1. Define the role of diagnostic PET in the staging of patients with lymphoma.

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1 The Oncologist PET Scans in the Staging of Lymphoma: Current Status JONATHAN W. FRIEDBERG, VASEEM CHENGAZI Lymphoma Program, James P. Wilmot Cancer Center, University of Rochester, Rochester, New York, USA Key Words. FDG-PET Non-Hodgkin s lymphoma Gallium scintigraphy Staging LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Define the role of diagnostic PET in the staging of patients with lymphoma. 2. Discuss the role of PET in the evaluation of residual masses in patients with lymphoma. 3. Explain the limitations of PET scanning and the special situations where PET scanning has been used in the evaluation of patients with lymphoma. CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Positron emission tomography (PET) is a novel functional imaging technique that provides several inherent advantages over conventional nuclear scintigraphy. Several studies have suggested a role for PET using the positron emitter fluorine-18 in the diagnosis and followup of patients with lymphoma. This review summarizes the existing data evaluating the role of 2-fluoro-2-deoxy- D-glucose (FDG)-PET in both the staging and follow-up of patients with lymphoma. Most studies of PET involve patients with either Hodgkin s disease or diffuse large B- cell non-hodgkin s lymphoma. PET detects more disease sites above and below the diaphragm on staging of lymphoma than gallium scintigraphy and may have particular utility in the evaluation of the spleen. Moreover, persistently positive PET scans during and after chemotherapy appear to have a high sensitivity for predicting subsequent relapse. A negative PET scan at the end of therapy provides very favorable prognostic information. Persistently positive PET scans at the end of therapy warrant close follow-up or additional diagnostic procedures, since some of those patients may remain in prolonged remission. Clearly, additional studies, including prospective blinded trials and cost-effectiveness analyses, are warranted to determine which subsets of patients with lymphoma ultimately will benefit from this modality. The Oncologist 2003;8: INTRODUCTION Staging has an important role in the treatment of all malignancies but is critically important for patients with lymphoma. Accurate staging allows minimization of toxic therapies, such as extended-field radiation or overly aggressive chemotherapy, decreasing the risk of secondary malignancies, which exceeds 10% in several historical series of patients with early-stage Hodgkin s disease [1]. Patient quality of life during and after treatment may also be improved with tailored therapy defined by staging [2]. There are two major roles for nuclear scintigraphy in the evaluation of a patient with lymphoma [3]. These functional scans are complementary to anatomic imaging, and may improve staging at the time of diagnosis, particularly through the detection of otherwise occult abdominal or splenic disease. Perhaps more importantly, nuclear scintigraphy may Correspondence: Jonathan W. Friedberg, M.D., 601 Elmwood Avenue, Box 704, Rochester, New York 14642, USA. Telephone: ; Fax: ; Jonathan_Friedberg@urmc.rochester.edu Received April 1, 2003; accepted for publication July 21, AlphaMed Press /2003/$12.00/0 The Oncologist 2003;8:

2 439 Current Status of PET Scan Staging of Lymphoma help to characterize a residual mass on anatomic imaging following therapy as either fibrosis or residual active lymphoma. Historically, gallium-67 (Ga-67), which binds to transferrin receptors in the tumor, has been the most widely used nuclear tracer in the evaluation of lymphoma [4-6]. The major limitations of this technique include relatively low sensitivity and accuracy, particularly in the abdomen and extranodal sites [7, 8]. Positron emission tomography (PET) is a novel functional imaging technique that can use a glucose analog (2-fluoro-2-deoxy-D-glucuse [FDG]) radiolabeled with the positron emitter fluorine-18 to evaluate glycolytic activity, which is greater in malignancies, including lymphoma. Several studies have suggested a role for FDG-PET in the diagnosis and follow-up of patients with lymphoma, and it is rapidly becoming a standard procedure for those patients in the U.S. [9-11]. PET provides several inherent advantages over other nuclear imaging techniques [10]. The short halflife of FDG allows patient convenience and improved imaging characteristics. With modern dedicated PET machines, a resolution of approximately 5 mm can be achieved, and the ability to coregister PET with anatomic computerized tomography (CT) imaging allows for ease of interpretation. Moreover, using a quantitative approach to interpretation with the standardized uptake value (SUV) (ratio of activity per volume unit over injected activity per body mass), PET imaging is more precise than conventional scintigraphy. Over the past 10 years, the fidelity of PET has dramatically improved, with technological advances including whole-body imaging, iterative reconstruction algorithms, three-dimensional acquisition, and image fusion between PET and CT. However, the data supporting widespread use of this modality for patients with lymphoma remain limited, and largely retrospective. The following review summarizes these data, emphasizing the current limitations of knowledge and recommended future directions of research. LYMPHOMA HISTOLOGY AND FDG UPTAKE The majority of studies evaluating FDG-PET in lymphoma include patients with diffuse large B-cell non- Hodgkin's lymphoma (NHL) or Hodgkin s disease. There are limited data available on the role of PET in other histologies. A retrospective review of 172 patients with various types of lymphoma who underwent FDG-PET imaging was completed at the University of Pennsylvania. Only 6% of those patients had no evidence of disease on PET scans. FDG-PET accurately detected disease in patients with diffuse large B-cell NHL, mantle cell lymphoma, follicular lymphoma, and Hodgkin s disease [12]. PET was less reliable at detecting marginal zone lymphoma, a finding that has been confirmed by other groups [13], particularly in the case of extranodal marginal zone lymphomas [14]. In another study, limited to patients with indolent B-cell lymphomas, PET appeared to have potential to contribute to the management of patients with follicular NHL, but sites of disease in patients with small lymphocytic lymphomas were only detected approximately 50% of the time [15, 16]. Small series have suggested that, using SUV to determine intensity of FDG uptake, PET may be able to predict histologic transformation of indolent lymphoma [17]; however, the relationship among pathological subtype, mitotic rate, and SUV remains controversial [18, 19]. This information is summarized in Table 1. ROLE OF PET IN DIAGNOSTIC IMAGING The majority of studies evaluating the role of PET in the diagnostic staging of lymphoma are retrospective in nature and often attempt to compare PET with other imaging modalities. In those studies, biopsies of questionable lesions are almost never performed and, usually, the interpretation of the PET scan is not blinded, meaning nuclear medicine physicians had access to multiple other imaging results while reading the PET images, resulting in the potential for bias [8]. Despite these limitations, PET is clearly emerging to have a significant role in the diagnostic evaluation of lymphoma, particularly diffuse large B-cell lymphoma and Hodgkin s disease. Small studies also suggest that the initial management of patients with lymphoma in clinical practice frequently changes based upon PET scan findings [20, 21]. A summary of selected published studies of diagnostic PET imaging is in Table 2. Table 1. Diagnostic PET scan by histology Reliable (>90% positive on PET) Diffuse large B-cell NHL Classical Hodgkin s disease Follicular NHL* Mantle cell NHL Less reliable (50%-90% positive on PET) Marginal zone/mucosa-associated lymphoma tissue (MALT) NHL Small lymphocytic NHL Unknown T-cell NHL Highly aggressive (Burkitt-type) NHL Lymphoplasmacytic NHL Lymphocyte-predominance Hodgkin s disease *Some studies suggest greater FDG uptake in grade 2-3 follicular NHL and in transformation.

3 Friedberg, Chengazi 440 Table 2. Selected series of diagnostic FDG-PET in the treatment of lymphoma Study Year n Histology Type Major Findings Buchmann et al. [27] NHL/HD P, B PET superior to CT scans in diagnosing disease sites; four patients upstaged due to PET. Bangerter et al. [22] HD P PET was positive in 86% of disease sites; five patients upstaged; one patient downstaged; 2 false-positive PET scans. Kostakoglu et al. [25] NHL/HD P Diagnostic PET superior to gallium. Wirth et al. [23] NHL/HD RPET superior to gallium scans in diagnosing disease sites. Weihrauch et al. [67] HD R, B Four patients upstaged due to PET. Friedberg et al. [26] HD P, B Diagnostic PET superior to gallium; spleen better imaged on PET. Hueltenschmidt et al. [28] HD RPET more accurate than conventional imaging. Abbreviations: HD = Hodgkin's disease; P = prospective; R = retrospective; B = readers of PET scans blinded to clinical history and other imaging modalities. The largest prospective pretreatment evaluation of Hodgkin s disease using FDG-PET scans was of 44 newly diagnosed German patients. As a consequence of PET findings in that study, five patients were upstaged and one patient was downstaged [22]. It was felt that false-positive PET scans occurred in two patients. Preliminary results in small numbers of patients with both Hodgkin s disease and NHL have suggested superior staging with PET when compared with gallium, although scan interpretation was not always performed in an independent, blinded fashion. In a retrospective, unblinded study of 50 patients with lymphoma (19 with Hodgkin s disease), PET identified more disease sites than gallium in 19 patients [23]. Similarly, in a study of 30 patients with lymphoma (14 with Hodgkin s disease), FDG-PET upstaged six patients in whom gallium scintigraphy detected disease sites partially [24]. Kostakoglu et al. reported on 51 contemporaneous FDG- PET and Ga-67 scintigraphy studies performed on patients with NHL (35 intermediate grade, three high grade) or Hodgkin's disease (13 patients). Sites of disease were correlated on a site-by-site basis on FDG-PET and Ga-67 images. PET imaged all sites of disease, compared with approximately 65% for gallium, and revealed higher stage disease in 13 patients compared with Ga-67 imaging [25]. In a series of 36 newly diagnosed patients with Hodgkin s disease at the Dana-Farber Cancer Institute, FDG-PET clearly had a superior ability to detect occult splenic disease, with five patients having isolated FDG-avid nodules in the spleen not detected with gallium imaging. In three of those patients, splenic nodules on PET scans were the only evidence of disease detected below the diaphragm [26]. Buchmann et al. undertook a prospective evaluation comparing FDG-PET imaging with CT imaging and bone marrow biopsy in the staging of both NHL and Hodgkin s disease [27]. FDG-PET was superior to CT, except in infradiaphragmatic regions, in which the two methods produced equivalent results. In detecting bone marrow infiltration, FDG-PET was equivalent to bone marrow biopsy. In 4 of 52 patients (8%), findings on FDG-PET led to an upstaging and a change of therapy. Finally, in a retrospective study of 81 patients, PET was compared with "conventional imaging methods." In a lesionto-lesion analysis, accuracy in the determination of the stage of disease was 96% for PET versus 56% for conventional imaging. PET led to a lower stage classification in 28% and a higher stage classification in 12% of cases, compared with the stage assumed with conventional imaging [28]. In conclusion, every published study to date has suggested a greater sensitivity of PET, compared with other imaging modalities, when used for lymphoma staging [29-31]. However, PET imaging does not allow for tumor measurements or the determination of exact anatomic locations of disease. PET can be misleading when there is an uptake of radioisotope within muscles of the neck, which can be unilateral and focal (for example, at the head of the sternocleidomastoid muscle), and may be mistaken for lymphomatous involvement in supraclavicular and pectoral lymph nodes. Moreover, physiologic FDG uptake in the brain, myocardium, and renal collecting system can obscure lymphoma evaluation in those sites (Fig. 1). Although PET appears superior to gallium in these diagnostic studies, PET should always be performed in combination with anatomic imaging (CT scans) to allow correlation. Future studies are required to define the subset of patients who benefit from this type of PET scanning [32], to establish the cost-effectiveness of the technique [33], and to determine whether combined CT and PET systems, or coregistration algorithms (Fig. 2), will provide additional useful diagnostic information.

4 441 Current Status of PET Scan Staging of Lymphoma Figure 1. Initial staging FDG-PET image. Maximum intensity projection image (anterior) in female with diffuse large B-cell lymphoma, showing several areas of abnormally high FDG uptake in the supraclavicular, axillary, mediastinal, abdominal, and inguinal regions, as well as extensive sites of involvement in the bone marrow (arrowheads pointing to the right). Several smaller areas are not marked. Note the normal areas of FDG uptake (arrows pointing to left) in the left ventricular myocardium, vascular organs, urinary tract, and shoulder arthropathy. ROLE OF PET IN EVALUATION OF RESPONSE TO THERAPY There is great interest in using PET to assess response to chemotherapy, as demonstrated in Figure 3. The optimal timing of PET scans and the potential role of quantitative PET using SUV in this setting remain to be defined [34, 35]. Kostakoglu et al. performed PET scans before and after one cycle of chemotherapy in 30 patients with NHL (n = 17) or Hodgkin s disease, and correlated results with disease status at the completion of treatment [36]. Of 15 patients with a positive PET scan after one cycle of therapy, 13 have had progressive disease; conversely, only 2 of 15 patients with negative PET scans after one cycle of therapy experienced disease progression. Progression-free survival actually correlated better with PET after the first cycle of therapy than with PET at completion of chemotherapy. Similar findings were noted in the Hodgkin s disease series from the Dana-Farber Cancer Institute, where PET scanning after three cycles of chemotherapy had a higher positive predictive value for disease recurrence than PET scanning after completion of therapy [26]. The majority of studies have correlated PET at the end of therapy with subsequent disease progression, as detailed in Table 3. Jerusalem et al. compared FDG-PET with conventional CT in the posttreatment evaluation of 54 patients with lymphoma, including 19 with Hodgkin's disease [37]. In that series, relapse occurred in all six patients with positive PET scans at the end of therapy and in 8 of 48 patients with negative PET scans. In a German study that included 43 patients with Hodgkin s disease and a residual mass, no recurrence occurred in 39 patients with negative PET scans; however, one of the remaining four patients with a positive PET scan had relapsed, with a follow-up of 21 to 50 months [38]. Figure 2. Image coregistration. Transaxial slices at the lower pelvic level showing CT data (left) and the same data overlaid with PET data (right, in color). Regions of interest marked in red on the left image show areas of abnormal FDG uptake in enlarged lymph nodes. Stent in left ureter is marked by a yellow arrowhead on the left image. This type of analysis clearly localizes areas of high FDG uptake to particular areas of anatomic abnormalities to aid diagnostic interpretation, and potentially radiation treatment planning. In this case, the intense FDG-avid focus in the right posterior pelvis and the larger focus on the left correlate with enlarged lymph nodes on anatomic CT imaging.

5 Friedberg, Chengazi 442 Figure 3. Splenic disease and response to chemotherapy. A) Anterior maximum intensity projection image in a 50-year-old male with diffuse large B-cell lymphoma showing intense uptake in the large left upper quadrant mass in association with the spleen (left arrow), but no other areas of abnormality. Arrowheads point to activity in kidney and bladder. B) The same image after three cycles of chemotherapy, showing dramatic resolution of the disease, with only minimal residual abnormality. The arrow pointing left now marks normal activity in the myocardium not seen previously; arrowheads show persistent urinary tract activity. Ninety-three patients with NHL, the majority with aggressive NHL, underwent whole-body PET imaging after completion of first-line chemotherapy in Belgium [39]. Of the 67 patients with normal scans, 56 remained in complete remission at a median follow-up of 2 years. Persistently abnormal FDG uptake was seen in 26 patients, and all had disease progression. In 14 of those patients, only PET predicted persistent disease. Similar findings were presented in a study by Mikhaeel et al. in 45 patients with large cell lymphoma, where all nine patients with persistently positive PET scans at the end of therapy had disease progression, and only 6 of 36 patients with negative PET scans at the end of therapy experienced progression [40]. However, several other studies have suggested that a negative PET scan is more informative than a positive result in the evaluation of a residual mass after therapy for lymphoma, due to a high false-positive rate [41-43]. Finally, Jerusalem et al. recently evaluated the role of PET in the follow-up of patients with Hodgkin s disease. Thirty-six patients underwent FDG-PET imaging at the end of treatment and then every 4-6 months for 2-3 years [44]. In cases of abnormal FDG accumulation, a confirmatory study was performed 4-6 weeks later. Four patients relapsed during this follow-up period, and PET identified all relapses. However, false-positive PET studies incorrectly suggested possible relapse in six other patients, but the confirmatory PET scan was always negative. The experience of readers and understanding of physiological uptake and artifacts associated with both FDG and gallium can minimize both false-positive and false-negative findings [45]. PET may have particular efficacy in the assessment of remission status in nodal sites, but, due to nonspecific uptake, may have disadvantages in the evaluation of extranodal disease sites [46]. Many patients have increased diffuse

6 443 Current Status of PET Scan Staging of Lymphoma Table 3. Selected series of follow-up FDG-PET in the treatment of lymphoma: evaluation of residual mass Study Year n Histology Type Major Findings Jerusalem et al. [37] HD/NHL P, B 6/6 patients persistently PET-positive have progressed; 3/29 PET-negative patients have progressed. Friedberg et al. [26] HD P, B Postchemotherapy: 4/8 patients persistently PET-positive have progressed; 1/29 PET-negative patients have progressed. Hueltenschmidt et al. [28] HD R10/12 patients persistently PET-positive have progressed. Spaepen et al. [39] NHL RPostchemotherapy: 56/67 PET-negative patients remain in remission; 26/26 PET-positive patients have progressed; 14/26 patients first evidence of disease recurrence on PET. Spaepen et al. [68] NHL RMidtreatment PET: 33/33 PET-positive patients have progressed; 6/37 PET-negative patients have progressed. Kostakoglu et al. [36] NHL/HD P After 1 cycle of chemotherapy: 13/15 PET-positive patients have progressed; 2/15 PET-negative patients have progressed. Naumann et al. [38] NHL/HD P Postchemotherapy: 5/8 PET-positive patients have recurred; 2/50 PET-negative patients have recurred. Weihrauch et al. [43] HD R, B Postchemotherapy: 6/10 patients persistently PET-positive have recurred; 3/19 PET-negative patients have recurred. Mikhaeel et al. [40] NHL RPostchemotherapy: 9/9 patients persistently PET-positive have recurred; 6/36 PET-negative patients have recurred. Abbreviations: HD = Hodgkin's disease; P = prospective; R = retrospective; B = readers of PET scans blinded to clinical history and other imaging modalities. bone marrow and muscle uptake at the completion of therapy, which may not represent recurrent disease. Before PET imaging should be routinely utilized in general practice, familiarity with the interpretation and limitations of nuclear imaging for lymphoma is necessary. Future studies will determine whether quantitative PET may minimize false-positive results, although one study comparing PET with CT scans suggested that SUV was not helpful in that regard [47]. Until then, PET may replace gallium imaging but, similar to previous experiences with gallium, it is prudent to correlate PET findings with other conventional imaging modalities and biopsy results before committing a patient to additional toxic therapy in response to an FDG-avid lesion at the completion of chemotherapy or in follow-up after treatment. SPECIAL CIRCUMSTANCES Evaluation of Bone Marrow Several reports have suggested that bone marrow involvement by lymphoma can be accurately imaged by FDG-PET scanning [27, 48-50]. In one study of 50 patients with Hodgkin s disease (n = 12) and NHL (n = 38), PET scans correlated with unilateral bone marrow core biopsy results in 39 patients. In eight patients, including four with focal marrow disease, PET scanning showed greater FDG uptake with negative-staging iliac crest biopsy; conversely, three patients had negative PET scans and positive bone marrow biopsies [51]. The largest study included 78 patients, 39 with Hodgkin s disease. Sixty-four patients had concordant results between bilateral bone marrow biopsy and PET scanning [50]. PET showed high levels of FDG uptake in 10 patients who had negative bone marrow biopsies, eight of whom had marrow involvement confirmed by magnetic resonance imaging, histology, or polymerase chain reaction. In four patients, PET did not detect marrow involvement. PET, therefore, appears to be largely concordant with bone marrow biopsy, and may provide additional information in a relatively small subset of patients. Similar to observations with gallium scintigraphy, the use of growth factors such as G-CSF may confound the interpretation of marrow disease, particularly in follow-up [52]. More recent retrospective series have suggested that FDG-PET is not reliable for detection of bone marrow involvement, particularly for indolent lymphoma subtypes [12, 15]. Clearly, additional studies are needed to determine the ability of PET to definitively diagnose marrow disease in specific situations; until that time, results of imaging will require correlation with bone marrow biopsy. Evaluation of the Central Nervous System There are inadequate data to support the routine use of PET as a diagnostic study for patients with central nervous system (CNS) lymphomas. PET is not able to differentiate among primary CNS lymphoma, infection, and other CNS malignant histologies [53]. However, in certain situations, PET may assist in defining an appropriate biopsy site. Ongoing studies, particularly in the setting of AIDS-related lymphomas, are

7 Friedberg, Chengazi 444 evaluating the use of PET in response assessment after therapy for CNS lymphomas. Evaluation of the Spleen A major limitation of both anatomic and conventional nuclear imaging techniques is the detection of lymphomatous involvement of the spleen. A recent study compared gallium with FDG-PET imaging in 38 patients with newly diagnosed Hodgkin s disease. Sensitivity and accuracy were higher using PET imaging [54]. Similarly, in a series of 36 patients with newly diagnosed Hodgkin's disease from the Dana- Farber Cancer Institute, FDG-PET clearly had a superior ability to detect occult splenic disease, with five patients having isolated FDG-avid nodules in the spleen not detected with gallium and three patients upstaged on the basis of PET scanning [26]. Although splenectomy was not performed, the appearance of the nodules, and subsequent correlation with anatomic imaging, along with resolution of the nodules following combination chemotherapy, make it likely that they did represent disease. Other studies including patients with NHL have verified splenic involvement detected on PET that was absent on other imaging studies [49]. Evaluation of Stem Cell Transplantation Similar to providing prognostic information following standard chemotherapy, PET appears to be able to predict outcome following autologous stem cell transplantation (ASCT) for relapsed lymphoma. In one series of 16 patients, seven of eight patients with positive PET scans before ASCT subsequently relapsed, whereas none of the remaining patients with negative PET scans before ASCT have had disease progression [55]. In a larger retrospective study from Belgium, 30 patients had negative PET scans before ASCT; 25 of those patients remained in remission and only three patients had disease progression following ASCT [56]. Persistently abnormal PET scans were seen in 30 patients, and 26 of those patients had disease progression. The predictive ability of PET was superior to conventional staging, or even the International Prognostic Index, for NHL [57] in those studies [58]. Future studies are needed to evaluate whether additional chemotherapy or localized external beam radiation therapy [59] in the setting of a positive PET scan might improve the outcome of ASCT for lymphoma. Other Special Situations Small studies have suggested the ability of PET to image lymphoma in the skin [60], small bowel and gastrointestinal tract [61, 62], and bone [63]. A retrospective study evaluating PET imaging in 27 children with lymphoma has been completed [64]. PET appeared to be sensitive for staging and evaluating response to therapy in that population. Of note, two patients had false-positive thymic FDG uptake following therapy, emphasizing the importance of correlating functional and anatomic imaging. NEW DIRECTIONS, CONCLUSIONS, AND RECOMMENDATIONS In conclusion, FDG-PET detects more disease sites both above and below the diaphragm on staging of lymphoma than gallium, and may have particular utility in the evaluation of the spleen. Moreover, persistently positive PET scans during and after chemotherapy have a high sensitivity for predicting subsequent relapse. A negative PET scan at the end of therapy appears to provide favorable prognostic information. Persistently positive PET scans at the end of therapy, or in follow-up, warrant close follow-up or additional diagnostic procedures, since some of those patients may remain in prolonged remission. Clearly, additional study is warranted to determine which subsets of patients benefit from this additional information, the optimal timing of imaging in clinical practice, and whether novel radiotracers may be superior to FDG [65, 66]. With these caveats, PET scans are rapidly replacing Ga-67 imaging in the staging and follow-up of patients with lymphoma. ACKNOWLEDGMENT Dr. Friedberg is a Lymphoma Research Foundation Clinical Investigator. REFERENCES 1 Ng AK, Bernardo MV, Weller E et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood 2002;100: Ng AK, Weeks JC, Mauch PM et al. Decision analysis on alternative treatment strategies for favorable-prognosis, early-stage Hodgkin's disease [see comments]. J Clin Oncol 1999;17: Mavromatis BH, Cheson BD. Pre- and post-treatment evaluation of non-hodgkin's lymphoma. Best Pract Res Clin Haematol 2002;15: 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 1997;15: 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 1994;5(suppl 2): 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 1997;15:

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