on the element and the isotope.
“We have treated about 150 patients. Part of this was a dose-escalation study. Also, we changed from a wholly murine to a human murine-chimeric antibody, and we have used two radioisotopes. So, although we have treated a large number of patients, the number in any one protocol is not large. The early results are encouraging nevertheless: we have seen some very good responses.”
Future Fusion
Both Wahl and Larson are enthusiastic about the latest scanners that combine anatomic and functional images. With this equipment, “you get the anatomic information of CT and the unique functional imaging of PET, so you can characterize lesions better and determine exactly where they are,” Wahl says.
“Fusion imaging will become a routine part of PET imaging” with these scanners, according to Larson. “These machines will not only provide automatic fusion images but will enhance the speed and accuracy of quantification of PET data. These properties are essential if PET is to be widely used in staging and monitoring cancer.”
Larson sees an increasing need for imaging data by surgeons. “Minimally invasive surgery is making rapid advances in the care of oncology patients,” he says. “PET and, especially, PET/CT will help guide the interventional radiologist and the surgeon, providing a metabolic view of the surgical field. In the future, informatics will permit fusion of images from PET, CT, MRI into a single virtual image that will be available in the operating room. Together with these other imaging modalities, PET will help optimize the extent of ablative therapy or resection.”
The growing demands for advanced imaging in oncology are leading to alliances of specialists who in the past might never have met.
“There is a new spirit of collaboration between basic and clinical researchers,” Larson observes. “This shared enthusiasm is directed at applying imaging science to cancer biology. For therapies of the new millennium, such as gene therapy and intensity-modulated radiation, we believe that high-resolution, computer-intensive imaging tools such as PET will be an essential part of optimum treatment of individuals with cancer.”
Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.
