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Gallium-67-citrate imaging in nuclear oncology
NW/.
Pergamon
0969~8051(93)EO030-9
Med.
Biol. Vol. 21, No. 5, pp. 731-738. 1994 Copyright 8 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0969~8051/94 $7.00 + 0.00
Gallium-67-Citrate Imaging in Nuclear Oncology HOMER A. MACAPINLAC,* ANDREW M. SCOTT, STEVEN M. LARSON, CHAITANYA R. DIVGI, SAMUEL D. J. YEH and STANLEY J. GOLDSMITH Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering 1275 York Avenue, New York, NY 10021. U.S.A.
Cancer Center,
Gallium-67-titrate is one of the most useful radiopharmaceuticals to detect tumors, stage extent of the disease, monitor response to treatment and distinguish recurrent disease from post-treatment changes. Gallium is likewise very sensitive to detect and locate infections and inflammatory foci. This application is extremely important in the management of immunocompromised cancer patients. Image interpretation should be tempered with full knowledge of the patients clinical condition, anatomic alterations due to prior surgery and correct timing of image acquisition. Early imaging at 46 h is useful to detect gastrointestinal infections, whereas 24 h imaging is used to evaluate chest infections. Although gallium-67 is a non-specific agent, the identification of the etiology of the inflammation may be improved by adequate clinical and laboratory information as well as correlation with other imaging modalities such as sonography and
computerized x-ray tomography (CT). High dose (10 mCi) gallium-67 single photon emission computed tomography (SPECT) imaging with image co-registration is important for accurate uptake localization.
Introduction Gallium-67xitrate was introduced by Edward and Hayes (1969) for tumor imaging and later by Lavender et al. (1971) to detect inflammatory lesions. Gallium-67 is currently one of the most versatile radiopharmaceuticals available to the nuclear physician and oncologist for the initial staging and followup of patients with cancer. Gallium-67 is also extremely important in the detection of infection or active inflammation in the immunocompromised cancer patient.
Mechanism of Uptake and Biodistribution Gallium-67 is a metal ion which behaves somewhat like the ferric ion. Its uptake in tumors appears to be mediated by its binding to transferrin and transferrin receptors in tumor cells. Following injection, gallium67 is bound to transfer+ and is slowly cleared from plasma (t l/2 = 4-6 h) and is taken up by the liver and becomes bound to ferritin. In this regard, gallium-67 is similar to iron and other transition metals that are bound in the +3 oxidation state to transferrin. But unlike iron, gallium-67 cannot be reduced to the +2 oxidation state, which would be required for incorporation into hemoglobin. The gallium67-transferrin complex is bound to tumor transferrin receptors via leaky capillary endothelium. The gal*Author for correspondence.
lium-67-transferrin complex is then taken into the cell by absorptive endocytosis and transported to the lysosome where gallium is released. The gallium is then probably bound by intracellular proteins. The mechanism of gallium-67 accumulation in inflammatory tissues and abscesses is not completely elucidated. Gallium-67 is bound by bacteria and inflammatory cells, apparently as a result of the increased requirement of trace metals by actively metabolizing cells attracted to the site of infection (Larson et al., 1979a, b; Larson and Carrasquillo, 1983). Others have shown that uptake in inflammatory lesions appears to be mediated by lactoferrin binding to granulocytes, lymphocytes, macrophages or to bacteria (Hoffer and Neumann, 1988). There is normal uptake in the liver, spleen, bone, nasal passageways, lacrimal and salivary glands. Diminished gallium-67 uptake in the liver and spleen is noted in states of iron overload or low transferrin levels (Weiner ef al., 1992). Normal uptake in the thymus is seen in normal children and may present as a problem in differentiation from tumors in patients after recent chemotherapy (Peylan-Ramu et al., 1989; Rossleigh et al., 1990). Prominent activity in the lungs may be due to chemotherapy toxicity (Beckerman et al., 1984) or drug toxicity (Zhu et al., 1988).
Technique Gallium-67 decay is characterized by a complex y-emission spectrum resulting in four principal en731
732
HOMER A. MACAPINLAC et ~1.
ergy peaks (91-93, 184,296, 388 keV) with the lower 3 peaks suitable for imaging and the highest peak a consideration for collimator design to avoid septal penetration. A dose of 1OmCi is used for adults to provide better quality images but without any significant radiation risk. A dual headed y-camera (e.g. ADAC Labs, Milpitas, Calif.) is used, considerably decreasing imaging time for whole body planar imaging, as well as SPECT imaging. 3-D volumetric reconstruction available in most commercially available systems allows good orientation for accurate localization of abnormal areas of uptake. At Memorial Sloan-Kettering Cancer Center, image co-registration with CT or magnetic resonance imaging (MRI) allows even more accurate localization of abnormal uptake, using the Pelizzari et al. (1989) program from the University of Chicago. The image datasets (SPECT/CT/MRI) are aligned with each other by a computer program which allow translation of the images in 3 axes so that optimal matching is achieved for accurate anatomic localization of the gallium-67 SPECT images. This appears to be extremely important in the evaluation of chest lesions
involving the mediastinum and lymph nodes. Further description of this technique is published elsewhere in this volume (Fig. 1). Lymphoma
The most important use of gallium-67 imaging in the lymphomas is the initial staging of patients prior to treatment to determine the gallium-67 avidity for the disease. Sequential imaging should be performed at intervals to monitor response to treatment and the early detection of recurrence. CT or MRI scans should routinely be available for anatomic comparison of suspected or unsuspected sites of disease to maximize the interpretation of the gallium-67 SPECT images. Gallium-67 imaging is extremely useful in the initial staging and monitoring of disease response or in Hodgkin’s and non-Hodgkin’s recurrence lymphoma (with the exception of low grade nonHodgkin’s lymphoma). With the use of 10 mCi (adult doses) gallium-67 SPECT imaging protocols; the sensitivity for the initial detection of disease in
Fig. I. 40-year-old male with non-Hodgkin’s lymphomas previously treated with chemotherapy now presents with a mediastinal mass detected on CT (upper right). Transaxial SPECT 48 h after 10mCi of 67Ga-citrate (upper left) resliced to the same plane and level of CT. Co-registered image (lower left) shows localization
of abnormal
uptake
of 67Ga-citrate
to the mediastinal
mass and normal
uptake
in sternum.
733
Gallium-67xitrate imaging in nuclear oncology
Fig. 2. (A) 1l-year-old boy with Hodgkin’s disease at diagnosis with anterior planar view showing intense gallium activity in the mediastinum extending to the right hilum. (B) Gallium scan showing normal distribution 4 years post-treatment. (C) Gallium scan showing tumor recurrence in the mediastinum 5 years post-treatment (bowel activity in pelvic region cleared on 96 h delayed views).
Hodgkin’s lymphoma approaches 100% with specificity ranging from 90 to 100% (Kaplan et al., 1983; Tumeh et al., 1987; McLaughlin ej al., 1990). Using similar techniques the sensitivity and specificity of gallium-67 SPECT in non-Hodgkin’s lymphoma is reported to be greater than 85% (McLaughlin et al., 1990) (see Fig. 2). Gallium-67 is crucial in monitoring response to treatment and has been shown (in gallium-67 avid disease) to be a good predictor of response to treatment and prognosis. However, the timing of the imaging should be 4-6 weeks following the last course of treatment so as to avoid false positive uptake in the region of the mediastinum due to post treatment fibrosis in adults with bulky mediastinal disease (Yeh rt al., 1979; Canellos, 1988; Kaplan et al., 1988, 1990) or rebound uptake in regenerating thymic tissue in children (Peylan-Ramu et al., 1989; Rossleigh et al., 1990). Particular attention to the proper positioning and sedation of children is required for good quality gallium-67 SPECT studies. Imaging of abdominal
disease should be done with attention to normal bowel uptake patterns and delayed imaging (96 h or later) should be done for adequate differentiation and in our experience is better than the use of cathartics/ laxatives.
Lung Cancer Gallium-67 uptake is found in various histologic types of lung cancer but has been found to have the greatest average uptake for small cell lung cancer and the least average uptake for adenocarcinoma and anaplastic large cell carcinoma (Higashi et al., 1980). Various series have shown that planar imaging has a sensitivity of 65-92% and specificity of 67-90% with an overall accuracy between 71 and 88% (Larson et al., 1975; Kramer and Divgi, 1991) for the primary tumor. These results may be dependent on tumor size. Detection limits to 1.5-2 cm (Waxman, 1986) have been reported. The crucial role for gallium-67 imaging in patients with lung tumors, however, is the detection of hilar and mediastinal metastases for accurate preoperative staging of these patients. Early studies by Alazraki et nl. (1978) have advocated the use of planar imaging as a screening method for detecting mediastinal involvement. In this series there was good sensitivity but relatively poor specificity. McKenna has reported contrasting results, however with low sensitivity (23%) but good specificity (82%) and only fair accuracy (67%) (McKenna et al., 1985). The apparent discrepancy is probably due to differences in interpretation criteria. A more recent series
734
HOMERA. MACAPINLAC et al
by Matsuno et al. (1992) has utilized gallium-67 SPECT in comparison to ‘OtTI SPECT. The main limitation of the study is the low dose of gallium (3 mCi/lll mBq). This series showed an improve-
ment in lesion detection using SPECT, 4 pts (total of 26) had ( + ) SPECT and ( - ) planar studies. Sensitivity was 50% (planar) and 65% (SPECT) for the primary lesion, but for mediastinal and hilar regions
Fig. 3. 77-year-old smoker with bronchitis and left lung mass. (A) 48 h gallium scans (10 mCi) showing uptake in the left lower lobe, central necrosis and uptake in the right bronchial tree, (B) CT scan showing tumor with central necrosis in the left lung posteriorly and (C) SPECT images showing uptake in the tumor and left paratracheal lymph nodes involved by tumor at surgery.
Gallium-67xitrate imaging in nuclear oncology the SPECT sensitivity was 100% with specificity of 56% for mediastinum and 32% for hilar nodes. There are no reports of a prospective study utilizing a high dose of gallium and multiheaded high resolution cameras for SPECT (see Fig. 3).
Soft Tissue Sarcomas Gallium-67 is useful in the initial staging of patients with soft tissue and bone sarcomas. Sensitivities exceeding 90% for detecting bony involvement with primary or metastatic tumors using gallium-67 has been noted (Yeh et al., 1984; Southee et ul., 1992). The utility of gallium-67 imaging is enhanced by its ability to detect distant metastases, extraosseous involvement or foci of active tumor within residual masses. The extent of gallium-67 uptake does correlate with the grade of malignancy in most tumor types except liposarcomas, mesotheliomas and synovial sarcomas (Southee et al., 1992). The role of gallium-67 imaging in the evaluation of treatment response is not yet well defined. Gallium-67 appears to be less accurate than “‘Tl as a means of assessing tumor extent and response to therapy (Ramanna et al., 1990).
Other Malignancies Hepatocellular carcinomas are gallium-67 avid in approx. 80-85% of cases (Hoffer and Neumann, 1988). Gallium-67 scanning is also useful in distinguishing hepatoma from pseudotumors of the liver in patients with cirrhosis. Normal background liver activity, however, may obscure some lesions with gallium-67 concentration equal to the liver. Thus 99mTc-sulfur colloid scans are recommended prior to gallium-67 scans to detect cold lesions that may be missed with the gallium-67 scan alone (Comelias and Atterbury, 1984). Studies have documented the utility of gallium-67 imaging in patients with malignant melanoma showing sensitivity of 82% and specificity of 99%. Tumors of the head and neck have been studied with sensitivities ranging from 56 to 87%. The technique may be more useful in the detection of recurrent disease where post operative changes do not allow adequate CT evaluation (Hoffer and Neumann, 1988).
Infections Gallium-67 has been widely used for the localization of infections and areas of inflammation (Staab and McCartney, 1978). Gallium-67 is highly sensitive for this purpose but has a low specificity because of
735
concomitant uptake in tumors, normal uptake in the liver, spleen and gut. Furthermore, it does not differentiate the various infectious etiologies (e.g. viral, fungal or bacterial infections). The use of gallium-67 scan imaging is particularly important in immunocompromised cancer patients with suspected infections because the presence of an infection is life threatening and has to be treated as an emergency. The gallium-67 scan should be interpreted with knowledge of the normal time-dependent accumulation in normal tissues, adequate information should be available as far as any recent surgery or alteration in normal anatomy (particularly in the abdomen), and any sonogram or CT scan available may assist in the interpretation of the gallium-67 study. Early imaging (46 h post-injection) is recommended particularly for abdominal infections prior to the normal excretion of gallium in the bowel by 24 h (Fig. 4). Evaluation of the chest in the early time frame may be particularly difficult because of blood pool activity in the heart, great vessels and lungs; this is likely to clear by 24 h. Because of the relatively slow clearance of transferrin bound gallium-67 from plasma, whole body imaging is usually performed at 48 h or later, with appropriate attention to technique, SPECT imaging may be performed providing improved contrast and detection of deep foci. Most cancer patients with solid tumors are managed surgically and infectious complications of various types can occur with both superficial (normal flora) or deep infections (Gram negative) up to a week post-operatively. These can be detected effectively by early and delayed gallium scanning, Infection in connection with venous access catheters, vascular grafts and various prostheses can also occur in this setting with Vorne et al. (1989) showing comparable detection rates using gallium-67xitrate and 99mTc-HMPA0 labeled leukocytes. In setting of FUO in a post-operative patient, gallium-67 scanning is the most appropriate survey method for detecting an occult site of infection. Gallium-67 has also been used to detect extrapulmonary tuberculosis in patients with prolonged fever (Yang et al., 1992). Twenty-four hour imaging has also been shown to be as accurate as 48 h delayed imaging for the diagnosis of pulmonary infections in immumocompromised patients (Derogatis et al., 1992) (Fig. 5). Gallium imaging has been particularly useful in the clinical management of immunocompromised patients with opportunistic infections, particularly pneumocystis pneumonia (PCP) which is more common in patients with the acquired immunodeficiency syndrome (AIDS) (Kramer and Divgi, 1991).
(Fig. 4 on p. 736) Fig. 4. 50-year-old female with leukemia and fever of unknown origin. (A) Gallium scan 4 h after 10 mCi i.v. showing intense accumulation in the RLQ indicating an inflammatory process and (B) CT scan showing thickened bowel wall in the cecum which was confirmed at surgery to be due to acute inflammation (typhlitis).
Fig. 4-legend on p. 735
Gallium-67xitrate imaging in nuclear oncology
Fig. 5. 9-year-old male with ALL, fever and cough. Virtually identical gallium scans showing diffuse bilateral lung uptake confirmed to be pneumocystis pneumonia were obtained 24 h (A) and 48 h (B) after injection of 5 mCi 67Gaeitrate.
Gallium uptake in the immunocompromised patient, however is non-specific as numerous other pathogens such as cytomegalovirus, mycobacterium, fungal infections and bacterial pneumonias can show similar diffuse patterns of uptake in the chest. It has been shown by Sfakianakis et al. (1982) that gallium-67 is more specific than “‘In-WBC in chronic infections. Inflammatory bowel diease, Cryptosporidium or Isospora infections and Candida esophagitis also produce abnormal gallium uptake in the gastrointestinal tract. Gastric uptake has been noted in 16 pts (both symptomatic and asymptomatic), with biopsy studies showing CMV (2) normal (2) and one pt each with ulcer, esophagitis and cryptosporidium (Nikpoor er al., 1992). In summary, gallium imaging is a sensitive method to detect infection or inflammation.
Conclusion Gallium is a tumor avid radiopharmaceutical useful to stage or determine extent of disease. It is useful to document tumor response to therapy as well as recurrence. In general, any condition causing a local or generalized inflammatory reaction will be detected with gallium imaging. Knowledge of the limitations
of the technique and utilization of complementary imaging modalities will maximize the usefulness of gallium. Image co-registration is a useful method for more accurate anatomic localization of abnormal gallium uptake
References Alazraki N., Ramsdeh J. and Taylor A. (1978) Reliability of gallium scan, chest radiography compared to mediastinoscopy for evaluating mediastinal spread in lung cancer. Am. Rea. Respir. Dis. 117, 415420. Beckerman C., Pave1 D.. Bitran J., Yun Ryo U. and Pinsky S. (1984) The effects of inadvertent administration of antineoplastic agents prior to gallium injection: a concise commumication. J. Nucl. Med. 25, 430435. Canellos G. P. (1988) Residual mass in lymphoma may not be residual disease (Editorial) J. Clin. Oncol. 6, 931-933. Cornelias E. and Atterbury C. (1984) Problems in the imaging and diagnosis of hepatoma. C/in. Nucl. Med. 9, 30-38. Derogatis A., Ramos J. and DePuey G. (1992) Accuracy of early gallium imaging in immunocompromised host. J. Nucl. Med. 33, 992 (abstract). Edwards C. and Hayes R. (1969) Tumor scanning with gallium citrate. J. Nucl. Med. 10, 103-105. Higashi T., Wakao H. and Nakamura A. (1980) Quantitative gallium 67 scanning for predictive value in lung carcinoma. J. Nucl. Med. 21, 628632.
738
HOMERA. MACAPINLAC et al.
Hoffer P. B. and Neumann R. D. (1988) Gallium and Infection. In Diagnostic Nuclear Imaging (Edited by Gottshalk A., Hoffer P. B. and Potchen E.), Vol. 2, pp. 1111-1124. Williams & Wilkins, Baltimore, Md. Kaplan W., Anderson K. and Leonard R. (1983) High dose gallium imaging in the evaluation of lymphoma. J. Nucl. Med. 24. 50.
Kaplan W., Jochelson M., Herman T. and Stomper T. (1988) Use of Gallium-67 citrate (aallium) \_ -, to .oredict response to therapy of diffuse large cell lymphoma. J. Nucl. Med. 29, 799.
Kaplan W., Jochelson M., Herman T., Nadler L., Stomper P., Takvorian T., Andersen J. and Canellos G. (1990) Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large cell lymphoma. J. Clin. Oncol. 8, 19661970. Kramer E. L. and Divgi C. R. (1991) Pulmonary applications of nuclear medicine. In Clinics in Chest Medicine. Vol. 12, pp. 55-75. Larson S. M. and Carrasquillo J. A. (1983) Nuclear oncology: current perspectives: In Nuclear Medicine Annual (Edited by Freeman and Weismann), pp. 167-198. Raven Press, New York. Larson S. M., Hilders M. S. and Johnson G. S. (1975) Tumor seeking radiopharmaceuticals: gallium-67. In Radiopharmaceuttcals (Edited by Subramanian G., Rhodes B. and Cooper J.), p. 413. Nuclear Medicine, New York. Larson S. M., Rasey J. S., Allen D. R. and Grunbaum Z. (1979a) A transferrin mediated uptake of gallium-67 in EMT6 sarcoma. Studies in uivo (Balb C mice). J. Nucl. Med. 20, 843-846.
Larson S. M., Rasey J. S., Allen D. and Nelson N. (1979b) Transferrin mediated uptake of gallium 67 by EMT-6 sarcoma. Studies in tissue culture. 1. Nucl. Med. 20, 837-842.
Lavender J., Lowe J., Bum J. and Chaudri M. (1971) Gallium citrate scanning in neoplastic and inflammatory lesions. Br. J. Radiol. 44, 361-366. Matsuno S., Masatada T., Kawasaki Y., Satoh K., Urrutia A., Ohkawa M. and Maeda M. (1992) Effectiveness of planar image and single photon emission tomography of thallium 201 compared -to gallium 67 in patients with nrimarv lung cancer. Eur. J. Nucl. Med. 19. 86-95. McKenna R.,-Haynie T. and Libshitz H. (1985) Critical evaluation of gallium 67 scan for surgical patients with lung cancer. Chest 87, 428431. McLauehlin A.. Manee M.. Greenouah R.. Allman K., SouthYeeA., MeikleS., Hutton B., Joshua D., Bautovich G. and Morris J. (1990) Current role of gallium scanning in the management of lymphoma. Eur. J. Nucl. Med. 16, 755-77 1. Neumann R. D. and Hoffer P. B. (1988) Gallium for detection of malignant disease. In Diagnostic Nuclear Medicine (Edited bv Gottshalk A.. Hoffer P. B. and Potchen E:), Vol. 2,pp. 107881081. Williams & Wilkins, Baltimore, Md.
Nikpoor
N., Dunn D. and Aliabadi I,. (1992) Gastric uptake of gallium in AIDS. 1. NW/. Med. 33, 643. Pelizzari C. A., Chen G. T. Y., Spelbring D. R., Weischelbaum R. R. and Chen C. T. (1989) Accurate three dimensional registration of CT, PET and/or MRI images of the brain. J. Comput. Assist. Tomogr. 14, 20-26. Peylan-Ramu N., Haddy T., Jones E., Horvath K., Adde M. and Magrath I. (1989) High frequency of benign mediastinal uptake of Gallium 67 after completion of chemotherapy in children with high grade non hodkin’s lymphoma. J. Clin. Oncol. 7, 1800-1806. Ramanna L., Waxman A., Binney, Mirra J. and Rosen C. (1990) Tl-201 scintigraphy in bone sarcoma: comparison with Gallium-67 and technetium MDP in the evaluation of chemotherapeutic response. J. Nuct. Med. 31, 567-572. Rossleigh M., Murray I. P. C., Mackey D., Bargwanna D. and Nayanar V. (1990) Pediatric solid tumors. Evaluation by gallium-67 SPECT studies. J. NW/. Med. 31, 168-172. Sfakianakis G. N., Al-Sheik W., Heal A., Rodman G., Zeppa R. and Serafini A. (1982) Comparison of scintigraphy with In-l I 1 leukocytes and Gallium-67 in diagnosis of occult sepsis. J. Nucl. Med. 23, 618626. Southee A., Kaplan W., Jochelson M., Gonin R., Dwyer J., Antman K. and Elias A. (1992) Gallium imaging in metastatic and recurrent soft-tissue sarcoma. J. NW/. Med. 33, 15941599. Staab E. and McCartney W. H. (1978) Role of Gallium 67 in inflammatory disease. Semin. Nucl. Med. 8, 219-234. Tumeh S., Rosenthal D., Kaplan W., English R. and Holman B. (1987) Lymphoma: evaluation with gallium SPECT. Radiology 164, 11l-l 14. Vorne M., Soini I., Lantto T. and Paakinen S. (1989) Tc-99m HMPAO leukocytes in the detection of inflammatory lesions: comparison with Gallium-67 citrate. J. Nucl. Med. 30, 1332-1336. Waxman A. D. (1986) The role of nuclear medicine in pulmonary neoplastic processes. Semin. Nucl. Med. 16, 285-295; Dambro J. and Klein B. (1992) Gallium distribution in a man with a decrease in both transferrin and hepatic gallium concentration. J. Nucl. Med. 33, 1701-1703.
Weiner R., Spencer R., Dambro J. and Klein B. (1992) Gallium distribution in a man with a decrease in both transferrin and hepatic gallium concentration. J. Nucl. Med. 33, 1701-1703. Yang S. O., Lee Y. I., Chung D. H., Lee M. C., Koh C. S., Choi B. I., Im J. G., Park J. H., Han M. C. and Kim C. W. (1992) Detection of extrapulmonary tuberculosis with gallium scans and CT. J. Nucl. Med. 33,2118-2122. Yeh S. D. J., Benua R. S. and Tan C. T. (1979) Gallium scan in recurrent Hodkin’s disease in children. Clin. Nucl. Med. 4, 359-367.
Yeh S. D. J., Rosen G., Caparros B. and Benua R. S. (1984) Semiquantitative gallium scintigraphy in patients with osteogenic sarcoma. C/in. Nucl. Med. 9, 175-183. Zhu Y., Botvinick E. and Dae M. (1988) Gallium lung scintigraphy in amiodarone toxicity. Chest 93, 11261131.
Pergamon
0969~8051(93)EO030-9
Med.
Biol. Vol. 21, No. 5, pp. 731-738. 1994 Copyright 8 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0969~8051/94 $7.00 + 0.00
Gallium-67-Citrate Imaging in Nuclear Oncology HOMER A. MACAPINLAC,* ANDREW M. SCOTT, STEVEN M. LARSON, CHAITANYA R. DIVGI, SAMUEL D. J. YEH and STANLEY J. GOLDSMITH Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering 1275 York Avenue, New York, NY 10021. U.S.A.
Cancer Center,
Gallium-67-titrate is one of the most useful radiopharmaceuticals to detect tumors, stage extent of the disease, monitor response to treatment and distinguish recurrent disease from post-treatment changes. Gallium is likewise very sensitive to detect and locate infections and inflammatory foci. This application is extremely important in the management of immunocompromised cancer patients. Image interpretation should be tempered with full knowledge of the patients clinical condition, anatomic alterations due to prior surgery and correct timing of image acquisition. Early imaging at 46 h is useful to detect gastrointestinal infections, whereas 24 h imaging is used to evaluate chest infections. Although gallium-67 is a non-specific agent, the identification of the etiology of the inflammation may be improved by adequate clinical and laboratory information as well as correlation with other imaging modalities such as sonography and
computerized x-ray tomography (CT). High dose (10 mCi) gallium-67 single photon emission computed tomography (SPECT) imaging with image co-registration is important for accurate uptake localization.
Introduction Gallium-67xitrate was introduced by Edward and Hayes (1969) for tumor imaging and later by Lavender et al. (1971) to detect inflammatory lesions. Gallium-67 is currently one of the most versatile radiopharmaceuticals available to the nuclear physician and oncologist for the initial staging and followup of patients with cancer. Gallium-67 is also extremely important in the detection of infection or active inflammation in the immunocompromised cancer patient.
Mechanism of Uptake and Biodistribution Gallium-67 is a metal ion which behaves somewhat like the ferric ion. Its uptake in tumors appears to be mediated by its binding to transferrin and transferrin receptors in tumor cells. Following injection, gallium67 is bound to transfer+ and is slowly cleared from plasma (t l/2 = 4-6 h) and is taken up by the liver and becomes bound to ferritin. In this regard, gallium-67 is similar to iron and other transition metals that are bound in the +3 oxidation state to transferrin. But unlike iron, gallium-67 cannot be reduced to the +2 oxidation state, which would be required for incorporation into hemoglobin. The gallium67-transferrin complex is bound to tumor transferrin receptors via leaky capillary endothelium. The gal*Author for correspondence.
lium-67-transferrin complex is then taken into the cell by absorptive endocytosis and transported to the lysosome where gallium is released. The gallium is then probably bound by intracellular proteins. The mechanism of gallium-67 accumulation in inflammatory tissues and abscesses is not completely elucidated. Gallium-67 is bound by bacteria and inflammatory cells, apparently as a result of the increased requirement of trace metals by actively metabolizing cells attracted to the site of infection (Larson et al., 1979a, b; Larson and Carrasquillo, 1983). Others have shown that uptake in inflammatory lesions appears to be mediated by lactoferrin binding to granulocytes, lymphocytes, macrophages or to bacteria (Hoffer and Neumann, 1988). There is normal uptake in the liver, spleen, bone, nasal passageways, lacrimal and salivary glands. Diminished gallium-67 uptake in the liver and spleen is noted in states of iron overload or low transferrin levels (Weiner ef al., 1992). Normal uptake in the thymus is seen in normal children and may present as a problem in differentiation from tumors in patients after recent chemotherapy (Peylan-Ramu et al., 1989; Rossleigh et al., 1990). Prominent activity in the lungs may be due to chemotherapy toxicity (Beckerman et al., 1984) or drug toxicity (Zhu et al., 1988).
Technique Gallium-67 decay is characterized by a complex y-emission spectrum resulting in four principal en731
732
HOMER A. MACAPINLAC et ~1.
ergy peaks (91-93, 184,296, 388 keV) with the lower 3 peaks suitable for imaging and the highest peak a consideration for collimator design to avoid septal penetration. A dose of 1OmCi is used for adults to provide better quality images but without any significant radiation risk. A dual headed y-camera (e.g. ADAC Labs, Milpitas, Calif.) is used, considerably decreasing imaging time for whole body planar imaging, as well as SPECT imaging. 3-D volumetric reconstruction available in most commercially available systems allows good orientation for accurate localization of abnormal areas of uptake. At Memorial Sloan-Kettering Cancer Center, image co-registration with CT or magnetic resonance imaging (MRI) allows even more accurate localization of abnormal uptake, using the Pelizzari et al. (1989) program from the University of Chicago. The image datasets (SPECT/CT/MRI) are aligned with each other by a computer program which allow translation of the images in 3 axes so that optimal matching is achieved for accurate anatomic localization of the gallium-67 SPECT images. This appears to be extremely important in the evaluation of chest lesions
involving the mediastinum and lymph nodes. Further description of this technique is published elsewhere in this volume (Fig. 1). Lymphoma
The most important use of gallium-67 imaging in the lymphomas is the initial staging of patients prior to treatment to determine the gallium-67 avidity for the disease. Sequential imaging should be performed at intervals to monitor response to treatment and the early detection of recurrence. CT or MRI scans should routinely be available for anatomic comparison of suspected or unsuspected sites of disease to maximize the interpretation of the gallium-67 SPECT images. Gallium-67 imaging is extremely useful in the initial staging and monitoring of disease response or in Hodgkin’s and non-Hodgkin’s recurrence lymphoma (with the exception of low grade nonHodgkin’s lymphoma). With the use of 10 mCi (adult doses) gallium-67 SPECT imaging protocols; the sensitivity for the initial detection of disease in
Fig. I. 40-year-old male with non-Hodgkin’s lymphomas previously treated with chemotherapy now presents with a mediastinal mass detected on CT (upper right). Transaxial SPECT 48 h after 10mCi of 67Ga-citrate (upper left) resliced to the same plane and level of CT. Co-registered image (lower left) shows localization
of abnormal
uptake
of 67Ga-citrate
to the mediastinal
mass and normal
uptake
in sternum.
733
Gallium-67xitrate imaging in nuclear oncology
Fig. 2. (A) 1l-year-old boy with Hodgkin’s disease at diagnosis with anterior planar view showing intense gallium activity in the mediastinum extending to the right hilum. (B) Gallium scan showing normal distribution 4 years post-treatment. (C) Gallium scan showing tumor recurrence in the mediastinum 5 years post-treatment (bowel activity in pelvic region cleared on 96 h delayed views).
Hodgkin’s lymphoma approaches 100% with specificity ranging from 90 to 100% (Kaplan et al., 1983; Tumeh et al., 1987; McLaughlin ej al., 1990). Using similar techniques the sensitivity and specificity of gallium-67 SPECT in non-Hodgkin’s lymphoma is reported to be greater than 85% (McLaughlin et al., 1990) (see Fig. 2). Gallium-67 is crucial in monitoring response to treatment and has been shown (in gallium-67 avid disease) to be a good predictor of response to treatment and prognosis. However, the timing of the imaging should be 4-6 weeks following the last course of treatment so as to avoid false positive uptake in the region of the mediastinum due to post treatment fibrosis in adults with bulky mediastinal disease (Yeh rt al., 1979; Canellos, 1988; Kaplan et al., 1988, 1990) or rebound uptake in regenerating thymic tissue in children (Peylan-Ramu et al., 1989; Rossleigh et al., 1990). Particular attention to the proper positioning and sedation of children is required for good quality gallium-67 SPECT studies. Imaging of abdominal
disease should be done with attention to normal bowel uptake patterns and delayed imaging (96 h or later) should be done for adequate differentiation and in our experience is better than the use of cathartics/ laxatives.
Lung Cancer Gallium-67 uptake is found in various histologic types of lung cancer but has been found to have the greatest average uptake for small cell lung cancer and the least average uptake for adenocarcinoma and anaplastic large cell carcinoma (Higashi et al., 1980). Various series have shown that planar imaging has a sensitivity of 65-92% and specificity of 67-90% with an overall accuracy between 71 and 88% (Larson et al., 1975; Kramer and Divgi, 1991) for the primary tumor. These results may be dependent on tumor size. Detection limits to 1.5-2 cm (Waxman, 1986) have been reported. The crucial role for gallium-67 imaging in patients with lung tumors, however, is the detection of hilar and mediastinal metastases for accurate preoperative staging of these patients. Early studies by Alazraki et nl. (1978) have advocated the use of planar imaging as a screening method for detecting mediastinal involvement. In this series there was good sensitivity but relatively poor specificity. McKenna has reported contrasting results, however with low sensitivity (23%) but good specificity (82%) and only fair accuracy (67%) (McKenna et al., 1985). The apparent discrepancy is probably due to differences in interpretation criteria. A more recent series
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by Matsuno et al. (1992) has utilized gallium-67 SPECT in comparison to ‘OtTI SPECT. The main limitation of the study is the low dose of gallium (3 mCi/lll mBq). This series showed an improve-
ment in lesion detection using SPECT, 4 pts (total of 26) had ( + ) SPECT and ( - ) planar studies. Sensitivity was 50% (planar) and 65% (SPECT) for the primary lesion, but for mediastinal and hilar regions
Fig. 3. 77-year-old smoker with bronchitis and left lung mass. (A) 48 h gallium scans (10 mCi) showing uptake in the left lower lobe, central necrosis and uptake in the right bronchial tree, (B) CT scan showing tumor with central necrosis in the left lung posteriorly and (C) SPECT images showing uptake in the tumor and left paratracheal lymph nodes involved by tumor at surgery.
Gallium-67xitrate imaging in nuclear oncology the SPECT sensitivity was 100% with specificity of 56% for mediastinum and 32% for hilar nodes. There are no reports of a prospective study utilizing a high dose of gallium and multiheaded high resolution cameras for SPECT (see Fig. 3).
Soft Tissue Sarcomas Gallium-67 is useful in the initial staging of patients with soft tissue and bone sarcomas. Sensitivities exceeding 90% for detecting bony involvement with primary or metastatic tumors using gallium-67 has been noted (Yeh et al., 1984; Southee et ul., 1992). The utility of gallium-67 imaging is enhanced by its ability to detect distant metastases, extraosseous involvement or foci of active tumor within residual masses. The extent of gallium-67 uptake does correlate with the grade of malignancy in most tumor types except liposarcomas, mesotheliomas and synovial sarcomas (Southee et al., 1992). The role of gallium-67 imaging in the evaluation of treatment response is not yet well defined. Gallium-67 appears to be less accurate than “‘Tl as a means of assessing tumor extent and response to therapy (Ramanna et al., 1990).
Other Malignancies Hepatocellular carcinomas are gallium-67 avid in approx. 80-85% of cases (Hoffer and Neumann, 1988). Gallium-67 scanning is also useful in distinguishing hepatoma from pseudotumors of the liver in patients with cirrhosis. Normal background liver activity, however, may obscure some lesions with gallium-67 concentration equal to the liver. Thus 99mTc-sulfur colloid scans are recommended prior to gallium-67 scans to detect cold lesions that may be missed with the gallium-67 scan alone (Comelias and Atterbury, 1984). Studies have documented the utility of gallium-67 imaging in patients with malignant melanoma showing sensitivity of 82% and specificity of 99%. Tumors of the head and neck have been studied with sensitivities ranging from 56 to 87%. The technique may be more useful in the detection of recurrent disease where post operative changes do not allow adequate CT evaluation (Hoffer and Neumann, 1988).
Infections Gallium-67 has been widely used for the localization of infections and areas of inflammation (Staab and McCartney, 1978). Gallium-67 is highly sensitive for this purpose but has a low specificity because of
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concomitant uptake in tumors, normal uptake in the liver, spleen and gut. Furthermore, it does not differentiate the various infectious etiologies (e.g. viral, fungal or bacterial infections). The use of gallium-67 scan imaging is particularly important in immunocompromised cancer patients with suspected infections because the presence of an infection is life threatening and has to be treated as an emergency. The gallium-67 scan should be interpreted with knowledge of the normal time-dependent accumulation in normal tissues, adequate information should be available as far as any recent surgery or alteration in normal anatomy (particularly in the abdomen), and any sonogram or CT scan available may assist in the interpretation of the gallium-67 study. Early imaging (46 h post-injection) is recommended particularly for abdominal infections prior to the normal excretion of gallium in the bowel by 24 h (Fig. 4). Evaluation of the chest in the early time frame may be particularly difficult because of blood pool activity in the heart, great vessels and lungs; this is likely to clear by 24 h. Because of the relatively slow clearance of transferrin bound gallium-67 from plasma, whole body imaging is usually performed at 48 h or later, with appropriate attention to technique, SPECT imaging may be performed providing improved contrast and detection of deep foci. Most cancer patients with solid tumors are managed surgically and infectious complications of various types can occur with both superficial (normal flora) or deep infections (Gram negative) up to a week post-operatively. These can be detected effectively by early and delayed gallium scanning, Infection in connection with venous access catheters, vascular grafts and various prostheses can also occur in this setting with Vorne et al. (1989) showing comparable detection rates using gallium-67xitrate and 99mTc-HMPA0 labeled leukocytes. In setting of FUO in a post-operative patient, gallium-67 scanning is the most appropriate survey method for detecting an occult site of infection. Gallium-67 has also been used to detect extrapulmonary tuberculosis in patients with prolonged fever (Yang et al., 1992). Twenty-four hour imaging has also been shown to be as accurate as 48 h delayed imaging for the diagnosis of pulmonary infections in immumocompromised patients (Derogatis et al., 1992) (Fig. 5). Gallium imaging has been particularly useful in the clinical management of immunocompromised patients with opportunistic infections, particularly pneumocystis pneumonia (PCP) which is more common in patients with the acquired immunodeficiency syndrome (AIDS) (Kramer and Divgi, 1991).
(Fig. 4 on p. 736) Fig. 4. 50-year-old female with leukemia and fever of unknown origin. (A) Gallium scan 4 h after 10 mCi i.v. showing intense accumulation in the RLQ indicating an inflammatory process and (B) CT scan showing thickened bowel wall in the cecum which was confirmed at surgery to be due to acute inflammation (typhlitis).
Fig. 4-legend on p. 735
Gallium-67xitrate imaging in nuclear oncology
Fig. 5. 9-year-old male with ALL, fever and cough. Virtually identical gallium scans showing diffuse bilateral lung uptake confirmed to be pneumocystis pneumonia were obtained 24 h (A) and 48 h (B) after injection of 5 mCi 67Gaeitrate.
Gallium uptake in the immunocompromised patient, however is non-specific as numerous other pathogens such as cytomegalovirus, mycobacterium, fungal infections and bacterial pneumonias can show similar diffuse patterns of uptake in the chest. It has been shown by Sfakianakis et al. (1982) that gallium-67 is more specific than “‘In-WBC in chronic infections. Inflammatory bowel diease, Cryptosporidium or Isospora infections and Candida esophagitis also produce abnormal gallium uptake in the gastrointestinal tract. Gastric uptake has been noted in 16 pts (both symptomatic and asymptomatic), with biopsy studies showing CMV (2) normal (2) and one pt each with ulcer, esophagitis and cryptosporidium (Nikpoor er al., 1992). In summary, gallium imaging is a sensitive method to detect infection or inflammation.
Conclusion Gallium is a tumor avid radiopharmaceutical useful to stage or determine extent of disease. It is useful to document tumor response to therapy as well as recurrence. In general, any condition causing a local or generalized inflammatory reaction will be detected with gallium imaging. Knowledge of the limitations
of the technique and utilization of complementary imaging modalities will maximize the usefulness of gallium. Image co-registration is a useful method for more accurate anatomic localization of abnormal gallium uptake
References Alazraki N., Ramsdeh J. and Taylor A. (1978) Reliability of gallium scan, chest radiography compared to mediastinoscopy for evaluating mediastinal spread in lung cancer. Am. Rea. Respir. Dis. 117, 415420. Beckerman C., Pave1 D.. Bitran J., Yun Ryo U. and Pinsky S. (1984) The effects of inadvertent administration of antineoplastic agents prior to gallium injection: a concise commumication. J. Nucl. Med. 25, 430435. Canellos G. P. (1988) Residual mass in lymphoma may not be residual disease (Editorial) J. Clin. Oncol. 6, 931-933. Cornelias E. and Atterbury C. (1984) Problems in the imaging and diagnosis of hepatoma. C/in. Nucl. Med. 9, 30-38. Derogatis A., Ramos J. and DePuey G. (1992) Accuracy of early gallium imaging in immunocompromised host. J. Nucl. Med. 33, 992 (abstract). Edwards C. and Hayes R. (1969) Tumor scanning with gallium citrate. J. Nucl. Med. 10, 103-105. Higashi T., Wakao H. and Nakamura A. (1980) Quantitative gallium 67 scanning for predictive value in lung carcinoma. J. Nucl. Med. 21, 628632.
738
HOMERA. MACAPINLAC et al.
Hoffer P. B. and Neumann R. D. (1988) Gallium and Infection. In Diagnostic Nuclear Imaging (Edited by Gottshalk A., Hoffer P. B. and Potchen E.), Vol. 2, pp. 1111-1124. Williams & Wilkins, Baltimore, Md. Kaplan W., Anderson K. and Leonard R. (1983) High dose gallium imaging in the evaluation of lymphoma. J. Nucl. Med. 24. 50.
Kaplan W., Jochelson M., Herman T. and Stomper T. (1988) Use of Gallium-67 citrate (aallium) \_ -, to .oredict response to therapy of diffuse large cell lymphoma. J. Nucl. Med. 29, 799.
Kaplan W., Jochelson M., Herman T., Nadler L., Stomper P., Takvorian T., Andersen J. and Canellos G. (1990) Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large cell lymphoma. J. Clin. Oncol. 8, 19661970. Kramer E. L. and Divgi C. R. (1991) Pulmonary applications of nuclear medicine. In Clinics in Chest Medicine. Vol. 12, pp. 55-75. Larson S. M. and Carrasquillo J. A. (1983) Nuclear oncology: current perspectives: In Nuclear Medicine Annual (Edited by Freeman and Weismann), pp. 167-198. Raven Press, New York. Larson S. M., Hilders M. S. and Johnson G. S. (1975) Tumor seeking radiopharmaceuticals: gallium-67. In Radiopharmaceuttcals (Edited by Subramanian G., Rhodes B. and Cooper J.), p. 413. Nuclear Medicine, New York. Larson S. M., Rasey J. S., Allen D. R. and Grunbaum Z. (1979a) A transferrin mediated uptake of gallium-67 in EMT6 sarcoma. Studies in uivo (Balb C mice). J. Nucl. Med. 20, 843-846.
Larson S. M., Rasey J. S., Allen D. and Nelson N. (1979b) Transferrin mediated uptake of gallium 67 by EMT-6 sarcoma. Studies in tissue culture. 1. Nucl. Med. 20, 837-842.
Lavender J., Lowe J., Bum J. and Chaudri M. (1971) Gallium citrate scanning in neoplastic and inflammatory lesions. Br. J. Radiol. 44, 361-366. Matsuno S., Masatada T., Kawasaki Y., Satoh K., Urrutia A., Ohkawa M. and Maeda M. (1992) Effectiveness of planar image and single photon emission tomography of thallium 201 compared -to gallium 67 in patients with nrimarv lung cancer. Eur. J. Nucl. Med. 19. 86-95. McKenna R.,-Haynie T. and Libshitz H. (1985) Critical evaluation of gallium 67 scan for surgical patients with lung cancer. Chest 87, 428431. McLauehlin A.. Manee M.. Greenouah R.. Allman K., SouthYeeA., MeikleS., Hutton B., Joshua D., Bautovich G. and Morris J. (1990) Current role of gallium scanning in the management of lymphoma. Eur. J. Nucl. Med. 16, 755-77 1. Neumann R. D. and Hoffer P. B. (1988) Gallium for detection of malignant disease. In Diagnostic Nuclear Medicine (Edited bv Gottshalk A.. Hoffer P. B. and Potchen E:), Vol. 2,pp. 107881081. Williams & Wilkins, Baltimore, Md.
Nikpoor
N., Dunn D. and Aliabadi I,. (1992) Gastric uptake of gallium in AIDS. 1. NW/. Med. 33, 643. Pelizzari C. A., Chen G. T. Y., Spelbring D. R., Weischelbaum R. R. and Chen C. T. (1989) Accurate three dimensional registration of CT, PET and/or MRI images of the brain. J. Comput. Assist. Tomogr. 14, 20-26. Peylan-Ramu N., Haddy T., Jones E., Horvath K., Adde M. and Magrath I. (1989) High frequency of benign mediastinal uptake of Gallium 67 after completion of chemotherapy in children with high grade non hodkin’s lymphoma. J. Clin. Oncol. 7, 1800-1806. Ramanna L., Waxman A., Binney, Mirra J. and Rosen C. (1990) Tl-201 scintigraphy in bone sarcoma: comparison with Gallium-67 and technetium MDP in the evaluation of chemotherapeutic response. J. Nuct. Med. 31, 567-572. Rossleigh M., Murray I. P. C., Mackey D., Bargwanna D. and Nayanar V. (1990) Pediatric solid tumors. Evaluation by gallium-67 SPECT studies. J. NW/. Med. 31, 168-172. Sfakianakis G. N., Al-Sheik W., Heal A., Rodman G., Zeppa R. and Serafini A. (1982) Comparison of scintigraphy with In-l I 1 leukocytes and Gallium-67 in diagnosis of occult sepsis. J. Nucl. Med. 23, 618626. Southee A., Kaplan W., Jochelson M., Gonin R., Dwyer J., Antman K. and Elias A. (1992) Gallium imaging in metastatic and recurrent soft-tissue sarcoma. J. NW/. Med. 33, 15941599. Staab E. and McCartney W. H. (1978) Role of Gallium 67 in inflammatory disease. Semin. Nucl. Med. 8, 219-234. Tumeh S., Rosenthal D., Kaplan W., English R. and Holman B. (1987) Lymphoma: evaluation with gallium SPECT. Radiology 164, 11l-l 14. Vorne M., Soini I., Lantto T. and Paakinen S. (1989) Tc-99m HMPAO leukocytes in the detection of inflammatory lesions: comparison with Gallium-67 citrate. J. Nucl. Med. 30, 1332-1336. Waxman A. D. (1986) The role of nuclear medicine in pulmonary neoplastic processes. Semin. Nucl. Med. 16, 285-295; Dambro J. and Klein B. (1992) Gallium distribution in a man with a decrease in both transferrin and hepatic gallium concentration. J. Nucl. Med. 33, 1701-1703.
Weiner R., Spencer R., Dambro J. and Klein B. (1992) Gallium distribution in a man with a decrease in both transferrin and hepatic gallium concentration. J. Nucl. Med. 33, 1701-1703. Yang S. O., Lee Y. I., Chung D. H., Lee M. C., Koh C. S., Choi B. I., Im J. G., Park J. H., Han M. C. and Kim C. W. (1992) Detection of extrapulmonary tuberculosis with gallium scans and CT. J. Nucl. Med. 33,2118-2122. Yeh S. D. J., Benua R. S. and Tan C. T. (1979) Gallium scan in recurrent Hodkin’s disease in children. Clin. Nucl. Med. 4, 359-367.
Yeh S. D. J., Rosen G., Caparros B. and Benua R. S. (1984) Semiquantitative gallium scintigraphy in patients with osteogenic sarcoma. C/in. Nucl. Med. 9, 175-183. Zhu Y., Botvinick E. and Dae M. (1988) Gallium lung scintigraphy in amiodarone toxicity. Chest 93, 11261131.