New Horizons in Nuclear Medicine


While there have been notable recent developments in diagnostic nuclear medicine, especially in PET imaging, equally exciting advances have also been made in the realm of therapeutic radionuclides, particularly in the oncology setting," reports Milton Guiberteau, M.D., FACR, chair of the ACR Nuclear Medicine Commission and chief of nuclear medicine at St. Joseph Hospital in Houston, Texas. He adds that therapy using elemental radionuclides such as iodine-131 (131I) for metastases of differentiated forms of thyroid cancer, strontium-90 and samarium-153 for palliation of bone pain caused by skeletal metastases, and certain therapeutic applications of phosphorous-32 have been nuclear medicine staples for quite some time. "However, years of research and development are beginning to pay off in providing forms of radioactive therapy targeting an ever-widening group of cancers. These often use sophisticated radiolabled radiopharmaceuticals and novel and/or more stable methods of delivering more traditional radionuclide therapy."

"The number of recent breakthroughs in therapeutic radionuclides is very promising," reports Guiberteau. "However, they are much more complex than the traditional armamentarium." Guiberteau adds that many of these techniques require additional training, patient interaction and multidisciplinary approaches to be successfully performed.

Targeted Therapy: New Applications and Novel Devices

"The novel applications entering the clinical arena include, but are not limited to, radioimmunotherapy, radiolabled peptides, balloon catheter brachytherapy and intra-arterial brachytherapy using radiolabled microspheres," reports Guiberteau. The common denominator to many of these new therapeutic options is the fact that they are considered "targeted" therapy, designed to target malignant cells while sparing the normal cells from damaging side effects.

Radioimmunotherapy

Radioimmunotherapy refers to intravenously administered radiolabled antibodies directed against specific tumor antigens. "After many years of monoclonal antibody research, the Food and Drug Administration has recently approved Zevalin™ and Bexxar™, which are two radiolabled antibodies used to treat non-Hodgkin''s lymphoma," notes Guiberteau. "Both drugs are murine antibodies directed against the CD20 antigen expressed on the surface of normal and malignant B-lymphocytes. In a real sense, FDA approval constitutes a major breakthrough in the recognition of the practical potential of radioimmunotherapy."

Bexxar™ is a dual-action therapy that pairs the tumor-targeting ability of a cytotoxic monoclonal antibody (Tositumobab) and the therapeutic potential of radiation (131I) with patient-specific dosing. The combination of these agents forms a radiolabled monoclonal antibody that is able to bind to the target antigen (CD20) found on non-Hodgkin''s lymphoma cells and subsequently initiate an immune response against the malignant cells and deliver a dose of radiation directly to tumor cells.

Bexxar™ is targeted for patients with late-stage or low-grade B-cell non-Hodgkin''s lymphoma. The regimen of Bexxar™ consists of four components administered in two steps of seven to 14 days, usually on an outpatient basis. The first set of infusions includes the nonradioactive antibody, which is used to improve the distribution of subsequent radioactive antibody and increase its uptake in the tumor, followed by a dosimetric infusion containing the antibody and a trace amount of radioactive 131I. The dosimetric step allows determination of the rate of clearance of radioactivity from the body using gamma camera counts obtained at three time points. From these determinations, the patient-specific amount of radioactivity necessary to deliver the targeted therapeutic total body dose of radiation is calculated. Seven to 14 days after the dosimetric step, the patient returns for the therapeutic step: two infusions, the first being the nonradioactive antibody followed by the calculated dose of radiolabeled antibody.

Radiolabled Peptides

Radiolabled peptides, which are also administered intravenously, are radiolabled analogues for tumor cell surface receptors such as yttrium-90 (90Y) somatostatin analogues, which are used to treat some neuroendocrine tumors.

Balloon Catheters and Brachytherapy

Balloon catheter brachytherapy entails intratumoral radiation administered via a unique catheter and balloon device, such as GliaSite®, used for brain tumors, and MammoSite®, used for breast cancer.

GliaSite®, a catheter–radioiodine combination, was recently approved by the FDA based on data indicating that it could deliver a readily quantifiable dose of radiation to target tissues. This device allows treatment of brain tumors by delivering aggressive intratumoral radiation: radiation therapy that irradiates cancerous cells from within the tumor cavity. "Radiation therapy for recurrent gliomas has been very challenging in the past," reports Kasty Karvelis, M.D., director of nuclear medicine at Henry Ford Hospital in Detroit, Mich. "In addition to the discomfort and risks associated with conventional brachytherapy, very high doses of radiation were needed, thus increasing the risk of radiation necrosis."

Unlike prior approaches to brain irradiation, GliaSite® appears to deliver an even, easily controlled dose of radiation to the targeted tumor area while minimizing exposure of nearby, healthy brain tissue.

"GliaSite® is usually used in patients with primary or metastatic brain tumors after surgeons have completed a resection and have concerns that there may be residual tumor at the margins," advises Karvelis. "The process entails implantation of the expandable GliaSite® balloon into the tumor cavity at the time of the debulking procedure." The balloon is connected by a thin catheter to a small reservoir, which is inserted just beneath the patient''s scalp.

The radiation oncologist plans the radiation dose, for example 6,500 rad to within 1 cm of the balloon, in close collaboration with the surgeon. One to two weeks after the implant, the balloon is filled with radioiodine (125I) for three to seven days, thus delivering high doses of radiation through the balloon directly to the tissues surrounding the cavity. At the end of the prescribed time, the radioactive material is removed, the catheter is flushed with saline and the material is measured in a dose calibrator to confirm that all material is removed. The surgeon subsequently removes the catheter because less than 1 percent of the patients undergo an additional course of brachytherapy.

"Although not a disadvantage per se, one of the challenges with GliaSite® and other targeted modalities in successfully performing the therapy is that they require close coordination between departments that typically do not work together on a day-to-day basis; in this case, nuclear medicine, neurosurgery, and radiation oncology," Karvelis says. "We have become new partners in our efforts to meet the needs of the program. The logistics, while not particularly complex, require extensive planning. In fact, to facilitate the program in our organization, we developed a 4-page, color-coded flow chart so that each department can easily visualize the next step."

He adds that an additional aspect of the therapy is that 125I has nuances of measurement of radioactivity. "Small changes in geometry can make a significant difference in dose; thus, this is an area in which expertise in radiopharmacy is essential to safely determine the correct dosage for each patient," he emphasizes.

Karvelis says that his institution was involved in several clinical trials prior to FDA approval for GliaSite® and has now used it clinically for three to four years. "The direct benefits of the procedure are numerous. External beam radiation therapy may be a lengthy process—often taking approximately six weeks. In addition, some normal brain tissue is exposed to radiation. With GliaSite®, therapy is completed in a matter of days and we are able to deliver radiation to a limited area, thus sparing normal tissue." He reports that GliaSite® has shown substantial effects on median survival rates compared with conventional therapy.

Intra-arterial Brachytherapy

Two additional forms of targeted therapy include TheraSphere® and SIRSphere®, which are examples of intra-arterial brachytherapy using radiolabled microspheres. TheraSphere® is a therapeutic device that consists of glass microspheres (mean diameter, 20 to 30 microns) that are chemically bonded to a radioactive pure beta emitter, 90Y, which has a physical half-life of 64.2 hours. After injection, it produces radiation to tissue with an average range of 2.5 mm and a maximum range of less than 1 cm.

In the case of hepatocellular carcinoma, TheraSphere® is delivered via a catheter that is inserted through an artery in the groin and delivered directly into the hepatic artery. Generally, a 1-day hospital stay is needed. For hepatocellular carcinoma, patients typically receive two treatments to each lobe of the liver (two treatments for unilobar tumors and a maximum of four treatments for bilobar tumors). Each treatment is given at approximately a 2-month interval.

Analogous to other novel techniques, TheraSphere® is relatively nontoxic and requires only a limited number of treatments to achieve the same therapeutic efficacy as conventional therapy. Both advantages contribute to its cost-effectiveness.

Similarly, however, a multifaceted, multistep approach to preparation for treatment and actual treatment is required. For example, before treatment a computed tomography of the liver is generally performed to determine the amount of liver volume to be treated; a radiation physicist and an authorized physician subsequently calculate the dosage of TheraSphere®. On the day of treatment, an angiogram is performed to verify that the hepatic artery does not deliver blood to any adjacent branches. A technetium-99 MAA scan is done that day as well to ensure that the hepatic arterial flow through the liver does not extend into the systemic circulation and lungs.

Regulation, Training and Reimbursement

"In the past, therapeutic procedures associated with nuclear medicine were relatively straightforward, such as 131I for thyroid disease in patients who were relatively healthy" reports Paul Wallner, D.O., FACR, chief, Clinical Radiation Oncology Branch, National Cancer Institute, Division of Cancer Treatment and Diagnosis, Radiation Research Program. "This is no longer the case. For example, patients undergoing many of the newer therapies are often seriously ill and require ongoing care. Dosimetry for some agents is a unitized dose; however, alternatively, other agents require calculation of numerous parameters. Due to this variation, the system needs built-in flexibility for what is actually done—not a theoretical model."

Wallner cautions that there is a new set of issues related to the new-generation compounds and techniques. "We are now encountering new drugs—such as Zevalin™ and Rituxan®—that reflect the beginning of a potential onslaught of newer compounds. This presents a new set of challenges for clinical issues that are significantly more difficult because these are therapies utilized in patients who by definition have failed chemotherapy, may have received local radiation therapy, have bone marrow compromise having received systemic therapies, and who may have open wounds."

Reimbursement issues are thus no longer related to a "simple" injection. Patients, who may have bone marrow compromise, require critical dose calculations that accommodate all relevant factors. "The physicians involved in the care of these patients must be able and willing to participate in their ongoing care because there are critical timing and sequencing issues, and critical follow-up issues," notes Wallner.

"The totality of the process relative to reimbursement issues should be based on the care that is necessary for a particular patient''s unique situation. I believe it is important to avoid "agent-specific" reimbursement and to deal with a process of clinical care required for the patient. While this may sound logical and intuitive, it is likely that reimbursement will become more complicated," reports Wallner.

"The determination of which specialty performs the procedures—radiation oncology or nuclear medicine—seems to vary by institution," reports Cassandra Foens, M.D., FACR, chair of the ACR Federal Regulations Committee and chair of the Cancer Program at Covenant Medical Center in Waterloo, Iowa. She notes that this is often determined by the certification of the available physicians in the community. "For example, we are a small community and do not have a nuclear medicine–certified physician; thus, the radiation oncologist will perform many of these services.

"One of the most critical features of these therapeutic modalities is that they require a team approach involving a multidisciplinary structure. Each member of the team must have the proper training and certification for their respective tasks as well as the ability to provide follow-up care to monitor for side effects of therapy," Foens cautions.

Regulatory authority over the use of ionizing radiation in medical use is shared among several federal, state and local government agencies. The U.S. Nuclear Regulatory Commission (or the responsible Agreement State) has regulatory authority over the possession and use of byproduct, source or special nuclear material in medicine. Karvelis notes, "The concept of unsealed sources, ''liquids,'' has traditionally been the purview of nuclear medicine, whereas radiation oncology dealt with external beam and sealed sources. In our model, we rely on those aspects and the expertise of team members."

"The NRC has traditionally classified these agents by making a determination of how those therapies best fit into the hierarchy of authorized user training for radioactive isotopes," reports Guiberteau. "However, because of the unique nature of these materials as well as our anticipation of an explosion in growth of similar therapy, the ACR has taken the lead in addressing these issues to ensure that the requisite regulatory guidelines are appropriate."

"The challenges in categorization of these therapies is complex because many, including GliaSite®, represent a hybrid of sealed and unsealed sources. It is a liquid, which is an unsealed source, but because it is administered in a balloon catheter, it behaves more like a source brachytherapy" reports Foens.

The FDA has approved new sealed sources and devices and categorized them as microsphere manual brachytherapy sources and devices. The difference between these new sources and devices and those typically licensed in accordance with 10 CFR § 35.400 is the physical size of the sources. This new category of sources and devices are less than or equal to 100 microns in diameter, are administered in aggregate and are not individually placed, and mimic an unsealed radioactive source should there be a contamination incident.

The ACR is collaborating with the American Society for Therapeutic Radiology and Oncology, the American Association of Physicists in Medicine and the Society of Nuclear Medicine to communicate consensus recommendations to the NRC''s Advisory Committee on Medical Use of Isotopes regarding administration of microsphere type–sealed source devices by physicians who are qualified as Authorized Users under 10 CFR § 35.390.

The ACR and the consensus group have submitted recommendations that:

  • Physicians certified in nuclear medicine who have met the training as specified in 10 CFR § 35.390 and physicians certified in radiation oncology who have met the training as specified in 10 CFR § 35.490 or until Oct. 25, 2004, 10 CFR § 35.940 be permitted to administer this class of sealed sources.
  • Physicians authorized to use unsealed sources until Oct. 25, 2004 in accordance with 10 CFR § 35.930 who do not meet the 700 hours training and experience as specified in 10 CFR § 35.390 are not authorized to administer sealed sources less than or equal to 100 microns in diameter without obtaining additional training and experience equivalent to the 700 hours specified in 10 CFR Part § 35.390.
  • Physicians authorized in accordance with 10 CFR § 35.390, 10 CFR § 35.490 or, until Oct. 25, 2004, 10 CFR § 35.940 must have experience in administering dosages to patients or human research subjects that includes at least three cases involving the administration of sealed sources less than or equal to 100 microns that are administered in aggregate and not individually placed, or completion of specific vendor training in the use of the microspheres and the microsphere delivery systems.

"We have extremely strict regulations regarding radiation safety in the United States," Foens adds. "We are working closely with the NRC to ensure that the dual goals of adequate training for practitioners and reasonable safety guidelines for patients are met. As these therapies evolve and these issues are resolved, I envision less debate over who will ''push'' the drugs because the process will include a multispecialty team comprising radiology, nuclear medicine, medical oncology and others. All will be trained in decision making for these modalities, including patient selection, radiation safety and management of potential side effects."

Multidisciplinary Involvement: A Critical Feature of Success

"While nuclear medicine has, and in many ways still serves, specific niches in cancer treatment, its role will surely broaden as its armamentarium increases. Radiologists must be ready to take advantage of these new therapeutic developments as they arise for their patients," notes Guiberteau. "As we move forward with novel applications of standard therapies and add new therapies to our armamentarium, the lines between the traditional approach as to who does the procedure are becoming blurred. These changes should serve as a wake-up call to radiologists that a multidisciplinary approach is essential in this forum."

"''Targeted therapy'' is the new buzzword and we will begin to witness enormous progress in the development of additional applications," predicts Wallner. "The appeal is that compared with conventional therapy, which may require 12 to 16 months to assess response to therapy, targeted therapy may allow us to monitor response to therapy in a matter of weeks. It has exquisitely seductive potential in the form of immediate benefit to the patient as well as an improved cost-benefit ratio."

"As radioisotopic therapies evolve, it is important that radiologists take an active role in assimilating them into their clinical practices when appropriate," cautions Guiberteau. "While there remain many questions, the ACR is carefully monitoring new developments and assuming a primary role in shaping the issues surrounding the practice implementation of these new cancer treatments."