Most of the excitement in nuclear medicine a year ago was about new technology. Today the great advances are coming from chemistry, protein engineering, and knowledge of the molecular changes that characterize cancer. Using the new tools, nuclear medicine is bringing the goal of noninvasive diagnosis and staging of cancer closer to reality. Like their colleagues who created interventional radiology, moreover, nuclear medicine specialists are increasingly being called on to treat patients.
The new methods of diagnosis, staging, and follow-up can be divided into those that take advantage of general features of cancer and those that exploit unique features of certain types of cancer. Positron emission tomography (PET) after injection of fluorine 18-labeled deoxyglucose (FDG) is an example of the former: it measures the rate of tissue metabolism. Cancers generally have a much higher metabolic rate-and thus higher glucose consumption-than benign tissues and so take up far larger amounts of the tracer. As a result, FDG PET is revolutionizing the diagnosis and staging of cancer. Common indications for its use are lung and colorectal cancer, melanoma, and lymphoma. [1]
One radiologist who has used the technique extensively is Richard L. Wahl, MD, director of the general nuclear imaging section, department of radiology, University of Michigan Medical Center in Ann Arbor.
Although lung cancer is common, it cannot be assumed that a solitary pulmonary nodule is malignant. Two new nuclear medicine methods are now available to characterize these nodules without a biopsy. In Wahl’s experience, FDG PET approaches 95% sensitivity in identifying cancer in solitary nodules and therefore can replace biopsy in many patients. (The other technique for characterizing nodules is described below.)
The utility of FDG PET in patients with lung lesions is not limited to diagnosis of the primary lesion.
“Body PET is a very good method for determining whether lung cancer has spread to the regional nodes or systemically,” Wahl says. “We recently published a meta-analysis [2] showing that PET is more accurate than CT scanning in staging lung cancer.” Some medical centers are fusing FDG PET or FDG single photon emission computed tomography (SPECT) images with spiral CT scans or technetium Tc 99m-labeled erythrocyte images to localize metastases more precisely. [3]
PET also is valuable in colorectal cancer to determine whether the disease has recurred when the serum concentration of carcinoembryonic antigen (CEA) is rising while the CT scan is negative.
“Surgeons often will operate if there is only a single spot of recurrence, and PET is good at identifying and localizing those sites,” Wahl notes. “On the other hand, if there are multiple sites of recurrence, it often is wiser not to operate.”
The University of Michigan has one of the largest clinics in the country for the treatment of melanoma, which strikes one American in 80. Studies with FDG PET have a role in managing higher stages of this disease.
“We use PET when resection of isolated lesions is planned,” Wahl says. “You may believe that a patient has a solitary metastasis under the arm, but when you do a PET scan, you see that there is much more extensive disease. In that case, you probably will change your treatment plan.”
Lymphoma is diagnosed in about 60,000 new patients each year in the United States. PET is used to stage the disease at the time of diagnosis, but its utility may be expanded beyond this indication.
“This cancer is hard to manage after induction therapy because you cannot always tell if the tumor has gone away,” Wahl points out. “The CT scans may never become normal: they show lumps, and you cannot tell if the lump is alive or dead. PET is proving to be useful in making that differentiation between scar and viable tumor.”
Imaging by FDG PET may be useful in diagnosis, staging, and follow-up of cervical cancer also, as recently shown by Wahl and his colleagues in a series of 21 women. [4]
Lymphoscintigraphy is a superior version of a traditional cancer staging method. For traditional lymphangiography, radiographic contrast medium was injected at the site of the primary tumor to opacify the draining lymph nodes. Theoretically, failure of lymph nodes in the chain to opacify in their entirety meant that cancer was present. However, there were many false-positive and false-negative studies, and lymphangiography passed from favor. The newer radioisotope agents have greatly improved the accuracy of lymph node imaging.
An example of the utility of lymphoscintigraphy is seen in melanoma. In the past, many people with this cancer had lymph node surgery that proved to have been unnecessary when the pathologist examined the tissue postoperatively. With lymphoscintigraphy, a small amount of the technetium Tc 99m sulfur colloid is injected around the lesion. The utility of the radioisotope continues intraoperatively. The surgeon uses a handheld probe to find out which lymph nodes are hot, suggesting cancer cells.
“The external scan is done preoperatively because some lesions drain to multiple lymph nodes,” Wahl explains. “If that is known before surgery, the surgeon can more rationally make a decision on how to operate.”
Wahl and his associates recently reported that almost 7% of 300 melanoma patients have intercalated lymph nodes between their primary tumors and the expected drainage basin. In eight patients, these intercalated nodes were biopsied, and in two patients, cancer was found even though the primary draining nodes were tumor-free. Thus, cancer was found that would have been missed by surgery.
A traditional approach to cancer surgery has encompassed removal, not only of the primary tumor, but also of the chain of lymph nodes draining that site. For more than 20 years, surgeons have sought to determine whether, instead of removing the entire chain, one can safely sample one or two nodes (sentinel nodes) to determine whether a complete lymphadenectomy is required. Recent efforts to identify and study sentinel nodes have been particularly strong in breast cancer.
“Lymphoscintigraphy to detect sentinel node involvement is still in evolution for breast cancer, but more and more women are requesting it,” Wahl reports. “Sometimes, its accuracy is clearly superior to that of a regular axillary dissection, and sometimes it is slightly lower, but clearly, there is much less morbidity. Our department is part of a multicenter study of whether the scan can better select those women who need sentinel node surgery. That is, if you can determine noninvasively that there is cancer in the lymph nodes, you probably would not excise the sentinel node, whereas in those women with a negative scan, you would remove the node just to be sure there was no cancer.”
Cancer-Specific Agents
As knowledge of cancer biology has grown, more agents specific to one or a few types of cancer have been developed. The US Food and Drug Administration (FDA) has approved a radiolabeled antibody against CEA for the detection of metastases of colorectal cancer. Some surgeons are studying the antibody as a means of identifying unresectable primary tumors. Radiolabeled antibodies also have been approved for cancers of the prostate and ovary. The product for prostate cancer may help select appropriate candidates for post-prostatectomy irradiation. An experimental technetium Tc 99m-labeled monoclonal antibody to the epidermal growth factor receptor used with SPECT shows promise in detecting primary and metastatic cancers of epithelial origin. [5]
Hospitals that cannot afford dedicated PET scanners are not precluded from offering some radioimmunodetection procedures, in large part because many cancers overexpress receptors for somatostatin, a small peptide hormone that inhibits the activity of growth hormone and thyroid-stimulating hormone.
Depreotide is a somatostatin analog. A technetium-labeled form was approved by the FDA in August 1999 for characterizing solitary pulmonary nodules as malignant or benign. Wahl describes its use as “like a PET scan except that you do not need a PET scanner.” The preliminary data suggest that the technique is almost as accurate as PET. If further experience proves this impression to be true, the product could have a large role, as it is likely to be more cost-effective than PET. Radiolabeled octreotide, another somatostatin analog, is used for detecting carcinoid tumors and, to a lesser extent, other cancers.
Nuclear medicine has become involved in diagnosing deep venous thrombosis, a common complication of cancer, since the approval of a labeled antibody to fibrin breakdown products. Adoption of the technique, however, has not been as rapid as anticipated by observers. “Diagnosis of thrombosis using a radiolabeled peptide is so different from the typical paradigm it is being adopted only slowly,” Wahl notes.
Yes, It is Reimbursable, But…
Medicare has approved reimbursement for five uses of FDG: characterization of a solitary pulmonary nodule, staging of malignant melanoma or of non-small-cell lung cancer, detection of recurrent colon cancer when there is a rising serum CEA concentration, and staging of lymphoma.
“That’s the good news,” says Robert Henkin, MD, FANP, FACR, director of nuclear medicine and acting chair of radiology, Loyola University Medical Center, Maywood, Ill. “The bad news is that the Health Care Financing Administration (HCFA) will not be ready to pay for radiopharmaceuticals until at least October and perhaps January. It is not that Medicare does not want to pay for them: it is simply that they cannot get the necessary work done earlier. However, it is extremely important that hospitals file claims separately for radiopharmaceuticals under the Medicare system because HCFA is going to use those data to determine the reimbursement.”
According to Henkin, a department with nuclear medicine capability can easily expand into studies for the diagnosis and staging of cancer.
“There is nothing in this field that cannot be done by anybody capable of doing high-quality nuclear medicine studies,” he notes. “The same technologists who can perform your gated SPECT studies of the heart can do your FDG work. The burden on the technologists is somewhat greater, however. They must be astute and alert to learn the potential pitfalls of some of these new techniques.
“The big problem,” he continues, “is the lack of hours in the day. You have more demand, but you have the same number of staff people and the same amount of equipment. Our volume is up sharply here, yet we have added only one person.”
Nor are extensive equipment purchases always necessary. A contemporary model gamma camera is required. For FDG studies, either a dedicated PET scanner or a coincidence camera is necessary. Loyola is using coincidence cameras as a bridge to a PET scanner.
“We have two coincidence cameras right now,” Henkin reports. “When our caseload exceeds a certain number of patients per week, the economics favor a dedicated PET scanner, and we will buy one. The critical mass of studies needed to justify purchase of a PET scanner differs from institution to institution depending on your local economics. For us, the number is about 15 studies.”
Marketing Nuclear Medicine
A hospital that can perform PET studies probably will not use the lung cancer diagnostic peptide, but Henkin sees an important potential role for it in a community hospital. Offering the new nuclear medicine studies can change the status and perception of a hospital.
“Most hospitals would like to portray themselves as full-service providers, but until recently, everybody acknowledged that certain things could be done only in academic centers,” he notes. “Now, many of those procedures are moving out into the community. As you discuss the future of your hospital, some of the visible new procedures in nuclear medicine may play a role in getting you there. So in positioning your hospital, you may want to consider investing in some of the new pharmaceuticals and equipment.”
At the same time, Henkin cautioned that the availability of a new technology does not automatically create a demand for it.
“Nuclear medicine always needs to market itself,” he stresses. “You are invisible if you do not. Most medical schools have no formal courses in nuclear medicine, and most community physicians know little about it. Somebody, be it the chief technologist or the radiologist, must communicate to the referring physicians that these new techniques are available. Even in an academic center, it has taken us a while. However, once a clinical champion starts saying to colleagues, ‘You ought to try this, it works well,’ you find yourself doing a lot of studies.”
New Forms of Radiation Therapy
An earlier article in this journal [6] described the utility of strontium 89 and samarium 153 lexidronam in the treatment of bone pain resulting from metastases. Another isotope with potential value against bone pain is rhenium. In a study recently conducted in The Netherlands, 14 of 24 of women with painful bone metastases from breast cancer reported benefit from rhenium 186 etidronate. Twelve patients were able to reduce their analgesic use by at least 25%, [7] a change that often improves quality of life.
Despite this and other studies indicating the value of radioisotopes for the relief of bone pain caused by cancer, medical oncologists may underutilize these agents or use them inappropriately. [8] That was the conclusion of Frank J. Papatheofanis, MD, PhD, of the Advanced Medical Technology Assessment and Policy Program at the University of California in San Diego. In that study, 100 board-certified medical oncologists were given clinical profiles of three patients with metastatic cancer and were asked to select the most and least appropriate methods of pain control. The oncologists generally perceived the appropriateness of systemic radionuclide therapy as low relative to opiates. They were particularly unlikely to favor radionuclides for a patient with less extensive metastases, where the literature indicates that benefit is most likely, and to consider the drugs appropriate in patients with widespread metastases, a situation in which published studies suggest that the likelihood of benefit is low.
A growing area of therapy is the use of antibodies or other targeting agents to deliver a cell-killing radioisotope specifically to a tumor while minimizing the damage to healthy cells. Partly because extensive investigation of the cell-surface antigens of blood cells has identified a number of targets, most of the present agents are designed for the treatment of lymphomas. The first such antibody for the treatment of cancer, rituximab, a 131I-labeled antibody against the lymphocyte antigen CD20, was approved by the FDA in November 1997. It has proved capable of inducing disease regression and prolonging life in many patients with non-Hodgkin’s lymphomas that have relapsed after or failed to respond to chemotherapy.
An agent now in clinical trials is a copper 67-labeled antibody against Lym-1, which is intended for use against B-cell non-Hodgkin’s lymphoma. The radioisotope emits both cell-killing beta radiation and, as a bonus, gamma radiation, which makes it possible to image the agent and thus the sites of disease. In 12 patients with stage III or stage IV lymphoma unresponsive to standard therapy, seven patients showed a response. [9] Injury to the bone marrow limited the dose that could be given to some patients.
In an attempt to reduce toxicity still further, some investigators are exploring a two-pronged method. The patient is first given a bispecific antibody that binds to a tumor-associated antigen. After a period of time to allow intratumor localization and excretion of unbound antibody, the patient receives a radioisotope linked to a protein that binds the other active site of the antibody. A product of this type, now in phase 1/2 trials for patients with small-cell lung cancer, received orphan drug designation from the FDA in March.
Even earlier in development is a peptide that binds to somatostatin receptors and delivers 188Re. In mice, this agent was able to induce regression of a human pancreatic tumor xenograft without evident damage to normal tissue.
Conclusion
Understanding of the chemical changes accompanying cancer is growing daily. It is likely that this knowledge and the work of protein engineers will quickly put new diagnostic and therapeutic tools into the hands of nuclear medicine specialists, expanding their role in the diagnosis and treatment of this common disease.
Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.
References:
- Delbeke D. Oncologic applications of FDG PET imaging: brain tumors, colorectal cancer, lymphoma, and melanoma. J Nucl Med. 1999;40:591–603.
- Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s—meta-analytic comparison of PET and CT. Radiology.1999;213(2):521-5.
- Burt R. Dual isotope F-18 FDG and Tc-99m RBC imaging for lung cancer. Clin Nucl Med. 1998;23:807–809.
- Sugawara Y, Eisbruch A, Kosuda S, Recker BE, Kison PV, Wahl RL. Evaluation of FDG PET in patients with cervical cancer. J Nucl Med. 1999;40:1125–1131.
- Ramos-Suzarte M, Rodrigues N, Oliva JP, et al. 99mTc-Labeled antihuman epithelial growth factor receptor antibody in patients with tumors of epithelial origin III: clinical trials—safety and diagnostic efficacy. J Nucl Med. 1999;40:768–775.
- Bronson JG. Aglow again: the excitement in nuclear medicine. Decisions in Axis Imaging News. 1998;11(3):66-70.
- Han SH, Zonnenberg BA, de Klerk JMH, et al. 186Re-Etidronate in breast cancer patients with metastatic bone pain. J Nucl Med. 1999;40:639–642.
- Papatheofanis FJ. Variation in oncologic opinion regarding management of metastatic bone pain with systemic radionuclide therapy. J Nucl Med. 1999;40:1420–1423.
- O’Donnell RT, DeNardo GL, Kukis DL. A clinical trial of radioimmunotherapy with 67Cu-2IT-BAT-Lym-1 for non-Hodgkin’s lymphoma. J Nucl Med. 1999;40:2014–2020.
