This publication is provided for historical reference only and the information may be out of date.
In 1997, 22,000 Minnesotans were diagnosed with cancer. 127 Breast, lung, prostate, head and neck, and colon cancer ccounted for 60 percent of these cancers. PET (positron emission tomography) is now being evaluated for its oncologic applications. Early studies show PET has potential value in viewing the region of the tumor, detecting, staging, grading, monitoring response to anticancer therapy, and differentiating recurrent or residual disease from post treatment changes.
PET is a three-dimensional imaging technique designed to measure the level of metabolic activity within the cell. The process of measuring begins when a radioisotope is injected into a vein or inhaled by the patient, carried to the site of interest, and undergoes radioactive decay. PETs' measurement of this decay is based upon the annihilation reaction between a positron and a tissue electron. Two photons created in the annihilation reaction, travel away from each other at a 180-degree angle, and are simultaneously sensed by detectors. This detection reveals their line of origin. A computer then constructs a three-dimensional image. The most commonly used radiotracer for PET oncologic imaging is fluorine-18-labeled fluorodeoxyglucose (18F-FDG).
This report was designed to address these major questions:
- Is PET an effective tool in diagnosing and/or monitoring patients with cancer?
- How does PET compare with alternative techniques used for diagnosing cancer and/or monitoring different cancers?
- What impact does PET have on clinical disease management and health outcomes?
- Is PET scanning cost-effective when used in cancer treatment?
- What effect will modified PET technologies have on cancer?
PET has primarily been used for the study of the neurological process. However, PET is also used for oncology applications. Data is readily available on the use of PET for evaluating or follow-up screening of cancer of brain, lung, and head and neck. PET shows promise for diagnosing and monitoring of certain cancers because it provides information unavailable by ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). PET is also used in determining if a tumor recurs after radiation treatment, radiation necrosis or if any other treatment-induced changes are present. 18F-FDG PET scanning has the ability to differentiate benign and malignant pulmonary lesions. Research is being done to assess the effectiveness of PET for breast and prostate cancer detection/management.
Evidence has yet to show a clear clinical benefit for PET over other imaging devices when used for certain cancers. Virtually all studies assessing PET for oncologic applications are hampered by small study samples, no comparison group, and inconsistent methodology. There is some question regarding the most appropriate method for interpreting PET images. Peer reviewed literature does not permit conclusive determinations regarding PET imaging for all oncologic applications despite a plethora of publications from academic institutions. There is also controversy about the lack of FDA approval for many of the radiopharmaceuticals used by PET, in addition to whether FDA approval is needed for cyclotron produced radiopharmaceuticals for clinical use.
Research on the use of PET for tumors of the brain, head and neck, and lung have been extensive and has shown that PET provides information unobtainable by other available techniques. It has not been proven whether this additional information translates into improved patient management or outcomes. PET clearly has the potential to provide useful information for diagnosing, staging, monitoring treatment progress, and determining prognosis for oncologic applications.
Further acceptance of PET will result if research finds new uses for the technology, equipment costs are lowered, camera imaging resolution continues to advance, software improves, more radioisotope distribution centers are available, new studies verify PET's validity and broader use of modified PET systems increases. The future may find PET being used independently and not complimentary to ultrasounds, CT, MRI, or biopsies.
Several controversies must also be resolved for widespread PET acceptance. Because PET is a measurement of metabolic function, a blood glucose standard should be developed so that PET image quality is not impaired. Food ingestion also has an effect on imaging quality, therefore, fasting guidelines should be initiated so that image reliability is maximized. Current FDA rules on the use of radioisotopes for image tracers, other than 18F-FDG, create an obstacle that should be resolved.
If the use and acceptance of PET technology increases, the detection and management of cancers may become more precise. Large scale acceptance of conventional PET sites in Minnesota will be limited because of equipment costs and required staffing. However, modified PET sites will become more common.
Brain Cancer. 18F-FDG PET in brain tumor imaging may be useful but its clinical application has yet to be established. 18F-FDG PET does not appear to be able to define tumor histology. 62 Additional studies are warranted regarding the value of 18F-FDG PET in detecting Central Nervous System (CNS) and nonCNS brain metastasis, differentiating malignant from nonmalignant lesions, detecting disease recurrence in subjects who have undergone intensive radiotherapy, and in pediatric brain tumors. Due to the paucity of data on radiotracers other then 18F-FDG, further study is required to validate the use of PET brain scanning with these radiotracers.
Head and Neck Cancer. Studies suggest that 18F-FDG PET is superior to MRI but comparable to CT in identifying the presence, absence or recurrence of cancer.
Pituitary Cancer, Thyroid Cancer, Urinary Cancer, Kidney Cancer. The paucity of data on the use of PET in pituitary tumors, thyroid tumors, urinary cancer, and kidney cancer prevents conclusions regarding its value at this time.
Lung Cancer. Numerous studies evaluating PET for lung cancer applications demonstrate that PET using 18F-FDG as a radiotracer is effective and may be more effective than other noninvasive techniques, particularly CT, in differentiating benign and malignant pulmonary lesions. Thus, 18F-FDG PET appears to be an effective means of diagnosing lung cancer, whether primary disease or secondary metastatic disease, and detecting disease recurrence following lung cancer therapy.
Breast Cancer. Preliminary data suggest that 18F-FDG PET can differentiate benign from malignant breast lesions, when used in breast cancer staging, and can determine the presence of axillary node involvement. While data are scarce regarding the utility of PET in monitoring the effects of breast cancer therapy, available data suggest that both 18F-FDG PET and 11C-MET PET may be useful for breast cancer and may show response earlier than conventional methods. Regardless, due to the small study samples and limited amount of available data, further study is required to confirm the efficacy of PET for breast cancer imaging.
Esophageal Cancer. 18F-FDG PET may be valuable in the staging of esophageal cancer. Evidence is limited by the small number of subjects in each study and the lack of additional trials.
Pancreatic Cancer. Studies indicate that PET may have a role in the imaging of pancreatic tumors, but further study is needed to verify this.
Renal Cancer. 18F-FDG PET shows promise for evaluating renal masses, further confirmation is required.
Ovarian Cancer. Preliminary data suggest a potential role for 18F-FDG PET in ovarian cancer, further study is required to confirm these findings.
Prostate Cancer. While 18F-FDG PET has been used in certain prostate cancer cases, it is possible that the use of radiotracers other than 18F-FDG may be of more value. However, there is insufficient data at this time to draw conclusions regarding the utility of PET in prostate cancer.
Testicular Cancer. With limited data no conclusions can be made at this time.
Malignant Melanoma. Additional study is needed to determine the role of PET in the imaging of malignant melanoma.
Colorectal Cancer. 18F-FDG PET may be a valuable tool for colorectal cancer in diagnosis, preoperative staging, and monitoring for recurrent disease or treatment response. However, further study is required to confirm these findings.
Neuroendocrine Gastrointestinal Cancer. PET proved superior to CT in detecting, delineating, and visualizing lesions. The study claimed that PET had a superior role, but further study is required to confirm this finding.
Malignant Lymphoma. Studies comparing 18F-FDG PET with alternative techniques found PET to be more accurate than CT,100,102 99mTc-MIBI SPECT, 37 and 111In-somatostatin scintigraphy, 13 in detecting untreated and treated lymphoma. Supportive evidence is limited to a few trials which are hampered by small study samples. No conclusions can be drawn at this time regarding the efficacy of PET for malignant lymphoma.
PET contributes to an improved diagnosis in carefully selected patients:
- For patients with possible lung cancer, PET can be useful in separating benign disease from malignant.
When used for separation of cancer limited to the lung, from lung cancer that has spread to adjacent tissue.
When used for brain tumor reevaluations where there is a question of mass effect due to necrotic tumor vs. recurrent tumor.
To determine PET's contribution in detecting, valuating, and follow-up of patients with cancer or possible cancer further study should be done. Better designed, multi-centered studies with larger patient samples, would facilitate determining the worth of using PET on some types of cancers.
PET accessibility should be limited to those patients where an essential clinical question has a reasonable likelihood of being answered.
In light of the equipment costs and high-level staffing requirements of PET sites, their numbers should remain limited. Whenever possible, the select patients for whom PET is appropriate should be assured access, with acknowledgment that travel and lodging costs will be incurred if the sites are limited. These institutions should also have the responsibility of defining clinical situations in which PET would have clinical value.
The American Cancer Society estimates that approximately 1.4 million new cases of cancer will be diagnosed in 1998. Approximately 560,000 cancer deaths will occur during the same year. In 1997, Minnesota had more than 22,000 new cases and 8,900 deaths due to cancer. 127 Sixty percent of all Minnesota cancers fall into the categories of brain, head and neck, lung, prostate, and breast. An estimated 5,600 prostate, 3,000 breast, 2,500 lung, and 1,800 head and neck cancers in Minnesotans will be reported during 1998.
The current technologies used in the diagnosis, management and treatment of cancer include; CT, MRI, ultrasound (US), biopsy, PET, and single photon emission computed tomography (SPECT). PET, the newest of these technologies, may be useful in the fight against cancer. PET has the ability to give the physician noninvasive information that is unavailable from other technologies or procedures.
The number of PET centers have increased over the last two years and with them so has the use of PET for oncology. There are 110 PET centers in the world. Seventy three of these exist in the US (up from 63 centers in 1997). Minnesota has two PET facilities, one is a conventional center and one has a modified PET system. Since 1989, the VA Hospital in Minneapolis has been using PET mainly as a research tool. However, due to the type and age of the PET device used by the Minneapolis VA, they are unable to perform a full body scan. The VA has done clinical scans on a referral basis but is limited to the types of cancers they consider. In 1998, Abbott Northwestern Hospital purchased a modified PET and has the capability to do full body scans.
A conventional PET imaging center consists of a PET scanner or gamma camera with computers for image reconstruction. Presently, these centers generally have a cyclotron for the production of radionuclides, a radiochemistry facility for incorporating the radionuclide into a biological compound. Image resolution and clarity is optimal when conventional PET centers are used.
In an effort to offset costs, modified PET systems have been developed. A modified PET center includes different cameras than the conventional PET center, no cyclotron, imports all radiopharmaceuticals, and does not use a scanner or scanner bed. Because modified PET images are not as clear as conventional PET images, new camera techniques are being developed to address the issue of image resolution, sensitivity, and count rate capabilities. Dual-headed coincidence camera systems or collimated camera systems are currently in use.
Another modified PET system recently developed and not yet approved for marketing by the Food and Drug Administration (FDA), is the positron emission mammography (PEM). It is a low cost, highly sensitive system which has been developed specifically for breast imaging. It is currently under evaluation in clinical trials.
How does PET work
PET utilizes tomography which is designed to show detailed images of structures in a selected plane of tissue by dimming the images of structures in all other planes. As classical x-ray imaging techniques designed to provide structural data have undergone refinement, so have techniques that are based upon the imaging of radiotracers (nuclear medicine or radionuclide studies) to characterize functional changes in physiology. The ability to acquire three-dimensional images with corresponding tomographic image reconstruction resulted in the emergence from scintigraphic imaging with rectilinear or planar gamma scanning to three-dimensional imaging with SPECT or PET. 120 Dionuclide imaging seeks to provide information about in vivo regional chemistry and can often detect abnormalities before structural changes have occurred. Although CT, MRI, and US imaging provide excellent structural information, these images alone are often inadequate when diagnosing or evaluating disease processes. Nuclear medicine studies are undertaken to provide data unavailable from other techniques.
Both SPECT and PET make use of gamma rays (photons) that are emitted during radioactive decay of unstable isotopes administered to the patient in the form of a radiotracer. Detection of these photons by special cameras and devices reveal their line of origin, which then allows construction of an image. (Figure 1) Because the images from SPECT and PET change with the decaying of radioisotopes and their movement through the body, they reflect dynamic activity within the body.
In general, radionuclide imaging involves assessment of regional blood flow, substrate metabolism, or information transfer via chemical "recognition sites" such as receptors and enzymes. 133 PET is a noninvasive technique that allows the localization of small (one to 3 cm3) anatomical structures. While planar gamma imaging, SPECT, and PET are all based upon the detection of radiotracers, PET is associated with improved sensitivity and spatial resolution, as well as an almost unlimited number of potential radiotracers. 120
PET uses positron emitting radionuclides incorporated into organic molecules such as water or glucose. Physiological function can be quantitatively assessed through the detection of small changes in the concentration of radioactively labeled tracers in tissues or organ systems. In addition, the short half-lives of PET radiotracers results in a minimal radiation dose to the patient and allow the performance of repeated blood flow measurements or multi parametric imaging to the same patient during the same scanning session. 35 A disadvantage to the short half-lives of PET radiotracers is the need for an on-site cyclotron and staff to produce these radiotracers or a distribution center in close proximity to the PET center. Both add to the overall cost of PET scanning.33,120
A conventional PET imaging center generally has a cyclotron facility for the production of radionuclides, a radiochemistry facility for incorporating the radionuclide into a biological compound, a PET scanner or gamma camera, and computers for image reconstruction. The PET scanner itself consists of a ring of scintillation crystals coupled to photomultiplier tubes. Once emitted, positrons travel only a short distance away from the parent atom before combining with an electron and annihilating to produce two high energy photons, which are emitted simultaneously at 180° to each other. When a crystal is struck by a photon of adequate energy, light is emitted. However, the detection of this photon is dependent upon the annihilation coincidence detection (ACD) system, which relies on pairs of crystal detectors linked by a coincidence circuit. Only when pairs of detectors register photons simultaneously, is the annihilation event recorded and processed. 35 The simultaneous detection of the photons reveals their line of origin. A computer then uses many such lines to construct a three-dimensional image of an organ system. 48 This image can provide an estimate of perfusion or metabolism. 117 By means of mathematical models and appropriate measurements, the results can be expressed in absolute units of meters, kilograms, and seconds or the percentage of the administered doses of a radiotracer accumulated by a specific tissue or organ. 133
Inaccuracies in PET imaging may all be minimized with appropriate shielding and electronics. During cardiac imaging, photons emitted from positron emitting radionuclides can also interact with thoracic tissue structures resulting in a loss, or attenuation, of detected photons. Too correct for attenuation, a blank scan consisting only of air in the camera's field of view after exposure to an external ring source of germanium-68 (68Ge), is obtained. This is then followed by the transmission scan of the patient. An attenuation correction factor can then be calculated for the degree of attenuation for each detector by determining the ratio of counts measured by each detector pair in the blank scan and the transmission scan. These data are used to correct for attenuation in the emission scans. 35
Description of the procedure
PET scanning is performed on an outpatient basis by qualified radiologists. The patient is positioned on the bed or table of the scanning device. PET imaging begins with the acquisition of a transmission scan using a gallium-filled plexiglass ring or a rotating positron emitting source. 72 A radiotracer, which may be intravenously injected or inhaled, depending upon the particular radiotracer, is then administered11,106 PET will then derive its signal from the decay of the radioactive substance. The distribution of the radiotracer is imaged and reconstructed along the distribution path. The particular radiotracer used is dependent upon the parameter to be measured, which may include blood flow or volume, level of hormones, enzymes or neuroreceptors, and metabolism of glucose, amino acids, nucleic acid, or oxygen. The number of radiotracers is virtually limitless. Those used for oncologic applications are reviewed in Table 1 of Appendix I. PET oncologic imaging is considered safe since it is associated with minimal radioactivity and there have been no reported complications.
While analysis of PET data initially relied on visual interpretation, the use of specific algorithms and equations (Table 2 of Appendix I) for semi-quantitative analysis involves an estimation of tracer uptake based on the ratio of tracer activity in regions of interest, to the dose of a tracer injected and the patient's body mass,36,39,67,76 or the ratios of tracer uptake in the tumor to that in the contra lateral tissue or muscle.118,123 Time activity curves, which involve plotting tracer activity over time during continuous dynamic imaging, may also be used. This involves a quantitative analysis using data from frequent blood sampling which determine the plasma concentration of the tracer at various times during the scan, determines the ratio of tissue tracer concentration to plasma tracer concentration, and then plots the ratio against time, taking into consideration the changing plasma concentrations during imaging. 67
Patient Selection Criteria
In patients with signs or symptoms suggestive of tumors, a variety of noninvasive tests, including CT, MRI, US, x-ray, planar nuclear scanning, and/or measurement of tumor marker levels, may be undertaken prior to a PET scan. When an abnormal mass is identified by one of these methods, an invasive procedure, such as biopsy or surgical removal procedure of the mass is generally performed to determine the nature and extent of the mass, including whether the mass is malignant or benign, whether it invades regional lymph nodes (stage), what types of cells are involved (histologic type), and how quickly the mass is growing (grade). Subsequent to treatment for malignant masses, any of the testing methods that initially identified the mass may be undertaken at regular intervals to ensure that potential regrowth of the mass is identified as early as possible. It is not clear when PET may be indicated in lieu of standard tests since available literature did not directly address this issue.
While PET with 18F-FDG may not be appropriate in subjects with diabetes, 95 it may be useful for patients as a:
- confirmatory test when clinical and radiographic findings are equivocal regarding the presence of a tumor.
- noninvasive method of determining the nature and the extent of a known tumor (malignancy/benignity, grade, and stage)
- method of distinguishing between residual or recurrent tumor and changes induced by treatment, such as necrosis and inflammation.
- early method of assessing the effects of therapy on the tumor so that appropriate changes in management may be instituted.
The clinical indications for oncologic PET use are still evolving and no firm consensus has been reached. Large, multi center, prospective studies are unavailable. A number of smaller studies have been published and evaluated by several groups, including the Society of Nuclear Medicine, the American College of Nuclear Physicians, and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Their endorsement of PET has been challenged by some investigators based on the potential bias of the expert committee and the absence of standards to evaluate the data that was reviewed. This criticism is similar to that directed against the early evaluations of MRI. 33
However, numerous studies have demonstrated that the rates of certain metabolic processes are increased in tumor tissue, as compared with normal tissue. These processes include protein synthesis, uptake of disaccharides, glycolysis, and transamination.74,91 When molecules such as sugars and amino acids are labeled with radiopharmaceuticals, their accumulation can be measured with PET. Due to the resolution limitations of some scanners and cameras, imaging of tumors less than 1 cm in diameter may be difficult with PET, but it still can add information unobtainable by other imaging modalities.68,87 There is evidence that PET is effective in providing physiologic and biochemical information that cannot be obtained though other means. While CT and MRI may be adequate in providing structural images, the acquisition of functional images demonstrating metabolic function is currently limited to nuclear scans such as PET and SPECT.
Because the actual clinical applications of PET are extremely varied and still evolving, review was limited to studies which involved the assessment of PET for the following application:
- Differentiating cancer from nonmalignant disease or normal tissue
- Tumor grading or staging
- Monitoring of response to therapy
- Assessment of patients for individualized therapy
- Identification of recurrent tumor
Summaries on each application can be found in Appendix III.
While PET is known to be effective in lung, head and neck, and brain, its efficacy for other oncologic applications has not been established due to the quality and paucity of evidence. Further study is required in order to determine how PET compares with alternative strategies for evaluating cancers. Although PET is known to be effective in limited situations, it has not been proven that PET improves patient management or prognosis in all cases.
Quality of Evidence
Evidence from studies pertaining to oncologic applications of PET primarily involves prospective studies where accurately calculated sensitivity, specificity, positive predictive value, and negative predictive value must be verified by a biopsy when PET is compared to other imaging devices. Furthermore, little research has been conducted to prove that PET can alter the treatment course or improve patient outcomes. The vast majority of available studies are hampered by small study populations, unblinded image analysis, unclear data on whether or not the study was blinded, and the existence of potential bias due to the high number of known malignancies included. It is difficult to compare studies on PET due to differences in patient groups, objectives or primary end points, and differences in PET protocols and devices. PET protocols and device differences include, durations of fasting prior to 18F-FDG PET, field of view and/or resolution of the device, the time to initiate emission scanning, (with respect to the administration of a tracer immediately or 30 to 60 minutes thereafter) duration of scanning time, use of dynamic or static imaging, the methods for image analysis, use of one or more scanning bed positions or whole body scanning, and different standards comparing increases in tracer uptake in scanning of any particular region (e.g., comparison to cerebellar uptake rate, salivary gland uptake rate, or uptake rate of other nearby normal tissue for head and neck scanning).
Another influencing factor is the timing of the posttherapy PET scan with respect to initiation of treatment. The use of different tracer substances also compounds the problem since some tracers have been found to be more effective than others. Therefore, the lack of efficacy of a particular tracer, for a particular purpose, does not necessarily mean that PET itself is ineffective or less effective than other technologies used for the same purpose.
Both visual and semiquantitative image analysis methods have been utilized in 18F-FDG PET oncologic imaging. There appears to be no consensus regarding the best approach for optimal image analysis. For detection of malignancy, some researchers assert that semiquantitative methods improve accuracy9,10 and that one type of semiquantitative method is superior to another. 67 Others report higher accuracy with visual analysis 36 and suggest that, although semiquantitative analysis may improve objectivity or confidence, it does not improve accuracy.131,135
PET images are now being employed for cancer staging, fusion or superimposition where CT was once used alone. Some researchers report improved precision in localizing lymph node tumor involvement with this technique, compared to PET alone,32,118,121 whereas others contend that this fusion technique is only needed in a few cases. 131 Regardless, the use of both CT and PET is time consuming and costly, and the use of semiquantitative analysis is time-consuming and reduces the scanner throughput, indirectly increasing PET costs. 119
There is speculation that automated fusion of PET emission scans (functional information) with PET transmission scans (anatomical orientation) produces a single image that can be analyzed visually with high accuracy for the detection and staging of tumors. This technique provides data similar to that achieved with the fusion of CT and PET scans. Regardless of which PET imaging method is used further study is needed to determine the optimal image analysis technique.
Cost of Pet
The acquisition costs of a conventional PET system range between $1 and $3 million, while the cost of modified PET systems (DHC gamma cameras) is approximately $750,000. There are additional costs for the radiopharmaceuticals. A center may install a cyclotron for the production of the radiopharmaceuticals at a cost of $2.8 million. The radiopharmaceuticals cost can be lessened by acquiring isotopes from a PET Net Pharmaceutical Service (established in 1996).
There are costs for personnel required to operate a PET center. Cost for a minimum staff has been estimated at between $700,000 and $1 million per year. Staff would include a Nuclear Pharmacist, Nuclear Engineer, Radiologist, Nursing Staff and a highly experienced Administrative/Office Manager. If the PET center is not associated with an already existing facility, the cost of the building and land would be dependent upon the community and location within the community.
Cost of Scan
Costs for the use of PET in psychiatry, range from $1,500 to $2,000, compared with $500 to $1,000 for SPECT. 109 While not oncologic imaging per se, it is likely that the cost of brain scanning for psychiatric purposes parallels that for oncologic. The cost for thoracic 18F-FDG PET, performed to evaluate lung cancer, averages $2,582, which compares favorably with the overall costs for transthoracic needle biopsies ($3,490), a transbronchial biopsy ($3,982), and an open lung biopsy ($15,982). 39 18F-FDG PET in the evaluation of breast cancer, including axillary involvement has an estimated cost of $1,150. Whereas the cost of a diagnostic breast biopsy, with or without the need for preoperative localization procedure, averages $3300 and $3625, respectively. The cost of axillary dissection runs approximately $8100.1,2
Although rubidium-82 (82Rb) use has not been discussed, the cost for its use in PET myocardial perfusion imaging and the use of thallium-201 (201Tl) in SPECT for myocardial perfusion imaging ranges from $1,100 to $2,800 and $1,100 to $1,400, respectively. 66 No information was available as to whether the use of different radiopharmaceuticals would alter the price of the PET scan however general cost comparisons can be made for alternative screening tools.
According to the Minnesota Department of Health and Human Services, a normal CT scan of the head, costs approximately $275 while a Contrast CT increases the cost to $312. An additional $75 cost for the analysis of the image and also professional fees which costs about the same amount as the scan and the analysis combined. A normal MRI cost $640 while a Contrast MRI costs approximately $700. There is an additional facility fee of $600 and charges for the radiologist as well as additional professional fees that are not included in the facility fee.
Cost Savings Analysis
Although no cost-effectiveness studies on PET could be found, studies utilizing PET have produce prospective cost analysis which shows that PET may prevent costly surgical or therapeutic procedures in cases where data indicate no advantage or poor likelihood of success with these interventions. The potential cost savings in such cases was demonstrated by Duhaylongsod who conducted a cost analysis to determine the economic impact of 18F-FDG PET on the diagnosis and management of benign and malignant focal pulmonary lesions. 39 The analysis was based on the assumptions that all lesions were indeterminate, by x-ray and CT, solitary pulmonary nodules < 3 cm in diameter; that the probability of malignancy was 50 percent; that SURs of 2.5 warranted thoracotomy and SURs of < 2.5 required only observation with periodic chest films; and that the thoracotomy complication rate was 0 percent and the hospital stay was five days. Additionally, the sensitivity and specificity of thoracic 18F-FDG PET were assumed to be 97 percent and 82 percent, respectively, as they were found to be in the group's assessment of 18F-FDG PET among 100 subjects with indeterminate focal pupulmonary abnormalities. Using these assumptions and the charges of $2,582 and $15,982 for 18F-FDG PET and thoracotomy, respectively, the use of thoracic 18F-FDG PET prior to thoracotomy would result in 41 fewer nontherapeutic operations and a 24.8 percent ($397,062) reduction in overall costs per every 100 patients. The authors emphasize that the savings with the PET strategy are likely underestimated since they do not account for potential preoperative complications, which may involve additional procedures, the longer hospital stay, or discomfort and lost wages incurred by the patient. Duhaylongsod and colleagues conclude that, by reducing the number of patients in whom benign lesions are found during thoracotomy, thereby increasing the diagnostic yield of thoracotomy, and by lowering expenses for hospitalization, 18F-FDG PET may significantly reduce health care costs. 39
Similar findings were demonstrated in a cost analysis by Adler who evaluated the utility of 18F-FDG PET as a replacement for axillary node dissection in patients with breast cancer.2 He found axillary involvement, the sensitivity and the negative predictive value of 18F-FDG PET were both 95 percent in this study involving 50 subjects with 52 axillary dissections. While specificity, positive predictive value, and accuracy were lower (66 percent, 63 percent, and 77 percent, respectively), the authors assert that the high sensitivity and negative predictive value of 18F-FDG PET are sufficient to warrant the use of 18F-FDG PET as a screening test to determine axillary involvement in breast cancer. Since the only false negative PET results in this series occurred in a case involving low quality scan due to excessive adipose tissue, axillary dissection may not be necessary in patients with negative 18F-FDG PET results. Patients with positive scans require axillary dissection to confirm the presence and number of nodes involved. Assuming the use of axillary dissection only in patients with positive PET scans (N=28 in the current study), dissection could have been avoided in 22 patients in the study with negative PET scans. The cost analysis was based on the assumptions that 18F-FDG PET was performed in all suspicious axillae (N=52), axillary dissection was avoided in patients with negative PET scans (N=22), and the charges of PET and dissection were $1150 and $8100 respectively. Based on these data, the net savings would have been approximately $2300 per patient or $120,000 overall, suggesting that 18F-FDG PET may be a cost-effective screening test to determine the need for axillary dissection.
Third party payment for PET procedures is being made by many of the leading insurance companies. The payment has to be prior approved in most cases and usually requires the center administrator to work closely with the individuals' insurance company. The benefit set of the insured policy and the attitude of the insurer to new technology have an effect on whether payment is made. Where patient access is limited and the patient has to go to the PET center for appropriate imaging, additional cost to the patient should be considered.
The PET industry has been seeking Medicare reimbursement from the Health Care Financing Administration (HCFA) since 1989. Approval was granted on Dec. 31, 1997 and became effective Jan. 1, 1998. The new policy will revise Sec. 50-36 of the Medical Coverage Manual. This agreement allows a certain amount of freedom in the marketing of radiopharmaceuticals but does put some limitations on the type of scans permitted for reimbursement. The policy will reimburse on an interim basis for 18F-FDG PET scans performed using dedicated freestanding PET scanners and coincident imaging gamma cameras for the "characterization of solitary pulmonary nodules, and for the initial staging of lung cancer." The policy is limited to scans using 18F-FDG and heart scans using rubidium-82. HFCA will pay $1,980 for a scan to diagnose lung cancer with an additional $75 payment to the physician who interprets the study.
BlueCross BlueShield of Minnesota reimburses for PET scans for localization of the epileptic seizure focus in patients meeting specific selection criteria. For oncology indications, the criteria must fall into one of the following categories: a) differentiation of recurrent brain tumors from radiation necrosis in patients with neoplasms of the brain, b) detection of lung cancer in patients who have a solitary pulmonary nodule and in whom chest x-ray and CT have failed to distinguish benign from malignant disease and when the results of the test could change medical management of the patient (e.g., avoidance of a biopsy), or c) staging of lung cancer. For all other diseases or conditions PET is considered investigative. They will look at each case on a case by case bases.
Issues of Controversy
Effects of Blood Glucose and Food Ingestion
Consideration of Blood Glucose Concentration
18F-FDG PET studies reported that blood glucose concentration must be taken into account when evaluating patients with 18F-FDG PET. 95 To assess the importance of hyperglycemia on tumor uptake of 18F-FDG and image quality, a study involving five patients with head and neck tumors who underwent 18F-FDG PET first in a fasting state, and then again two to five days later, after glucose loading with an oral glucose solution (Glucodyne). Findings demonstrated that the standard uptake value (SUVs) of 18F-FDG in tumors ranged from 4.1 to 10.9 in the fasting state but decreased significantly (2.2 to 5.9), after glucose loading in some patients. Additionally, after glucose loading, 18F-FDG uptake decreased in the cerebellum but increased in the muscles of the tongue and neck, resulting in a blurring of tumor margins and in less clear localization of tumors. 18F-FDG PET studies may be particularly unreliable in diabetic patients. According to the findings, this decrease in 18F-FDG uptake in hyperglycemia states has been demonstrated in vitro studies of human breast cancer cells, mammary tumors in rats, and in human lung tumors. It was concluded that, since hyperglycemia may decrease tumor uptake of 18F-FDG and impair PET image quality, patients undergoing 18F-FDG PET should be in a fasting state and that blood glucose concentrations should be considered. 95
It should be noted that, in the vast majority of studies reviewed involving 18F-FDG PET, patients were reported to be in a state of fasting for > four hours prior to imaging. In some studies, imaging was begun immediately upon 18F-FDG administration with frequent blood sampling to determine blood glucose concentration. In other studies imaging was begun 20 to 60 minutes after 18F-FDG administration, with or without blood sampling. Scheidhauer reported that, since glucose metabolism achieves a steady-state phase approximately 45 to 60 minutes after 18F-FDG injection, blood monitoring during this interval is not necessary. 119 However, since the deduced ability of lesions depends largely on tracer concentration, 36 different timing of emission scans may provide different results, with the possible exception of results obtained during the steady-state phase. For studies utilizing blood sampling, reported results are generally those derived from periods of maximal tracer concentration. For studies not employing blood sampling or steady-state-phase imaging, results may be less accurate. The duration of fasting prior to 18F-FDG PET may also influence study results. For example, although the heart primarily metabolizes fatty acids in the fasting state, myocardial 18F-FDG uptake may occur in 60 percent of the subjects even after fasting for 16 hours. 125
Effect of Food Ingestion on Uptake of 11C-MET
Data showed that shortly before imaging with carbon-11-labeled Methionine (11C-MET) PET, food ingestion may decrease tumor uptake of the tracer, influencing the accuracy of the PET results. 93 This was demonstrated in a study involving five subjects with untreated primary head and neck cancers. These individuals underwent 11C-MET PET in a fasting state and again six to seven days later after ingestion of a liquid meal. While tumors were well-delineated in both the fasting and postmeal states, SUVs at all tumor sites decreased by an average of 15 percent, as compared with those observed in the fasting state (range, 3.3 to 10.0 versus 3.7 to 11.4, respectively). Although no substantial change was observed in tumor 11C-MET influx constants (k1 values), both SUVs and k1 values decreased by 15% to 25% in bone marrow after the meal. Moreover, 11C-MET uptake increased by 20% to 30% in the parotid glands but changed only slightly in the submandibular glands after the meal. Since PET image quality was not impaired in the study, the authors assert that, while fasting may not be necessary prior to 11C-MET PET, more reliable results can be obtained in the fasting state.
The current FDA position on all compounds which carry a radioisotope and are used for PET imaging is that they require FDA approval. To date only one, Fluorine-18-labeled fluorodeoxyglucose (FDG), has been approved by the FDA all others are considered investigational. With the passage of the 1997 FDA Modernization Act, manufacturers of the radiopharmaceuticals have a four year or more window of time before FDA approval will be required.
Researchers contend that history of radioisotope compounds and the short half life of the isotopes make the need for approval of each special compound by the FDA unnecessary. They contend, for example, that water or glucose which has an attached short life isotope, is not significantly altered from the original substance.
Future of PET
Further study is required to define the role of PET in the evaluation of cancer and to determine its efficacy with respect to other noninvasive techniques. Increasing efforts to improve PET image resolution and image analysis will help PET's ability to provide reliable data. Additional research confirming the utility of PET will likely lead to increased use of this modality in the clinical setting and may result in a change in the FDA stance on radiopharmaceuticals or in the HCFA coverage policy.
Factors which are part of the PET evaluation process are cost and image clarity. An attractive feature of the modified PET system is it's lower overall cost, portability, and minimal loss in image quality.
Data shows that costs increase as image quality improves. Conventional PET is the most expensive but gives the best images. As for quality images, the dual-headed coincidence system is next, followed by the collimated systems.
The following conclusions are based on the clinical trials found in Appendix III.
PET contributes to an improved diagnosis in carefully selected patients:
- For patients with possible lung cancer, PET can be useful in separating benign disease from malignant.
- When used for separation of cancer limited to the lung, from lung cancer that has spread to adjacent tissue.
- When used for brain tumor reevaluations where there is a question of mass effect due to necrotic tumor verses recurrent tumor.
To determine PET's contribution in detecting, valuating, and follow-up of patients with cancer or possible cancer further study should be done. Better designed, multi centered studies with larger patient samples, would facilitate determining the worth of using PET on some types of cancers.
PET accessibility should be limited to those patients where an essential clinical question has a reasonable likelihood of being answered.
In light of the equipment costs and high-level staffing requirements of PET sites, their numbers should remain limited. Whenever possible, the select patients for whom PET is appropriate should be assured access, with acknowledgment that travel and lodging costs will be incurred if the sites are limited. These institutions should also have the responsibility of defining clinical situations in which PET would have clinical value.
Appendix III: Clinical Studies Summaries
Brain/Central Nervous System Tumors
Brain tumors, along with spinal cord tumors, are included in the larger category of central nervous system (CNS) tumors that include benign and malignant tumors as well as primary tumors and metastasis secondary to tumors originating in sites other than the brain or spinal cord. The majority of brain and spinal cord tumors are primary gliomas, which are sub classified into astrocytomas (the most common), oligodendro gliomas, ependymoma's, and ganglioglioma's. Though less common, craniopharyngioma's and choroid plexus papilloma's are also primary CNS tumors. While primary CNS tumors are basically malignant, some are considered benign according to their rate of growth and response to therapy. Other characteristics, such as cellular atypism, the incidence of endothelial hyperplasia, and the presence of mitotic figures or necrotic areas, are also considered in determining the degree of malignancy. Surgery allows a definite pathologic diagnosis as well as a reduction in the tumor burden. In areas not amenable to direct surgery, stereotactic biopsy may be used as an alternative. Once the diagnosis is established and the maximal surgical intervention is achieved, other therapeutic strategies are indicated. However, posttherapeutic recurrence of disease is common. 64
The utility of 18F-FDG PET in CNS tumors, particularly of the brain, has been studied extensively. In technology assessments, literature reviews, and introductory or commentary portions of individual studies, numerous authors have cited a wide variety of studies that have found 18F-FDG PET to be useful in primary brain tumors for the following applications. (Due to the vast number of cited studies, the citing sources, rather than the cited studies, are referenced after each application.)
- Defining tumor histology (type of cells involved). 62
- Identifying patients for whom surgery would be inappropriate. 61
The majority of the studies cited by these authors were conducted in the 1980's and have not been included herein. These studies primarily involved the use of 18F-FDG PET in the imaging of primary brain tumors in adults.63,65 Data from more recent studies are provided in Table 1 of Appendix II, with a summation of major points following the table. Studies were included in this and all subsequent tables based on the following inclusion criteria: English language peer-reviewed article, primary data collection (i.e., not a review article), human subjects, and sample sizes of 15 or greater. No randomized controlled trials were published and few studies with any comparison group were available for evaluation. Thus, the majority of published studies were small, retrospective case series.
Analysis of PET images in these studies involved a variety of semi-quantitative techniques, including calculation of tumor-to-gray-matter ratios (TGMRs), tumor-to-white-matter-ratios (TWMRs), tumor-to-normal-tissue ratios (TNTRs), differential absorption rates (DARs), differential uptake ratios (DURs), normalized uptake values (NUs), time activity curves (TACs), Patlak values, and kinetic models of tracer uptake rates, such as tracer influx from blood to tissue (k1), tracer efflux from tissue to blood k2), and tracer trapping (k3). 115
While 18F-FDG PET may distinguish between high-grade and low-grade primary and residual tumors, it may be incapable of distinguishing between different grades of high-grade tumors. Griffeth observed heterogenous FDG accumulation in CNS and nonCNS brain metastasises, which occurred in lesions of the same histological type, even in the same. 5 In contrast to findings regarding primary and residual brain tumors, however, Griffeth and colleagues found that the sensitivity of 18F-FDG PET was only fair (68 percent) for the detection of brain metastasises due to their small size or location in gray matter with similar glucose uptake.
Findings from available studies regarding the prognostic value of PET were inconsistent. Janus reported that, although decreased FDG uptake suggested prolonged survival, increased uptake did not predict survival. 75 Moreover, Hoffman found no correlation between FDG uptake and prognosis. 62 They noted that the lack of correlation was likely due to heterogenous tumor types and previous therapy, as well as the small study sample. Conversely, Mineura found that PET determination of cerebral circulation (with 15C-O2, 15C-O, and 15O2) and metabolism (with FDG) is useful for predicting the survival in patients with glioma and can provide data for the diagnosis and prognosis of glioma. 98
Two available studies involving the combined use of 18F-FDG PET and CT for guiding stereo tactic brain biopsy demonstrated that this technique may improve the selection of targets for biopsy samples.89,90. The latter study, in which at least two targets were selected for each subject, revealed that 18F-FDG PET shows the extent of tumor infiltration better than CT. Findings from this study suggest that 18F-FDG PET guidance may reduce the number of biopsy samples taken without impairing diagnostic yield. In fact, PET guidance may increase the diagnostic yield by reducing sampling error, which is a frequent problem with biopsies of this type. 90
Although most subjects in the studies reviewed underwent CT or MRI, few direct comparisons between these modalities and PET were undertaken. Roelcke reported that 26 (87 percent), 28 (93 percent), and 29 (97 percent) of 30 tumors were visualized with MRI/CT, 82Rb PET, and 11C-MET PET, respectively, suggesting that PET is slightly superior to MRI and CT in etecting brain tumors. 115 However, the objective of the study was not to compare these techniques, and it is not clear how many of the subjects underwent MRI or CT. A direct comparison of gadolinium-enhanced MRI (Gd-MRI) and 18F-FDG PET also demonstrated improved detection of brain tumors with 18F-FDG PET than with Gd-MRI (97 percent and 81 percent, respectively, of 32 active brain neoplasms). 34 Two additional studies revealed improved detection and delineation of the extent of brain tumors with 11C-MET PET, 105 or 18F-FDG PET, 60 as compared with CT.
Head and Neck Tumors
Lesions classified as head and neck cancers include malignancies of the oral cavity, oropharynx, larynx, hypopharynx, cervical esophagus, nasopharynx, nasal cavity, paranasal sinuses, salivary glands, and the neck itself, although malignancies of the neck are predominantly (75%) metastasises from other primary sites. 63 Since the American Cancer Society classifies thyroid cancer and pituitary cancer separately, rather than including them with head and neck cancers. 63 PET assessment of these cancers is distinguished herein from PET assessment of head and neck lesions. While laryngoscope, MRI, and CT have led to improved management of patients with head and neck lesions, several areas in tumor evaluation remain problematic. These include an unacceptable rate of false-positive findings in patients with squamous cell neoplasms, difficulty in identifying the primary malignancy in some patients, difficulty in staging disease due to reliance on lymph node size as criteria for determining malignancy, and difficulty in detecting residual or new tumors in areas of dense scarring and necrosis induced by cancer therapy.12,112 Although biopsies may confirm or exclude malignancy, they may miss the focus of active tumor, if present, and may cause additional disruption of treated tissue. 31 Several studies have assessed the utility of PET in evaluating head and neck lesions. Findings from these studies are provided in Table 2 of Appendix II Radiotracers used for PET imaging of head and neck tumors include 18F-FDG and 11C-MET. Research has shown that the metabolic activity of the cerebellum is high, as compared with surrounding normal tissue, but relatively stable. Since imaging of head and neck tumors inevitably includes the cerebellum, the cerebellar metabolic rate provides a standard by which to compare the metabolic activity of head and neck lesions. 137
Findings from available studies suggest that 18F-FDG PET may be an effective modality for detecting both primary tumors and lymph node metastasis of the head and neck. For detecting primary head and neck tumors, the sensitivity of 18F-FDG PET ranged from 89% to 100%.12,31,51,111,112,137 For identifying lymph node metastasis, the sensitivity of 18F-FDG PET ranged from 92% to 100% in most studies reporting this separately,31,50,112 but was only 71 percent in one study. 12 Greven noted that 18F-FDG PET detected nodal metastasis not detected by other imaging techniques (CT and MRI). 51 Some studies reported on the sensitivity of 18F-FDG PET for detecting both primary and metastatic lesions combined, which ranged from 90% to 100%.18,94,113,114 Only two studies reported the specificity of 18F-FDG PET, which was 100 percent for detecting primary tumors, 137 and 98 percent in identifying lymph node metastasis. 12 The accuracy of 18F-FDG PET for correctly identifying the presence or absence of lymph node metastasis was reportedly 82 percent in the only study that reported this. 97 While this value seems low considering the high values reported by others for sensitivity and specificity, the accuracy of 18F-FDG PET was confirmed by neck dissection in 45 of the 49 subjects in that study.
11C-MET PET also appears to be an effective method for detecting and staging head and neck tumors, although studies assessing PET with 11C-MET are scarce. For detecting both primary tumors and lymph node metastasis combined, Lindholm reported a sensitivity of 90 percent 94, and Leskinen-Kallio reported a sensitivity of 91.3 percent, 87 when not counting lesions that required clarification of anatomic location, and 97.8 percent, when counting lesions that required clarification of anatomic location. For detecting lymph node metastasis alone, 11C-MET PET had a sensitivity of 100 percent and identified unsuspected metastasis. 87 There was no correlation between the uptake of 11C-MET and tumor grade. 87
18F-FDG PET may also be an effective method for monitoring the effects of therapy for head and neck tumors. While data are scarce regarding the use of 11C-MET PET for monitoring response to therapy, data from one study utilizing 11C-MET PET before and after completion of radiotherapy demonstrated a good correlation between PET findings and histologic or clinical findings. 92 In this study, high postirradiation SUVs (> 3.1) were indicative of persistent disease. In several studies, 18F-FDG PET was highly accurate in distinguishing disease recurrence from radiation necrosis or other treatment-induced changes.18,31,51,85,94,137 Lindholm also found 11C-MET PET accurate in doing so. 94 Nevertheless, findings from two studies suggested that the timing of PET scans, with respect to initiation of treatment, may influence the efficacy of 18F-FDG PET in distinguishing recurrence from radiation-induced changes.18,51
Several studies compared 18F-FDG PET with CT and/or MRI in the imaging of head and neck tumors. The values reported for sensitivity, specificity, and accuracy of each modality are listed in Table 3 of Appendix II.
Three studies compared 18F-FDG PET with CT in head and neck cancers. McGuirt found that 18F-FDG PET and CT were associated with similar accuracy in identifying the presence or absence of lymph node metastasis of head and neck cancer (82 percent versus 84 percent, respectively) and concluded that the high expense and limited resolution of PET preclude its routine clinical use for head and neck cancers. 97 The second study also assessed MRI. 12 While these authors found similar sensitivity for 18F-FDG PET, CT, and MRI in detecting primary tumors (100 percent, 94 percent, and 94 percent, respectively) and similar specificity for excluding lymph node metastasis (98 percent for all three modalities), the sensitivity of 18F-FDG PET for detecting lymph node metastasis was superior to that of CT and MRI (71 percent, 58 percent, and 58 percent, respectively). Bailet and colleagues noted that the inability of PET to delineate subtle anatomical findings, such as bony erosion and soft-tissue infiltration, make CT or MRI more useful in certain situations, including vascular invasion or intra cranial extension of tumor or in the planning of radiotherapy ports. The third study revealed that the sensitivity of 18F-FDG PET for detecting recurrence after radiation therapy varied according to the way images were analyzed. 85 Sensitivity values were 75 percent and 86 percent for static (SUV) analysis and dynamic (rMRg) analysis, respectively, when using maximum FDG uptake in benign lesions as a cutoff threshold, and were 88 percent and 94 percent for visual analysis if considering only clearly malignant lesions or clearly malignant and suspicious lesions, respectively. While specificity was not provided for static and dynamic quantitative analyses, it was greater in visual analysis if only clearly malignant lesions were considered (86 percent and 43 percent, respectively). Sensitivity and specificity of CT in this study were 92 percent and 50 percent, respectively. The authors concluded that CT and 18F-FDG PET should play complementary, rather than alternative, roles in detecting disease recurrence. An additional study compared 18F-FDG PET with MRI and CT but combined the findings of MRI and CT since subjects underwent only one of these anatomic procedures. 8 Sensitivity and specificity were, respectively, 88 percent and 100 percent for PET versus 25 percent and 75 percent for anatomic studies when considering only lesions thought to be definite recurrence, and 88 percent and 75 percent for PET versus 75 percent and 50 percent for anatomic studies when considering lesions thought to be definite recurrence and those thought to be probable recurrence. These authors assert that, if no lesion is identified with physical examination, PET should precede MRI and CT, which should only be undertaken if PET results are positive.
In contrast to the findings of Bailet regarding MR,12 Rege and Chaiken found that 18F-FDG PET was more sensitive than MRI in detecting primary tumors (91 percent to 100 percent versus 68 percent to 78 percent, respectively),31,112 but had a sensitivity similar to that of MRI in detecting lymph node metastasis (94 percent to 100 percent versus 91 percent to 100 percent, respectively), and Rege found that 18F-FDG PET was more sensitive than MRI in detecting both primary tumors and nodal metastasis combined (100 percent versus 82 percent, respectively). With respect to accurately identifying the presence or absence of recurrence, Rege found that 18F-FDG PET was superior to MRI (90 percent versus 60 percent, respectively, for sensitivity; 100 percent versus 57 percent, respectively, for specificity). 112 Additional findings (not included in Table 3) from the study by Chaiken 31 also showed that 18F-FDG PET was superior to MRI for detecting or excluding recurrence. Although statistical analysis was not provided, 18F-FDG PET correctly identified the presence or absence of recurrence in 14 (93 percent) of 15 subjects, whereas MRI was negative or inconclusive in seven (47 percent) of these subjects.
The most common lesions occurring in the sellar and parasellar regions of the head and neck are pituitary adenomas and meningiomas, which may be difficult to differentiate with conventional techniques in cases involving nonhormonal active (nonsecreting) pituitary adenomas. 17 To determine the utility of PET in differentiating between these two types of lesions, Bergström conducted a prospective study at the Uppsala University PET Centre (Uppsala, Sweden) involving 12 subjects with nonsecreting pituitary adenomas or meningiomas confirmed by histological and immunohistochemical studies. 17 All subjects underwent PET with two radiotracers, 11C-MET and carbon-11-labeled L-deprenyl (11C-L-DEP). Image interpretation involved calculation of SUVs, TACs, and Patlak values. The uptake of 11C-MET was higher than that in normal brain tissue in all tumors. However, the uptake pattern of 11C-L-DEP differed between adenomas and meningiomas. In adenomas, 11C-L-DEP uptake was high and rapid initially but steadied at a level that was higher than or equal to that in normal brain tissue; whereas, in meningiomas, 11C-L-DEP uptake was high initially but decreased to a level lower than that in normal brain tissue. There was a clear separation of adenomas and meningiomas based on average 11C-L-DEP uptake ratios of 1.7 and 0.5, respectively. The authors concluded that 11C-L-DEP PET can be used to differentiate between benign nonsecreting pituitary adenomas and malignant parasellar meningiomas. Despite this, the study is hampered by a small study sample, and it is not clear if image analysis was blinded.
The exclusion or confirmation of malignancy is the most important factor in determining appropriate therapy for nodular thyroid disease. While thyroid function tests, thyroid scanning, and ultrasonography may be helpful in determining the status of lesions, fine-needle aspiration biopsy (FNAB) is associated with the highest sensitivity and specificity for this purpose. Despite this, the accuracy of FNAB is dependent upon the skill and experience of the operator and cytopathologist and there is a risk of sampling error for small nodules. 22 Widely used techniques for detecting local disease recurrence or lymph node and distant metastasis include serum thyroglobulin (Tg) measurement and whole-body scintigraphy with thallium, hexakis (2-methoxyisobutyl-isonitrile) technetium-99m (99mTc-MIBI or iodine-131 (131I) as the radiotracer. 131I is also useful as a noninvasive treatment option in thyroid tumors and metastasis that are 131I-positive. 55
To determine whether PET could differentiate between malignant and benign thyroid lesions, Bloom conducted a prospective study at the University Hospitals of Cleveland (Cleveland, OH) that involved 19 subjects with a single thyroid nodule (n=12) or multinodular goiter (n=7). 22 Subjects underwent whole-body PET using radiolabeled water (H 2 15O) and radiolabeled carbon monoxide (C15O) to determine blood flow and volume, respectively, as a method for localizing the carotid artery and internal jugular vein, and using 18F-FDG PET to determine lesion metabolism. Blinded visual analysis and DUR analysis were used to interpret PET scans. Lesion status was confirmed in all subjects by post-PET thyroidectomy and histopathology. Of 12 solitary lesions, four were malignant papillary or follicular lesions and eight were benign follicular adenomas. The dominant nodules in all nine subjects with multinodal goiters were benign. All of the benign lesions showed either increased FDG uptake or increased blood flow (H 2 15O) with normal or equivocally increased FDG uptake. However, benign lesions could be differentiated from malignant lesions due to the difference in FDG DUR in each type (< 7.6 versus > 8.5, respectively). Three of the four malignant lesions were easily identified as malignant by 18F-FDG PET but the fourth, a 1.1-cm lesion, had only mildly increased tracer uptake and was more difficult to visualize. An 8-mm malignant lesion in a patient with papillary cancer and a 1-mm malignant lesion in a patient with a multinodal goiter were not visualized by PET. The authors concluded that 18F-FDG PET appears promising in the evaluation of hyroid nodules but added that further study is needed to compare the technique with other modalities. The study is limited by a small study sample and the lack of statistical analysis.
To determine the utility of 18F-FDG PET as a method of follow-up for thyroid cancer, Grünwald conducted a prospective study at the University of Bonn (Bonn, Germany), which included 33 subjects with differentiated papillary (N=26) or follicular (N=7) thyroid cancer who underwent treatment with thyroidectomy and 131I. 55 Whole-body 18F-FDG PET was performed after two or three courses of 131I and was compared with whole-body 131I scintigraphy (N=25), whole-body 99mTc-MIBI scintigraphy (N=20), and serum Tg (N=26). 18F-FDG PET was normal in 18 subjects and revealed local recurrence in one case, lymph node metastasis in 10 cases (one false positive due to sarcoidosis), and distant metastasis in three cases. While results from 18F-FDG PET were concordant with those from the other techniques in several cases, there were numerous discrepancies. Distant metastasis revealed with 131I, as well as with elevated Tg levels, in three patients were not visualized by PET. Lymph node metastasis revealed with PET in four patients were not detected by 131I and were found positive in two cases and negative in two cases by 99mTc-MIBI. Among four patients with elevated Tg levels, PET results were negative in all four and 131I results were positive in three. In contrast, among four patients with normal Tg levels, PET results were positive in four (one false positive sarcoidosis) and 131I results were positive in three (not done in one). Moreover, even in cases of concordant findings between PET and 131I, exact lesion localization differed between the two techniques. Analyses of individual cases demonstrated no difference between papillary and follicular tumors with respect to the sensitivity of 18F-FDG PET; a greater sensitivity for 131I, as compared with 18F-FDG PET, in highly differentiated tumors; and a greater sensitivity for 18F-FDG PET, as compared with 131I, in poorly differentiated tumors. Noting that the routine use of 18F-FDG PET as follow-up for thyroid cancer is not recommended, the authors assert that 18F-FDG PET may be useful in cases involving elevated Tg levels and negative 131I scintigraphy, those involving low Tg levels but unclear thoracic uptake of 131I, those involving suspected recurrence or cervical lymph node metastasis and negative 99mTc-MIBI scintigraphy, and those involving 131I-detected or otherwise proven metastasis, particularly in poorly differentiated tumors. The study is limited by a small study sample and the lack of statistical analysis, control, and randomization.
Approximately 130,000 solitary pulmonary nodules are discovered annually in the United States. While plain chest x-ray and CT are commonly used to determine whether such nodules are benign or malignant, the only criteria for defining these nodules as benign are the presence of central, concentric, or stippled calcification on radiographic studies and no change in the nodule for over two years. 36 With these criteria, approximately 63 percent of benign lung masses are correctly identified by CT 67 ; however, a considerable number of nodules remain radiographically indeterminate. 36 Although histological confirmation may be obtained through invasive techniques, including thoracotomy, bronchoscopy, and transthoracic needle aspiration biopsy, an improved noninvasive means of differentiating benign and malignant masses could improve evaluation and treatment of pulmonary nodules. 36 Additionally, response to lung cancer treatment is typically evaluated with x-ray or CT, which suggest response by a decrease in tumor volume. However, residual mass after treatment reflects the balance between cell loss and growth fraction and the balance between necrosis absorption and replacement of fibrosis; therefore, it does not necessarily indicate residual disease. Monitoring metabolic tumor activity may help to overcome this problem. 83 Recently, much interest has been focused on the ability of metabolic and biochemical imaging with SPECT or PET to characterize lung masses. 67
According to Hübner, and Itoh who assessed SPECT for this purpose and reported a sensitivity, specificity, and accuracy of 91 percent, 85 percent, and 89 percent, respectively, using thallium-201 (201Tl) as a radiotracer; 54 percent, 100 percent, and 66 percent, respectively, using gallium-67 as a radiotracer; and a sensitivity of 62 percent and accuracy of 57 percent using technetium-99m-labeled hexamethyl- propyleneamine-oxime (HMPAO) as a radiotracer.67,73 These findings suggest that SPECT may have limited potential for distinguishing between benign and malignant lesions, with the possible exception of 201Tl SPECT. Thus, although SPECT is more readily available, more research has been directed toward PET. Data from available studies assessing the use of PET for lung cancer applications are provided in Table 4 of Appendix II. For characterizing lung masses with PET, 18F-FDG is almost universally used as the radiotracer. However, 11C-MET has been used to evaluate response to treatment of lung cancer. 83 Image interpretation is primarily visual (qualitative) but may also involve semi-quantitative analysis using calibrated estimates of tracer activity (SUV, SUR, DUR, TNTR, or TMR), time activity curves (TACs), and/or Patlak analysis.36,67,123 Moreover, depending upon the purpose of the PET study, PET may involve regional scanning (thorax alone or with abdominal and/or mediastinal scans) or whole-body scanning. Whole-body scans have been used primarily to increase the field of view to include lymph nodes and sites distant from the lungs for assessing potential nodal tumor involvement and distant metastasis of lung cancer.
Findings from several studies have demonstrated that thoracic 18F-FDG PET is highly accurate in distinguishing benign from malignant pulmonary lesions.32,36,39,44,67,68,123,135 Among these studies, the overall accuracy of 18F-FDG PET for this purpose ranged from 82 percent to 100 percent, with sensitivities ranging from 83 percent to 100 percent and specificities ranging from 60 percent to 100 percent, with the exception of one study, which reported a specificity of only 33 percent. 32 In this same study, the negative predictive value was also only 33 percent. Otherwise, positive and negative predictive values ranged from 62.5 percent to 94 percent and 71 percent to 100 percent, respectively. In two studies that directly compared thoracic 18F-FDG PET and thoracic CT, PET was found superior to CT.44,135 Wahl reported a sensitivity, specificity, and accuracy of 100 percent, 0 percent, and 83 percent, respectively, for CT and 100 percent, 100 percent, and 100 percent, respectively, for PET using a mean SUV of 6.82 for malignant lesions and 1.04 for benign lesions 137 ; whereas Frank reported comparable values of 67 percent, 85 percent, and 82 percent, respectively, for CT and 100 percent, 89.3 percent, and 92.5 percent, respectively, for PET using three as the DUR cutoff for defining malignancy. 44
Similarly, whole-body 18F-FDG PET has been found useful for differentiating benign and malignant pulmonary lesions. Moreover, this scanning method allows detection of distant metastasis. False-positive PET results with thoracic scanning primarily occurred in areas of active infectious and inflammatory processes, which tend to accumulate FDG. False-negative PET results in the studies reviewed tended to occur with malignancies of small size. PET devices with improved resolution may minimize false-negative results.
With respect to tracer concentration, wide variation in FDG uptake has been observed in normal tissue in different thoracic regions and in different thoracic malignancies. In a study involving 31 subjects with lung lesions or with known or suspected primary breast cancer but no lung lesions, Miyauchi and ahl reported that mean SUVs in normal lung tissue were significantly higher in posterior portions than in anterior and mid portions (0.663 to 0.804, 0.537 to 0.595, and 0.515 to 0.679, respectively) and significantly higher in the lower lung field than in the upper and middle lung fields (0.712, 0.583, and 0.584, respectively). 99 These authors note that high background FDG activity in the posterior and lower lung may be due to recovery coefficient factors, increased blood flow and FDG delivery, and/or scatter from the heart and liver. In another study involving 54 subjects with unknown primary lung masses, previous history of lung cancer, or extra pulmonary cancer with a secondary chest mass, Hübner also reported wide variability of FDG uptake in normal thoracic tissue, with mean SUVs ranging from 0.74 in lung parenchyma to 7.49 in normal myocardium.67 Additionally, this group found wide variability of FDG uptake in malignant areas, with mean SUVs ranging from 2.62 in primary lung lymphomas to 8.07 in lung metastasis. Therefore, differences in FDG uptake, with respect to region and type of malignancy, should be considered when interpreting PET images. This practice should also result in increased accuracy for thoracic and whole-body 18F-FDG PET.
In addition to accurately differentiating benign and malignant pulmonary lesions, both regional and whole-body 18F-FDG PET appear to be effective means of staging lung cancer. Findings from five studies comparing the ability of regional 18F-FDG PET with that of CT for lung-cancer staging demonstrated that PET was superior to CT for defining the extent of tumor invasion into regional lymph nodes.29,32,118,121,135 The sensitivity, specificity, accuracy, positive predictive values, and negative predictive values of regional 18F-FDG PET and CT for identifying involvement of mediastinal nodes (stage N2 or N3) are listed in Table 5 of Appendix II. These data suggest that 18F-FDG PET may be effective in monitoring the effects of therapy and distinguishing between tumor recurrence and radiation-induced necrosis or other posttreatment tumor changes. Despite this, no studies directly assessed the utility of 18F-FDG PET in monitoring therapy, and only two studies assessed the ability of 18F-FDG PET to detect tumor recurrence in radiation-treated subjects.44,60 In the study by Frank, 18F-FDG PET, with a sensitivity, specificity, and accuracy of 100 percent, 89.3 percent, and 92.5 percent, respectively, was found more effective than CT, with comparable values of 67 percent, 85 percent, and 82 percent, respectively, in detecting malignancy. 44 The authors concluded that 18F-FDG PET appears to be effective in detecting recurrent lung cancer in radiation-treated patients and that the detection of tumor recurrence earlier than the occurrence of clinical signs and symptoms may prolong survival in some patients. In contrast, findings from the study by Hebert showed no consistent correlation of post-therapy PET findings with clinical follow-up in subjects that showed partial or no response to radiotherapy. 60 These authors concluded that the value of PET for distinguishing recurrence from radiation necrosis needs further study.
Findings from several other studies demonstrate that 18F-FDG PET is an effective means for staging lung cancer. While both regional and whole-body FDG PET were shown to be effective in detecting nodal disease involvement and locoregional metastasis, whole-body 18F-FDG PET has the advantage of detecting metastasis beyond the thoracic area. All these studies involved comparison of 18F-FDG PET with CT and found 18F-FDG PET to be superior to CT. However, groups assessing regional PET generally concurred that the anatomical data provided by CT were necessary to help localize disease or provide a more confident diagnosis due to difficulty in accurately localizing nodal disease in cases involving concomitant malignancies in adjacent areas. These groups concluded that FDG PET and CT should be used together for lung cancer staging. This was not the case with whole-body PET. It has not yet been proven that the results from these clinical case series can be extrapolated to patient populations; the clinical efficacy of PET has not yet been shown.
Currently, noninvasive imaging techniques for evaluating breast masses typically include mammography, MRI, and ultrasonography. While mammography is highly sensitive in detecting breast masses, it is associated with a specificity of only 10 percent to 54 percent. Contrast-enhanced MRI is also highly sensitive but no more specific than mammography since contrast enhancement also occurs in benign breast lesions. 10 Comparison of physical examination and ultrasound revealed sensitivities of 45 percent and 73 percent, respectively, and a specificity of 97 percent for both procedures combined for detecting breast masses1; however, these procedures cannot characterize such masses as benign or malignant.1,10 For determining lymph node involvement, CT was found to have a sensitivity and specificity of 50 percent and 75 percent, respectively, but was limited to detection of the level of axillary node involvement or extra capsular lymph node extension only if nodes were enlarged. 1 Generally, excisional breast biopsy or fine-needle aspiration biopsy are required to accurately characterize breast masses, and node dissection is required to evaluate locoregional tumor extension. While these procedures are highly accurate, their invasive nature and expense have prompted attempts to reduce the number of unnecessary biopsies with improved noninvasive techniques to diagnose breast malignancies and assess response to therapy.1,10,80 Recently, scintimammography using 99mTc-sestamibi as a radiotracer was shown to have a sensitivity of 95.8 percent, a specificity of 86.6 percent, a positive predictive value of 82.1 percent, and a negative predictive value of 97.1 percent for the detection of breast cancer. 80 However, further evaluation of this technique is required before conclusions can be drawn regarding its utility for breast cancer. Data from available studies assessing PET for breast cancer applications are provided in Table 7 of Appendix II.
For differentiating benign and malignant breast masses, the sensitivity and specificity of 18F-FDG PET ranged from 68 percent to 96 percent and 86 percent to 100 percent, respectively. While specificity did not vary substantially, sensitivity depended upon the size of the tumor (68 percent for all tumors versus 78 percent for tumors > 1 cm in diameter using standard visual analysis) and the type of analysis applied to image interpretation (68 percent to 80 percent for standard visual analysis; 91 percent for visual analysis based upon software-automated fusion of transmission and emission PET images; 75 percent for SUV analysis uncorrected for partial volume effect; 92 percent for SUV analysis using partial volume correction; 96 percent for DUR analysis. 1,10,119,128
For determining the presence of axillary nodal involvement, 18F-FDG PET was found to have a sensitivity of 79 percent to 100 percent, a specificity of 66 percent to 100 percent, a positive predictive value of 63 percent, a negative predictive value of 95 percent to 100 percent, and an accuracy of 77 percent to 94 percent.1,2,9,103,120,130 Aggressive malignancies generally showed higher FDG uptake than less aggressive malignancies. 1 Adler reported a significant correlation between DURs and the histologic grade of malignancy, with a mean DUR of 2.5 for ductal carcinoma in situ, 6.2 for nuclear grade 1 malignancies, 10.8 for nuclear grade 2 malignancies, and 16.2 for nuclear grade 3 malignancies.1 Although 18F-FDG PET could identify axillary nodal involvement, it frequently could not determine the number of pathologic nodes involved due to their appearance on images as large clumps of irregular FDG activity. As compared with PET, axillary node dissection revealed significantly more pathologic nodes (28 versus 95, respectively, in 19 subjects). 1 Findings suggest that 18F-FDG PET may be useful in determining the most appropriate strategy for managing breast cancer since it appears to be highly accurate in determining the presence or absence of axillary involvement.1,9,103,120 While some experts assert that 18F-FDG PET cannot substitute for histopathologic analysis due to its limitations in detecting small lesions 9 , others contend that the high sensitivity and negative predictive value of 18F-FDG PET make it an appropriate screening test for axillary involvement and may eliminate the need for axillary dissection in patients without axillary FDG uptake.2,130 Findings from four studies suggest that PET is effective in monitoring the effects of breast cancer therapy but also is able to show response earlier than conventional methods.69,74,137 However, no study has shown that treatment is altered or clinical outcome is improved by using PET imaging.
As with other types of cancer, accurate staging of esophageal cancer is necessary for identifying patients likely to benefit from surgical intervention. Conventional imaging techniques used for staging esophageal cancer include CT of the chest and abdomen, bone scan, endoscopic ultrasound, and, sometimes, MRI. While these techniques combined accurately identify metastatic disease in 70 percent to 90 percent of the cases, advanced disease is found at surgery in a substantial number of patients.21,96
At the Washington University School of Medicine (St. Louis, MO), Block evaluated the efficacy of whole-body 18F-FDG PET in staging esophageal malignancy in 58 subjects with biopsy-proven esophageal cancer. 21 The study involved urinary catheterization to assure adequate clearance of FDG activity in the bladder, blinded visual analysis of PET scans, and contrast-enhanced chest and upper abdominal CT for all subjects. PET detected primary tumors in all but two cases, both involving small lesions confined to the mucosa. Among 17 subjects classified as having unresectable disease, sites responsible for this classification were detected by PET in all 17 but by CT in only five. Biopsy of metastatic sites was available for 12 of the 17 subjects and confirmed PET results in all 12; two of five subjects not undergoing biopsy of metastatic sites died of disease at four and sixteen months after PET. The 35 subjects considered to have resectable disease underwent surgery and pathologic staging, which revealed involvement of adjacent and nonadjacent lymph nodes in 21 and eight subjects, respectively. PET and CT correctly identified adjacent nodal involvement in 11 and 6 of 21 subjects, respectively, and nonadjacent nodal involvement in two and zero of eight subjects, respectively. Among all 38 subjects found to have metastatic disease, metastasis were detected by CT alone in 17 (45 percent) and by PET plus CT in 31 (82 percent), with PET alone identifying otherwise undetected metastasis in 20 percent of the subject group. The authors conclude that, for esophageal cancer, 18F-FDG PET improves staging and facilitates the selection of patients for surgical intervention by detecting metastatic sites not found by CT alone.
Luketich also evaluated PET in staging esophageal cancer. 96 Their study, conducted at the University of Pittsburgh Medical Center (Pittsburgh, PA), included 35 subjects considered to have resectable disease based on findings from CT, endoscopic US, and bone scan. Whole-body 18F-FDG PET with visual analysis revealed primary esophageal cancer in 34 (97 percent) of the subjects and locoregional or distant metastasis in 18 (51 percent). Metastasis were confirmed in 16 of the 18 by video-assisted thoracoscopy or laparoscopy (N-15) or by MRI and clinical correlation (N=1). The sensitivity, specificity, and accuracy of PET were 88 percent, 93 percent, and 91 percent, respectively, for identifying distant metastasis and 45 percent, 100 percent, and 48 percent, respectively, for identifying locoregional metastasis. The inability of PET to detect lesions of 2 mm to 10 mm in diameter was responsible for false-negative findings (1 distant site and 11 locoregional sites) and the lower sensitivity in detecting locoregional metastasis. Regardless, all distant metastasis detected by PET were missed by standard imaging techniques. The authors conclude that, as compared with conventional methods, 18F-FDG PET improves the ability to detect distant metastasis and may facilitate treatment planning in up to 20 percent of the patients with negative findings by conventional staging techniques.
Neuroendocrine Gastro intestinal Tumors
Eriksson evaluated the use of PET for detecting Neuroendocrine gastrointestinal tumors and assessing response to treatment. 40 Of the 18 patients evaluated, most had elevated levels of urinary 5-hydroxy indoleacetic acid (U-5-HIAA) and all but one patient had liver metastasis. Since Neuroendocrine tumors are characterized by an excessive production of serotonin, one of the precursors of serotonin, 5-hydroxy tryptophan (5-HTP), was labeled with 11C and utilized as the tracer substance for PET. Moreover, for purposes of comparison, contrast-enhanced CT was performed in all but one patient. Patients were treated with alpha-interferon, octreotide, somatuline, and/or octastatin. PET showed increased uptake of 11C-5-HTP in the tumorous tissue in all patients, as well as in metastasis of the liver, lymph nodes, pleura, and skeleton. PET showed more lesions than CT in 10 of 17 patients but was equal to CT in six patients and was difficult to evaluate in one patient due to increased renal uptake and excretion of 5-HTP. Tumor visibility with PET was superior to CT in 11 of 17 patients, equal to CT in four patients, and inferior to CT in two patients, one with multiple liver metastasis and one with only a partial uptake of the tracer in the primary tumor of the pancreas. In areas with active tumor cells, the uptake of 5-HTP was relatively homogenous. Among 10 patients who were examined with PET at different times during treatment, a good correlation was found between changes in U-5-HIAA and changes in the uptake of 11C-5-HTP in tumorous tissue, which cannot be determined with CT or US.
Conventional procedures used to diagnose pancreatic masses include transabdominal CT, transabdominal or endoscopic US, and endoscopic retrograde cholangiopancreaticography (ERCP).15,71 However, clear differentiation between malignant pancreatic carcinoma and benign pancreatic carcinoma or chronic pancreatitis is difficult with conventional procedures. 71 Additionally, precise localization of pancreatic Neuroendocrine tumors, those with the capacity to synthesize and release hormones, is frequently problematic even with the use of a combination of techniques, such as US, CT, MRI, angiography, and per cutaneous transhepatic portal vein catheterization with sampling from pancreatic veins. 3 As with other types of cancer, 18F-FDG was the predominant radiotracer studied. However, Neuroendocrine tumors have the capacity to take up and decarboxylate the amine precursors 5-HTP and L-dihydroxyphenylalanine (L-dopa) and store their respective amine forms, serotonin and dopamine; thus, 11C-5-HTP and 11C-L-DOPA were used as radiotracers in one study involving subjects with Neuroendocrine pancreatic tumors. 3
Findings from five studies on the use of 18F-FDG PET for pancreatic cancer suggest that this technique may be useful for diagnosing pancreatic cancer due to its demonstrated ability to detect primary pancreatic carcinomas and to differentiate between pancreatic cancer and chronic pancreatitis.14,15,71,79,127 While most of these studies compared 18F-FDG PET with CT, US, and/or ERCP, no clear consensus can be reached regarding the superiority of one modality over the others for detecting and differentiating pancreatic masses. Stollfuss reported that 18F-FDG PET was significantly more sensitive and specific than CT in distinguishing pancreatic carcinoma from chronic pancreatitis. 127 In this study, the respective sensitivity and specificity for correctly identifying primary pancreatic tumors were 95 percent and 90 percent for 18F-FDG PET versus 80 percent and 74 percent for CT. In contrast, Bares found no significant difference between 18F-FDG PET, CT, US, and ERCP in detecting primary tumors. Of 13 primary tumors, 12 (92 percent), 12 (92 percent), 11 (85 percent), and 13 (100 percent) were correctly identified by PET, CT, US, and ERCP, respectively. 15 However, only PET correctly identified 2 of 2 cases of chronic pancreatitis, whereas the other modalities were each correct in only one case. In the study by Inokuma, 18F-FDG PET, transabdominal US, CT, and endoscopic US were associated with similar sensitivities for detecting primary pancreatic cancers (94 percent, 89 percent, 89 percent, and 97 percent, respectively) although specificity for excluding pancreatic cancer was higher for 18F-FDG PET than the other modalities (82 percent, 45 percent, 73 percent, and 64 percent, respectively). 71 For identifying malignancy in pancreatic disorders, Bares reported sensitivities that were similar for 18F-FDG PET, 14 and CT but lower for US (92 percent, 100 percent, and 75 percent, respectively); whereas the specificity of 18F-FDG PET in this study was clearly superior to that of CT and US (85 percent, 23 percent, and 33 percent, respectively.
Findings from these studies also suggest that 18F-FDG PET may be useful for staging pancreatic cancer since if appears to be effective in detecting lymph node and liver metastasis. However, evidence to confirm this was confined to two of the studies.14,15 In these studies, 18F-FDG PET, CT, and US detected 76 percent to 89 percent, 18 percent to 22 percent, and 0 percent to 29 percent, of the nodal metastasis, respectively, and detected 57 percent to 80 percent, 29 percent to 60 percent, and 71 percent to 80 percent of the liver metastasis, respectively. Thus, 18F-FDG PET was superior to CT and US in detecting lymph node metastasis and superior to CT but similar or inferior to US in detecting liver metastasis. While Stollfuss and Inokuma noted that findings suggestive of lymph node or liver metastasis were observed, these were not confirmed by histology or nodal dissection.71,127
Several researchers reported specific problems associated with the use of 18F-FDG PET in pancreatic disorders. Due to its limitations in visualizing lesions < 15 mm, 18F-FDG PET may not be of value in detecting early pancreatic cancer or small metastatic deposits. 71 Metabolic conditions, particularly insulin-dependent diabetes mellitus (IDDM), may have a profound influence on 18F-FDG PET findings. In the study by Bares, all patients with IDDM showed markedly low tumor uptake of FDG, accounting for the majority of false-negative findings in the study. 14 The low tumor uptake of FDG in IDDM patients may be due to altered distribution of FDG mediated by insulin-dependent glucose transporter proteins expressed in many organs and by pancreatic cancer cells. 14 Plasma glucose concentrations alone may modify FDG uptake, and high blood glucose levels are likely to occur not only in patients with IDDM and nonIDDM but also in patients with pancreatitis or pancreas cancer.14,79 Additionally, Kato assert that the cellularity of the visualized mass, particularly the metabolic activity per cell and the cell density, must be considered for correct interpretation of findings. 79 In their study, false results occurred in a benign inflammatory mass consisting of a dense accumulation of lymphocytes and in a muconodular malignancy consisting primarily of mucinous substance and only a small accumulation of viable tumor cells. Moreover, malignancy is frequently accompanied by an inflammatory immune response and pancreatic cancer is usually accompanied to some degree by pancreatitis. In many cases, it is not possible with 18F-FDG PET to make a clear distinction between the cancerous and inflammatory areas, although this is true for CT and MRI also. 79
In the study by Ahlström evaluating the utility of PET in Neuroendocrine pancreatic tumors, CT and 11C-L-DOPA PET showed similar efficacy in detecting the primary tumor and/or its metastasis in subjects with functional tumors (those that produce hormones and symptoms). 3 However, 11C-L-DOPA PET missed detecting nonfunctional tumors, those that produce hormones but no symptoms, that were detected by CT in two subjects, US in one subject, and laparotomy in two subjects. There was a good correlation between 11C-L-DOPA PET and 11C-5-HTP PET among subjects undergoing both. Although tumors and metastasis were generally visualized better with PET than with CT, variation in tracer uptake was noted between different lesions in 2 subjects. One subject showed high L-dopa uptake in some liver metastasis but not in the primary tumor and the second showed high L-dopa uptake in the primary tumor but not in its metastasis. The authors explain this may have been due to the presence of subpopulations of tumor cells within different tumors having varying levels of metabolism, Neuroendocrine differentiation, and hormone production or by differences in blood flow to different sites of the tumor. Ahlström concluded that, while PET may be valuable as a complement to CT in identifying functional Neuroendocrine tumors of the pancreas, it offered no advantage in detecting nonfunctional tumors. 4
Urinary Bladder Cancer
Since there are two general types of urinary bladder cancer, a superficial type associated with relatively good prognosis and a deep-growing, muscle-invading type associated with high mortality within the first year of diagnosis, the ideal diagnostic strategy should define the depth of bladder wall infiltration and determine the extent of disease involvement. This is generally achieved with cystoscopy, biopsy, and bimanual palpation, but may include CT and MRI. However, these techniques may be suboptimal and further improvement is needed in evaluating urinary bladder tumors. 4 Because 18F-FDG and other radiotracers are excreted via the urine, tracer uptake in the urine or structures of urinary elimination, such as the kidneys or bladder, may prevent visualization of nearby tumors or metastasis. 4,126 This problem may be overcome with catheterization of the urinary bladder 25 or by pre-PET saline irrigation of the bladder. 88
These studies assess 18F-FDG PET and/or 11C-MET PET for a variety of applications, interpret images via SUV and Patlak analyses, and, in most study subjects, utilize saline irrigation as bladder preparation. Findings from these studies suggest that 18F-FDG PET may be useful in the detection of perivesical tumor growth and distant metastasis of advanced bladder cancer and in the early detection of posttreatment recurrent disease 81 and that 11C-MET PET may be useful in staging bladder cancer 4 and monitoring response to therapy. 88 However, the role and appropriateness of PET for these uses as well as other applications in bladder cancer is not clear. Among subjects with proven recurrent or residual disease in the study by Kosuda, 18F-FDG PET detected only 60 percent of the lesions and missed 40 percent due to intense FDG accumulation in the urinary bladder, although image interpretation was improved with Patlak, rather than SUV, analysis and with urination after saline irrigation. 81 In the same study, 18F-FDG PET differentiated between disease recurrence and treatment-induced tissue changes and detected 100 percent of distant metastatic foci, but these factors were reported for only two patients each. In the study by Letocha, 11C-MET PET identified none of the lesions in subjects with biopsy-proven recurrence and the authors concluded that this technique has poor diagnostic accuracy. 88 In the study by Ahlström, while 11C-MET PET detected 15 (75 percent) of the primary tumors in 20 subjects undergoing pre-PET saline irrigation, it was inferior to CT, which identified 2 additional tumors, both 1 cm in size. Thus, the diagnostic role of 11C-MET is questionable. 4 Moreover, all of the available studies are hampered by small study samples, lack of control, and unblended image analysis.
Due to the extensive use of CT and US in evaluating abdominal processes, incidental detection of renal masses has become commonplace. While most such masses are determined to be simple cysts, neoplasms are also discovered and 5 percent to 10 percent of the renal masses cannot be classified as either simple cyst or neoplasm by CT or US. 49 At the Beaumont Hospital (Dublin, Ireland), Goldberg assessed the utility of 18F-FDG PET in detecting renal tumors and in characterizing indeterminate renal masses. 49 Subjects were given a diuretic to decrease FDG concentration in the kidney, and PET images were interpreted by SUV and DAR analyses. Among 10 subjects with pathologic proof of renal tumor, PET correctly identified the tumor in nine and missed it in one, a diabetic patient. Among 8 subjects with pathologic characterization of previously indeterminate renal masses, PET correctly identified the mass as benign in seven but erroneously classified a 4-mm tumor as benign. Since there were no false-positive PET findings, the authors assert that a positive PET scan obviates the need for cyst aspiration and that a negative PET scan combined with negative findings via cyst aspiration confirms benignity.
Whether for primary diagnosis or detection of posttherapy residual or recurrent disease, the typical work up for suspected ovarian cancer may include CT, MRI, US, and measurement of tumor markers such as serum CA-125, serum NB/70-K, and plasma lipid-associated sialic acid (LASA-P).30,68 However, the imaging techniques are not specific for ruling out malignancy and, although tumor markers are useful for determining tumor activity when their levels are elevated beyond normal values, these levels may remain within the normal range even in the presence of active tumor. 68 Therefore, negative values do not rule out active disease.30,78 Additionally, the majority of patients with ovarian cancer present with advanced disease due to the lack of symptoms in early disease. 78 Since appropriate management depends upon accurate characterization of disease, laparotomy is also generally undertaken to allow extensive exploration of the abdominopelvic cavity. 68 Moreover, surgical reexploration, or second-look laparotomy (SLL), generally has been performed following treatment to determine the presence of residual disease and to remove any resectable disease. 30 Even laparoscopic procedures, however, are not always accurate in determining the presence or absence of tumor, and they add considerably to the cost and potential morbidity of managing ovarian cancer.68,78 Thus, more specific, precise, noninvasive methods to identify and characterize ovarian cancer are needed. 63 The use of FDG in PET studies may require urinary catheterization due to the close proximity of regions being imaged to the urinary bladder.
Only three studies could be found regarding the use of PET in ovarian cancer. Findings from all three indicate that 18F-FDG PET may have a role in distinguishing between benign and malignant ovarian masses and in identifying recurrent diseases.30,67,78 In the study by Karlan, 18F-FDG PET concurred with surgical findings with respect to gross tumor in 12 (92 percent) of 13 subjects and detected unknown distant metastasis in one subject. 78 However, in six subjects considered free of disease clinically, PET missed microscopic disease that was confirmed by SLL (n=5) or biopsy (n=1). While Karlan and associates assert that 18F-FDG PET will not replace surgery for detecting microscopic peritoneal involvement, Hübner speculated that 18F-FDG PET may replace or postpone SLL in patients with suspicious CT scans or rising tumor markers. For distinguishing between benign and malignant ovarian masses, Hübner reported similar sensitivities for CT and 18F-FDG PET alone (82 percent versus 83 percent, respectively) but greater specificity (80 percent versus 53 percent), accuracy (82 percent versus 72 percent), positive predictive value (86 percent versus 77 percent), and negative predictive value (76 percent versus 62 percent) for PET than for CT. 68 However, by combining CT and PET data, positive predictive and negative predictive values were substantially increased if CT and PET data concurred (95 percent and 100 percent, respectively). In the study by Casey, 18F-FDG PET was found to be superior to tumor markers, US, and CT in detecting residual tumor or disease recurrence (findings consistent with SLL or clinical follow-up in 67 percent, 57 percent, 78 percent, and 89 percent of the patients, respectively). 30
Although prostate cancer is potentially curable with radical prostatectomy or radiation therapy, approximately 35 percent of the patients undergoing surgery will have residual disease or micrometastasis in the regional lymph nodes. 39 In addition to the regional lymph nodes, other principal sites of metastasis associated with prostate cancer are the liver, lungs, and bone. 123 Since optimal clinical management of prostate cancer depends on the extent of disease, disease staging is of crucial importance. 58 Transrectal US, CT, and MRI do not adequately define the volume and extent of disease in a large number of patients. 39 Moreover, while bone scintigraphy is a sensitive method for identifying bone metastasis, its specificity for this purpose is hampered by tracer uptake in areas of degenerative joint disease and previous skeletal trauma and it does not identify lymph node metastasis. 123 Thus, alternative methods for evaluating prostate cancer are under investigation. These include PET scanning with 18F-FDG and planar or SPECT imaging with radiolabeled monoclonal antibodies (mAbs) directed against human prostate cancer cell lines. 58
Only three studies could be found regarding the use of PET in prostate cancer. For identifying and grading prostate cancer, Effert found 18F-FDG PET to be of little value. 39 In this study, 81 percent of the subjects with prostate cancer and 81 percent of the subjects with benign prostatic hyperplasia (BPH) showed similar FDG uptake when images were analyzed visually, and there were no significant differences in FDG uptake between tumors of differing stages, between tumors of differing grades, or between subjects with BPH and those with prostate cancer of different stages when images were analyzed semi-quantitatively. Shreve reported that, although 18F-FDG PET can help to identify bone and soft-tissue metastasis of prostate cancer, it is less sensitive than bone scintigraphy in identifying bone metastasis. 123 In this study, PET consistently underestimated the number and extent of bone metastasis, as compared with bone scintigraphy, and did not detect small solitary metastasis that were equivocal abnormalities by scintigraphy. The sensitivity and positive predictive value of 18F-FDG PET in detecting bone metastasis in untreated patients were 65 percent and 98 percent, respectively. Further, the detection of pelvic nodal metastasis was hampered by bladder FDG activity. Haseman compared 18F-FDG PET with mAb imaging for identifying recurrent prostate cancer. 58 For detecting recurrence in the prostate bed, mAb imaging was found superior to PET, with respective sensitivities of 86 percent and 17 percent, specificities of 43 percent and 50 percent, positive predictive values of 60 percent and 33 percent, negative predictive values of 75 percent and 29 percent, and accuracies of 64 percent and 30 percent. For detecting recurrence in the lymph nodes, no conclusions were drawn. While nodal results with PET and mAb imaging were consistently discordant, CT showed no lymph node enlargement so biopsies were considered inappropriate.
These data do not suggest a role for 18F-FDG PET in the evaluation of prostate cancer. Shreve explain that, while the uptake of FDG in prostate cancer metastasis is increased, the extent to which it is increased in low compared with other types of cancer. 123 This is consistent with the concept that prostate cancer is slow-growing but it limits the sensitivity of 18F-FDG PET, particularly in small metastatic deposits.
For metastatic testicular cancer, response to therapy is typically evaluated by CT and measurement of serum levels of the tumor markers, beta human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP). However, approximately 20 percent of testicular tumors are negative for these markers, and differentiation between residual malignancy and scar tissue is not possible with CT. 104 Nuutinen conducted a study at the University of Turko (Turko, Finland) to determine the value of 18F-FDG PET in detecting residual testicular cancer following chemotherapy. 104 The study included 15 subjects with testicular cancer who, after three to nine courses of chemotherapy, underwent 20 PET scans with visual and SUV analyses. Confirmation of the status of residual masses was obtained via biopsy in seven subjects or morphological studies, tumor markers, and event-free follow-up for a median of 16 months in the remaining eight subjects. Among 20 PET scans (25 lesions), PET with visual analysis was positive for malignancy in nine and negative for malignancy in 11. Confirmatory methods revealed three false-positives due to inflammatory changes and one false-negative in the retro peritoneum with visual analysis. While interpretation by SUV analysis was comparable to that of visual analysis, the median SUV value of tumors did not significantly differ from that of inflammatory tissue (2.7 versus 4.2, respectively), and there was a large overlap of SUV values between viable tumor and benign residual mass (range, 0.7 to 5.5 versus 2.0 to 5.5, respectively). The overall sensitivity, specificity, and accuracy of PET in detecting postchemotherapy residual tumor were 77 percent, 86 percent, and 80 percent, respectively. The authors conclude that 18F-FDG PET is of limited value in imaging postchemotherapy metastatic testicular cancer due to the potential for high FDG accumulation in inflammatory tissue. The study is hampered by a small study sample, and no additional studies could be found regarding the use of PET in testicular cancer.
Once the vertical growth phase begins, malignant melanoma spreads to lymph nodes and is likely to metastasize to any organ in the body. 52 With distant metastasis, median survival is only four to six months.20,25 Therefore, early diagnosis of regional metastasis and an accurate understanding of the extent of disease is crucial. For staging, physical examination, chest x-ray, CT, MRI, and US are used, and, if lesions are detected, biopsies or follow-up examination are required to characterize these lesions as malignant or benign.20,25,125 However, the noninvasive techniques are time-consuming and are not always accurate in detecting tumor involvement in normal-sized lymph nodes or small tumor foci in the abdomen.52,125 The reported efficacy of FDG PET in the imaging of other types of cancer has prompted interest in utility of this modality for malignant melanoma.
For detecting lymph node metastasis associated with malignant melanoma, 18F-FDG PET was found to have a sensitivity of 66 percent to 100 percent, a specificity of 66.7 percent to 100 percent, and an accuracy of 81 percent to 100 percent for all anatomic areas except the thorax for which sensitivity was reported to range from 15 percent to 100 percent.20,25,52,125,135 Specificity and accuracy for the thoracic area were not reported. Previously undetected lesions and metastasis in areas other than lymph nodes were also detected by 18F-FDG PET.24,25,52 These findings suggest that 18F-FDG PET may be a valuable technique for staging of metastatic melanoma. Despite this, the poor anatomical resolution of PET may require that PET emission scans be correlated with those from other imaging modalities or with PET transmission scans for exact localization of metastasis.24,25
Böni assert that 18F-FDG PET is more sensitive than conventional imaging techniques (x-ray, CT, and MRI) in identifying metastatic lesions in the abdominal viscera.25 In contrast, Gritters reported that 18F-FDG PET was less sensitive than CT in detecting pulmonary lesions < 1 cm in size. In their study, 22 of 23 false-negatives in the thoracic region were < 1 cm.52 Gritters and colleagues emphasize that respiratory movement may have resulted in blurred images or that the limited resolution of PET in pulmonary regions may be due to the lower density of normal lung tissue and increased position range. Additionally, 14 of the 23 false-negatives were in two subjects who had undergone chemotherapy or immunotherapy, which may reduce the amount of FDG uptake in tumors. Regardless, Böni reported that 18F-FDG PET detected all known pulmonary metastasis (n=4) in their series, although the size of these lesions was not provided. 25 For detecting all lymph node metastasis, Blessing reported comparable sensitivities and specificities for 18F-FDG PET and ultrasound (sensitivity of 74 percent and 76 percent, respectively, and specificity of 93 percent for both) and concluded that PET does not offer significant advantages over ultrasound for this application. 20 In an editorial response to Blessing, Böni argued that the advantage of PET, particularly for malignant melanoma with its unpredictable metastasis, is the ability to detect lymph node metastasis in unexpected areas and to detect or exclude distant metastasis.20,25 Two-small scale studies demonstrated that whole-body 18FDG-PET was more sensitive than whole-body scintigraphy using iodine-123-labeled (123I) iodobenzofuran (IBF) and alpha-methyl-tyrosine, respectively, in detecting melanoma metastasis.24,26 Regardless, studies are few in number and methodologically weak.
Preoperative staging in patients with liver metastasis secondary to colon and rectal cancer is performed in order to select patients who may benefit from curative hepatic resection and avoid unnecessary surgery in those who would not. 84 Preoperative staging in these cases typically includes a combination of clinical, endoscopic, radiographic, and minimally invasive surgical techniques. 41 CT or MRI angiography are used to determine repeatability of hepatic metastasis, and abdominal and thoracic CT and chest x-ray are used to detect extra hepatic metastasis. 34 Monitoring for tumor recurrence may involve determination of the tumor marker, carcinoembryonic antigen (CEA); abdominal and pelvic CT, CT portography, chest x-ray, colonoscopy, ultrasonography of the liver, and, when recurrence is suspected or identified, endorectal ultrasonography, pelvic MRI, and thoracic CT.16,133 Recently, planar or SPECT imaging with indium-111-labeled satumomab pendetide (111In Oncoscint) and 18F-FDG PET have also been used to detect recurrence of colorectal cancer and liver metastasis. 23 Due to the close proximity of many of the anatomical structures being imaged to the kidneys and urinary bladder, urinary catheterization is usually employed during 18F-FDG PET imaging for colorectal cancer.16,23,41 Data from studies assessing the utility of 18F-FDG PET in colorectal cancer are provided in Table 8 of Appendix II.
For the preoperative staging of colorectal cancer, particularly the identification of hepatic metastasis, 18F-FDG PET has demonstrated a sensitivity of 87 percent to 90 percent, a specificity of 67 percent to 100 percent, and an accuracy of 83 percent to 93 percent.41,84,133 While only one study reported positive and negative predictive values, these were 93 percent and 50 percent, respectively. 41 As in PET studies for other types of cancer, false-negatives occurred in lesions smaller than the spatial resolution of the scanner, in lesions of close proximity to other malignancies, and in lesions with central necrosis and limited FDG uptake. False-positives occurred in areas of inflammation and, in one case, in an obstructed urinary holding system. For this application, however, there is no clear consensus on whether FDG PET is superior to or may replace other imaging techniques. Reported values for sensitivity, specificity, and accuracy were 47 percent to 100 percent, 58 percent to 100 percent, and 56 percent to 76 percent, respectively, for CT41,84,133 and 97 percent, 0.9 percent, and 76 percent, respectively, for CT portography. 133 While Falk and colleagues conclude that PET is more sensitive and accurate than CT, Vitola et al. assert that PET is more specific and accurate than CT or CT portography but CT portography is the most sensitive of the three.
18F-FDG PET also appears to be useful in accurately identifying the presence or absence of disease recurrence.16,41,55,84,133 Moreover, for this application, 18F-FDG PET was found more sensitive than planar scintigraphy or SPECT with 111In-Oncoscint, 23 more accurate than CT, 55 and more efficient than CT and CT portography, particularly in differentiating between disease recurrence and postsurgical changes. 133 Additionally, PET influenced disease management in 25 percent to 40 percent of the patients by clarifying equivocal pelvic CT findings. 16
Findings from a single study suggest that 18F-FDG PET may also be a reliable technique for monitoring treatment response. 42 In this study, PET data obtained at four to five weeks after chemotherapy and analyzed by the tumor-to-normal-liver ratio (TNLR) on a lesion-to-lesion basis had a sensitivity and specificity of 100 percent and 90 percent, respectively, in differentiating responding tumors from nonresponding tumors. Specificity was lower (75 percent) when assessed on the basis of overall patient response. Moreover, TNLR data obtained earlier in the course of therapy and data obtained at four to five weeks but analyzed by the standard uptake value (SUV) method correlated with response and nonresponse but appeared to be less reliable than four to five week TNLR.
The two major forms of malignant lymphoma, Hodgkin's disease (HD) and nonHodgkin's lymphoma (NHL), are both characterized by progressive enlargement of lymph nodes and potential spread of disease to the bone marrow or any organ system. 63 Standard techniques for evaluating and staging HD and NHL include surgical exploration, chest X-ray, lymph angiography, mediastinoscopy, and, more recently, gallium-67 (67Ga) scintigraphy, ultrasonography (US), CT, and MRI.37,63,100,102 CT, MRI, and US provide excellent data on the size, location, and infiltration of a mass, and CT and MRI are relatively reliable in evaluating nodal involvement. However, detection of nodal disease with these techniques is based on lymph node size. Therefore, they are limited by the inability to identify malignancy in normal-sized nodes, to exclude malignancy in enlarged benign nodes, and to characterize residual masses after therapy.100,102 Functional imaging with metabolically active tracers may be particularly useful in these cases. 67Ga scintigraphy surpasses CT in evaluation of residual masses due to more intense 67Ga uptake in viable tumor than in necrotic tissue. 102
Since high-affinity somatostatin receptors have been found in a variety of tumor types, including HD and NHL, scintigraphy with an indium-111-labeled (111In) somatostatin analog has been tested as a method to detect or localize malignant lymphoma lesions. 13 Technetium-99m-labeled sestamibi (99mTc-MIBI) SPECT has been tested as a method of evaluating posttreatment disease status due to its purported ability to determine multidrug resistance. 37 A few studies have also evaluated the use of 18F-FDG PET in lymphoma. Details from those available can be found in Table 9 of Appendix II.
Appendix IV: Government Agencies and Professional Organizations
Food and Drug Administration (FDA)
While FDA-approval status for PET devices could not be obtained from the FDA, this information could be obtained from the manufacturers of these devices. A spokesperson from Positron Corporation (Houston, TX), in a telephone conversation, stated that several of their PET scanning devices, which were submitted to the FDA for "Premarket Notification" [ 510(k)], were approved for manufacture and marketing. The spokesperson explained that FDA approval for a specific device can be obtained by one of two processes. If the device is new, premarket trials demonstrating the safety and efficacy of the device are required. However, if the device is similar to one that has already obtained FDA approval, approval for the manufacture and sale of the device (510(k) approval) requires a review of the data on the device but does not require submission of clinical outcome data. The 510(k) approval process is typical for most imaging devices since new models are generally improved versions of previously approved devices. Among PET scanning devices manufactured by Positron Corporation, those holding 510(k) approval included the Posicam 6.5 BGO (an early model), the Posicam Auricle series, and the Posicam HZ and HZ-L, which are higher resolution models. In a telephone conversation on the same date, a spokesperson from Computer Technology Imaging (Knoxville, TN) stated that all of their PET scanning devices have 510(k) approval. These devices include the ECAT 931 tomograph, the ECAT Exact tomograph, the ECAT Exact HR Plus (a higher resolution model), and the ART (Advanced Rotating Tomograph).
FDA approval for radiopharmaceuticals may not only be limited to a particular indication but, since the half-life of many of these compounds is too short to allow transport to any great distance, may also be limited to the particular area where the compound is produced. Fluorine-18-labeled fluorodeoxyglucose (18F-FDG) has been approved for the diagnosis of seizure disorders, but its approval is limited to use at a single site in Peoria, Illinois. Rubidium-82 (82Rb) is approved for use in myocardial perfusion PET scanning. Its approval, however, extends to any location since it is produced in generator form and is more readily available. In a telephone conversation on January 28, 1999, a spokesperson from the FDA confirmed this information and stated that no other PET radiopharmaceuticals have received FDA-approval to date but many of the radiopharmaceuticals being used are being used by an investigational new drug (IND), new drug application (NDA), or abbreviated new drug application (ANDA) or under Section 121 of the Food and Drug Modernization Act of 1997. All PET centers have to be registered and can be inspected by the FDA for compliance to the current good manufacturing practices.
Health Care Financing Administration (HCFA)
In a telephone conversation, a spokesperson from HCFA stated that the agency will approve coverage for 18F-FDG PET when used for characterizing solitary pulmonary nodules and for initial staging of demonstrated lung cancer. However, the coverage policy involves limitations that apply to the potential use of biopsy. In the case of a negative PET scan for characterizing solitary pulmonary nodules or a negative PET scan and a negative CT scan for staging demonstrated lung cancer, coverage for biopsy would not be routinely approved. While this decision is based upon claims in the literature that 18F-FDG PET eliminates unnecessary biopsies, the spokesperson noted that this has not yet been proven. Therefore, physicians must make a choice regarding the most appropriate diagnostic modality for each case. This choice should be made with the knowledge that FDG PET may miss cancer and with consideration of whether test findings will make a difference in the management of the patient. Modifications in this coverage policy will be made in the event that PET makes no difference in the clinical management of patients, which will be determined by examination of Medicare claims.
National Cancer Institute (NCI)
The National Cancer Institute Workshop Panel, a group of 24 biomedical scientists, clinical investigators, and physicians familiar with PET, met in 1988 to address the status, current clinical applications, and future directions of PET. The conclusions of the group were reported in a subsequent position statement (National Cancer Institute Workshop Panel, 1990). The group stated that PET is an accurate method for evaluating function and metabolism in different organs, data that were previously unavailable or available only through invasive or a less accurate technique. Based upon findings from studies that showed a correlation between glucose accumulation in brain tumors, as determined by 18F-FDG PET, and the degree of tumor malignancy, as determined by histologic grading, and studies that showed the ability of PET to discriminate between recurrence of brain tumor and damage to normal brain tissue after radiation therapy and/or chemotherapy, the group reported that PET is useful for grading of brain tumors and for detecting disease recurrence after therapy for such tumors. With respect to the latter application, it was noted that CT and MRI are not able to make this distinction. Considering the success of PET in imaging brain tumors, the group added that PET studies of other tumors are likely to result in improved knowledge of the tumor aggressiveness, patient prognosis, response to radiotherapy or chemotherapy, optimal localization of biopsy sites, and distinction between tumor invasion and response of normal tissue.
American Medical Association (AMA)
The AMA Council on Scientific Affairs (1988) evaluated the use of positron emission tomography in oncology. While noting that PET had already demonstrated potential utility in evaluating patients with malignant tumors and that metabolic studies using PET appeared promising, they stated that, "Positron emission tomography is the best diagnostic imaging methodology for assessing recurrence of malignant brain tumors after radiation therapy."
On January 7, 1998, a spokesperson from the AMA stated that the agency has not conducted any further assessment of PET since the evaluation by the Council on Scientific Affairs.
Health Insurance Association of America (HIAA)
According to a report generated by the Health Insurance Association of America (HIAA, 1991), PET is superior to CT and MRI in delineating brain tumors and demonstrating the extent of disease in such tumors. Displacement of structures in the brain caused by brain tumors can result in disruptions of the blood-brain barrier (separation between compartments of the brain and compartments of blood). Brain CT involves the use of a contrast agent that flows through the blood and, in areas with a disrupted blood-brain barrier (BBB), escapes into the surrounding tissues. If the BBB is intact at the outer edges of the tumor, the margins of the tumor cannot be clearly delineated since the contrast agent cannot escape. While contrast-enhanced MRI provides improved resolution over CT and may demonstrate disruption of the BBB, MRI images may not coincide with the extent of the tumor and do not demonstrate the actual tumor or areas of necrosis. Since tumors do not fully break down glucose, they use more glucose than normal tissue and 18F-FDG may be used as a PET tracer. However, resolution with 18F-FDG PET may not be any better than that achieved with contrast-enhanced MRI, and other tracer substances may provide more complete tumor delineation (HIAA, 1991).
With respect to the diagnosis of brain tumors, the benefits of PET primarily relate to the planning of treatment or surgical options once a tumor is detected. Advantages of PET include (HIAA, 1991):
- Differentiation of tumor tissue from normal tissue and delineation of the site and degree of malignancy, thereby increasing diagnostic accuracy.
- Identification of patients with diffuse abnormalities for which aggressive surgical procedures may be inappropriate.
- Direction of surgical approach through preoperative assessment.
- Posttherapy differentiation of radio-induced injury from recurrent tumor.
American College of Nuclear Physicians (ACNP) Society of Nuclear Medicine (SNM)
In a joint effort, the American College of Nuclear Physicians (ACNP) and the Society of Nuclear Medicine (SNM) appointed a task force to review the clinical utility of PET and to submit a document to HCFA regarding PET applications considered appropriate for reimbursement. In a summarized version of the full document (ACNP/SNM Task Force on Clinical PET, 1988), the task force reported on the value of PET in managing brain tumors and concluded that PET was useful for determining the degree of malignancy in brain tumors (tumor grading) and for differentiating tumor necrosis from recurrent disease in radiation-treated brain tumors.
AMERICAN I (AAN)< Neurology of Academy>
In an assessment of PET representing a synthesis of literature available at the time and expert opinion, the AAN Therapeutics and Technology Assessment Subcommittee (AAN, 1991) also endorsed PET for determining the degree of malignancy in brain tumors and for differentiating tumor necrosis from recurrent disease in radiation-treated brain tumors.
Acronyms and Abbreviations
- Annihilation coincidence detection
- Adrenocorticotropic hormone
- Blood-brain barrier
- Benign prostatic hyperplasia
- Carcinoembryonic antigen
- Central nervous system
- Computed tomography
- Carbon-11-labeled 5-hydroxy tryptophan
- Carbon-11-labeled L-deprenyl
- Carbon-11-labeled L-dihydroxyphenylalanine
- Carbon-11-labeled methionine
- Carbon-11-labeled tyrosine
- 15C-carbon monoxide
- Cerebral blood flow
- Cerebral blood volume
- "the use of a particular medical technology improves patient clinical status, as measured by medical condition, technology demonstrates a clinical advantage over other technologies"
- Cerebral metabolic rate of glucose
- Cerebral metabolic rate of oxygen
- "the economic costs of using a particular technology to achieve improvement in a patient's health outcome are justified given a comparison to both economic costs and the improvement in patient health outcome resulting from use of alternative technologies"
- Differential absorption rate or ratio
- Differential uptake ratio
- "does the technology have the power to produce a desired effect"
- Endoscopic retrograde cholangiopancreaticography
- Endoscopic ultrasonography
- Evaluate -
- "The review or reviewing of research and technology assessments conducted by other entities relating to specific technologies and their specific use and application"
- False negatives
- "people who have the disease who may be incorrectly identified as not having it."
- Fluorine-18-labeled fluorodeoxyglucose
- Fluorine-18-labeled fluorodeoxyglucose
- Fluorine-18-labeled fluoro-2'- deoxyuridine
- Fine-needle aspiration biopsy
- Gadolinium-enhanced MRI
- Hydroxy indoleacetic
- Hexamethyl propyleneamine oxime
- H 2 15O
- Oxygen-15-labeled water
- Hydroxy tryptophan
- Insulin-dependent diabetes mellitus
- Indium-111-satomomab pendetide
- Patlak value (graphic)
- Tracer influx from blood to tissue
- Tracer influx from tissue to blood
- Tracer trapping
- Lipid-associated sialic acid
- Magnetic resonance imaging
- Nonsmall cell lung cancer
- Normalized uptake value
- Prostate-to-skeletal-muscle ratio
- "If specificity is low, then persons who do not have the disease or condition may be improperly identified as having the condition."
- Protein synthesis rate
- Regional cerebral blood flow
- Regional cerebral blood volume
- Regional cerebral metabolic rate of glucose
- Regional cerebral metabolic rate of oxygen
- Regional metabolic rate of glucose
- Regional oxygen extraction fraction
- Region of interest
- "a judgment of the acceptability of risk of using a technology in a specified situation"
- Small cell lung cancer
- "Among people who have the disease, the proportion with a positive test."
- Second-look laparotomy
- "Among people who do not have the disease, the proportion with a negative test."
- Single photon emission computed tomography
- Standardized integral uptake
- Standardized uptake value
- Time activity curve
- Tumor-to-gray-matter ratio
- Tumor-to-liver ratio
- Tumor-to-muscle ratio
- Tumor-to-normal-cerebellar ratio
- Tumor-to-normal-liver ratio
- Tumor-to-normal-tissue ratio
- Transabdominal ultrasonography
- Tumor-to-white-matter ratio
- Urinary 5-hydroxy indoleacetic
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Created: March 1999.
Minnesota Department of Health, St. Paul (MN)
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