Diagnosing, staging, and re-staging of cancer, as well as the monitoring and planning of cancer treatments, has traditionally relied on anatomic imaging with computed tomography (CT) or magnetic resonance imaging (MRI). These anatomic imaging modalities provide exquisite anatomic detail and are indispensable specifically for guiding surgical intervention. However, they are limited in their ability to characterize masses reliably as malignant or benign. Necrotic, scar, or inflammatory tissue often cannot be differentiated from malignancy based on anatomic imaging alone.

In contrast, molecular F-18 deoxyglucose (FDG)-PET imaging utilizes the markedly increased glucose metabolic activity of tumor cells and provides images of the whole body distribution of phosphorylated FDG. Increased glucose utilization and, thus, increased uptake of FDG in tumor cells is facilitated by: 1) increased activity of cell membrane glucose transporters, 2) increased hexokinase activity, and 3) increased rates of the hexose monophosphate shunt.

The fundamental differences between anatomic (i.e., CT and MRI) and molecular (i.e., PET) imaging can be summarized as follows: anatomic imaging detects structural abnormalities with a high accuracy. Size criteria fail to characterize structural abnormalities reliably as malignant or benign. This implies that anatomic imaging generally has a high sensitivity for the detection of structural alterations, but a low specificity for further characterizing these abnormalities.

THE POWER OF MOLECULAR PET IMAGING

More recently, the medical community has embraced molecular imaging with PET and the glucose analogue FDG as a means to discriminate benign from malignant lesions accurately. This is based on the fact that malignant tissue exhibits markedly increased rates of glucose consumption. Because cell alterations at the molecular level precede anatomic tissue alterations, whole-body imaging with FDG consistently diagnoses, stages, and re-stages cancer with a substantially higher accuracy than CT. For instance, Dwamena et al ¹ conducted a meta-analysis to compare the performance of PET and CT for mediastinal lymph node staging in lung cancer patients. Using stringent selection criteria, this analysis included 514 lung cancer patients studied with PET (included in 14 published studies) and 2226 patients evaluated with CT (derived from 29 studies). They concluded that PET demonstrated both higher sensitivity (79% versus 60%) and specificity (91% versus 77%) than CT for correctly classifying mediastinal lymph nodes.

Similar observations have been made in patients with lymphoma, ² colorectal cancer, ³ breast cancer, ⁴ and many other malignancies. FDG-PET has also been established as a powerful prognostic tool in cancer patients. ⁴ Finally, the effects of various treatments on cancer tissue can be monitored reliably early after the initiation of treatment.

Gambhir and coworkers ⁵ have recently summarized the power of FDG-PET based on tabulated research data obtained in more than 26,000 patients with a variety of cancers. PET was 10% to 20% more accurate than conventional imaging for diagnosing staging and restaging most cancers. ⁵

Based on this body of evidence, Medicare is now covering PET for diagnosis, staging, and restaging of lung cancer, colorectal cancer, lymphoma, melanoma, head and neck cancer, and esophageal cancer. CMS recently has also approved FDG-PET for restaging and monitoring the treatment of patients with breast cancer.

While molecular PET imaging evaluates cancer patients more accurately than anatomic imaging, several issues remain unresolved. First, PET using FDG or more specific tracers does not provide exact localization of molecular abnormalities. Thus, additional anatomic imaging for localizing abnormalities is necessary in many patients. Secondly, clinical whole-body PET studies are relatively time-consuming, requiring 45 to 60 minutes of imaging time.

MOLECULAR AND ANATOMIC IMAGING

Several studies have shown that PET and CT, when evaluated together, increased the accuracy of both tests. Chin et al ⁶ reported a series of 30 patients studied with PET and CT to determine mediastinal lymph node involvement. They concluded that the combined information of PET and CT yielded the highest diagnostic accuracy (90%). Similarly, Weng et al ⁷ also reported a higher diagnostic accuracy for PET and CT than for PET or CT alone for lung cancer staging. Magnani et al ⁸ reported that 25 of 28 patients were staged correctly with PET+CT, while only 21 and 22 patients, respectively,, were staged correctly with CT or PET alone.

Vansteenkiste et al ⁹ compared the accuracy of visually analyzed FDG-PET and CT images with that of CT alone for the mediastinal staging of 68 lung cancer patients. State-of-the-art spiral CT and a dedicated whole-body PET scanner were used. Invasive surgical staging was used as the gold standard in all patients for a total of 690 lymph node stations. Overall, the diagnostic accuracy was better for PET+CT than for CT alone (87% versus 59%). PET+CT was also superior to CT alone for detecting locally advanced disease (N2/N3). Sensitivity, specificity, and accuracy of CT alone were 75%, 63%, and 68% compared with 93%, 95%, and 94% for PET+CT ( P = 0.0004). Based on their findings of a very high negative predictive value of PET, these authors reported that mediastinoscopy could have been omitted in 29 of 68 patients.

DUAL-MODALITY PET/CT IMAGING

Analysis of retrospectively aligned PET and CT images is, however, error-prone, time-consuming, and tedious. Moreover, true image fusion is difficult given the different patient positioning between the PET and the CT scan. ¹⁰

To avert these problems, a team at the University of Pittsburgh headed by Drs. David Townsend in collaboration with CTI Molecular Imaging, Inc.(Knoxville, TN) and Siemens Medical Solutions (Hoffman Estates, IL) developed a dual-modality PET/CT tomograph combining both PET and CT scanning in one device. ¹¹ This first prototype to be used clinically consisted of a rotating partial-ring PET system and single-slice CT scanner mounted to the same rotating support. Since the introduction of this prototype, several PET/CT devices have been introduced and are now available commercially (CTI Molecular Imaging, Inc.; GE Medical Systems, Waukesha, WA; Philips Medical Systems, Bothell, WA; Siemens Medical Solutions). As of the time of this writing, nedarly 100 PET/CT scanners have been installed worldwide.

INITIAL RESEARCH EXPERIENCE WITH PET/CT IMAGING

The first clinical studies investigating the advantages of PET/CT over PET or CT imaging alone have been published. Martinelli and co-workers ¹² reviewed more than 100 oncology studies acquired with the prototype PET/CT scanner at the University of Pittsburgh. From their observations in patients with a variety of malignancies, they concluded that PET/CT offered significant advantages including more accurate localization of FDG-uptake, distinction of pathological from physiologic uptake, and improvements in monitoring treatment.

The same group also investigated in a small case series the impact of the PET/CT on patient management. ¹³ Management changes included, for instance, modifications of surgical or medical approaches.

As mentioned above, PET/CT should prove especially useful for evaluating "difficult-to-image" regions of the body. These include the head and neck, the mediastinum, and the postsurgical abdomen. Kamel and co-workers ¹⁴ from the University Hospital of Zurich reported focal FDG uptake in the lower anterior neck in 6 of 184 patients who underwent lung cancer staging. Using the PET/CT device revealed that the FDG uptake was localized in hypertrophied normal laryngeal muscle caused by contralateral laryngeal nerve tumor invasion. Obviously, the PET/CT assessment avoided the false positive findings of PET alone.

Makhija et al ¹⁵ used PET/CT to evaluate patients with suspected recurrent ovarian cancer. PET/CT identified the site of recurrence in 5 (62%) of 8 patients who had negative CT findings.

Published evidence on the merits of PET/CT for evaluating cancer patients is currently evolving. This is because the technology is new and initial clinical evaluations of PET/CT imaging have not been finalized. However, during the 2002 meeting of the American Society of Nuclear Medicine more than 50 abstracts addressed the role of PET/CT imaging. Several of these scientific papers shed light on the merits of PET/CT imaging.

Cohade and co-workers ¹⁶ evaluated in 358 patients the supraclavicular "muscle-uptake" PET artifact using PET/CT. They found in a significant portion that this artifact might be caused by "brown" fat and not by increased glucose metabolic rates of striated muscle.

Equivocal PET lesions were also evaluated with PET/CT by Yeung et al. ¹⁷ Analyzing the findings in the first 100 patients studied with PET/CT, they reported that 57% of the equivocal PET findings could be classified correctly into normal or abnormal categories. Thus, PET/CT aids in differentiating benign or artifactual lesions from malignant disease.

The role of PET/CT for evaluating patients for lung cancer recurrence was assessed by Keidar et al. ¹⁸ This study of 26 patients revealed that PET/CT provided important additional information in 56% of the patients. The added value of PET was related to improved lesion localization and differentiation between physiological and pathological FDG uptake. Importantly, lesions missed by CT initially were visualized by PET/CT and were identified subsequently on CT images.

Another study examined the added value of PET/CT imaging in cancer patients. ¹⁹ PET/CT improved the accuracy of PET in 48% of the patients mainly by improving lesion localization, and led to retrospective detection of CT abnormalities in a considerable number of patients.

The impact of PET/CT imaging on the preoperative staging of lung cancer patients was evaluated by Steinert et al. ²⁰ These authors reported an incremental impact of PET/CT imaging with increasing patient stage. While PET/CT altered the stage in only 1 of 9 patients with stage I or II disease, it impacted stage IIIA in 5 of 6, 6 of 6 patients with stage IIIB, and 8 of 8 patients with stage IV disease. The authors concluded that PET/CT was superior to PET or CT alone in initial staging of lung cancer.

Another advantage of PET/CT in the staging/restaging of lung cancer patients was provided by Osman et al ²¹ in 34 patients. These authors reported significantly fewer "probable" or "equivocal" lesions with PET/CT than with PET alone. Further, lesion localization was improved significantly by PET/CT.

One important emerging clinical contribution of PET/CT is its role in the field of radiation oncology, specifically radiation planning. This is because CT alone can only delineate mass lesions, but frequently fails to determine reliably the amount and extent of viable tumor. Dizendorf et al ²² evaluated prospectively the impact of PET/CT on radiation planning in 30 consecutive patients scheduled to undergo external beam radiation. CT determined the target volume of PET/CT. Combined PET/CT changed the radiation treatment strategy from curative to palliative in 20% of the patients. In 30% of the patients, the radiation dose was changed and changes of the target volume were reported in 40% of the patients. The impact of these modifications on patient outcomes will need to be addressed in future studies.

TECHNICAL CONSIDERATIONS

Several technical limitations of PET/CT need to be addressed. Foremost among these are artifacts induced by patient or respiratory motion, ²³ or artifacts from dental metallic implants. ²⁴ For instance, respiratory or patient motion induces artifacts on CT and thus, PET/CT images. ²³ Goerres and co-workers attempted to optimize respiration during the CT portion of the study. They concluded from their study in 28 cancer patients that a normal expiration protocol during CT provides the best image co-registration. The authors further stated, "that a perfect match between PET and CT is not possible, but the attainable quality of image co-registration is in the range of the resolution of the PET camera."

Limitations of PET/CT imaging were discussed by Osman et al. ²⁵ These authors analyzed the frequency of inaccurate lesion localization with PET/CT. Such incorrect localization induced by respiratory or patient motion occurred in 6 of 285 patients and was most frequently explained by mislocalization of liver lesions into the base of the right lung.

The same group evaluated the influence of metallic dental work on the quality of PET images. ²⁴ The authors reported artifacts on both PET images corrected with CT data and those corrected for photon attenuation using a conventional 68Ge transmission source. They concluded from their findings that non-attenuation corrected PET images should be reviewed in these patients in order to avoid this artifact.

CURRENT PET/CT IMAGING PROTOCOLS

The standard patient preparation employed for PET and CT studies is applied to the PET/CT device. Patients receive 370 to 550 MBq of FDG 45 to 60 minutes prior to the start of the image acquisition. After the patient is positioned on the scanner, an initial topogram is acquired. The topogram is used subsequently to define the examination range for the PET/CT image acquisition. The spiral CT scan is performed next, regardless of the use of intravenous or oral contrast. After completion of the CT portion, the scanner bed is moved to the starting position and the emission scan is started. The emission scan duration and bed position varies with the detector technology used. With conventional bismuth germanate oxy-ortho silicate (BGO) system, acquisition times will range from 4 to 6 minutes per bed position. The new lutetium oxy-ortho-silicate (LSO) technology reduces emission scans to 2 to 3 minutes per bed position.

The CT data are used to perform attenuation correction. Image reconstruction is completed a few minutes after the PET image acquisition is completed. Because the CT data are used for attenuation correction, the actual scan duration of a PET/CT protocol is shorter than that required for a dedicated PET scan.

PET/CT technology is advancing at a breath-taking pace. The demands for devices consisting of "state-of-the-art" PET and CT systems that allow for high patient throughput need to be met. Among the most exciting developments is the introduction of the LSO detector technology into PET/CT. LSO has a higher light output than the conventional BGO detectors and a shorter scintillation decay time resulting in markedly improved count rate capabilities while the physical detector properties of BGO are maintained. Thus, high FDG doses can be injected and images can be acquired in the three-dimensional mode resulting in improved resolution. This allows for the completion of whole-body PET/CT studies in ¾15 minutes (Figures 1, 2, and 3).

PET/CT devices have been introduced to the clinic and are now available commercially. This new technology has generated enormous interest within the medical community. Radiologists and nuclear medicine specialists worldwide have embraced the concept of merging molecular with anatomic imaging.

The power of molecular imaging, together with the detailed anatomic landmarks provided by CT, will dramatically change diagnosing, staging and restaging of cancer patients; selection of treatment modalities; planning of radiation therapy; and the monitoring of surgical, medical, and radiation treatments. Thus, PET/CT imaging is changing the care of cancer patients in several ways:

a) Metabolic and anatomic whole-body staging of patients can be performed in one examination and much reduced scan times, thus, increasing patient comfort.

b) Because of limited patient motion, near ideal fusion of metabolic and anatomic images can be achieved.

c) Anatomic landmarks provided by CT will greatly facilitate the assignment of functional abnormalities to anatomic structures.

d) "Difficult to image" regions of the body (such as the head and neck, mediastinum, and postsurgical abdomen) will be evaluated with a high diagnostic accuracy.

e) Fused images can be used to target radiation treatment more accurately and monitor the effects of chemotherapy, surgery, and radiation treatment.

INSTRUCTIONS

The Institute for Advanced Medical Education designates this continuing medical education activity for 1 hour in Category 1 of the Physician's Recognition Award of the American Medical Association.

This CME article consists of text and related images appearing in this newsletter article. You should read the article and accompanying images in the PDF file, refer to the references, and complete the self-evaluation quiz available online in order to be awarded CME credits.

To go directly to the quiz please click here

Estimated time for completion: One hour

Date of release: November 2005

Expiration date: November 2007

Program: PET-002

Dr. Czernin is the Director of Nuclear Medicine and an Associate Professor in the Department of Molecular and Medical Pharmacology, the Deptartment of Nuclear Medicine, and the Department of Medicine, University of California, Los Angeles School of Medicine, Los Angeles, CA.

In compliance with the Essentials and Standards of the ACCME, the author of this CME tutorial is required to disclose any significant financial or other relationships he may have with the manufacturer(s) of any commercial product(s) or provider(s) of any commercial service(s) discussed in this program.

Dr. Czernin has disclosed that he has a relationship with CPS Innovations through his participation as board member.

Category 1 CME

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of ArcMesa Educators and Anderson Publishing, Ltd. ArcMesa Educators is accredited by the ACCME to provide continuing medical education for physicians.

ArcMesa Educators designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

LEARNING OBJECTIVES

After completing this program, the reader will:

* Understand the differences in information provided by molecular positron emission tomography (PET) and conventional anatomical computed tomographic (CT) imaging.

* Understand the concept of dual-modality imaging with PET/CT

* Understand the advantages of PET/CT imaging over PET or CT imaging alone.

Medicare Reimbursement for PET Imaging

Breast Cancer *NEW*

G0252 PET imaging for initial diagnosis of breast cancer and/or surgical planning for breast cancer (e.g., initial staging of axillary lymph nodes), not covererd by Medicare

G0253 PET imaging for breast cancer, staging/restaging of local regional recurrence or distant metastases, i.e., Staging/restaging after or prior to course of treatment

G0254 PET imaging for breast cancer, evaluation of response to treatment, performed during course of treatment

Lung Cancer

G0210 PET Imaging whole body; diagnosis; lung cancer, non-small cell

G0211 PET Imaging whole body; initial staging; lung cancer; non-small cell (replaces G0126)

G0212 PET Imaging whole body; restaging; lung cancer; non-small-cell colorectal cancer

G0213 PET Imaging whole body; diagnosis; colorectal cancer

G0214 PET Imaging whole body; initial staging; colorectal cancer

G0215 PET Imaging whole body; restaging; colorectal cancer (replaces G0163)

Melanoma

G0216 PET Imaging whole body; diagnosis; melanoma

G0217 PET Imaging whole body; initial staging; melanoma

G0218 PET Imaging whole body; restaging; melanoma
(replaces G0165)

G0219 PET Imaging whole body; melanoma for non-covered indications (no payment)

Lymphoma

G0220 PET Imaging whole body; diagnosis; lymphoma

G0221 PET Imaging whole body; initial staging; lymphoma (replaces G0164)

G0222 PET Imaging whole body; restaging; lymphoma
(replaces G0164)

Head and Neck Cancer

G0223 PET Imaging whole body or regional; diagnosis; head and neck cancer; excluding thyroid and CNS cancers

G0224 PET Imaging whole body or regional; initial staging; head and neck cancer; excluding thyroid and CNS cancers

G0225 PET Imaging whole body or regional; restaging; head and neck cancer, excluding thyroid and CNS cancers

Esophageal Cancer

G0226 PET Imaging whole body; diagnosis; esophageal cancer

G0227 PET Imaging whole body; initial staging; esophageal cancer

G0228 PET Imaging whole body; restaging; esophageal cancer

Seizure

G0229 PET Imaging; Metabolic brain imaging for pre-surgical evaluation of refractory seizures solitary pulmonary nodule

G0125 PET Imaging whole body or regional single pulmonary nodule

Heart

G0230 PET Imaging; Metabolic assessment for myocardial viability following inconclusive SPECT study

*NEW*

78459 Heart Muscle imaging determination of myocardial viability as primary or initial diagnosis prior to revascularization

Above Information abtained from www.CMS.gov

Applications in PET is published by Anderson Publishing, Ltd., 1301 West Park Ave., Ocean, NJ 07712; (732) 695-0600. O. Oliver Anderson, Publisher, Elizabeth A. McDonald, Managing Editor; Karen King, Art Director

Sponsored by a grant from CTI Molecular Imaging, Inc. The views and opinions expressed in this publication are those of the authors and do not necessarily reflect those of the publisher or sponsor. Full and complete prescribing information should be reviewed regarding any product mentioned prior to use.

2002 Anderson Publishing, Ltd.