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Preliminary experience in oncology of positron emission tomography with a dual headed gamma camera
Radiography (2000) 6, 11–17 doi:10.1053/radi.1999.0218, available online at http://www.idealibrary.com on
Preliminary experience in oncology of positron emission tomography with a dual headed gamma camera S. E. Old, MRCP, FRCR, Specialist Registrar, Clinical Oncology*, P. P. Dendy, BA, PhD, Chief Physicist† and K. K. Balan, BSc, MD, FRCP, Consultant in Nuclear Medicine* *Department of Nuclear Medicine, Box 170; †Department of Medical Physics and Engineering, Box 152, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, U.K. (Received 8 March 1999; revised 21 July 1999; accepted 7 October 1999)
Key words: PET; 18-FDG; coincidence imaging; cancer.
Purpose: To evaluate positron emission tomography (PET) performed using a modified dual-headed gamma camera for the imaging of malignancy. Methods: Using a modified dual-headed gamma camera (Picker 2000XP) we performed 18-FDG PET scans on 19 patients with non-small cell lung cancer (NSCLC) and 27 with lymphoma. Results were compared to computed tomography (CT) findings and pathology, when available. Results: All untreated primary NSCLC were identified. Response to chemotherapy was demonstrated in one case. For staging mediastinal lymph nodes in untreated NSCLC, gamma camera PET was superior to CT, with sensitivity 75%, specificity 89%, accuracy 85%, positive predictive value (PPV) 75% and negative predictive value (NPV) 89%. All adrenal masses in NSCLC were correctly identified as benign, but in one case bone metastases were missed. In lymphoma, gamma camera PET had sensitivity 82%, specificity 97%, accuracy 96%, PPV 74% and NPV 98% but it missed lesions smaller than 10 mm in the thorax and neck, and <17 mm in the abdomen and pelvis. Conclusions: These early results suggest that functional tumour imaging with 18-FDG PET is a useful technique in the management of cancer. Modified dual-headed gamma cameras can be used to acquire 18-FDG PET images in oncology patients.
Introduction One of the advantages of nuclear medicine over conventional radiology is the ability to provide physiological rather than anatomical information since this technique maps the biodistribution of an administered radiopharmaceutical. Thus, in spite of the markedly inferior image quality, nuclear medicine finds a number of applications where physiological information is important. A further limitation of imaging with a gamma ray camera is that the most important physiological elements, e.g. hydrogen, carbon, nitrogen, and oxygen have no radioisotope that directly emits 1078–8174/00/010011+07 $35.00/0
© 2000 The College of Radiographers
gamma radiation. However, three of them, carbon, nitrogen, and oxygen have a radioisotope that emits positrons (positively charged electrons), and are therefore amenable to imaging by positron emission tomography (PET) using the secondary 511KeV gamma radiation—see methods section. In recent years there has been rapid development in the applications of PET in neurology, cardiology, and oncology [1]. Unfortunately, as shown in Table 1 all the above positron emitters have very short half-lives so imaging is only possible when there is a dedicated cyclotron on site. A further important radiopharmaceutical is fluorodeoxyglucose labelled with © 2000 The College of Radiographers
12
Old et al.
Table 1. Positron emitters currently used in PET imaging Radionuclide
Half-life
Carbon-11 Nitrogen-13 Oxygen-15 Fluorine-18
20.3 min 10.0 min 122 s 110 min
F-18 (18F-FDG) the half-life of which is also quite short but long enough for limited distribution to sites remote from the cyclotron. Most work to date has been carried out with a dedicated positron imager, which has been designed to optimize the imaging process. However, the cost of the dedicated imager is high and, since there is already considerable spare capacity for radionuclide production by existing cyclotrons, there is an urgent need to diffuse the imaging technology in order to meet the anticipated demand for PET in hospitals where there are no specialized facilities. Almost all nuclear medicine departments now have dual headed gamma cameras and recent work has shown that many such cameras can be adapted to perform PET imaging. This paper provides early evidence that the adapted gamma camera may be a useful adjunct to a dedicated scanner. Biology of FDG-PET in malignancy Oncology has been chosen for this preliminary study for two reasons. Firstly because for some of the more common cancers there is likely to be a substantial unmet demand for PET imaging and secondly because the physiology of uptake of 18-F FDG is reasonably well understood. Abnormalities of glucose metabolism arise early in malignancy. Malignant cells have oncogenemediated upregulation of glucose transporters and of enzymes involved in glucose metabolism, especially hexokinase. Thus, FDG enters malignant cells in large amounts via insulin independent glucose transporters. Inside the cell, FDG is phosphorylated by hexokinase but it is not a suitable substrate for any of the further enzymes of glycolysis. The phosphorylated FDG is trapped and acts as a tracer for the functional abnormalities of cancer cells. In a normal resting subject there is very little uptake of FDG except in the myocardium and
brain, which rely heavily on glucose metabolism. FDG is excreted in the urine, and will accumulate in the kidneys and bladder. Two common cancers have been selected: (a) Lung cancer PET has two main roles in lung cancer management, firstly in the diagnosis of solitary pulmonary nodules (SPN) and secondly as a method of staging. Unfortunately CT has poor specificity in the differential diagnosis of SPN, and most patients require biopsy with its attendant costs and risks. Gambhir has shown that PET is the most costeffective strategy for the evaluation of SPN over a wide range of cancer prevalence [2]. In the United States, Medicare and some private health insurance organizations now fund both dedicated and gamma camera PET for the investigation of SPN. In pre-operative staging of NSCLC a crucial question is whether the mediastinal lymph nodes (N2/3 by TNM staging) are involved, as this would render the tumour inoperable. Lymph nodes >10 mm in short axis are usually considered abnormal on CT, but with tumour obstructing bronchi, nodes may be enlarged due to inflammation and infection rather than metastasis. In fact, 75% of lymph nodes 10–15 mm diameter are benign, and therefore such nodes require biopsy [3]. Some lymph nodes, especially those in the subcarinal area, are difficult to biopsy and therefore staging information may not be complete before definitive surgery. Magnetic resonance imaging (MRI) does not add to the information from CT. The advantage of PET is that it identifies malignant nodes by metabolic abnormalities rather than size criteria. It cannot only rule out malignancy in benign nodes >10 mm in diameter, but it can also detect metastasis to normal sized nodes. PET images the whole body and therefore has the potential to identify more distant metastatic spread to the bones, liver or adrenals, which would make the primary unsuitable for radical surgery. (b) Lymphoma CT and MRI are the mainstay of lymphoma staging but they rely on anatomical criteria. Residual masses are common after lymphoma treatment and size criteria alone cannot differentiate fibrosis from residual active tumour. Gallium-67 scintigraphy can differentiate fibrosis from active lymphoma, but not all lymphomas take up gallium, the test is inconvenient as it demands recall of the patients after several days, and the radiation dose to the patient is relatively high (about 17 mSv). All
Oncology positron emission tomography
13
To electronics which includes coincidence circuits
A
B
D
C
Matched Nal Crystals 19 mm (3/4 inch) thick
A1 C
1
D1 B1
To electronics which includes coincidence circuits
Figure 1. Image formation by coincidence detection in PET. AA1 =a ‘good event’ correctly identifying the line of origin of decay; B=a ‘single’ from activity in the field of view—B1 is lost; C1 =a ‘single’ from activity outside the field of view—C is lost; D=a scattered photon that would incorrectly locate the event if not rejected (the event does not lie along the line DD1).
lymphomas take up 18F FDG and the test can be completed in one session with a dose to the patient of only about 5 mSv. Using PET as well as CT may correctly restage as many as 59% of patients with Hodgkin’s disease, and this has obvious implications for management [4].
Methods The principle of PET is that when a positron is emitted it travels no more than a few millimetres, losing kinetic energy, and then spontaneously annihilates with a free electron. This results in simultaneous emission of two gamma photons which leave the point of production at virtually 180 to each other (see Fig. 1). Thus the major modification to the dual headed camera is to fit additional electronic circuitry which
will only accept events that occur simultaneously in both crystals. The line joining these events passes through the point of annihilation and by rotating the camera heads around the patient as in single photon emission computed tomography, sectional images can be reconstructed. By conservation of mass–energy both photons have exactly 511 keV energy, so pulse height analysis may be used to discriminate against scatter (see Fig. 1). The gamma ray energy is much higher than that from Tc-99m gamma rays (140 keV) so crystal thickness has been increased from 9.5 mm (3/8 inch) to 19 mm (3/4 inch). Barber et al. have shown that this does not degrade the performance of the camera for conventional bone scanning [5]. The system electronics must process and reject a large number of spurious events, especially when only one of the gamma ray pair is detected—‘singles’ (see Fig. 1). This severely limits the amount of activity that may be used for the
14
study and is a serious problem when there is a lot of activity just outside the field of view. In such cases it may not be possible to use all the valid counts (three-dimensional reconstruction) and collimators have to be used to limit the field (two-dimensional reconstruction). For these studies we used a Picker 2000XP dual headed gamma camera with Positron Coincidence Detection option. A collimator with lead septa restricted the axial acceptance angle to about 12. Patients fasted for 4 h before injection of 185 MBq of 18F-FDG. Images were obtained after 45 min bed rest. Since September 1997 we have performed gamma camera PET on 19 patients undergoing investigation for possible radical surgery for lung cancer. At the start of the study, patients were recruited on the basis of CT findings of mediastinal nodes of 10 mm or greater or adrenal enlargement suspicious of metastasis. However, after September 1998, all patients referred for radical surgery were considered for PET. All patients gave informed consent and the local Ethics Committee approved the study. One patient was scanned before and after cisplatin containing neoadjuvant chemotherapy. We have also done 38 PET scans on 27 patients with lymphoma, either Hodgkin’s disease or Non-Hodgkin’s lymphoma. For the conventional staging of NSCLC cases we used a Somatom Plus 4 system for CT imaging. Spiral scans of 3 mm with 1.6 pitch were acquired after injection of 100 ml of intravenous contrast. Images covered the thorax and upper abdomen to include the liver and adrenals. Nodes of 10 mm or greater were considered abnormal. One Consultant Radiologist who was unaware of the PET findings and surgical outcome reviewed all of the CTs. The lymphoma patients had CT either at this institution, or one of our referring hospitals. Most of these had spiral scans, with slice thickness of 10 mm but without intravenous contrast. One Consultant Radiologist reviewed all these images. PET images were reviewed by one Nuclear Medicine Consultant without knowledge of the findings at surgery. All PET images were read blind to the CT findings initially. However, in the lymphoma cases, where normal anatomy is frequently seriously disturbed by massive lymphadenopathy, it proved difficult to accurately localize areas of 18F FDG uptake. Therefore the CT was used to accurately locate positive 18F FDG uptake on the PET scan. A particular problem arose in the thorax, where 18F FDG uptake was seen, but it was
Old et al.
not certain whether this was in the lung or enlarged hilar nodes, which is important from the staging viewpoint. Recourse to the CT images helped to localize this accurately.
Results Primary lung tumours All untreated primary lung tumours were identified. One patient had no 18F-FDG uptake in a left upper lobe mass. When this was subsequently resected, the histology revealed tuberculosis only. The patient who underwent neoadjuvant chemotherapy had no abnormal 18F-FDG uptake after treatment, and at lobectomy the histology confirmed a complete pathological response (see Fig. 2(c) and (d)). Mediastinal nodes in NSCLC PET had sensitivity of 75%, specificity 89%, accuracy 85%, positive predictive value (PPV) 75% and negative predictive value (NPV) 89% [6] (see Table 2). Comparable figures for CT were 100%, 44%, 62%, 44%, 100% but most patients were selected because of abnormal CT findings. The smallest metastatic node was 15 mm and this was identified on PET. Adrenal masses in NSCLC The four adrenal masses investigated were all found to be benign and showed no 18F-FDG uptake on PET. Bone metastases One patient had bone metastases demonstrated by conventional bone scintigraphy. These were not identified on gamma camera PET. Lymphoma For the lymphoma cases the gold standard used was a combination of CT findings and subsequent follow-up. This allowed us to confirm the benign nature of some residual masses after treatment. In lymphoma, gamma camera PET had sensitivity of 82%, specificity 97%, accuracy 96%,
Oncology positron emission tomography
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Figure 2. Examples of PET images obtained using our Picker 2000XP system with positron coincidence detection. (a) A 40-year-old male with diffuse large B cell Non-Hodgkins lymphoma. Coronal view of PET scan of thorax showing extensive mediastinal disease. (b) The same patient following chemotherapy. There has been a complete response with the only visible FDG uptake now in the normal myocardium. (c) A 61-year-old female with a squamous carcinoma of the right upper lobe. In this coronal PET image of the thorax, FDG uptake is seen in the primary tumour and lymph nodes at the right hilum and in the right paratracheal region. Normal myocardial activity is seen once again, along with some uptake in the extraocular muscles. (d) The same patient now demonstrating histologically confirmed complete response. Normal renal FDG excretion is visible.
PPV 74%, and NPV 98% when compared to conventional imaging and clinical follow-up as the gold standard (see Table 3). We were able to detect all lymphomatous nodes of >10 mm above the diaphragm, and all >17 mm below the diaphragm. However, the failure of PET to detect small lesions, particularly lung nodules, impaired its ability to stage the patients correctly.
Discussion PET imaging with a dual headed gamma camera is at a relatively early stage of development and methods of image reconstruction have not been optimized [7]. The body images we have obtained have not been corrected for attenuation, although work is in progress to implement a novel method being developed in house [19]. Further corrections are required to allow for random coincidences and
Table 2. Results of CT (taking nodes >10 mm as abnormal) and gamma camera PET for mediastinal node staging. Results for the 13 NSCLC patients who have pathology as gold standard
True positive False positive True negative False negative Sensitivity Specificity Accuracy PPV NPV
CT
PET
4 5 4 0 100% 44% 62% 44% 100%
3 1 8 1 75% 89% 85% 75% 89%
scattered events that fall within the energy window of unscattered events. Such corrections are essential for quantitative work and desirable for detection of
16
Old et al.
Table 3. Results of conventional imaging and clinical follow-up (CI) compared to PET in lymphoma in the 433 regions examined
PET lesion present PET no lesion present
CI lesion present
CI no lesion present
31 7
11 384
Table 4. Comparison of methods for staging mediastinal nodes in NSCLC. Gamma camera results are compared to average figures for CT and dedicated PET from five recent series [8–12] Sensitivity Specificity Accuracy PPV NPV CT Dedicated PET Gamma camera
64% 81% 75%
77% 92% 89%
74% 87% 85%
62% 81% 86% 90% 75% 89%
hot spots since they improve the signal-to-noise ratio. In view of these further potential improvements, early clinical images are encouraging. Gamma camera PET was able to identify the primary lung cancers in all cases. It also successfully identified the case of tuberculosis as benign. In staging of the mediastinal nodes in NSCLC, gamma camera PET performed better than CT and almost as well as dedicated PET, see Table 4 [8–12]. The smallest involved node in our series was 15 mm in short axis and this was detected by gamma camera PET. All the adrenal masses studied have been benign, and further cases will be required to truly determine the value of gamma camera PET in the identification of adrenal metastases. In the lymphomas, gamma camera PET has identified all lesions above the diaphragm >10 mm diameter, although it performed less well below the diaphragm. This is to be expected because of the lack of attenuation correction and the effect of activity in the bladder from urinary excretion of 18F-FDG. Shreve et al. demonstrated that in a direct comparison gamma camera PET only picked up 27% of the lesions below the diaphragm visible with a dedicated PET facility [13]. The failure to detect small lesions hampered the ability of gamma camera PET in our series to accurately stage the lymphomas.
Lesions in the chest are seen against the low background activity of the lungs, and can thus still be detected with gamma camera coincidence imaging despite inferior intrinsic contrast resolution of this technology compared to detected PET. However, the detection of abnormal foci in liver and bone, where there is higher normal tissue background activity, requires higher scanner contrast resolution, which is currently significantly better on dedicated PET scanners [13]. In addition to the refinements to image reconstruction already discussed, a further way to improve the signal-to-noise ratio may be to increase the administered activity, possibly with a delayed imaging time. Nolop et al. and Hamberg et al. have shown that for 18F-FDG in lung cancer the tumour-to-background ratio did not reach a maximum by 1 h and waiting for a longer time interval after injection (e.g. 2 h) might have improved lesion detectability [17, 18]. In breast cancer, delayed imaging has been shown to be superior [14]. The effective dose to the patient from 185 MBq of 18F-FDG is 4.6 mSv, compared to 3 mSv from 600 MBq of Tc-99m phosphonate for a bone scan and 17 mSv from 150 MBq of Ga-67 for tumour imaging [15]. Doubling the administered activity would increase the signal-to-noise ratio by √2 for a scan at 45 min, or provide sufficient activity for a scan at a later time [16]. Gamma camera PET shows promise as a useful tool for hospitals needing functional imaging of tumour deposits of at least 10 mm diameter above the diaphragm, and 17 mm below the diaphragm. Minimum detectable size may decrease a little as image reconstruction techniques are improved. Centres with a heavy PET workload, or where very short half-life radionuclides are used may need to invest in a dedicated PET camera. Gamma camera PET technology may permit the widespread use of functional tumour imaging in oncology. Acknowledgements Dr R. A. R. Coulden and Dr C. S. Ng for reviewing the CT scans and Dr D. Gilligan and Dr R. E. Marcus for allowing us to recruit their patients.
References 1. Cook GJR, Maisey MN. Review: The current status of clinical PET imaging. Clin Radiol 1996; 51: 603–13.
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2. Gambhir SS, Shepherd JE, Shah BD et al. Analytical decision model for the cost-effective management of solitary pulmonary nodules. J Clin Oncol 1998; 16: 2113–25. 3. Libshitz HI, McKenna RJ. Mediastinal lymph node size in lung cancer. Am J Radiol 1984; 143: 715–8. 4. Young CS, Young BL, Smith SM. Staging Hodgkin’s disease with 18-FDG PET: comparison with CT and surgery. Clin Pos Imaging 1998; 1: 161–4. 5. Barber RW, Irwin AG, Bird NJ et al. The effect of crystal thickness on gamma camera performance. IPEM Conf. Records (Dundee 1997) 183. 6. Campbell MJ, Machin D. Diagnostic tests. In: Medical Statistics: A Commonsense Approach, 2nd edn. Chichester, John Wiley and Sons Ltd, 1993, 34–6. 7. Jarritt PH, Acton PC. PET Imaging using gamma camera systems: A review. Nucl Med Comm 1996; 17: 758–66. 8. Bury T, Dowlati A, Paulus P et al. Whole body 18-FDG positron emission tomography in the staging of nonsmall cell lung cancer. Eur Respir J 1997; 10: 2529–34. 9. Chin R, Ward R, Keyes JW et al. Mediastinal staging of non-small cell lung cancer with positron emission tomography. Am J Respir Crit Care Med 1995; 152: 2090–6. 10. Steinert HC, Hauser M, Allemann F et al. Non-small cell lung cancer: Nodal staging with FDG PET versus CT with correlative lymph node mapping and sampling. Radiology 1997; 202: 441–6. 11. Vansteenkiste JF, Stroobants SG, De Leyn PR et al. Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer: a prospective analysis of 50 cases. Chest 1997; 112: 1480–6.
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12. Valk PE, Pounds T, Hopkins DM et al. Staging nonsmall cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg 1995; 60: 1573– 82. 13. Shreve PD, Steventon RS, Deters EC, Kison PV, Gross MD, Wahl RD. Oncologic diagnosis with 2-[Fluorine18]Fluoro-2-deoxy-D-glucose imaging: dual-head coincidence gamma camera versus positron emission tomography scanner. Radiology 1998; 207: 431–7. 14. Boerner AR, Weckesser M, Herzog H et al. Optimal scan time for fluorine-18 fluorodeoxyglucose positron emission tomography in breast cancer. Eur J Nucl Med 1999; 26: 226–30. 15. Administration of Radioactive Substances Advisory Committee (ARSAC). Notes for Guidance on the Clinical Administration of Radiopharmaceuticals and Use of Sealed Radioactive Sources. Chilton, Didcot, Oxon: National Radiological Protection Board, 1998. 16. Visvikis D, Fryer TD, Downey SD. Optimisation of Noise Equivalent Count Rates for Brain and Body FDG Imaging Using Gamma Camera PET. IEEE (MIC), Toronto. November 1998. 17. Nolop KB, Rhodes CG, Brudin LH et al. Glucose utilisation in vivo by human pulmonary neoplasms. Cancer 1987; 60: 2682–9. 18. Hamberg LM, Hunter GJ, Alpert NM, Choi NC, Babich JW, Fischmann AJ. The dose uptake ratio as an index of glucose metabolism: useful parameter or oversimplification? J Nucl Med 1994; 35: 1308–12. 19. Bird NJ, Fryer TD, Barber RW. Transmission scanning for gamma camera PET and SPECT imaging of the heart. Abstract. J Nucl Med 1999; 40: 34P.
Preliminary experience in oncology of positron emission tomography with a dual headed gamma camera S. E. Old, MRCP, FRCR, Specialist Registrar, Clinical Oncology*, P. P. Dendy, BA, PhD, Chief Physicist† and K. K. Balan, BSc, MD, FRCP, Consultant in Nuclear Medicine* *Department of Nuclear Medicine, Box 170; †Department of Medical Physics and Engineering, Box 152, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, U.K. (Received 8 March 1999; revised 21 July 1999; accepted 7 October 1999)
Key words: PET; 18-FDG; coincidence imaging; cancer.
Purpose: To evaluate positron emission tomography (PET) performed using a modified dual-headed gamma camera for the imaging of malignancy. Methods: Using a modified dual-headed gamma camera (Picker 2000XP) we performed 18-FDG PET scans on 19 patients with non-small cell lung cancer (NSCLC) and 27 with lymphoma. Results were compared to computed tomography (CT) findings and pathology, when available. Results: All untreated primary NSCLC were identified. Response to chemotherapy was demonstrated in one case. For staging mediastinal lymph nodes in untreated NSCLC, gamma camera PET was superior to CT, with sensitivity 75%, specificity 89%, accuracy 85%, positive predictive value (PPV) 75% and negative predictive value (NPV) 89%. All adrenal masses in NSCLC were correctly identified as benign, but in one case bone metastases were missed. In lymphoma, gamma camera PET had sensitivity 82%, specificity 97%, accuracy 96%, PPV 74% and NPV 98% but it missed lesions smaller than 10 mm in the thorax and neck, and <17 mm in the abdomen and pelvis. Conclusions: These early results suggest that functional tumour imaging with 18-FDG PET is a useful technique in the management of cancer. Modified dual-headed gamma cameras can be used to acquire 18-FDG PET images in oncology patients.
Introduction One of the advantages of nuclear medicine over conventional radiology is the ability to provide physiological rather than anatomical information since this technique maps the biodistribution of an administered radiopharmaceutical. Thus, in spite of the markedly inferior image quality, nuclear medicine finds a number of applications where physiological information is important. A further limitation of imaging with a gamma ray camera is that the most important physiological elements, e.g. hydrogen, carbon, nitrogen, and oxygen have no radioisotope that directly emits 1078–8174/00/010011+07 $35.00/0
© 2000 The College of Radiographers
gamma radiation. However, three of them, carbon, nitrogen, and oxygen have a radioisotope that emits positrons (positively charged electrons), and are therefore amenable to imaging by positron emission tomography (PET) using the secondary 511KeV gamma radiation—see methods section. In recent years there has been rapid development in the applications of PET in neurology, cardiology, and oncology [1]. Unfortunately, as shown in Table 1 all the above positron emitters have very short half-lives so imaging is only possible when there is a dedicated cyclotron on site. A further important radiopharmaceutical is fluorodeoxyglucose labelled with © 2000 The College of Radiographers
12
Old et al.
Table 1. Positron emitters currently used in PET imaging Radionuclide
Half-life
Carbon-11 Nitrogen-13 Oxygen-15 Fluorine-18
20.3 min 10.0 min 122 s 110 min
F-18 (18F-FDG) the half-life of which is also quite short but long enough for limited distribution to sites remote from the cyclotron. Most work to date has been carried out with a dedicated positron imager, which has been designed to optimize the imaging process. However, the cost of the dedicated imager is high and, since there is already considerable spare capacity for radionuclide production by existing cyclotrons, there is an urgent need to diffuse the imaging technology in order to meet the anticipated demand for PET in hospitals where there are no specialized facilities. Almost all nuclear medicine departments now have dual headed gamma cameras and recent work has shown that many such cameras can be adapted to perform PET imaging. This paper provides early evidence that the adapted gamma camera may be a useful adjunct to a dedicated scanner. Biology of FDG-PET in malignancy Oncology has been chosen for this preliminary study for two reasons. Firstly because for some of the more common cancers there is likely to be a substantial unmet demand for PET imaging and secondly because the physiology of uptake of 18-F FDG is reasonably well understood. Abnormalities of glucose metabolism arise early in malignancy. Malignant cells have oncogenemediated upregulation of glucose transporters and of enzymes involved in glucose metabolism, especially hexokinase. Thus, FDG enters malignant cells in large amounts via insulin independent glucose transporters. Inside the cell, FDG is phosphorylated by hexokinase but it is not a suitable substrate for any of the further enzymes of glycolysis. The phosphorylated FDG is trapped and acts as a tracer for the functional abnormalities of cancer cells. In a normal resting subject there is very little uptake of FDG except in the myocardium and
brain, which rely heavily on glucose metabolism. FDG is excreted in the urine, and will accumulate in the kidneys and bladder. Two common cancers have been selected: (a) Lung cancer PET has two main roles in lung cancer management, firstly in the diagnosis of solitary pulmonary nodules (SPN) and secondly as a method of staging. Unfortunately CT has poor specificity in the differential diagnosis of SPN, and most patients require biopsy with its attendant costs and risks. Gambhir has shown that PET is the most costeffective strategy for the evaluation of SPN over a wide range of cancer prevalence [2]. In the United States, Medicare and some private health insurance organizations now fund both dedicated and gamma camera PET for the investigation of SPN. In pre-operative staging of NSCLC a crucial question is whether the mediastinal lymph nodes (N2/3 by TNM staging) are involved, as this would render the tumour inoperable. Lymph nodes >10 mm in short axis are usually considered abnormal on CT, but with tumour obstructing bronchi, nodes may be enlarged due to inflammation and infection rather than metastasis. In fact, 75% of lymph nodes 10–15 mm diameter are benign, and therefore such nodes require biopsy [3]. Some lymph nodes, especially those in the subcarinal area, are difficult to biopsy and therefore staging information may not be complete before definitive surgery. Magnetic resonance imaging (MRI) does not add to the information from CT. The advantage of PET is that it identifies malignant nodes by metabolic abnormalities rather than size criteria. It cannot only rule out malignancy in benign nodes >10 mm in diameter, but it can also detect metastasis to normal sized nodes. PET images the whole body and therefore has the potential to identify more distant metastatic spread to the bones, liver or adrenals, which would make the primary unsuitable for radical surgery. (b) Lymphoma CT and MRI are the mainstay of lymphoma staging but they rely on anatomical criteria. Residual masses are common after lymphoma treatment and size criteria alone cannot differentiate fibrosis from residual active tumour. Gallium-67 scintigraphy can differentiate fibrosis from active lymphoma, but not all lymphomas take up gallium, the test is inconvenient as it demands recall of the patients after several days, and the radiation dose to the patient is relatively high (about 17 mSv). All
Oncology positron emission tomography
13
To electronics which includes coincidence circuits
A
B
D
C
Matched Nal Crystals 19 mm (3/4 inch) thick
A1 C
1
D1 B1
To electronics which includes coincidence circuits
Figure 1. Image formation by coincidence detection in PET. AA1 =a ‘good event’ correctly identifying the line of origin of decay; B=a ‘single’ from activity in the field of view—B1 is lost; C1 =a ‘single’ from activity outside the field of view—C is lost; D=a scattered photon that would incorrectly locate the event if not rejected (the event does not lie along the line DD1).
lymphomas take up 18F FDG and the test can be completed in one session with a dose to the patient of only about 5 mSv. Using PET as well as CT may correctly restage as many as 59% of patients with Hodgkin’s disease, and this has obvious implications for management [4].
Methods The principle of PET is that when a positron is emitted it travels no more than a few millimetres, losing kinetic energy, and then spontaneously annihilates with a free electron. This results in simultaneous emission of two gamma photons which leave the point of production at virtually 180 to each other (see Fig. 1). Thus the major modification to the dual headed camera is to fit additional electronic circuitry which
will only accept events that occur simultaneously in both crystals. The line joining these events passes through the point of annihilation and by rotating the camera heads around the patient as in single photon emission computed tomography, sectional images can be reconstructed. By conservation of mass–energy both photons have exactly 511 keV energy, so pulse height analysis may be used to discriminate against scatter (see Fig. 1). The gamma ray energy is much higher than that from Tc-99m gamma rays (140 keV) so crystal thickness has been increased from 9.5 mm (3/8 inch) to 19 mm (3/4 inch). Barber et al. have shown that this does not degrade the performance of the camera for conventional bone scanning [5]. The system electronics must process and reject a large number of spurious events, especially when only one of the gamma ray pair is detected—‘singles’ (see Fig. 1). This severely limits the amount of activity that may be used for the
14
study and is a serious problem when there is a lot of activity just outside the field of view. In such cases it may not be possible to use all the valid counts (three-dimensional reconstruction) and collimators have to be used to limit the field (two-dimensional reconstruction). For these studies we used a Picker 2000XP dual headed gamma camera with Positron Coincidence Detection option. A collimator with lead septa restricted the axial acceptance angle to about 12. Patients fasted for 4 h before injection of 185 MBq of 18F-FDG. Images were obtained after 45 min bed rest. Since September 1997 we have performed gamma camera PET on 19 patients undergoing investigation for possible radical surgery for lung cancer. At the start of the study, patients were recruited on the basis of CT findings of mediastinal nodes of 10 mm or greater or adrenal enlargement suspicious of metastasis. However, after September 1998, all patients referred for radical surgery were considered for PET. All patients gave informed consent and the local Ethics Committee approved the study. One patient was scanned before and after cisplatin containing neoadjuvant chemotherapy. We have also done 38 PET scans on 27 patients with lymphoma, either Hodgkin’s disease or Non-Hodgkin’s lymphoma. For the conventional staging of NSCLC cases we used a Somatom Plus 4 system for CT imaging. Spiral scans of 3 mm with 1.6 pitch were acquired after injection of 100 ml of intravenous contrast. Images covered the thorax and upper abdomen to include the liver and adrenals. Nodes of 10 mm or greater were considered abnormal. One Consultant Radiologist who was unaware of the PET findings and surgical outcome reviewed all of the CTs. The lymphoma patients had CT either at this institution, or one of our referring hospitals. Most of these had spiral scans, with slice thickness of 10 mm but without intravenous contrast. One Consultant Radiologist reviewed all these images. PET images were reviewed by one Nuclear Medicine Consultant without knowledge of the findings at surgery. All PET images were read blind to the CT findings initially. However, in the lymphoma cases, where normal anatomy is frequently seriously disturbed by massive lymphadenopathy, it proved difficult to accurately localize areas of 18F FDG uptake. Therefore the CT was used to accurately locate positive 18F FDG uptake on the PET scan. A particular problem arose in the thorax, where 18F FDG uptake was seen, but it was
Old et al.
not certain whether this was in the lung or enlarged hilar nodes, which is important from the staging viewpoint. Recourse to the CT images helped to localize this accurately.
Results Primary lung tumours All untreated primary lung tumours were identified. One patient had no 18F-FDG uptake in a left upper lobe mass. When this was subsequently resected, the histology revealed tuberculosis only. The patient who underwent neoadjuvant chemotherapy had no abnormal 18F-FDG uptake after treatment, and at lobectomy the histology confirmed a complete pathological response (see Fig. 2(c) and (d)). Mediastinal nodes in NSCLC PET had sensitivity of 75%, specificity 89%, accuracy 85%, positive predictive value (PPV) 75% and negative predictive value (NPV) 89% [6] (see Table 2). Comparable figures for CT were 100%, 44%, 62%, 44%, 100% but most patients were selected because of abnormal CT findings. The smallest metastatic node was 15 mm and this was identified on PET. Adrenal masses in NSCLC The four adrenal masses investigated were all found to be benign and showed no 18F-FDG uptake on PET. Bone metastases One patient had bone metastases demonstrated by conventional bone scintigraphy. These were not identified on gamma camera PET. Lymphoma For the lymphoma cases the gold standard used was a combination of CT findings and subsequent follow-up. This allowed us to confirm the benign nature of some residual masses after treatment. In lymphoma, gamma camera PET had sensitivity of 82%, specificity 97%, accuracy 96%,
Oncology positron emission tomography
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Figure 2. Examples of PET images obtained using our Picker 2000XP system with positron coincidence detection. (a) A 40-year-old male with diffuse large B cell Non-Hodgkins lymphoma. Coronal view of PET scan of thorax showing extensive mediastinal disease. (b) The same patient following chemotherapy. There has been a complete response with the only visible FDG uptake now in the normal myocardium. (c) A 61-year-old female with a squamous carcinoma of the right upper lobe. In this coronal PET image of the thorax, FDG uptake is seen in the primary tumour and lymph nodes at the right hilum and in the right paratracheal region. Normal myocardial activity is seen once again, along with some uptake in the extraocular muscles. (d) The same patient now demonstrating histologically confirmed complete response. Normal renal FDG excretion is visible.
PPV 74%, and NPV 98% when compared to conventional imaging and clinical follow-up as the gold standard (see Table 3). We were able to detect all lymphomatous nodes of >10 mm above the diaphragm, and all >17 mm below the diaphragm. However, the failure of PET to detect small lesions, particularly lung nodules, impaired its ability to stage the patients correctly.
Discussion PET imaging with a dual headed gamma camera is at a relatively early stage of development and methods of image reconstruction have not been optimized [7]. The body images we have obtained have not been corrected for attenuation, although work is in progress to implement a novel method being developed in house [19]. Further corrections are required to allow for random coincidences and
Table 2. Results of CT (taking nodes >10 mm as abnormal) and gamma camera PET for mediastinal node staging. Results for the 13 NSCLC patients who have pathology as gold standard
True positive False positive True negative False negative Sensitivity Specificity Accuracy PPV NPV
CT
PET
4 5 4 0 100% 44% 62% 44% 100%
3 1 8 1 75% 89% 85% 75% 89%
scattered events that fall within the energy window of unscattered events. Such corrections are essential for quantitative work and desirable for detection of
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Old et al.
Table 3. Results of conventional imaging and clinical follow-up (CI) compared to PET in lymphoma in the 433 regions examined
PET lesion present PET no lesion present
CI lesion present
CI no lesion present
31 7
11 384
Table 4. Comparison of methods for staging mediastinal nodes in NSCLC. Gamma camera results are compared to average figures for CT and dedicated PET from five recent series [8–12] Sensitivity Specificity Accuracy PPV NPV CT Dedicated PET Gamma camera
64% 81% 75%
77% 92% 89%
74% 87% 85%
62% 81% 86% 90% 75% 89%
hot spots since they improve the signal-to-noise ratio. In view of these further potential improvements, early clinical images are encouraging. Gamma camera PET was able to identify the primary lung cancers in all cases. It also successfully identified the case of tuberculosis as benign. In staging of the mediastinal nodes in NSCLC, gamma camera PET performed better than CT and almost as well as dedicated PET, see Table 4 [8–12]. The smallest involved node in our series was 15 mm in short axis and this was detected by gamma camera PET. All the adrenal masses studied have been benign, and further cases will be required to truly determine the value of gamma camera PET in the identification of adrenal metastases. In the lymphomas, gamma camera PET has identified all lesions above the diaphragm >10 mm diameter, although it performed less well below the diaphragm. This is to be expected because of the lack of attenuation correction and the effect of activity in the bladder from urinary excretion of 18F-FDG. Shreve et al. demonstrated that in a direct comparison gamma camera PET only picked up 27% of the lesions below the diaphragm visible with a dedicated PET facility [13]. The failure to detect small lesions hampered the ability of gamma camera PET in our series to accurately stage the lymphomas.
Lesions in the chest are seen against the low background activity of the lungs, and can thus still be detected with gamma camera coincidence imaging despite inferior intrinsic contrast resolution of this technology compared to detected PET. However, the detection of abnormal foci in liver and bone, where there is higher normal tissue background activity, requires higher scanner contrast resolution, which is currently significantly better on dedicated PET scanners [13]. In addition to the refinements to image reconstruction already discussed, a further way to improve the signal-to-noise ratio may be to increase the administered activity, possibly with a delayed imaging time. Nolop et al. and Hamberg et al. have shown that for 18F-FDG in lung cancer the tumour-to-background ratio did not reach a maximum by 1 h and waiting for a longer time interval after injection (e.g. 2 h) might have improved lesion detectability [17, 18]. In breast cancer, delayed imaging has been shown to be superior [14]. The effective dose to the patient from 185 MBq of 18F-FDG is 4.6 mSv, compared to 3 mSv from 600 MBq of Tc-99m phosphonate for a bone scan and 17 mSv from 150 MBq of Ga-67 for tumour imaging [15]. Doubling the administered activity would increase the signal-to-noise ratio by √2 for a scan at 45 min, or provide sufficient activity for a scan at a later time [16]. Gamma camera PET shows promise as a useful tool for hospitals needing functional imaging of tumour deposits of at least 10 mm diameter above the diaphragm, and 17 mm below the diaphragm. Minimum detectable size may decrease a little as image reconstruction techniques are improved. Centres with a heavy PET workload, or where very short half-life radionuclides are used may need to invest in a dedicated PET camera. Gamma camera PET technology may permit the widespread use of functional tumour imaging in oncology. Acknowledgements Dr R. A. R. Coulden and Dr C. S. Ng for reviewing the CT scans and Dr D. Gilligan and Dr R. E. Marcus for allowing us to recruit their patients.
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