The value of Ga-67 scintigraphy and F-18 fluorodeoxyglucose positron emission tomography in staging and monitoring the response of lymphoma to treatment

The Value of Ga-67 Scintigraphy and F-18 Fluorodeoxyglucose Positron Emission Tomography in Staging and Monitoring the Response of Lymphoma to Treatment Rachel Bar-Shalom, Maya Mor, Nikolai Yefremov, and Stanley J. Goldsmith Gallium-67 scintigraphy (GS) has the ability to provide important diagnostic and prognostic information for the evaluation of patients with lymphoma. GS is superior to morphologic imaging techniques because of its affinity to viable lymphoma cells. The value of GS lies not in the initial diagnosis but primarily in assessing the results of treatment and in the follow-up of patients w i t h lymphoma. Nevertheless, GS has not gained the expected wide acceptance, possibly because of the meticulous technique required and the expertise needed for optimal interpretation. The introduction of positron emission tomography (PET) with

F-18 fluorodeoxyglucose (FDG) as a tumor-seeking agent, which provides images of superior quality, may have an impact on the current role of GS in the management of patients with lymphoma. FDG-PET seems to share w i t h GS the advantages of a t u m o r viability agent. It appears to be more sensitive for detecting nodal and extranodal sites of disease than GS and may have predictive value during and after therapy for lymphoma. These potential clinical and economic advantages of FDG-PET need to be confirmed in systematic, large-scale prospective studies. Copyright 9 2001 by W.B. Saunders Company

a-67 SCINTIGRAPHY (GS) provides important clinical information for the evaluation of patients with lymphoma, primarily in monitoring the response to treatment. With the introduction of positron emission tomography (PET) with the use of F-18 fluorodeoxyglucose (FDG), the potential role of this modality in the management of lymphoma is currently being evaluated. This article describes and compares the role of functional imaging with Ga-67 and FDG in patients with lymphoma.

duced shortly thereafter and provided superior anatomic images at a time when GS was suboptimal because of the use of low doses of Ga and rectilinear scanners. 4 Over time, with the improvement of scanning technique and instrumentation, the role for GS in the management of lymphoma patients has been proved.

G

GA-67 SCINTIGRAPHY IN THE MANAGEMENT OF LYMPHOMA In 1969, Edward and Hayes reported their chance observation of Ga-67 uptake in a lymphoma mass and suggested its use for imaging various malignant tumors. 1 There is a high concentration of Ga in viable tumor tissue, and it therefore serves as a tumor viability agent. 2'3 Ga is transported in the circulation bound to plasma proteins, mainly transferrin. The mechanism of Ga uptake by malignant tissue is controversial, probably involving several factors (with not all of them completely understood), such as increased permeability of tumor blood vessels, binding of Ga-transferrin complex to transferrin receptors on the tumor cell surface and subsequent endocytosis, as well as a transferrin-independent mechanism. Inside the cell, Ga concentrates in the cytoplasm bound to lysosomelike proteins and other intracellular macromolecules.2"4-7 GS was the first whole-body, noninvasive imaging modality for the diagnosis and staging of lymphoma before treatment. However, the initial enthusiasm for this application has declined considerably. Computed tomography (CT) was intro-

GS in the Staging of Lymphoma The cooperative group studies published in 19778 and 19789 reported patient and site sensitivity of GS to be 88% and 69%, respectively, for the detection of untreated Hodgkin's disease (HD), and 76% and 53%, respectively, for the detection of non-Hodgkin's lymphoma (NHL). Low sensitivity was also reported by other authors; however, GS provided additional information on previously unsuspected sites of disease that were not detected by other radioiogic modal ities, lo-t2 Improved technology, injection of high-dose Ga, and the use of single photon emission computed tomography (SPECT) considerably increased the accuracy of GS in the staging of HD and NHL. ]3-16 Front et al found in 77 patients with HD and NHL that overall sensitivity of GS for initial staging increased from From the Department of Nuclear Medicine, Rambam Medical Center, Haifa. Israel; and the Division of Nuclear Medicine, Department of Radiolog3. The New York Presbyterian Hospital Weill-Medical College of Cornell Universit3, New York, NY. Address reprint requests to Rachel Bar-Shalom, MD, Department of Nuclear Medichle, Rambam Medical Center, Haifa 35254, Israel. Copyright 9 2001 by W.B. Saunders Company 0001-2998/01/3103-0002535.00/0 doi: 10.1053/snuc. 2001.23519

Seminars in NuclearMedicine,Vol XXXl, No 3 (July), 2001: pp 177-190

177

178

78% with planar imaging to 85% with the use of SPECT. ~5 Sensitivity of GS for the initial detection of lymphoma is related not only to technical factors but also to the histologic type of disease and to the size and location of lesions. High sensitivity was reported in the mediastinum (96%) but only about 60% sensitivity for abdominal pelvic disease. 13 High-grade NHL and HD are highly Ga-avid. 13'17 Ga uptake in low-grade NHL is controversial. Some authors consider it to be low compared with other types of lymphomas, whereas others have found GS useful in low-grade N H L . 7"9'13"18-23 Andrews et al found patient sensitivity of GS of 89% for histiocytic NHL and only 59% for welldifferentiated lymphocytic NHL. 9 In a recent retrospective study of 48 patients with low-grade NHL, GS identified only 41% of nodal sites detected by CT or clinical examination. 22 In this study, however, SPECT was performed only in selected cases. Ben-Haim et al analyzed GS sensitivity according to histologic subtypes of lowgrade NHL. 23 In 57 patients who underwent GS at initial diagnosis or during treatment, the overall sensitivity per patient was 79%, and site sensitivity was 69%. Sensitivity of GS for the more common histologic subtypes of low-grade NHL was much higher than for the rare types, and it was not significantly different from that reported for HD or high-grade NHL (91% for follicular mixed small and large cell and 84% for follicular, small cleaved NHL). 23 In spite of its limitations in the staging of a newly diagnosed lymphoma, GS performed before treatment is of added value in identifying a site suitable for biopsy when there is a strong clinical suspicion of lymphoma but no adenopathy on physical examination, in excluding sites of disease, in detecting additional previously unknown sites, and in characterizing Ga-avidity of the lymphoma before treatment for subsequent evaluation during the course of disease. 13 GS in Evaluating the Response to Treatment and Assessing the Nature of a Residual Mass The value of GS for assessing the response to treatment of lymphoma is based on the observation that Ga is a tumor viability agent. Iosilevsky et al showed in a mouse tumor model that uptake of Ga and of [H-3] deoxyglucose in a tumor after treat-

BAR-SHALOM ET AL

ment depends on the amount of viable malignant cells in the mass. 3 Morphologic imaging modalities need anatomic changes to detect disease. However, anatomic changes in size, weight, and volume are not always indicative of the presence or absence of viable malignant cells in a tumor m a s s . 3'24-26 The important distinction between mass and tumor, expressed by the recognition that "residual mass may not be a residual disease," was established by many studies that showed the excellent ability of Ga to detect viable tumors. 27 This made GS superior to CT in characterizing a residual mass after therapy and thus in monitoring the response to treatment. 15'28-36 The sensitivity of GS for the detection of a viable tumor after treatment also depends on the timing of the procedure as related to chemotherapy. The biodistribution of Ga appears to be significantly affected by chemotherapy and radiotherapy. 13'37'38 Wylie et al recommended empirically a 6-week interval between the last chemotherapy course and the injection of Ga. 29 The commonly accepted rule today is a 2- to 3-week interval from the prior treatment and a 24- to 48-hour interval between injecting Ga and starting the n e x t cycle. 4A3'39'4~ Increasing the clinical specificity of GS, especially after treatment, is achieved by recognizing physiologic and nonlymphomatous uptake patterns of Ga. These include Ga uptake in thymic hyperplasia after cessation of chemotherapy in children and young adults, bilateral hilar uptake, and diffuse lung uptake (usually appearing on follow-up studies during or after treatment). 41-45 The combination of timing of appearance, age group, location, and shape of uptake may be helpful in excluding viable lymphoma. Israel et al showed that a negative GS at the end of treatment in patients with a Ga-avid lymphoma accurately identified complete remission (CR) in 95% of patients. CT at the end of treatment was negative in only 57% of patients who achieved a CR. GS remained positive in all 4 patients who did not achieve remission. 2s In HD, 89% of patients with a positive GS at the end of treatment either died or had tumor progression, as compared with 88% of patients with a negative posttreatment GS who achieved a C R . 29 The value of Ga-SPECT to exclude disease in residual masses after treatment was shown in 77 patients with HD and NHL. 15 Sensitivity and specificity of GS after treatment was 92% and

GA-67 AND FDG-PET IN LYMPHOMA

99%, respectively. Superior sensitivity of GS over CT in detecting mediastinal disease was shown by Kostakoglu et al in 30 adult patients with HD. 34 Sensitivity of GS was 96%, and that of CT was 68%. Specificity was 96% and 60%, respectively. 34 The use of a new technique, transmission emission tomography (TET), that allows the precise registration of data from combined Ga and CT scanning may prove useful in assessing the response to treatment (Fig 1). Initial data on the use of Ga-TET in patients with lymphoma show advantages in differentiating residual tissue from active tumor and in excluding the presence of active disease. 46 The accurate definition of remission at the end of treatment is important to avoid unnecessary toxic treatment or to indicate early the need for second-line chemotherapy. At the end of treatment, GS reflects not only the state of disease at that specific time point but also has implications on long-term prognosis. 35"36-47-52The predictive value of posttreatment GS is somewhat different in HD and NHL. The negative and positive predictive values (NPV and PPV) of GS for response to treatment in 43 patients with HD were 84% and 80%, respectively. 35 The NPV and PPV for CT was 88% and 29%, respectively. A significant difference in disease-free and overall survival was found between HI) patients with positive and negative GS at the end of treatment. No such difference was found between patients with positive and negative CT at the end of treatment. 35'36 It should be noted, however, that relapse may occur in patients with a negative GS after treatment, especially in advanced HD.36,51-54 The NPV of posttherapy GS was higher

Fig 1. Assessing residual mass by GS. Ga-TET (Hawkeye-VG, GEMS, Milwaukee, Wl), performed after chemotherapy end radiotherapy of Hodgkin's disease, shows a residual mediastinal mass on the transmission (CT) study (left), with no abhorreal Ga uptake on the corresponding SPECT (center). Fusion at the same anatomic level (right) confirms the absence of residual active lymphome.

179

in patients with limited disease (92%) than in those with advanced HD (65%). 51 In a retrospective assessment of 48 patients with mediastinal HD, a positive GS at the end of treatment was highly predictive of poor prognosis, but 27% of patients with a negative GS relapsed. 53 The NPV of GS after treatment of HD was suggested to be related to the stage of disease; therefore, a negative posttherapy GS in high-risk patients should be evaluated with caution. 53'54 More consistently, high predictive values were reported for GS after treatment for patients with NHL. 47"5~ Front et al found GS at the end of treatment for patients with NHL to have an NPV of 84% versus 80% for CT, and a PPV of 73% versus 35% for CT. 47 There was a significant difference in disease-free and overall survival between patients with positive and negative GS posttreatment. No such difference was found between patients with negative and positive CT after treatment. Vose et al found GS performed after high-dose chemotherapy and marrow transplantation to be highly predictive of outcome in 143 patients with aggressive NHL. 5~ GS in Detecting Recurrence Sixty-five percent of patients with large-cell NHL and up to 80% of patients with HD initially achieve CR. 55"56 However, recurrence of disease may occur and require aggressive second-line regimens, including high-dose chemotherapy and bone marrow transplantation. Salvage therapy appears to be more effective when tumor load is small. Early detection of recurrent lymphoma, therefore, may improve the long-term survival of patients. 4"57"58 No optimal strategy has yet been

180

established for the early detection of preclinical relapse. There are limited data on the role of GS in detecting recurrence. 5L55'59 Weeks et al assessed the sensitivity of various follow-up procedures for the detection of relapse of large-cell NHL. 55 In 90% of 51 patients evaluated, relapse was diagnosed only when clinically evident by the presence of symptoms and/or palpatory findings. CT had a low sensitivity of 45% and 55% for chest and abdominal disease, respectively. GS was performed in only 10 patients with relapse and was positive in 9 of them. Front et al reported the sensitivity and specificity of GS for detecting relapse to be 95% and 89%, respectively. 59 In 27% of patients, relapse occurred in new sites of disease, emphasizing the advantage of GS as a wholebody screening procedure. In 12 events of recurrence, GS was abnormal on an average of 6.8 months before the appearance of clinical symptoms or radiologic abnormalities. 59 CT cannot identify lymphomatous tissue in a normal-sized lymph node, and it cannot differentiate adenopathy resulting from nonlymphomatous processes or residual enlarged fibrotic mass from a viable recurrent mass. GS can contribute functional data and additional information by whole-body screening, detecting viable sites of disease and guiding diagnostic biopsy sites. Even if the specificity of GS is not enough to justify treatment based only on a positive scan, it can identify patients who will benefit from further evaluation and close follow-up (Fig 2).

GS in Predicting the Response and Prognosis During Therapy The development of new aggressive regimens for salvage therapy has increased the survival of patients with a poor prognosis, but it has also increased the risk of treatment-related toxicity. Stratification of patients according to their predicted long-term prognosis may enable optimization of treatment protocols. Low-risk patients with a favorable response to initial treatment should be spared further aggressive toxic treatment. Unsuccessful therapy should be stopped and replaced by aggressive therapy as early as possible, while tumor load is small and beneficial therapeutic effect is still possible. Various pretherapy clinical factors related to both tumor biology and patient status were found

BAR-SHALOM ET AL

to have a prognostic significance regarding risk for tumor progression or relapse. Shipp et al6o and Hasenclever et al61 established a prognostic index based on various clinical pretherapy variables for patients with NHL and HD. Potential nonresponders may thus be separated from respondcrs and may be selected for an appropriate therapeutic regimen. Still, the early, accurate evaluation of response is needed during therapy to assess the specific tumor chemosensitivity in the individual patient (Fig 3). Armitage et al showed that chemosensitivity of lymphoma to the specific therapy is reflected by the rapidity of tumor regression during treatment. 57 Increased rate of tumor regression is predictive of better outcome with higher cure rate. 57'62 Several studies used GS for the early assessment of response to treatment. 63-67 Janicek et al showed that a positive GS after 2 cycles of high-dose chemotherapy in 30 patients with aggressive NHL was predictive of treatment failure in 82% of patients 64 A negative GS during treatment predicted prolonged response in 94% of patients. CT could not differentiate patients according to their outcome. 64 In another study of 118 patients with aggressive NHL, assessed prospectively, a negative GS after the first cycle of chemotherapy predicted long-term, continuous CR in 82% of patients. 67 A positive GS after 1 cycle predicted treatment failure in 71% of patients. There was a statistically significant difference in disease-free survival between patients with a negative or positive GS after 1 cycle of chemotherapy. No such difference was found between negative or positive CT scan at midtreatment. 67 In 98 patients with HD, a negative GS after the first cycle of treatment predicted prolonged CR in 92% of patients. 66 Early positive GS was less predictive of outcome. GS predicted treatment failure in only 57% of these patients, and a significant number of patients with positive GS achieved CR. Front et al suggested that patients with HD with a negative GS after 1 cycle may receive a reduced dose of chemotherapy without affecting survival. Patients with NHL with a positive GS early during treatment may be considered for a more aggressive therapy. 66"67Decreasing the dose of chemotherapy in children with earlystage lymphoma, which is predicted to have a favorable outcome on the basis of a negative GS after 2 cycles of chemotherapy, has been reported. 68'69 The important potential role of GS in determining long-term outcome should be assessed in larger

GA-67 AND FDG-PET IN LYMPHOMA

181

Jt

m

I

n

B mB I

|

Fig 2. Early (Istection of recurrence by GS. Whole-body (A), SPECT traneaxlal (B), coronal (C), and eagittal (D) GS images, performed 10 months after therapy of an aggressive NHL, show a small focus of increased Ga-67 uptake in the posterior aspect of the right lower hemithorax. Physical examination, laboratory tests, and CT were normal, and the patient rerosined on follow-up. Whole-body GS performed 5 months later (E) shows the same area of abnormal uptake in the posterior right lower chest, increased In size and intensity. A new focus of mild abnormal Ga-67 uptake is seen In the right axllla (arrowhead). Repeat CT showed an extrapleural mass In the posterior right hemithorax st the level of the lower the. racic vertebrae and right axlllary adenopathy. Axillary biopsy confirmed recurrent disease.

182

BAR-SHALOM ET AL

L Fig 3. Assessing the response during therapy by GS. Baseline whole-body GS (A) in a patient with aggressive NHL shows pathologic uptake in lymphoma sites involving the left mediastinum and paravertebral region bilaterally. Whole-body GS at midtreatment (B) shows persistent increased activity in the right paravertebral region. There is resolution of mediastinal and left paravertebral uptake. The study indicates partial response and the presence of chemoresistant lymphoma. Initial treatment was discontinued, and second-line chemotherapy was administered.

groups of patients and in various types and stages of disease. The ultimate goal should be to assess whether early modification of treatment according to results of GS performed early during treatment will improve patient outcome. FDG-PET IN THE MANAGEMENT OF LYMPHOMA

FDG uptake by malignant cells is an expression of the altered metabolism occurring during malignant transformation, in which glycolysis becomes the main metabolic pathway. 7~ Because of the increased number of glucose transporters on the tumor cell surface and the enhanced activity of some glycolytic enzymes, there is an increased

uptake of FDG by malignant cells as compared with normal tissues. Inside the cells, FDG is converted to FDG-6-phosphate, which is not a suitable substrate for further glycolysis, and is dephosphorylated at a decreased rate. FDG is therefore trapped intracellularly in the viable tumor. The intracellular accumulation of FDG reflects the glycolytic metabolic rate in malignant cells and is useful for imaging cancerous t i s s u e . 7~

High avidity of FDG has been described for most types of lymphoma. 73-78 Increased FDG uptake in lymphoma was first described in 5 patients with NHL by using a conventional gamma camera and a special, ultrahigh-energy collimator. 73 Okada et al detected various types of lymphoma in 21

GA-67 AND FDG-PET IN LYMPHOMA

patients who underwent PET with FDG before treatment. 74 High-grade NHL with poor prognosis had intense uptake. The lowest uptake was seen in l o w - g r a d e N H L . 74 La-pela et al studied 22 patients with newly diagnosed NHL by FDG-PET. 75 There was a significantly higher FDG uptake in patients with a higher histo-logic grade and with increased proliferative activity. 75 Correlation between FDG uptake and the grade of the lymphoma, with lower sensitivity for low-grade as compared with aggressive NHL, was confirmed by further studies. 76-8~In contrast, other authors found no difference in uptake between low- and high-grade NHL, with some of the highest standardized uptake values being measured in patients with low-grade NHL. 8L82 Intensity of FDG uptake at initial diagnosis was found to be predictive of long-term prognosis by some authors, 74"83 whereas others found no correlation with outcome, s4

FDG-PET in the Staging of Lymphoma FDG-PET has been suggested by several studies to be at least as good as (and probably superior to) CT for the staging of lymphoma. 78"81"82"85-91 Moog et al showed FDG-PET to be superior to CT in the initial staging of nodal lymphoma. 9z FDG-PET detected all nodal sites of disease that were seen by CT. Of the sites detected by PET only, 77% were confirmed as true-positive for lymphoma, whereas 50% of sites detected by CT only were shown to be false-positive. Detection of additional sites by FDG-PET resulted in upstaging of 8% of patients. In a study of 89 patients with HD and NHL, Bangerter et al found FDG-PET to have a sensitivity of 98%, a specificity of 90%, and a PPV and NPV of 92% and 97%, respectively, for detecting hilar and mediastinal sites of disease before treatment. 87 The overall sensitivity of FDG-PET for the staging and restaging of lymphoma was 86%, compared with 81% for CT. 82 PET detected lesions that were not seen on anatomic imaging modalities and excluded disease in suspicious sites, thus changing stage and treatment in 14% of patients. 86 FDG-PET was found to significantly affect staging as compared with CT in 41% of patients, and it led to a change in treatment in 25% of patients. 9~ Others reported a change of clinical management because of upstaging of disease in only 3% of patients. 78 The incremental clinical value of FDGPET over CT for initial staging still needs to be

183

investigated in large series of patients, especially in view of the current trend to administer chemotherapy even in early-stage HD. 54 The detection of extranodal lymphoma involving organs such as the liver, spleen, or bone marrow by anatomic imaging techniques is suboptimal. 93'94 Upstaging in 50% of patients by FDGPET at baseline was due to the detection of extranodal disease previously undiagnosed by CT. 9~ Of 15 extranodal lymphoma sites detected only by FDG-PET, 14 were confirmed as disease, and 5 of 6 extranodal sites seen only on CT were found to be false-positive. PET, again, changed the stage of disease in 16% of patients. 93 Several studies reported encouraging results for FDG imaging in the detection of lymphomatous involvement of the bone m a r r o w . 86'95"96 The accuracy of visual assessment of FDG uptake in the bone marrow of 50 patients before treatment w a s 7 8 % . 96 PET detected bone marrow disease even in the presence of an initial negative bone marrow biopsy, upstaging disease in 10% of patients. 95 FDGPET may be useful for whole-body screening of the bone marrow, for directing magnetic resonance imaging and bone m a r r o w biopsy. 94-96 FDG-PET is suggested to be cost-effective for accurate staging, compared with other imaging modalities. The use of FDG-PET-based algorithms for staging in 18 patients with lymphoma (in whom selected conventional imaging studies were performed after and were directed by wholebody PET) resulted in a total savings of about $30,000. s5

FDG-PET in Evaluating the Response to Treatment and in Assessing the Nature of a Residual Mass FDG-PET has been shown to be of value in assessing the response to treatment. It has the ability to characterize residual masses after therapy, when morphologic imaging modalities are of limited value (Fig 4). 8~ 97-1o3FDG-PET had significantly higher specificity and PPV than CT for assessing residual disease in 27 patients with lymphoma. 8~ The specificity and PPV for PET were 92% and 94%, respectively, whereas for CT they were 17% and 60%, respectively. 8~ The predictive value for relapse was 100% for a positive FDG-PET at the end of treatment and only 42% for a positive CT. io~ The NPV of PET (83%) did not differ significantly

184

BAR-SHALOM ET AL

Fig 4. Assessing response to therapy by FDG-PET. Baseline FDG-PET (A) of a patient with Hodgkin's disease shows multiple sites of disease in the left neck, left axilla, and the mediastinum. Repeated FDG-PET (B) after therapy shows partial regression of the lesions with multiple residual sites of active disease, indicating the need for salvage therapy. (Courtesy of M. Donald Blaufox, MD, PhD.)

from that of CT (87%). 101 The combined use of PET and CT is complementary for assessing the response to treatment. Relapse occurred in 26% of patients with a negative posttreatment FDG scan and positive CT scan, compared with only 10% recurrence in patients in whom both FDG and CT scans were negative after treatment. 1ol Several studies reported suboptimal PPV of FDG-PET for assessing the response to treatment. Whereas a negative FDG-PET at the end of treatment had a NPV of 100%, only 61% of patients with a positive FDG-PET were diagnosed with a relapse. 99 This may be related to the short-term follow-up of up to 63 weeks. 99 A trend of better sensitivity than specificity for FDG-PET at a site of a residual mass after treatment was also described. 98'1~ Of patients with a negative PET, 93% achieved CR, whereas 56% of patients with a positive scan relapsed. 98 As suggested for GS, the predictive value of FDG-PET for residual masses after treatment is probably also dependent on other prognostic factors. 54"1~176 Although in high-risk patients, the NPV of FDG-PET is only 50% to 67%, FDG-PET predicts CR in about 90% of patients with moderate risk for residual disease. 1~ This low NPV may be related to the size of the study population, inadequate technique, and improper timing of scanning in relation to prior therapy. 1~ It may, however, point out a more important limitation of the predictive value of FDG-PET, which is its possible dependence on the prevalence of treatment failure in the population studied, as was

suggested for G S . 54 Separate evaluation of patients with different stage and prognostic index may be more accurate. FDG-PET at the end of treatment may be of value for the prediction of relapse-free and overall survival. 1~176176 As such, it may potentially be used to direct management after first-line therapy. A positive study may indicate the need for additional radiotherapy or for more aggressive second-line protocols, whereas a negative study may obviate unnecessary, potentially harmful treatment. Jerusalem et al found a significantly lower relapse and progression-free survival and overall survival in patients with a positive PET, compared with patients with a negative study after treatment. 1~ These authors identified 3 different patterns of PET and CT findings that could be used to stratify patients according to their risk for disease relapse. Patients with both negative PET and CT at the end of treatment were considered at low risk, with a progression-free survival rate of 87% at 2 years. In the presence of negative PET and a residual mass on CT, the rate decreased to 60% at 2 years. Patients with a positive FDG-PET scan at the end of treatment had significantly reduced progressionfree and overall survival rates, regardless of their CT findings at the end of treatment.

FDG-PET in Detecting Recurrence Few studies have described the ability of FDGPET to detect relapse in old or new sites of lymphoma. 78'87"99'1~ Bangerter et al found FDGPET to have a sensitivity and specificity of 86%

GA-67 AND FDG-PET IN LYMPHOMA

185

!

Fig 5. Detection of recurrence by combined PET/CT. Combined PET/CT (Elgems [Haifa, israel], GEMS) with FDG was performed in a patient with NHL to assess the nature of left axillary adenopathy unchanged on repeat follow-up CT examinations. Fused image (right) localizes the increased FDG uptake (center) to the site of the axillary adenopathy seen on CT (left). Recurrent lymphoma was diagnosed by biopsy.

and 96%, respectively, for detecting recurrent disease in mediastinal or hilar nodes in 58 patients with HD and NHL. 87 NPV and PPV were 98% and 75%, respectively. Jerusalem et al found FDG-PET to be sensitive for restaging aggressive NHL, including the detection of additional sites not seen on CT. 78 Initial data on the use of FDG-TET in patients with cancer indicate the potential of this modality for the accurate localization of active lymphoma in a residual mass and in excluding disease in suspected sites (Fig 5). 1~

FDG-PET in Predicting the Response and Prognosis During Therapy The occurrence of relapse in spite of a negative FDG-PET scan at the end of treatment reflects the inability of PET to detect residual microscopic disease. A more accurate assessment may be achieved by evaluating the rate of response of lymphoma cells to the tumoricidal effect early during chemotherapy and not at a fixed point in time after therapy. Early characterization of chemosensitivity of lymphoma cells by FDG-PET may direct further therapy and predict prognosis. A few studies with a small number of patients have shown that the evaluation of FDG uptake by lymphoma sites as early as after 1 cycle of chemotherapy can predict the response to treatment. Jo6-~o9 Heokstra et al performed planar FDG imaging with a special collimator before and during treatment.~~ Negative FDG studies after 2 cycles of treatment predicted CR in 8 of 13 patients with HD and in 7 of 13 patients with NHL. Two patients who had a positive FDG scan after the first cycle of chemo-

therapy did not respond to treatment) ~ Romer et al showed a 60% decrease of FDG uptake in sites of lymphoma as early as 7 days after the initiation of chemotherapy.I~ A decrease of 76% in uptake of FDG compared with the baseline uptake values was observed 42 days after initiating treatment. Patients who responded had a significantly lower FDG uptake early during treatment than nonresponders) ~ Similar additional results indicate that a single FDG-PET study early during chemotherapy can separate patients according to their prognosis. 97'1=o The value of FDG-PET performed early during treatment as an independent prognostic factor has yet to be validated in large series of patients, in comparison with pretreatment clinical prognostic factors and with GS. COMPARISON OF FDG AND GS IN THE MANAGEMENT OF LYMPHOMA

GS has been proved useful in assessing response to treatment, in detecting recurrence, and in providing prognostic information during and after treatment. The limitations of GS are its low resolution and its physiologic biodistribution, which may complicate abdominal evaluation and require imaging up to 2 to 14 days after injection, which is both inconvenient and costly. The advantages of FDG-PET include its being a 2-hour, highresolution technique with better dosimetry, less bowel uptake, and a better quantitation potential than GS. Both techniques provide whole-body screening in a disease such as lymphoma, which has potential for multiple lesions at presentation and unpredictable sites of recurrence.

186

BAR-SHALOM ET AL

Fig 6. Comparison of GS and FDG dualheed coincidence (DHC) scintigraphy for staging of lymphoma. GS and FDG-DHC were performed in a patient with low-grade NHL before therapy. Ga-SPECT views of the chest (top panel) are negative. Corresponding FDG-DHC views (bottom panel) show multiple sites of disease in left infraclavicular and bilateral cervical and axillary lymph nodes.

Limited data are available regarding the comparison of GS and FDG imaging (Fig 6). 73'94'106' 111,112. These studies have generally evaluated a small number of patients and have sometimes used suboptimal imaging techniques. Paul et al was the first to compare GS (planar scan at 48 hours after injection of 5 mCi Ga) with FDG-SPECT (by using a conventional gamma camera with a special collimator) in 5 patients with N H L . 73 The FDG study was positive in 4 of the 5 patients; GS was positive in only 2 of the patients. Hoekstra et al found that planar FDG imaging provided the same information as GS on baseline studies in 26 patients. Only 1 patient with intermediate-grade NHL had a non-FDG and a non-Ga avid lymphoma. 1~ Higher contrast of tumor uptake was found with FDG-PET than with GS.74 '94 In a recent study by Kostakoglu et al, FDG imaging was compared with GS in 62 patients with NHL and HD. 94 GS missed 27% of lymphoma lesions, whereas FDG detected all sites of disease. FDG coincidence imaging in 18 patients with low-grade NHL had 100% sensitivity for detecting lymphoma, compared with 59% for GS. 94 In 46 lymphoma patients, Kostakoglu et al found FDG-PET to be superior to GS in evaluating the response after treatment. 112 In 6 patients with discordant FDG-PET and GS results, short-term follow-up confirmed FDG-PET results. 112 Lymphoma is a treatable cancer, in which cure and prolonged disease-free survival can be achieved. Successful therapy depends on the optimization of

individual patient management after the accurate assessment of staging and response to therapy. The present state-of-the-art routine for evaluating lymphoma patients, although not necessarily optimal, involves physical examination, laboratory data, bone marrow biopsy, and various imaging modalities. Morphologic imaging, such as CT, although still considered the gold standard for diagnosis and staging, is of limited sensitivity and specificity for detecting viable cancer tissue. The unique functional metabolic information provided by both Ga and FDG is the basis for the incremental value of these agents in the management of patients with lymphoma. GS has been shown to have an important role in monitoring response and predicting prognosis in patients with lymphoma. FDG imaging appears to be useful in both staging and further management. Based on the limited number of patients in whom GS and FDG imaging have been compared, FDG-PET appears to be more sensitive for the detection of viable lymphoma. It is unclear whether this is the result of inherent biochemical characteristics of lymphoma cells, identified differently by the 2 tracers, or of different properties of the radionuclides and imaging devices used. The basis for the differences between FDG and Ga uptake has not yet been thoroughly investigated. If these differences are found to stem from different biologic characteristics with possible prognostic implications, a strategy of using GS and FDG in different subgroups of patients should be considered.

GA-67 AND FDG-PET IN LYMPHOMA

187

REFERENCES

1. Edward CL, Hayes RL: Tumor scanning with Ga-67 citrate. J Nucl Med 10:103-105, 1969 2. Hayes RL, Nelson B, Swartzendruber DC, et al: Gallium-67 localization in rat and mouse tumors. Science 167:289-290, 1970 3. Iosilevsky G, Front D, Bettman L, et al: Uptake of Gallium-67 citrate and [2-3H] deoxyglucose in the tumor model, following chemotherapy and radiotherapy. J Nucl Med 26:278-282, 1985 4. Israel O, Front D: Lymphoma, in Aldolun C, Tauxe WN (eds): Nuclear Oncology (ed 1). Berlin, Springer Verlag, 1999 5. Sohn MH, Jones B J, Whiting JH, et al: Distribution of Gallium-67 in normal and hypotransferrinemic tumor-bearing mice. J Nucl Med 34:2135-2143, 1993 6. McLaughlin AF, Southee AE: Gallium scintigraphy in tumor diagnosis and management, in Murray IPC, Ell PJ (eds): Nuclear Medicine in Clinical Diagnosis and Treatment (ed 1). New York, Churchill Livingstone, 1994 7. Nejmeddine E Raphael M, Martin A, et al: Ga-67 scintigraphy in B-cell non-Hodgldn's lymphoma: Correlation of Ga-67 uptake with histology and transferrin receptor expression. J Nucl Med 40:40-45, 1999 8. Johnson GS, Go ME Benua RS, et al: Gallium-67 citrate imaging in Hodgkin's disease: Final report of cooperative group. J Nucl Med 18:692-698, 1977 9. Andrews GA, Hubner KF, Greeniaw RH: Ga-67 citrate imaging in malignant lymphoma: Final report of cooperative group. J Nucl Med 19:1013-1019, 1978 10. Seabold JE, Votau ML, Keyes JW, et al: Gallium-67 citrate scanning. Arch Intern Med 136:1370-1374, 1976 11. Rudders RA, McCaffrey JA, Kahn PC: The relative roles of gallium-67-citrate scanning and lymphangiography in the current management of malignant lymphoma. Cancer 40:14391443, 1997 12. Longo DL, Schilsky RL, Blei L, et al: Gallium-67 scanning: Limited usefulness in staging patients with nonHodgkin's lympboma. Am J Med 68:695-700, 1980 13. Bekerman C, Hoffer PB, Bitran JD: The role of gallium-67 in the clinical evaluation of cancer. Semin Nucl Med 25:72-103, 1985 14. Anderson KC, Leonard RCE Canellos GE et al: Highdose gallium imaging in lymphoma. Am J Med 75:327-331, 1983 15. Front D, Israel O, Epelbaum R, et al: Ga-67 SPECT before and after treatment of lymphoma. Radiology 175:515519, 1990 16. Tumeh SS, Rosenthal DS, Kaplan WD, et al: Lymphoma: Evaluation with Ga-67 SPECT, Radiology 164:111114, 1987 17. Galss RB, Fernbach SK, Conway JJ, et al: Gallium scintigraphy in American Burkitt lymphoma: Accurate assessment of tumor load and prognosis. AIR Am J Roentgenol 145:671-676, 1985 18. Brown ML, O'Donnell JB, Thrall JH, et al: Gallium-67 scintigraphy in untreated and treated non-Hodgkin lymphomas. J Nucl Med 19:875-879, 1978 19. Hoffer P: Status of gallium-67 in tumor detection. J Nucl Med 21:394-398, 1980

20. Sandrock D, Lastoria S, Magrath IT, et al: The role of gallium-67 scintigraphy in patients with small, non-cleaved cell lymphoma. Eur J Nucl Med 20:119-122, 1993 21. Waxman AD, Eller D, Ashook G, et al: Comparison of gallium-67 ciuate and thallium-201 scintigraphy in peripheral and intrathoracic lymphoma. J Nucl Med 37:46-50, 1996 22. Gallamini A, Biggi A, Fruttero A, et al: Revisiting the prognostic role of gallium scintigraphy in low-grade nonHodgkin's lymphoma. Eur J Nucl Med 24:1499-1506, 1997 23. Ben-Haim S, Bar-Shalom R, Israel O, et al: Utility of gallium-67 scintigraphy in low-grade non-Hodgkin's lymphoma. J Clin Oncol 14:1936-1942, 1996 24. Jochelson M, Mauch P, Balikian J, et al: The significance of the residual mediastinal mass in treated Hodgkin's disease. J Clin Oncol 3:637-640, 1985 25. Radford JA, Cowan RA, Flanagan M, et al: The significance of residual mediastinal abnormality on the chest radiograph following treatment for Hodgkin's disease. J Clin Oncol 6:940-946, 1988 26. Surbone A, Longo DL, DeVita VT, et al: Residual abdominal massess in aggressive non-Hodgkin's lymphoma after combination chemotherapy: Significance and management. J Clin Oncol 6:1832-1837, 1988 27. Canellos GP: Residual mass in lymphoma may not be residual disease. J Clin Oncol 6:931-933, 1988 (editorial) 28. Israel O, Front D, Lam M, et al: Gallium-67 imaging in monitoring lymphoma response to treatment. Cancer 61:24392443, 1988 29. Wylie BR, Southee AE, Joshua DE, et al: Gallium scanning in the management of mediastinal Hodgkin's disease. Eur J Haematol 42:344-347, 1989 30. Israel O, Front D, Epelbaum R, et al: Residual mass and negative gallium scintigraphy in treated lymphoma. J Nucl Med 31:365-368, 1990 31. Drossman SR, Schiff RG, Kronfeld GD, et al: Lymphoma of the mediastinum and neck: Evaluation with Ga-67 imaging and CT correlation. Radiology 174:171-175, 1990 32. Weiner M, Leventhal B, Cantor A, et al: Gallium-67 scan as an adjunct to computed tomography scans for the assessment of a residual mediastinal mass in pediatric patients with Hodgkin's disease. Cancer 68:2478-2480, 1991 33. Karimjee S, Brada M, Husband J, et al: A comparison of gallium-67 single photon emission computed tomography and computed tomography in mediastinal Hodgkin's disease. Eur J Cancer 28A: 1856-1857, 1992 34. Kostakoglu L, Yeh SDJ, Portlock C, et al: Validation of gallium-67-citrate single photon emission computed tomography in biopsy-confirmed residual Hodgkin's disease in the mediastinum. J Nucl Med 33:345-350, 1992 35. Front D, Israel O, Ben-Haim S: The dilemma of a residual mass in treated lymphoma: The role of gallium-67 scintigraphy, in Freeman L (ed): Nuclear Medicine Annual. New York. Raven Press, 1991 36. Ionescu 1, Brice P, Simon D, et al: Restaging with gallium scan identifies chemosensitive patients and predicts survival of poor-prognosis mediastinal Hodgkin's disease patients. Med Oncol 17:127-134, 2000

188

37. Chilton HM, Witcofski RL, Watson NE, et al: Alteration of gallium-67 distribution in tumor-bearing mice following treatment with methotrexate: Concise communication. J Nucl Med 22:1064-1068, 1981 38. Dambro TJ, Slavin JD, Epstein NF, et al: Loss of radio-gallium from lymphoma after initiation of chemotherapy. Clin Nucl Med 17:32-33, 1992 39. Kaplan WD: Residual mass and negative gallium scintigraphy in treated lymphoma: When is the gallium scan really negative? J Nucl Med 31:369-371, 1990 (editorial) 40. Front D, Israel O: The role of Ga-67 scintigraphy in evaluating the results of therapy of lymphoma patients. Semin Nucl Med 25:60-71, 1995 41. Peylan-Ramu N, Haddy TB, Jones E, et al: High frequency of benign mediastinal uptake of gallium-67 after completion of chemotherapy in children with high grade nonHodgkin's lymphoma. J Clin Oncol 7:1800-1806, 1989 42. Even-Sapir E, Bar-Shalom R, Israel O, et al: Singlephoton emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake. J Clin Oncol 13:942-946, 1995 43. Champion PE, Groshar D, Hooper HR, et al: Does gallium uptake in the pulmonary hila predict involvement by nonHodgkin's lymphoma? Nucl Med Commun 13:730-737, 1992 44. Israel O, Front D: Benign mediastinal and parahilar uptake of gallium-67 in treated lymphoma: Do we have all the answers? J Nucl Med 34:1330-1332, 1993 (editorial) 45. Bar-Shalom R, Israel O, Haim N, et al: Diffuse lung uptake of Ga-67 after treatment of lymphoma: Is it of clinical importance? Radiology 199:473-476, 1996 46. Israel O, Yefremov N, Mor M, et al: A new technology of combined transmission (CT) and emission (Ga-67) tomography (TET) in the evaluation of patients with lymphoma. J Nucl Med 41:70P, 2000 (abstr) 47. Front D, Ben-Halm S, Israel O, et al: Lymphoma: Predictive value of Ga-67 scintigraphy after therapy. Radiology 182:359-363, 1992 48. Hagemeister FB, Purugganan R, Podoloff DA, et al: The gallium scan predicts relapse in patients with Hodgkin's disease treated with combined modality therapy. Ann Oncol 5:$59-$63, 1994 (suppl 2) 49. King SC, Reiman RJ, Prosnitz LR: Prognostic importance of restaging gallium scans following induction chemotherapy for advanced Hodgkin's disease. J Clin Oncol 12:306-311, 1994 50. Vose JM, Bierman PJ, Anderson JR, et al: Single-photon emission computed tomography gallium imaging versus computed tomography: Predictive value in patients undergoing highdose chemotherapy and autologus stem-cell transplantation for non-Hodgkin's lymphoma. J Clin Oncol 14:2473-2479, 1996 51. Salloum E, Brandt DS, Caride VJ, et al: Gallium scans in the management of patients with Hodgkin's disease: A study of 101 patients. J Clin Oncol 15:518-527, 1997 52. Bogart JA, Chung CT, Mariados NF, et al: The value of gallium imaging after therapy for Hodgkin's disease. Cancer 82:754-759, 1998 53. Cooper DL, Caride VJ, Zloty M, et al: Gallium scans in patients with medistinal Hodgkin's disease treated with chemotherapy. J Clin Oncol 11:1092-1098, 1993 54. Cooper DL, Neumann RD, Caride VJ: A critical assessment of the prognostic value of gallium-67 scintigraphy in

BAR-SHALOMET AL

lymphoma, in Freeman LM (ed): Nuclear Medicine Annual. Philadelphia, PA, Lippincott-Raven, 1998 55. Weeks JC, Yeap BY, Canellos GP, et al: Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission. J Clin Oncol 9:1196-1203, 1991 56. DeVita VT, Hellman S, Jaffe ES: Hodgkin's disease, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 4). Philadelphia, PA, LippincottRaven, 1993 57. Armitage JO, Weisenburger DD, Hutchins M, et al: Chemotherapy for diffuse large-cell lymphoma: Rapidly responding patients have more durable remissions. J Clin Oncol 4:160-164, 1986 58. Vose JM, Armitage JO, Bierman PJ, et al: Salvage therapy for relapsed or refractory non-Hodgkin's lymphoma utilizing autologous bone marrow transplantation. Am J Med 87:285-288, 1989 59. Front D, Bar-Shalom R, Epelbaum R, et al: Early detection of lymphoma recurrence with gallium-67 scintigraphy. J Nucl Med 34:2101-2104, 1993 60. Shipp MA, Harrington DP: A predictive model for aggressive non-Hodgkin's lymphoma. The International NonHodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993 61. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. N Engl J Med 339:1506-1514, 1998 62. Verdonck LF, Van Putten WLJ, HagenbeekA, et al: Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with ag~essive non-Hodgkin's lymphoma. N Engl J Med 332:1045-1051, 1995 63. Kaplan WD, Jochelson MS, Herman TS, et al: Gallium-67 imaging: A predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Oncol 8:1966-1970, 1990 64. Janicek M, Kaplan W, Neuberg D, et al: Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive non-Hodgkin's lymphoma treated with high-dose CHOP chemotherapy. J Clin Oncol 15:1631-1637, 1997 65. Gasparini M, Bombardieri E, Castellani M, et al: Gallium-67 scintigraphy evaluation of therapy in nonHodgkin's lymphoma. J Nucl Med 39:1586-1590, 1998 66. Front D, Bar-Shalom R, Mor M, et al: Hodgkin disease: Prediction of outcome with Ga-67 scintigraphy after one cycle of chemotherapy. Radiology 210:487-491, 1999 67. Front D, Bar-Shalom R, Mor M, et al: Aggressive non-Hodgkin lymphoma: Early prediction of outcome with Ga-67 scintigraphy. Radiology 214:253-257, 2000 68. Link MR Shuster JJ, Donaldson SS, et al: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337:1259-1266, 1997 69. Magrath I: Limiting therapy for limited childhood nonHodgkin's lymphoma. N Engl J Med 337:1304-1305, 1997 70. Warburg O: The metabolism of tumors. IVY, Smith RR, 1931 71. Weber G: Biochemical strategy of cancer cells and the design of chemotherapy. GHA Clowes memorial lecture. Cancer Res 43:3466-3492, 1983 72. Bar-Shalom R, Valdivia AY, Bahifox MD: PET imaging in oncology. Semin Nucl Med 30:150-185, 2000

GA-67 AND FDG-PET IN LYMPHOMA

73. Paul R: Comparison of fluorine- 18-2-fluorodeoxyglucose and gallium-67 citrate imaging for detection of lymphoma. J Nucl Med 28:288-292, 1987 74. Okada J, Yoshikawa K, Imazeki K, et al: The use of FDG-PET in the detection and management of malignant lymphoma: Correlation of uptake with prognosis. J Nucl Med 32:686-691, 1991 75. Lapela M, Leskinen S, Minn HRI, et al: Increased glucose metabolism in untreated non-Hodgkin's lyrnphoma: A study with positron emission tomography and fluorine-18fluorodeoxyglucose. Blood 86:3522-3527, 1995 76. Leskinen-Kallio S, Ruotsalainen U, Nagren K, et al: Uptake of carbon-ll-methionine and fluorodeoxyglucose in non-Hodgkin's lymphoma: A PET study. J Nucl Med 32:12111218, 1991 77. Rodriguez M, Rehn S, Ahlstrom H, et al: Predicting malignancy grade with PET in non-Hodgkin's tymphoma. J Nucl Med 36:1790-1796, 1995 78. Jerusalem G, Warland V, Majjar F, et al: Whole-body 18F-FDG-PET for the evaluation of patients with Hodgkin's disease and non-Hodgkin's lymphoma. Nucl Med Commun 20:13-20, 1999 79. Hoffmann M, Kletter K, Demling M, et al: Positron emission tomography with fluorine-18-2-fluoro-2-deoxy-Dglucose (F18-FDG) does not visualize extranodal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type. Ann Oncol 10:1185-1189, 1999 80. Cremerius U, Fabry U, Neuerburg J, et al: Positron emission tomography with 18F-FDG to defect residual disease after therapy for malignant lymphoma. Nucl Med Commun 19:1055-1063, 1998 81. Newman JS, Francis IR, Kaminski MS, et al: Imaging of lymphoma with PET with 2-[F-18] fluoro-2-deoxy-D-glucose: Correlation with CT. Radiology 190:111-116, 1994 82. Stumpe KDM, Urbinelli M, Steinert HC, et al: Wholebody positron emission tomography using fluorodeoxyglucose for staging of lymphoma: Effectiveness and comparison with computed tomography. Eur J Nucl Med 25:721-728, 1998 83. Okada J, Oonish H, Yoshikawa K, et al: FDG-PET for predicting the prognosis of malignant lymphoma. Ann Nucl Med 8:187-191, 1994 84. Okada J, Yoshikawa K, Itami M, et al: Positron emission tomography using fluorine-18-fluorordeoxyglucose in malignant lymphoma: A comparison with proliferative activity. J Nucl Med 33:325-329, 1992 85. Hoh CK, Glaspy J, Rosen P, et al: Whole-body FDGPET imaging for staging of Hodgkin's disease and lymphoma. J Nucl Med 38:343-348, 1997 86. Bangerter M, Moog F, Buchmann I, et al: whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease. Ann Oncol 9:1117-1122, 1998 87. Bangerter M, Kotzerke J, Griesshammer M, et al: Positron emission tomography with 18-fluorodeoxyglucose in the staging and follow-up of lymphoma in the chest. Acta Oncol 38:799-804, 1999 88. Kotzerke J, Guhlmann A, Moog F, et al: Role of attenuation correction for fluorine-18 fluorodeoxyglucose positron emission tomography in the primary staging of malignant lymphoma. Eur J Nucl Med 26:31-38, 1999

189

89. Klose T, Leidl R, Buchmann I, et al: Primary staging of lymphomas: Cost-effectiveness of FDG-PET versus computed tomography. Eur J Nucl Med 27:1457-1464, 2000 90. Partridge S, Timothy A, O'Doherty MJ, et al: 2-fluorine18-fluoro-2-deoxy-D glucose positron emission tomography in the pretreatment staging of Hodgkin's disease: Influence on patient management in a single institution. Ann Oncol 11:12731279, 2000 91. Kostakoglu L, Goldsmith SJ: Fluorine-18 fluorodeoxyglucose positron emission tomography in the staging and follow-up of lymphoma: Is it time to shift gears? Eur J Nucl Med 27:1564-1578, 2000 92. Moog F, Bangerter M, Diederichs CG, et al: Lymphoma: Role of whole-body 2-deoxy-2-[F-18}fluoro-D-glucose (FDG) PET in nodal staging. Radiology 203:795-800, 1997 93. Moog E Bangerter M. Diederichs CG, et al: Extranodal malignant lymphoma: Detection with FDG PET versus CT. Radiology 206:475-481, 1998 94. Kostakoglu L, Goldsmith SJ: Positron emission tomography in lymphoma: Comparison with computed tomography and gallium-67 single photon emission computed tomography. Clin Lymphoma 1:67-74, 2000 95. Moog F, Bangerter M, Kotzerke J, et al: 18-Ffluorodeoxyglucose positron emission tomography as a new approach to detect lymphomatous bone marrow. J Clin Oncol 16:603-609. 1998 96. Carr R, Barrington SF, Madan B. et al: Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood 91:3340-3346,1998 97. Dimitrakopoulou-Strauss A, Strauss LG, Goldschmidt H, et al: Evaluation of tumor metabolism and multidrug resistance in patients with treated lymphoma. Eur J Nucl Med 22:434-442, 1995 98. Bangerter M, Moog F, Griesshammer M, et al: Role of whole-body FDG-PET in predicting relapse in residual masses after treatment of lymphoma, Br J Haematol 102:148, 1998 (abstr) 99. de Wit M, Bumann D, Beyer W, et al: Whole-body positron emission tomography (PET) for diagnosis of residual mass in patients with lymphoma Ann Oncol 8:57-60, 1997 100. Zinzani PL, Magagnoli M, Chierichetti F, et al: The role of positron emission tomography (PET) in the management of ]ymphoma patients. Ann Oncol 10:1181 - 1184, 1999 101. Jerusalem G, Beguin Y, Fassotte ME et al: Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and nonHodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood 94:429-433, 1999 102. Maisey NR, Hill ME, Webb A, et al: Are 18fluorodeoxyglucose positron emission tomography and magnetic resonance imaging useful in the prediction of relapse in lymphoma residual masses ? Eur J Cancer 36:200-206, 2000 103. Cremerius U, Fabry U, Kroll U, et al: Clinical value of FDG PET for therapy monitoring of malignant lymphoma-Results of a retrospective study in 72 patients. Nuklearmedizin 38:24-30, 1999 104. Alavi JB. Benard F, Alavi A: Detection of unsuspected recurrent lymphoma with fluorodeoxyglucose positron emission

190

tomography imaging after induction chemotherapy. Am J Clin Oncol 21:126-128, 1998 105. Front D, Israel O, Mor M, et al: A new technology of combined transmission (CT) and 18F fluorodeoxyglucose (FDG) emission tomography (TET) in the evaluation of cancer patients. J Nucl Meal 41:284P, 2000 (abstr) 106. Hoekstra OS, Ossenkoppele GJ, Golding R, et al: Early treatment response in malignant lymphoma, as determined by planar fluorine-18-fluorodeoxyglucose scintigraphy. J Nucl Med 34:1706-1710, 1993 107. Hoekstra OS, van Lingen A, Ossenkoppele GJ, et al: Early response monitoring in malignant lymphoma using fluorine-18 fluorodeoxyglucose single-photon emission tomography. Eur J Nucl Meal 20:1214-1217, 1993 108. Barrington SF, Can" R: Staging of Burkitt's lymphoma and response to treatment monitored by PET scanning. Clin Oncol 7:334-335, 1995

BAR-SHALOM ET AL

109. Romer W, Hanauske AR, Ziegler S, et al: Positron emission tomography in non-Hodgkin's lymphoma: Assessment of chemotherapy with fluorodeoxyglucose. Blood 91:44644471, 1998 110. Wiedmann E, Baican B, Hertel A, et al: Positron emission tomography (PET) for staging and evaluation of response to treatment in patients with Hodgkin's disease. Leuk Lymphoma 34:545-551, 1999 111. Willkomm E Palmedo H, Grunwald E et al: Functional imaging of Hodgkin's disease with FDG-PET and gaUium-67. Nuklearmedizin 37:251-253, 1998 112. Kostakoglu L, Leonard JP, Coleman M, et al: Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and gallium-67 scintigraphy in staging and follow-up of patients with lymphoma. Blood 94:84A, 1999 (abstr)