PET in oncology: Will it replace the other modalities?

PET in Oncology: Will it Replace the Other Modalities? Carl K. Hoh, Christiaan Schiepers, Marc A. Seltzer, Sanjiv S. Gambhir, Daniel H.S. S i l v e r m a n , J o h a n n e s Czernin, J a m s h i d Maddahi, and Michael E. Phelps Medical imaging technology is rapidly expanding and the role of each modality is being redefined constantly. PET has been around since the early sixties and gained clinical acceptance in oncology only after an extreme number of scientific publications. Although PET has the unique ability to image biochemical processes in vivo, this ability is not fully used as a clinical imaging tool. In this overview, the role of PET in relation to other tumor imaging modalities will be discussed and the reported results in the literature will be reviewed. In predicting the future of PET, technical improvements of other imaging modalities need to be dealt with. The fundamental physical principles for image formation with computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), photon-emission tomography (PET), and single photon emission CT (SPECT) will not change. The potential variety of radiopharmaceuticals which may be developed is unlimited, however, and this provides nuclear imaging techniques with a significant advantage and adaptive features for future biologic imaging. The current applications of PET in oncology have been in characterizing tumor lesions, differentiating recur-

rent disease from treatment effects, staging tumors, evaluating the extent of disease, and monitoring therapy. The future developments in medicine may use the unique capabilities of PET not only in diagnostic imaging but also in molecular medicine and genetics. The articles discussed in this review were selected from a literature search covering the last 3 years, and in which comparisons of PET with conventional imaging were addressed specifically. PET studies with the glUcose analogue fluorine-18-1abeled deoxyglucose (FDG) have shown the ability of detecting tumor foci in a variety of histological neoplasms such as thyroid cancer, breast cancer, lymphoma, lung cancer, head and neck carcinoma, colorectal cancer, ovarian carcinoma, and muscuIoskeletal tumors. Also, the contribution of the whole body PET (WBPET) imaging technique in diagnosis will be discussed. In the current health care environment, a successful imaging technology must not only change medical management but also demonstrate that those changes improve patient outcome. Copyright9 1997by W.B. Saunders Company

HE RAPID ADVANCES in medical imaging technology pose a challenge for the imaging specialist who must assess the utility of these new technologies and also for the clinicians who must integrate these technologies for optimum patient management and improved patient outcome. Although positron-emission tomography (PET) has been in existence since the 1960s, it has experienced a prolonged period in gaining clinical acceptance. Some of the pioneering work by Di Chiro et al, ~-5 almost a decade ago, on differentiating recurrent brain tumor from radiation necrosis, has only recently been recognized as a valid indication for tumor imaging with PET. The acceptance has been achieved after a large number of scientific papers were published on a particular clinical indication. No other imaging technology has so much clinical potential because of its unique ability to image biochemical processes in vivo and yet society has

been less willing to accept its cost and implementation as a clinical imaging modality. Perhaps some perceive PET as a complicated and expensive imaging technology, only available at large medical centers, or perhaps practicing clinicians and specialists outside the PET field simply avoid the technological and financial complexities of PET. To predict the future of an imaging modality such as PET, the technical improvements in the other imaging modalities also need to be taken into account. These modalities will be evolving with improved resolution, faster acquisitions, and improved injectable contrast. Although all of these other modalities will improve technically over time. their basic physical principles for image formation will not change: computed tomography (CT) will rely on attenuation of x-ray photons by tissue density, ultrasonography (US) will rely on the reflection of high frequency sound waves on tissue planes, and magnetic resonance imaging (MRI) will rely on radio-frequency signals from tissues in a magnetic field. The basic principles of PET and single photon emission computed tomography (SPECT) will continue to be based on the detection of photons emitted from the patient. However, what is unlimited is the potential variety of radiopharmaceuticals or radiotracers which may

T

From the Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA. Address reprint requests to Carl K. Hoh. MD. Department of Molecular and Medical Pharmacology, UCLA School of Medicine, 10833 LeConte Ave, CHS AR-128, Los Angeles, CA 90095-6942. Copyright 9 1997 by W.B, Saunders Company 0001-2998/97/2702-000255.00/0

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Seminars in NuclearMedicine, Vol XXVlI, No 2 (April), 1997:pp 94-106

PET IN ONCOLOGY: REPLACE OTHER MODALITIES?

be developed in the future. The continuing development of new and specific diagnostic and therapeutic tracers is one of the unique adaptive features of nuclear medicine and PET which will help maintain its role in clinical imaging and medicine. As some nuclear medicine procedures become obsolete because of competing imaging technologies, new tracers with better or different biological characteristics will evolve. To understand the role of PET in relation to other tumor imaging modalities and to see where it may have theoretical advantages in potential clinical applications now and in the future of oncology, the unique technological features of PET and some of its current clinical appl!cations will be reviewed. The articles and papers discussed in this review are selected from a literature search covering the last 3 years, which specifically address the comparison of PET to conventional imaging. This review does not attempt to include all PET studies in oncology. BACKGROUND: TECHNOLOGICAL FEATURES OF PET

As an imaging modality, there are four features of PET which enable scientists and clinicians to noninvasively measure biochemical and/or physiological processes in vivo: radiopharmaceuticals which resemble endogenous biological compounds, quantification of the tracer distribution, rapid simultaneous volumetric acquisitions, and whole body tomographic images. The first feature, unique to PET, is the intravenous administration of radiopharmaceuticals which closely mimic endogenous compounds. A list of more commonly used positron emitting radiotracers and their biochemical analogs is given in Table 1. The most commonly used PET radiotracer for tumor imaging is the glucose analog 2-[F- 18]fluoro2-deoxy-D-glucose (FDG). The ability to noninva-

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sively image glucose utilization is important, because a high rate of glyco!ysis is found in many malignant tumor cells.6.7 Many PET studies have shown the ability of FDG to detect tumor foci of a wide variety of histological types including thyroid cancer,s-" breast cancer, 12"16 !ymphoma, 17-2~ lung Cancer, 22-2a squamous cell carcinomas of the head and neck region,29-34 colon cancer, 35-3s ovarian carcinoma,39 and musculoskeletal tumors.4~ The second feature of PET is its ability to accurately measure the actual three-dimensional radiotracer distribution, which makes PET similar to autoradiography. This feature is an important aspect for the objective quantification o f tracer activity in dynamic or static images. A numerical value representing the local tracer concentration or accumulation rate in a lesion gives scientists and clinicians a new parameter for characterizing unknown or suspicious lesions. The third feature of PET is its ability to rapidly acquire (as fast as 10 see/frame) a dynamic set of tomographic images (15-63 slices) through a volume of tissue. This is possible through the design and arrangement of multiple rings of coincidence detectors in the scanner. A rapid frame acquisition is important in studying the tracer kinetics of compartmental models, because the dynamic changes in blood and tissue activity need to be adequately sampled as time activity curves. Currently, no other imaging modality is capable of simultaneously acquiring rapid dynamic tomographic images in a volume of tissue. The fourth and more recent feature of PET, developed at UCLA, is the capability to acquire tomographic whole body images. Most modem PET Scanners can simultaneously acquire multiple image planes in a 10 to 15 cm axial span. By advancing the bed position relative to the scanner

Table 1. Commonly Used Positro n Emitting Tracers Radiotracer

BiologicAnalog

2-Deoxy-2(~SF)flouro-D-glucose (FDG)

Glucose

5-(lSF)flouro-DOPA (1BF)Fluoromethyltyrosine (~SF)Fluoro-2'-deoxyuridine (~aF)fluoroacyclovir (~C)Acetate (1aN)Ammonia (~60)Water (=Ga)EDTA

Dopamine Tyrosine Fluorodeoxyuridine Acyclovir Acetate None Water None

Measured Response

IsotoPeHalf-life(rnin)

Glucose metabolism Phosphorylation by hexokinase Amino acid metabolism Amino acid metabolism Nucleic acid metabolism Phosphorylation by thymidins kinase Fatty acid metabolism "tissue perfusion "tissue perfusion Capillary integrity; blood brain barrier

110 110 110 110 1 !0 20 10 2 60

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gantry at set time intervals, the patient can be imaged in multiple sections, and a whole body PET (WBPET) image can be created by appending the images of each bed position to the total image volume. The WBPET images are large volumetric data sets which can be displayed as tomographic images in the transaxial, coronal, or sagittal planes, whereas conventional single photon whole body scans are usually planar two-dimensional projection images. It isthe combination of these four features which provides PET the ability to model and quantitate in vivo biochemical or physiologicaI processes, because the tissue concentration of radiotracer activity can be serially imaged over time after tracer injection. CHARACTERIZATION OF INDETERMINATE LESIONS ON ANATOMICAL IMAGING

With the technological features o f PET described previously, there are clinical applications where it has Shown diagnostic utility. One of the main applications of PET has been the biochemical characterization of lesions which are indeterminate on anatomical imaging (ie, CT or MRI). In lesions which are already detected by anatomical imaging but require further biochemical differentiation, a dedicated PET scan localized to that anatomical area is usually performed. This localized scan provides high count statistics and allows attenuation correction so that the optimum image quality is obtained and lesion activity can be visually assessed, or quantified. To allow an objective assessment of the amount of tracer uptake, many clinical studies are analyzed semiquantitatively using parameters such as the standardized uptake value (SUV), also known as the differential uptake ratio (DUR), or differential absorption ratio (DAR). Although this semiquantitative method has been criticized by some in the PET field, 42 the method, if properly performed, offers a more objective reporting of the amount of tracer uptake in a lesion compared with visual interpretation. In addition, the SUV does not require multiple blood samples as would be necessary in tracer kinetic modeling. So far, the SUV technique appears to be satisfactory for clinical purposes and appears to work very well for some tumors. 43 For other applications, the distinction between benign and malignant lesions is less clear

and absolute quantification or an entirely different radiotracer may be required. Because it is known that the distribution of FDG in the body is not uniform (caused by higher FDG uptake in muscle tissue compared to fat tissue), modifications of the SUV method have been investigated to account for this heterogeneity of tracer distribution. Improved semiquantitative FDG uptake values have been found by using the patient body surface area44 or lean body mass. 45 Although the SUV and DUR methods are not truly quantitative kinetic measurements of biochemical processes, they have the advantage of circumventing the problems of the unknown lumped constant; the assumed model configuration, and the multiple blood samples required for obtaining the plasma tracer concentration as a function of time. However, it is important t ~ realize that the SUV or DUR calculations are not time independent, and that the uptake of FDG seen on the final image is caused by the same underlying factors related to FDG kinetics. Therefore, the time at which the SUV is determined is important. It is generally assumed that the tumor achieves a Plateau concentration at the time of image acquisition; however, many tumor kinetics are not known and tracer uptake may still be increasing at the time of imaging. Therefore, standardization of the SUV is necessary to compare results between institutions:

Differentiation of Solitary Pulmonary Nodules A specific application of FDG PET in differentiating benign from malignant lesions has been reported for solitary pulmonary nodules. 46 In this prospective study, increased uptake in malignant compared with benign lung nodules was found in 30 patients who presented with indeterminate solitary pulmonary nodules. Visual analysis and DURs were used in interpretation of the lesions. Histological specimeng were obtained in 29 patients by either thoracotomy (n = 20), transthoracic needle aspiration biopsy (n = 8) or bronchoscopy (n = 1). In this study, Dewan et al found the sensitivity and specificity of PET for detection of malignant pulmonary nodules to be 95%, and 80% respectively (see Table 2). Two false-positive results were because of inflammatory lesions: granulomatous disease with active inflammation and laistoplasmosis. One falsenegative result was in a patient with a 1 cm nodule with adenocarcinoma. In a similar report,47 FDG PET was found to have a sensitivity of 97% and a

PET IN ONCOLOGY: REPLACE OTHER MODALITIES?

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Table 2. FDG PET in the Differentiation of Solitary Pulmonary Nodules LesionAnalyzed Dewan et al'~

Solitary pulmonary nodule Dewan et also Pulmonary lesion with TTNA Duhaylonsod et al4~ Primary & recurrent lung CA Gupta et al4s Solitary pulmonary nodule Inoue et a l s o Recurrent lung CA vs scar Knight et al~ Pulmonary lesions with history Patz et alzs Focal pulmonary abnormality

Sensitivity (%) 19/20 (95%)

Specificity (%)

Accuracy (%)

PPV(%)

8/10(80%) 27/30 (90%) 19/21 (90%)

26/26(100%) 7/9 (78%)

33/35(94%) 26/28 (93%)

NPV(%)

SUV SUV Malignant Benign

8/9 (89%)

5.6 • 2.8 0.9 • 1.0

7/7 (100%)

--

57/59 (97%) 23/28(82%) 80/87 (92%) 57/62 (92%)

23/25 (92%) 6.6 -+ 3.1 2.0 • 1.6

42/45 (93%) 14/16(88%) 56/61 (92%) 42/44 (95%)

14/17 (82%) 6.3•

1.1• 1.0

26/26 (100%) 8/13 (62%) 34/39 (87%) 26/31 (83%)

8/8(100%) 11.2 -- 5.7 3.5 • 1.8

14/14 (100%) 7/12 (58%) 21/26 (81%) 14/19 (74%)

7/7 (100%)

29/33 (89%) 18/18 (100%) 47/51 (92%) 29/29 (100%) 18/22 (82%)

specificity of 82% for differentiating benign from malignant focal pulmonary lesions in patients with suspected primary or recurrent lung cancer. In a more recent report, 4s several factors which influence the pretest probability for tumor in a solitary nodule were included to determine the risk estimate or probability of cancer in radiographically indeterminate solitary pulmonary nodules. As shown in Table 2, the sensitivity, specificity and accuracy, were 93%, 88%, and 92%. Similarly, another FDG PET study which grouped patients into those with and without clinical histories of malignancy,49 found that PET could identify malignant pulmonary lesions in both groups with high sensitivity and high negative predictive values. Again, inflammatory lesions accounted for the false-positive studies in both groups of patients. In another study which evaluated suspicious lung lesions, FDG PET was compared with transthoracic fine needle aspiration (TTNA). 5~In this study, TTNA had an 81% sensitivity for detecting malignant lesions, missing five lesions which were correctly characterized by PET. TTNA obviously had a specificity of 100% for malignancy. Because more than half of indeterminate solitary pulmonary nodules are benign sl.52 and if FDG PET has a high negative predictive value (NPV) for malignant lung nodules, perhaps no further work-up is necessary after a negative PET scan. In the 30% of patients where the lesions are positive on FDG, a TTNA can then be used to establish the tissue diagnosis, significantly reducing the frequency of morbidity and mortality due to TTNA. In all of these studies, FDG PET was used to evaluate indeterminate solitary pulmonary nodules.

8.9 -- 4.9 3.3 • 3.2 6.5•

1.7• 1.2

Another similar application would be in the differentiation of recurrent tumor from benign scar in lung cancer patients who have already been treated. In a study by Inoue et al, 38 patients with 39 lung lesions were scanned by FDG PET to distinguish recurrent lung carcinoma lesions from benign scar tissue, and were compared with thoracic CT and MRI. 53 Semiquantitative analysis using the SUV was performed in 25 lesions and the FDG PET interpretations were correlated with pathological diagnoses and clinical outcome. FDG PET was found to be highly sensitive for recurrent carcinoma; however, there were some limitations in the specificity of the uptake. The five false-positive results were from acute inflammation, reactive mesothelial cells, and a pleural effusion. The authors felt that FDG PET scans should be interpreted in conjunction with other anatomical imaging modalities such as chest CT or MRI. For solitary pulmonary nodules, PET has shown high sensitivity for detecting malignant lesions (90%-100%), but with lower specificity (60%100%) because of benign inflammatory lesions. As an imaging test to further characterize a nodule discovered on a chest radiograph, this high sensitivity at the expense of lower specificity is acceptable so that few patients with malignancy will go undiagnosed and untreated. The cost-effectiveness of this algorithm can be evaluated by decision tree sensitivity analysis as has been shown in the cost-effectiveness of FDG PET in mediastinal staging of non-small-cell lung carcinomaP4 It is possible that a cost-effective diagnostic algorithm for solitary pulmonary nodules may consist of a chest radiograph, followed by an FDG PET scan,

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which if positive, then proceeds to a CT guided TTNA.

Detection of Colorectal Carcinoma: Recurrence and Metastases Another tumor which has been studied with PET in the context of biochemical characterization, is colorectal carcinoma versus scar tissue. A classic study is one by Strauss et al where 21 patients with recurrent colorectal malignancy, and 8 patients with nonmalignant masses were imaged with FDG PET. The benign lesions showed low FDG accumulation on images obtained 60 minutes after injection. In addition, the SUV and tumor-soft tissue ratios were able to differentiate tumor from nonmalignant tissue. In a more recent study of 76 patients presenting with or suspected of recurrent colorectal carcinoma, PET was found to be superior to pelvis CT in detecting local disease recurrence. 55 The accuracy for local disease recurrence was 95% for PET and 65% for pelvic CT. No significant difference was found for the accuracy in detecting lesions in the liver, 98% for PET and 93% for CT or US. In this study, additional extrahepatic sites of disease were found in 10 patients. In another study, WBPET affected management in 14 of 35 patients who were evaluated for recurrent disease. 56 In eight patients with presacral masses and equivocal CT findings, FDG PET correctly identified the five patients who had tumor recurrence. In a double-blinded study, FDG PET was compared with conventional radiological imaging for identifying operable colorectal cancer metastases to the l i v e r y In 11 of 34 patients (32%), PET found unsuspected extrahepatic malignant disease that was missed by conventional radiological imaging. The lesions included retroperitoneal nodal metastases (n = 6), pulmonary metastases (n = 3), and locoregional cancer recurrences (n = 2). An influence on clinical management occurred in 10 of 34 (29%) of cases. FDG PET enabled the selection of patients with apparently curable colorectal cancer

metastases to the liver for hepatic resection; however, clinical follow-up of these patients will determine whether PET truly detected all lesions in the liver. As long as surgical resection of recurrent colon carcinoma is considered, anatomical imaging for lesion localization with CT or MRI will be required. However, in patients suspected of recurrent colo-rectal carcinoma who have a negative PET study, additional imaging with CT or MRI may not be necessary. Further studies will be needed to confirm this hypothesis.

Detection of Head and Neck Carcinomas As stated previously, many prior studies have evaluated the use of PET in head and neck carcinomas. A more recent study used tyrosine PET to detect lymphogenic metastases in 11 patients with squamous cell carcinoma of the oral cavity.58 Tyrosine PET had a high sensitivity and specificity compared with CT or MRI, (Table 3). In another study which compared FDG PET with anatomical methods, PET showed improved diagnostic accuracy for recurrent head and neck cancer. 59 In this study, 12 adult patients with a clinical suspicion for recurrence had FDG PET, MRI, and or CT imaging. The lesions were scored on a scale from 0 to 5 confidence level, with score 4 as positive. The PET sensitivity was 7 of 8 (88%), specificity 4 of 4 (100%), whereas MRI and or CT had a sensitivity of 2 of 8 (25%) and specificity of 3 of 4 (75%). In the Receiver Operating Curve (ROC) study, better diagnostic accuracy occurred with FDG PET than with MRI and/or CT (area under curve was 0.96 for PET v 0.55 for CT or MRI, P < .03). Although the accuracy of PET imaging may surpass that of anatomical imaging in head and neck carcinomas, the surgical or radiation treatment of this Cancer will most likely require anatomical localization of the abnormal PET foci. Because of the complex anatomy of the head and neck region, the optimal diagnostic modality may be a fusion image showing the abnormal metabolic lesions superimposed onto the anatomical locations.

Table 3. Comparison of PET and CT Imaging of Head and Neck Cancers PET

Anzai et al s9 Braams et a158

MRI

CT

LesionAnalyzed

Sensitivity (%)

Specificity(%)

Sensitivity (%)

Specificity(%)

Sensitivity (%)

Specificity(%)

Recurrent ca CA oral cavity

7/8 (88%) 20/24 (83%)

4/4 (100%) 251/263 (96%)

2/6 (25%)* 5/15 (33%)

3/4 (75%)* 134/140 (96%)

5/9 (55%)

113/123 (91%)

*Combined MRI and CT imaging. ?Results from lymph node basis.

PET IN ONCOLOGY: REPLACE OTHER MODALITIES?

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Differentiation of Pancreatic Masses Over the last 2 years, several reports have been published on the use of FDG PET for the characterization of pancreatic masses. It seems logical to use a metabolic signal for imaging in a tumor and in a location which has been a challenge for conventional imaging. The potential of PET for assessing patients with indeterminate CT findings for pancreatic carcinoma was shown in a study in which 12 patients with indeterminate masses and two patients with typical findings of malignancy were scanned with FDG PET.6~Eight patients had pancreatic cancers and six had benign lesions. Using an SUV cutoff of 2.5, all eight malignant lesions and 4 of 6 benign lesions were correctly identified, (Table 4). In another report, using FDG PET for detection of pancreatic cancer a comparison was performed on visual and quantitative image interpretation.6! In this study, 73 patients with suspected pancreatic cancer or chronic pancreatitis underwent imaging with CT and FDG PET. The SUV threshold for malignancy was set at 1.53 resulting in both sensitivity and specificity of 93% for lesion detection. Visual interpretation gave a slightly higher sensitivity of 95% but lowered specificity to 90%. With either method for FDG PET interpretation, the results were better than that of abdominal CT which had sensitivity and specificity of 80% and 74%, respectively. Similar results were obtained in another study which compared FDG PET with abdominal CT, abdominal US, and endoscopic US in 46 patients. 62 PET had higher sensitivities and specificities compared with these other modalities. False-positive cases were attributed to chronic active pancreatitis and a serous cystadenoma. Less encouraging results were found when FDG PET was used to differentiating pancreatic carcinoma from mass-forming pancreatitis (MFP). PET was compared with MRI in 15 patients with cancer and nine patients with MFP. In this study there was

a significant overlap in the DAR in pancreatic cancer 4.64 • 1.94, as well as in MFP 2.84 • 2.22. The DAR was calculated at 50 minutes into the study and whether or not other methods of FDG quantification will improve the results are unknown. The problem of increased FDG activity in intense inflammatory lesions will require further studies as this is a problem which has occurred in other types of lesions evaluated by FDG PET. In another study, FDG PET for the detection of pancreatic cancer was compared with CT and ultrasound US. 63 In 40 patients with suspected pancreatic cancer, the PET images were analyzed using visual interpretation, the DUR, and tumor to liver ratios (TLRs). In this study, PET had a sensitivity of 92%, and an accuracy of 90% for differentiating pancreatic masses. The relatively lower specificity of 84% was because of falsepositive cases with retroperitoneal fibrosis and chronic pancreatitis. In this study, PET had a sensitivity of 76% for detecting tumor involved lymph nodes, which was superior to both CT (17%) and US (6%). If further FDG PET studies in patients with pancreatic masses corroborate these encouraging results, FDG-PET may obviate further invasive diagnostic procedures in many patients with benign disease and only patients with abnormal FDG activity will need CT guided biopsies.

Differentiation of Adrenal Masses In a study differentiating indeterminate adrenal masses in patients with cancer, FDG PET images were correlated with findings at CT, surgery, and/or percutaneous biopsy.43 In 14 malignant and in 10 benign adrenal masses, PET had 100% sensitivity and 100% specificity for differentiating malignant versus benign lesions. The tumor to background ratios were 7.4 (2.9-16.6) for tumors and 0.8 (0.2-1.2) for benign adrenal lesions. The clinical application of FDG PET imaging of adrenal masses should be quite useful in patients with malignancy

Table 4. Comparison of FDG PET and CT Imaging of Pancreatic Carcinoma

Bares et aP3 Ho et aP~ Inokuma et a162 Stollfuss et a161

Modality

Criteria

Sensitivity(%)

Specificity(%)

Accuracy(%)

PPV (%)

NPV (%)

FDG PET FDG PET FDG PET FDG PET FDG PET Abd CT

Visual and DUR SUV cutoff = 2.5 Visual assessment Visual assessment SUV cutoff = 1 . 5 3 Visual assessment

25127 (92%) 8/8 (100%) 30/35 (94%) 41/43 (95%) 40/43 (93%) 33/41(80%)

11/13 (84%) 4/6 (67%) 9/11 (82%) 27/30 (90%) 28/30 (93%) 20/27 (74%)

36/40 (90%) 12/16 (86%) 39/46 (85%) 68/73 (93%) 68/73 (93%) 53/68 (78%)

25/27 (93%) 8/10 (80%) 30/32 (94%) 41/44 (93%) 40/42 (95%) 23/40 (83%)

11/13 (85%) 4/4 (100%) 9/14 (64%) 27/29 (93%) 28/31(90%) 20/28 (71%)

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HOH ET AL Table 5. Comparison of FDG PET and CT Imaging in Mediastinal Staging in Lung Cancer

Modality Chin et a168 Sasaki et a169 Wahl et a167

FDG PET Chest CT FDG PET Chest CT FDG PET Chest CT Fusion

Criteria

Sensitivity(%)

Specificity(%)

Accuracy(%)

PPV(%)

NPV (%)

Visual Visual Visual Visual Visual Visual Visual

7/9 (77%) 5/9 (56%) 13/17 (76%) 11/17 (65%) 9/11 (82%) 7/11 (64%) 9/11 (82%)

17/21 (81%) 18/21 (86%) 54/54 (98%) 47/54 (87%) 13/16 (81%) 7/16 (44%) 13/16 (81%)

24/30 (80%) 23/30 (77%) 66/71 (93%) 58/71 (82%) 22/27 (81%) 14/27 (52%) 22/27 (81%)

7/11 (64%) 5/8 (63%) 13/14 (93%) 11/18 (61%) 9/12 (75%) 7/16 (44%) 9/12 (75%)

17/19 (89%) 18/22 (82%) 53/57 (93%) 47/53 (89%) 13/15 (87%) 7/11 (64%) 13/15 (87%)

and indeterminate adrenal lesions, potentially obviating an invasive biopsy. STAGING MALIGNANCIES WITH PET

An obvious application of PET and WBPET is in the staging of tumors. Because the pathological stage of most tumors is associated with patient prognosis, a single accurate imaging method for detecting local and distant metastases would be clinically useful. Current modalities for whole body tumor surveys include Technetium 99m (99mTc)-methylenediphosphonate, 67Ga-citrate, 20~Thallium-chloride, 99mTc-methoxyisobutylisonitrile (99mTc-MIBI), and 1]lln_pentetreotide (Octreoscan). Complete body imaging with radiograph computed tomography or MRI of the chest, abdomen and pelvis also can be used for tumor surveys and offers the advantage of high contrast tomographic images. SPECT, on the other hand, would require prior knowledge of the affected area in question or require multiple SPECT acquisitions along the patient's length. The fact that PET acquires multiple volumetric datasets simultaneously, easily lends itself to producing highcontrast tomographic whole body images. 64-66Compared with planar images, lesion contrast can be increased by a factor of 10 on tomographic PET images, enabling a higher sensitivity for detecting small loci.

CT, in comparison, and had a sensitivity of 65%, specificity of 87%, and an accuracy of 82%. In another study of mediastinal staging of NSCLC with PET,68 30 patients with clinical stage I (T1-2, NO, M0) disease were compared with chest radio-

Mediastinal Staging in Lung Cancer One of the clinical applications where an extended field acquisition with PET is important is in the staging of non-small-cell lung carcinoma (NSCLC), (see Fig 1). Studies have shown that FDG PET is superior to CT when used for the detection of mediastinal lymph node metastases in these patients. 67-69In the study by Sasaki et al, 69 29 patients with 132 mediastinal lymph nodes and 146 mediastinal regions had FDG PET scans to evaluate mediastinal involvement. PET had a sensitivity of 76%, specificity of 98% and accuracy of 93%.

Fig 1. Single coronal image from a whole body FDG PET scan in a woman being staged for newly diagnosed squamous cell carcinoma of the right lung. Chest CT with adrenal cuts found no evidence of mediastinal or adrenal metastases. FDG PET also found no mediastinal involvement. However, a distant metastasis was found in the lower pole of the right kidney (lower arrow) which was outside of the CT imaging field.

PET IN ONCOLOGY: REPLACE OTHER MODALITIES?

graph, CT, and FDG PET. The "gold standard" was surgical exploration of the mediastinum. In 7 of 9 patients (77%) with mediastinal metastasis, FDG PET was positive. In 21 patients with negative mediastinal nodes by surgical dissection, four patients had false-positive lymph nodes on FDG PET. The diagnostic accuracy of combining both FDG PET and CT was 90%. In an earlier study, FDG PET was also found to be more accurate than CT in staging disease in the mediastinum in NSCLC patients. 67 This was a prospective trial with 23 patients with newly diagnosed or suspected NSCLC. Blinded interpretations of CT, PET and combined CT plus PET, and computer-generated "fusion" images were correlated to pathological results. For these investigators, PET appeared to be the preferred imaging method for mediastinal staging. Although FDG PET imaging appears more accurate in detecting the extent of mediastinal involvement of NSCLC in preoperative staging, the issues of bronchial wall, pleural, and vascular invasion of tumor will be difficult to image with PET. Here, anatomical imaging will be superior. The fusion image described by Wahl et al, 67 is probably the method which best optimizes the strengths of both imaging technologies. However, their data did not reflect any additional benefit in the fusion image. From a surgical perspective, an anatomical image remains necessary for operative planning. The cost-effectiveness of performing both PET and CT in the preoperative staging of patients with NSCLC was shown in a recent article on decision tree sensitivity analysis by Gambhir et al. 54

Staging of Lymphomas The accuracy of FDG PET imaging in thoracicabdominal lymphoma compared with that of CT was studied in 11 patients with non-Hodgkin's lymphoma (NHL) and 5 patients with Hodgkin's disease. 21 In this study, FDG PET detected 54 lesions, whereas CT detected 49 lesions. There were no lesions which were missed by PET. In addition, PET detected five lesions which were not seen on CT. Newman et a121 found no difference between low- and intermediate-grade lymphomas. PET appeared to have an excellent accuracy for imaging thoracic-abdominal lymphomas regardless of their tumor grade. In a more recent study comparing WBPET with that of conventional staging in 18 patients, both staging algorithms detected

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33 out of 37 lesions, although not all lesions detected were the same. 7~ Staging using WBPET was concordant with conventional staging in 14 of 17 patients, better than conventional staging in three patients, and worse in one patient. The actual total cost for the conventional staging was $66,292, whereas the cost for the WBPET based staging was almost half ($36,250).

Staging of Metastatic and Recurrent Breast Carcinoma In a WBPET study for staging recurrent or metastatic breast carcinoma, 57 patients were imaged with a history of breast cancer and referred for suspicion of disease recurrence.71 Patients were followed for at least 6 months, so that positive or negative diagnoses could be confirmed by biopsy, or follow-up procedures. Lesions were scored from 1 to 5, with 1 as definitely negative and 5 as definitely positive. On a patient-based analysis, pooling scores 4 and 5 as positive for disease recurrence, the sensitivity and specificity were 93% and 79%, respectively. On a lesion based analysis, if scores 4 or 5 were considered positive, the sensitivity and specificity of WBPET for detecting breast cancer foci was 85% and 79%, respectively. False-negative lesions were five bone lesions and one breast lesion; whereas, false-positive lesions were caused by muscle uptake (n = 5), inflammation (n = 4), blood pool activity (n = 2), bowel activity (n = 1), and unknown causes (n = 6).

Staging of Metastatic Melanoma In a small study for staging of metastatic melanoma, PET imaging had an overall accuracy of 100%, detecting 7 of 7 metastatic lesions and correctly predicting 13 of 13 negative lymph node regions. 72 For intraabdominal, visceral, and lymph node metastases FDG PET sensitivity for lesion detection was 15 of 15 (100%). PET found three metastatic foci which were later noted retrospectively on CT. Two metastatic foci were seen only on follow-up CT several months later. The sensitivity of the PET technique for detecting small pulmonary lesions was lower than CT and were attributed to respiratory motion or prior cancer therapy.

Staging of Prostate Cancer In a recent study, FDG PET helped identify osseous and soft-tissue metastases of prostate cancer with a high-positive predictive value but had a

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more limited sensitivity (65%) compared with that of routine bone scintigraphy in the identification of osseous metastases. 73 In another FDG PET study of prostate cancer, Yeh et al74 alSO found a low sensitivity (20%) for osseous metastases. It is interesting to note that many of the false-negative lesions on whole body PET staging of breast carcinoma were also located in the bones. 7~ A reason for this could be that the bone marrow metabolism, which is usually high compared with skeletal FDG metabolism, decreases the contrast with an osseous metastasis. 75 The study from Yeh et al confirmed a finding from Effert et al, 76 that the SUV is relatively low in prostate carcinoma (2.5-3.5). One observation of these authors was that in a subgroup of four patients with metastases having SUVs in excess of 5.0, all patients had rapid progression of disease and did not respond well to subsequent hormone deprivation or radiation therapy. The relatively low FDG uptake by prostate carcinoma in the study patients may reflect a characteristic of a slow growing or indolent neoplasm. However, Shreve et al also found that an abnormal FDG PET scan had a high positive predictive value for the presence of tumor (PPV = 9 8 % ) . 73

Staging of Ovarian Cancer In a study of nine patients evaluated for recurrent ovarian carcinoma and confirmed by second look laparotomy, PET had a sensitivity of 83%, whereas CT and US had sensitivities of 67% and 33%, respectively. 77 In a larger study of 33 patients, PET had a sensitivity for recurrent disease of 93%, whereas CT had an 87% sensitivity for recurrent disease. The specificity of PET was 80% and CT 50%.78 These authors found a good correlation between PET and histological findings and concluded that patient management will benefit from PET by identifying occult foci that are not apparent on morphological imaging studies.

Summary: Staging Malignancies with PET The goal in any staging method is to be able to detect small tumor foci with the highest sensitivity and specificity. The limiting factor for PET in its sensitivity for lesion detection will be its image resolution. The limiting factor for specificity will be the radiotracer's specificity for the tumor involved. The difficulty in analyzing and comparing the accuracy of tumor staging between various imaging modalities is that lesions identified can not

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always be confirmed histologically for ethical reasons. A possible solution might be rigorous patient follow-up and comparison of the sensitivities of detected lesions to the current standard imaging technique. The true "gold standard', will be if a new imaging technology can more accurately categorize Patients into their correct stages. By correctly removing patients with latent but advanced disease from the earlier stages, the remaining patients in the earlier staged group, will have improved prognosis. MONITORING TUMOR RESPONSE TO TREATMENT

One of the unique features of PET i s the ability to directly measure Changes in tissue or tumor metabolism which have been induced by therapy. The potential as a tool for research and develo pment of new chemotherapeutic agents is encouraging, (Fig 2). Recently, several investigators have used this feature of PET in clinical s t u d i e s . 79-81 In a study comparing FDG PET and tumor size measured by CT, 18 patients with liver metastases from colorectal cancer were imaged before and during their first month of chemotherapy.79 In 11 of 18 patients with measurable lesions on CT, objective partia! responses were observed. In 27 metastatic lesions, assessments were made by tumor to liver ratio (TLR) and SUV, both were associated with tumor responses at 1 to 2 weeks and 4 to 5 weeks. Responding lesions had greater reductions in metabolism TLR ratios (67% vs. 99%). At 4 to 5 weeks, the TLR ratio was able to discriminate responders from nonresponders both on a lesion-bylesion basis and overall patient response assessment. In anotlaer study, FDG PET was compared with lipiodol retention on CT in 30 patients with hepatocelluar carcinoma with 32 lesions. 8~ FDG PET was performed after interventional therapy and the SUV ratio of tumor to nontumor appeared to predict the presence of viable tumor. In this study, liPiodol retention on CT images was not as accurate as FDG PET results, Monitoring therapeutic effects in head and neck cancers has been previously reported. 31 In a more recent study, FDG PET was used to evaluate therapeutic effects in patients with advanced head and neck cancers. 81 PET was performed before chemotherapy (cisplatin and 5-FU) and after the first cycle of Chemotherapy in 11 patients. Tumor and/or lymph node volumes were measured on CT and these were correlated to SUV from PET

PET IN ONCOLOGY: REPLACE OTHER MODALITIES?

a

103

b

c

t

T 15.81 (p.g/gm/min)

12.04 (,ug/gm/min)

0.86 (,ug/gm/min)

Fig 2. Transaxial images I=DG images of the chest in a patient with metastatic prostate carcinoma being treated in a protocol to evaluate the effect of e potentially new chemotherapeutic agent, Suramin. The right lung base lesion (arrows) was imaged: (a) before chemotherapy, (b) after I week of chemotherapy, and (c) after 8 weeks of chemotherapy. The decrease in metabolic activity because of the effect of treatment can be seen visually and quantitatively in the estimated glucose metabolic rate obtained with tracer kinetic modeling.

measurements. The growth rates and changes in FDG uptake were highly correlated with different regression functions for tumors and lymph node metastases. In a study monitoring breast cancer therapy with FDG PET, quantitative FDG PET scans of primary breast cancers showed a rapid and significant decrease in tumor glucose metabolism after effective treatment was initiated, s2 The decrease in metabolic activity occurred before any decrease in tumor size. In nonresponding patients, no significant decrease in FDG uptake was observed after three cycles of treatment.

Summary: Monitoring Tumor Response to Therapy Quantitative PET may have a clinical role in the monitoring of therapy induced changes in a tumor, where a pretherapy PET study of a patient is used as a baseline and a follow-up scan is used to assess the early therapy response. The recent studies discussed previously and earlier studies s3-85 have investigated this important clinical role with promising success. In therapy monitoring, the absolute value of the glucose metabolic rate may not be necessary, because the relative change between a baseline and post-therapy scan may be sufficient; however, some form of quantitative method needs to be performed with high reproducibility, not only at a single PET site but also for comparison in multicenter studies.

CONCLUSION The unique imaging capabilities of PET enable scientists and physicians to observe and to measure a disease process or effect of treatment from a different perspective. The current applications of PET in oncology, as discussed in this review, have been in differentiating and characterizing indeterminate lesions, differentiating recurrent disease from treatment effects, staging and evaluating the extent of disease, and monitoring the success or failure of therapy. The future developments in medicine may use the unique capabilities of PET not only in diagnostic imaging but also in basic drug development and in monitoring or evaluating the eligibility of patients for new therapies. To predict the role of PET in clinical practice also requires some predictions on the potential therapies which may evolve because of the tremendous advances in molecular medicine and genetics. The role of clinical imaging 10 or 20 years from now may be quite different compared with what currently exists, especially if future treatments such as gene therapy become routine procedures. Likewise, if there is no effective therapy for a given disease, an imaging procedure which accurately detects that disease process may not be relevant in clinical practice. Scientifically, however, that imaging procedure may play a very important role in the understanding of that disease and assist in the

104

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d e v e l o p m e n t o f n e w therapies. In the current h e a l t h

imaging

care e n v i r o n m e n t , a s u c c e s s f u l i m a g i n g t e c h n o l o g y m u s t not o n l y c h a n g e m e d i c a l m a n a g e m e n t , but

whether a sequence or combination of imaging

also s h o w that t h o s e c h a n g e s i m p r o v e patient

more

outcome.

i m p r o v e clinical m a n a g e m e n t d e c i s i o n s and treat-

In the end, the q u e s t i o n is not w h e t h e r o n e

t e c h n o l o g y will r e p l a c e

another,

but

t e c h n o l o g i e s in a w e l l - d e f i n e d a l g o r i t h m acquires accurate i n f o r m a t i o n that u l t i m a t e l y will

ment outcomes.

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