Thallium-201-chloride scintigraphy in staging and monitoring radiotherapy response in follicular lymphoma patients

Radiotherapy and Oncology 69 (2003) 323–328 www.elsevier.com/locate/radonline

Thallium-201-chloride scintigraphy in staging and monitoring radiotherapy response in follicular lymphoma patients Rick L.M. Haasa,*, Renato A. Valde´s-Olmosb, Cornelis A. Hoefnagelb, Marcel Verheija, Daphne de Jongc, Augustinus A.M. Harta, Harry Bartelinka a

Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands b Department of Nuclear Medicine, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands c Department of Pathology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands Received 6 June 2003; received in revised form 24 July 2003; accepted 13 August 2003

Abstract Purpose: To study thallium-201-chloride scintigraphy (201Tl-S) in staging and monitoring response after radiotherapy in follicular lymphoma (FL) patients. Patients and methods: Forty-one consecutive and unselected FL patients were examined by ‘Conventional Standard Staging’ (CSS) procedures (history and physical examination, ultrasound, CT scans, biopsies and fine needle aspiration cytology) prior to irradiation. Eight standardized potentially affected lymphoma localizations (neck, axilla, mediastinum, spleen, paraaortic, parailiac, femoral and extranodal) per patient were separately studied, resulting in the investigation of 328 localizations. Thirty minutes after the intravenous administration of a tracer dose of 150 MBq thallium-201-chloride total body images were made, immediately followed by single photon emission computed tomography acquisition. All lymphoma localizations were subsequently irradiated. Patients were re-examined after a median of 4 weeks (range 3 – 6 weeks) by all CSS modalities and 201Tl-S. Diagnostic performance was evaluated both per site and per patient, both in the diagnostic phase of the study as well as in the post-treatment re-evaluation phase. Results: In staging, 201Tl-S was positive in 82 of the 129 initial positive regions by CSS (64%). This percentage increased to 70% when eliminating upper abdominal lymph nodes from the analysis. In 24 patients all lesions were visualized by 201Tl-S, in 11 patients some but not all lesions were detected. In six patients none of the lesions were detected by 201Tl-S. In four patients, four additional lesions were initially found by 201Tl-S only. After irradiation, 83 of the total 86 positive regions reached a complete or partial remission by CSS. Eighty-one of these were also diagnosed as remission by 201Tl-S and two as stable disease. In 31 out of 35 patients (89%; 95% CI: 73 – 97%) the overall response in all irradiated sites was identical by 201Tl-S and CSS. Only two patients, in remission on CSS modalities, showed stable disease on 201 Tl-S, while two others were diagnosed as CR by CSS and PR by 201Tl-S. Conclusions: 201Tl-S has limited additional value in staging FL patients, since only two-thirds of all localizations are detected. However, 201 Tl-S is accurate in monitoring radiation treatment response in FL patients. If an FL patient with a positive 201Tl-S at diagnosis is treated by irradiation, the treatment response can be reliably ascertained by only performing a 201Tl-S. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Thallium-201 scintigraphy; Lymphoma; Staging; Response assessment; Radiotherapy

1. Introduction Scintigraphic imaging techniques, such as thallium-201chloride scintigraphy ( 201Tl-S), gallium-67-citrate scintigraphy and 18F-deoxyglucose positron emission tomography (FDG-PET), play important roles in staging and monitoring treatment response in malignant lymphomas. * Corresponding author. 0167-8140/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2003.08.001

Adequate staging results in a proper treatment choice for the individual patient. Adequately defining response to treatment enables the responsible physician to estimate an appropriate prognosis and to decide on further therapeutic actions. Early stage (Ann Arbor stages I and II) follicular nonHodgkin’s lymphoma (FL) patients can show prolonged disease-free survival over 15 years in about 50% of cases by radiotherapy only [11,28,45,46]. However, for advanced

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stage (Ann Arbor stages III and IV) cure is not an option; disease inevitably recurs over and over again and becomes therapy-resistant after a median survival of 5 – 8 years. Treatment options should be chosen accordingly. Watchful waiting in advanced stage patients with no or little symptoms is a widely accepted approach [20,33]. This management is not advocated for early stage patients. Therefore, staging of FL patients is directly correlated to the treatment approach and prognosis. Generally accepted diagnostic and staging procedures include full history and physical examination, full blood count completed with at least the serum LDH, a representative complete lymph node and bone marrow biopsy and diagnostic imaging [8]. These procedures have to be performed also after treatment to assess the response. Imaging techniques, such as ultrasound of neck nodes, chest X-ray and contrast enhanced CT of chest and abdomen are considered the minimum requirements. Scintigraphic imaging techniques, such as 201Tl-S, gallium-67-citrate scintigraphy and FDG-PET provide diagnostic information as well. FDG-PET scan facilities are not widely available. Gallium-67-citrate scintigraphy has shown in previous studies to have a lower sensitivity and specificity in FL than in aggressive non-Hodgkin’s lymphomas and in Hodgkin’s lymphomas [5,37,48]. Furthermore, gallium67-citrate scintigraphy is time consuming for patients, since imaging can only be performed about 2 days after the administration of the radiopharmaceutical. Since 201Tl-S can be performed on an out-patient basis within 2 h, we were interested to investigate the role of this patientconvenient modality in FL patients. The main study endpoints were twofold: 1.

201

Tl-S in staging FL patients in all possible lymphoma bearing areas. 2. 201Tl-S in monitoring radiation response in FL patients.

2. Patients and methods 2.1. Patient characteristics Forty-one FL patients, 19 females and 22 males, median age 56 years (range 32– 90 years), admitted to the Radiotherapy Department between January 1998 and December 2001 were investigated prospectively. Patients were only selected on their histological diagnosis of FL. None of the patients in the cohort of that time period were excluded. All available histological and cytological slides were reviewed and a diagnosis of FL was confirmed. For all patients complete data sets were available on staging procedures, 201 Tl-S imaging results and radiation response assessment. The combined information from history and physical examination, ultrasound, CT scans, biopsies and fine needle aspiration cytology was considered as the ‘Conventional Standard Staging’ (CSS). Eight standardized lymphoma

localizations (neck, axilla, mediastinum, spleen, paraaortic, parailiac, femoral and extranodal) per patient were separately studied, resulting in 328 investigated localizations. 2.2. 201Tl-S procedure 201

Tl-S was performed after intravenous administration of 150 MBq thallium-201-chloride. After 30 min total body images were made (1024 £ 512 matrix, 8 cm/min). Immediately after total body acquisition, single photon emission computed tomography (SPECT) was performed (noncircular rotation, 68 step angles, 60 s/frame, 64 £ 64 £ 16 matrix, zoom factor 1.85 for head and neck and 1.0 for thorax and abdomen, iterative reconstruction). A dual-head gamma camera (ADAC Vertex, USA) was used, equipped with low-energy high-resolution collimators. 2.3. Treatment and response assessment All lymphoma localizations were irradiated with curative intent in five patients (irradiation dose 30– 36 Gy in 2 Gy fractions) or with palliative intent in 36 patients (irradiation dose twice 2 Gy) by megavoltage photon and/or electron beams. The four regions, initially discovered by scintigraphy, were among these 36 patients. So, thallium increased the number of fields irradiated but not the stage. Patients were re-examined after treatment after a median time of 4 weeks (range 3 – 6 weeks) by all CSS modalities and by 201Tl-S. The time period in which all CSS modalities and the repeat 201Tl-S were performed was maximally 1 week in order to rule out further ongoing remission or early progressive disease. Irradiated sites and treatment response per irradiated site (complete remission (CR), partial remission (PR), stable disease or progressive disease) were kept blinded to the Nuclear Medicine physician to avoid any influence on his 201Tl-S interpretation. A remission was defined as either a CR or a PR. Response parameters were defined according to generally accepted guidelines [8]. Data were correlated both per site and per patient, both in the diagnostic phase of the study and in the post-treatment re-evaluation phase. 2.4. Diagnostic performance Sensitivity, positive predictive value (PPV) and negative predictive value (NPV) relative to CSS were estimated. An additional parameter of interest is the number of extra positive or responding regions identified by 201Tl-S. Ninetyfive percent confidence intervals (95% CI) of percentages were calculated according to the exact method of Clopper and Pearson [10].

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3. Results 3.1.

201

Tl-S as a staging tool

201

Tl-S was successfully performed in all patients on an outpatient clinical basis. All scan procedures were completed within 90 min without any complications. To be able to conclude whether 201Tl-S is an equally adequate imaging tool for all lymph node areas, all 328 regions were investigated; 133 were positive for lymphoma, 195 negative (Table 1). Of these 133 true positive localizations 129 were initially found based on CSS modalities and an additional four (in four different patients) were found on 201Tl-S (two axillas, one parailiac and one femoral) and subsequently confirmed by CSS (cytology). Of the 129 positive localizations found by CSS, 82 were also positive by 201Tl-S giving a 64% sensitivity relative to CSS (Table 1). This rises to 70% after exclusion of upper abdominal lymph nodes from the analysis. Paraaortic (41%) and spleen (36%) lesions showed worst sensitivity. Of 195 sites diagnosed free of lymphoma activity by CSS, four (in four different patients) were positive on 201Tl-S (two axillas, one nasopharygeal cyst and one oropharynx). Even after thorough re-examination no lymphoma activity could be shown in these sites. In 24 patients all lesions were visualized by 201Tl-S, in 11 patients some but not all lesions were detected. In six patients none of the lesions were detected by 201Tl-S. 3.2.

201

Tl-S as a response assessment tool

To be able to conclude whether 201Tl-S is adequate for the assessment of radiotherapy response, all 86 sites positive on CSS modalities and scintigraphic imaging were investigated. By CSS, 70 regions were diagnosed as having a CR, 13 as PR and three as SD. Of the 70 sites reaching a CR by CSS, 64 (91%) were diagnosed by 201Tl-S as CR as well. Of 83 lesions reaching any remission by CSS 81 (98%) were diagnosed as such by 201Tl-S. None of the sites were diagnosed by 201Tl-S as having reached a CR or PR if the CSS modalities indicated SD. No marked differences between sites were found.

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In a total of 80 out of 86 positive lesions (93%) the remission status was diagnosed identically by 201Tl-S and CSS. Considering a patient-based analysis in 31 out of 35 patients (89%; 95% CI: 73 – 97%) the response in all irradiated sites was diagnosed identically by 201Tl-S and CSS. (Table 2). In all situations—both region-based (80 out of 86 regions) and patient-based (31 out of 35 patients)—where CSS and 201Tl-S disagreed, the latter modality showed less response to treatment. Typical examples of a pre- and posttreatment 201Tl-S are shown in Figs. 1 and 2.

4. Discussion The first aim of this study was to evaluate the role of thallium-201-chloride scintigraphy (201Tl-S) in staging FL patients. In our study, 201Tl-S cannot replace the standard imaging tools of ultrasound of neck nodes, chest Xradiograph and contrast enhanced CT scan of chest and abdomen. 201Tl-S in FL patients do miss a considerable number of positive localizations, especially upper abdominal lesions, probably as a result of a physiological radiopharmaceutical uptake in liver, spleen and small intestines. This drawback is also known for gallium-67-citrate scintigraphy and FDG-PET as well. 201Tl-S did reveal four additional lymphoma localizations in 328 evaluable regions that were not initially discovered by CSS modalities. On re-examination (ultimately confirmed by cytology), these lesions showed to be FL. Hence, addition of 201Tl-S to the standard diagnostic procedure for FL patients may result in a modest enhancement of its accuracy. 201 Tl-S is hypothesized to visualize active sodium – potassium pumping and reflects both tissue and tumor viability [32,41]. The time to maximal tumor uptake after intravenous injection ranges from 8 to 20 min and does not differ significantly between different kinds of tumors [40]. In lymphomas the peak is reached after about 12 min [40]. However uptake times as late as 2 h have also been reported [3]. 201Tl-S is positive in a wide variety of tumors including lung cancer [4,40,42], hypopharyngeal carcinoma [4], oropharyngeal cancer [15], breast cancer [6,40,42,44],

Table 1 Thallium-201-chloride scintigraphy as a staging tool Region

Neck

Axilla

Mediast

Spleen

Para aortic

CSS þ /201Tl þ (n) CSS þ /201Tl 2 (n) CSS 2 /201Tl þ (n) CSS 2 /201Tl 2 (n) Total (n) PPV (%) NPV (%)

21 3 0 17 41 100 85

11 (þ2*) 7 2 19 41 87 73

8 3 0 30 41 100 91

4 7 0 30 41 100 81

7 10 0 24 41 100 71

Para iliac

9 (þ 1*) 7 0 24 41 100 77

Femoral

14 (þ 1*) 7 0 19 41 100 73

Extra nodal

All except upper abdomen

8 3 2 28 41 80 90

75 30 4 137 246 95 82

All

82 (þ 4*) 47 4 191 328 96 80

133 195

Abbreviations: CSS, Conventional Standard Staging; 201Tl, results of thallium-201-chloride scintigraphy; PPV, positive predictive value; NPV, negative predictive value; (þnumber*), number of sites initially diagnosed CSS—that after 201Tl imaging showed þ confirmed on re-examination by CSS þ (cytology).

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Table 2 Thallium-201-chloride scintigraphy as a response assessment tool per patient in 35 patients and per site in 86 sites (bold-italic between parenthesis) where both CSS modalities and scintigraphic imaging were positive Conventional Standard Staging CR Thallium-201-chloride scintigraphy

CR PR SD PD Total

PR

SD

20 (64)

PD

Total 20 (64)

2 (4) 1 (2)

11 (13) 1

(3)

13 (17) 2 (5)

23 (70)

12 (13)

(3)

35 (86)

thyroid neoplasias (both malignant and benign) [7,18,43], parathyroid neoplasias (malignant and benign) [9,34], esophageal cancer [4], multiple myeloma [4,22,36,39], and malignant lymphomas, both non-Hodgkin’s lymphomas and Hodgkin’s disease [12,40,42]. In multiple myeloma 201 Tl-S is able to visualize bone marrow localizations [4,22, 36,39], even better than plain radiographs. In AIDS-related central nervous system localizations of malignant lymphoma 201Tl-S has a high sensitivity and specificity [24,27]. Concurrent infections, however, pose a major problem on interpreting 201Tl-S as infection foci are usually 201Tl-S positive [1,2,42]. If the 201Tl-S in a malignant lymphoma patient is positive prior to treatment a negative scan after therapy may predict

Fig. 2. In this patient the total body study (panel A) shows only faint uptake in left groin lymphadenopathy (horizontal arrow), but in panel B SPECT images clearly show the hot spot in the left inguinal lymph node area (oblique arrow). Panels C and D show the same patient in complete remission after radiotherapy.

Fig. 1. Panel A shows 201Tl total body study. The arrows indicate lymphadenopathy in both necks and axillae. Tracer accumulation in heart, liver, kidneys and small intestines is physiological. Panel B shows SPECT images revealing also mediastinal nodes. Panels C and D show the same patient after irradiation in complete remission.

outcome [35]. Rebound thymic hyperplasia after treatment for malignancy can be 201Tl-S positive, creating a potential pitfall [38]. Gallium-67-citrate scintigraphy is especially valuable in staging and response evaluation in Hodgkin’s lymphoma and aggressive non-Hodgkin’s lymphoma patients and helps in distinguishing residual tumor from fibrosis [13,14,47]. False-positive gallium-67-citrate scintigraphy (without evidence of tumor), however, has also been reported [17]. Several series have suggested that 201Tl-S may be more useful than gallium-67-citrate scintigraphy in the evaluation of indolent (low-grade) lymphomas [5,37,48]. 201Tl-S offers a distinct advantage over gallium-67-citrate scintigraphy because of its short total procedure time, which makes it far more convenient for patients, pediatric and adult [31]. The gallium-67-citrate scanning procedure has to be performed over several days and patients have to be prescribed a laxative to ensure prompt elimination of large bowel gallium-67-citrate accumulation. The role of FDG-PET in staging FL patients has also been investigated, but controversial data have been obtained. FDG uptake values in lymphomas are thought to correlate with malignancy grade, the low-grade lymphomas showing the lowest uptake. Uptake can be so low that contrast to normal tissues is lost [23,25,30]. Bone marrow infiltration (present in about 80% of all FL patients especially in recurrent disease) is almost never visualized on FDG-PET. In small lymphocytic

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lymphomas and extranodal marginal zone lymphomas of MALT-type, like FL indolent lymphoma subtypes, FDGPET showed only about half the number of lymphoma localizations per patient as compared to conventional staging and none of the MALT-sites [19]. Like 201Tl-S, FDG-PET and gallium-67-citrate scintigraphy can all miss upper abdominal localizations [23]. Therefore, all three nuclear medicine imaging modalities have advantages and drawbacks in staging procedures in lymphoma patients. Referring to our results and the literature, it can be concluded that in FL patients of all three scintigraphic imaging techniques, 201Tl-S plays the most important but still the modest role. The second aim of this study was to evaluate the role of 201 Tl-S in monitoring response to radiotherapy. The agreement between 201Tl-S and conventional diagnostic tools to predict radiation treatment response is high. In 31 out of 35 patients and in 80 regions out of 86 irradiated 201 Tl-S and CSS concluded to the same response. An interesting feature occurs when studying Table 2. In all situations—both region- and patient-based—where CSS and scintigraphy disagreed, the latter modality showed less response to treatment. In four out of 35 patients the 201Tl-S images still showed more lymphoma activity than did the CSS modalities (three patients in CR by CSS of whom two were in PR and one in SD on 201Tl-S and one patient in PR by CSS was in SD on 201Tl-S). In six out of 86 sites 201Tl-S also showed worse results (PR in four and SD in two where CSS modalities diagnosed CR). Perhaps CSS modalities overestimate the remission status after radiotherapy since they only show the size of the nodes and extranodal localizations. 201 Tl-S reflects the viability of the lymphoma sites, which might be a better response assessment. For patients defining the right quality of response (CR or PR) to involved field radiotherapy is important. In a recently published study [16] we have shown that CR patients are four times longer locally controlled: a median time to local progression of 42 months when reaching CR compared to 10 months in PR patients. A CR is defined as the disappearance of all measurable disease. This, of course, may be influenced by the diagnostic tool used. Generally, when FL patients are diagnosed to have attained CR, the disappearance of all disease activity is measured by physical examination and imaging techniques. However, disease activity in FL patients may be measured by molecular-biological tests as well. Molecular minimal residual disease may be found up to 10 years after successful local irradiation of early stage patients. Hence, using this tool CR as defined above may not be reached by most FL patients. The clinical importance of molecular-biological minimal residual disease detection in FL, however, remains uncertain, because it does not seem to be associated with decreased overall survival [21,26,29]. In conclusion, 201Tl-S may give a modest improvement in staging FL patients especially in extra-abdominal lymphoma sites. 201Tl-S as a staging modality performs better than gallium-67-citrate scintigraphy in FL patients,

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although the opposite may be true for patients with intermediate or high-grade non-Hodgkin’s lymphomas and Hodgkin’s disease. 201Tl-S is inadequate in diagnosing upper abdominal FL localizations, but gallium-67-citrate scintigraphy and FDG-PET score no better in this region. 201 Tl-S seems to be accurate in monitoring radiation treatment response in FL patients. The most important conclusion is that the treatment response in a FL patient with a positive 201Tl-S at diagnosis, treated by irradiation, can be reliably ascertained by only performing a 201Tl-S.

References [1] Abdel-Dayem HM, Bag R, Macapinlac H, et al. Diffuse Tl-201 uptake in the lungs. Etiologic classification and pattern recognition. Clin Nucl Med 1995;20:164–72. [2] Abdel-Dayem HM, Bag R, DiFabrizio L, et al. Evaluation of sequential thallium and gallium scans of the chest in AIDS patients. J Nucl Med 1996;37:1662 –7. [3] Abdel-Dayem HM, Naddaf SY, Omar WS, Aziz M, Gillooley J. Delayed positive thallium uptake in large B-cell non-Hodgkin’s malignant lymphoma. J Nucl Med 1997;38:1213–5. [4] Arbab AS, Koizumi K, Arai T, Toyama K, Araki T. Application of Tc-99m-tetrofosmin as a tumor imaging agent: comparison with Tl201. Ann Nucl Med 1996;10:271 –4. [5] Arthur JE, Kehoe K, Van den Abbeele AD. Thallium-201 scintigraphy in low grade non-Hodgkin’s lymphoma. J Nucl Med 1998; 43:258. [6] Buscombe JR, Cwikla JB, Thakrar DS, Hilson AJ. Scintigraphic imaging of breast cancer: a review. Nucl Med Commun 1997;18:698–709. [7] Cavalieri RR. Nuclear imaging in the management of thyroid carcinoma. Thyroid 1996;6:485–92. [8] Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999;17:1244–53. [9] Coakley AJ. Parathyroid imaging. Nucl Med Commun 1995;16: 522–33. [10] Collett D. Modelling binary data. London: Chapman & Hall; 1991. [11] De Los Santos JF, Mendenhall NP, Lynch JW. Is comprehensive lymphatic irradiation for low grade non-Hodgkin’s lymphoma curative treatment? Long-term experience at a single institution. Int J Radiat Oncol Biol Phys 1997;38:3–8. [12] Fletcher BD, Kauffman WM, Kaste SC, et al. Use of Tl-201 to detect untreated pediatric Hodgkin disease. Radiology 1995;196:851 –5. [13] Fletcher BD, Xiong X, Kauffman WM, Kaste SC, Hudson MM. Hodgkin’s disease: use of Tl-201 to monitor mediastinal involvement. Radiology 1998;209:471 –5. [14] Front D, Israel O. The role of Ga-67 scintigraphy in evaluating the results of therapy of lymphoma patients. Semin Nucl Med 1995;25: 60–71. [15] Gregor RT, Valdes-Olmos R, Koops W, Balm AJ, Hilgers FJ, Hoefnagel CA. Preliminary experience with thallous chloride Tl201labeled single-photon emission computed tomography scanning in head and neck cancer. Arch Otolaryngol Head Neck Surg 1996;122: 509–14. [16] Haas RLM, Poortmans Ph, de Jong D, et al. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 2003;21:2474–80. [17] Harris EW, Rakow JI, Weiner M, Agress Jr. H. Thallium-201 scintigraphy for assessment of a gallium-67-avid mediastinal mass following therapy for Hodgkin’s disease. J Nucl Med 1993;34: 1326– 30.

328

R.L.M. Haas et al. / Radiotherapy and Oncology 69 (2003) 323–328

[18] Hoefnagel CA, Delprat CC, Marcuse HR, de Vijlder JJM. Role of thallium-201 total-body scintigraphy in follow-up of thyroid carcinoma. J Nucl Med 1986;27:1854–7. [19] Hoffmann M, Kletter K, Diemling M, et al. Positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D -glucose(F18-FDG) does not visualise extranodal B-cell lymphoma of the mucosaassociatedlymphoid tissue (MALT)-type. Ann Oncol 1999;10: 1185–9. [20] Horning SJ. Natural history of and therapy for the indolent nonHodgkin’s lymphomas. Semin Oncol 1993;20:75–88. [21] Husson H, Carideo EG, Neuberg D, et al. Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arays. Blood 2002;99:282 –9. [22] Ishibashi M, Nonoshita M, Uchida M, et al. Bone marrow uptake of thallium-201 before and after therapy in multiple myeloma. J Nucl Med 1998;39:473–5. [23] Jerusalem G, Beguin Y, Najjar F, et al. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) for the staging of low-grade non-Hodgkin’s lymphoma (NHL). Ann Oncol 2001;12: 825–30. [24] Kessler LS, Ruiz A, Donovan Post MJ, Ganz WI, Brandon AH, Foss JN. Thallium-201 brain SPECT of lymphoma in AIDS patients: pitfalls and technique optimization. Am J Neuroradiol 1998;19: 1105–9. [25] Leskinen-Kallio S, Ruotsalainen U, Nagren K, Teras M, Joensuu H. Uptake of carbon-11-methionine and fluorodeoxyglucose in nonHodgkin’s lymphoma: a PET study. J Nucl Med 1991;32:1211–8. [26] Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood 1995;85: 2528–36. [27] Lorberboym M, Wallach F, Estok L, et al. Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 1998;39:1366 –9. [28] MacManus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? J Clin Oncol 1996;14:1282–90. [29] Mandigers CM, Meijerink JP, Mensink EJ, et al. Lack of correlation between numbers of circulating t(14;18)-positive cells and response to first-line treatment in follicular lymphoma. Blood 2001;98:940–4. [30] Moog F, Bangerter M, Diederichs CG, et al. Lymphoma: role of whole-body 2-deoxy-2-[F-18]fluoro-D -glucose (FDG) PET in nodalstaging. Radiology 1997;203:795 –800. [31] Nadel HR. Thallium-201 for oncological imaging in children. Semin Nucl Med 1993;23:243–54. [32] Niemeyer MG, Kuijper AF, Meeder JG, Cramer MJ, Cleophas AJ, van der Wall EE. Comparison of thallium scintigraphy and positron emission tomography. Angiology 1997;48:843–53.

[33] O’Brien ME, Easterbrook P, Powell J, et al. The natural history of low grade non-Hodgkin’s lymphoma and the impact of a no initial treatment policy on survival. Q J Med 1991;80:651 –60. [34] Prekeges JL, Eisenberg B. Parathyroid scintigraphy. J Nucl Med Technol 1997;25:59– 65. [35] Roach PJ, Janicek MJ, Kaplan WD. Bone lymphoma. Comparison of Tl-201 and Ga-67 citrate scintigraphy in assessment of treatment response. Clin Nucl Med 1996;21:689–94. [36] Roach PJ, Arthur CK. Comparison of thallium-201 and gallium-67 scintigraphy in soft tissue and bone marrow multiple myeloma: a case report. Australas Radiol 1997;41:67 –9. [37] Roach PJ, Cooper RA, Arthur CK, Ravich RB. Comparison of thallium-201 and gallium-67 scintigraphy in the evaluation of nonHodgkin’s lymphoma. Aust N Z J Med 1998;28:33–8. [38] Roebuck DJ, Nicholls WD, Bernard EJ, Kellie SJ, Howman-Giles R. Misleading leads. Thallium-201 uptake in rebound thymic hyperplasia. Med Pediatr Oncol 1998;30:297 –300. [39] Sayman HB, Sonmezoglu K, Altiok E, Devranoglu G, Ferhanoglu B. Unexpected bone marrow uptake of thallium-201 in nonsecretory myeloma. J Nucl Med 1995;36:250–1. [40] Sehweil A, McKillop JH, Ziada G, Al-Sayed M, Abdel-Dayem H, Omar YT. The optimum time for tumor imaging with thallium-201. Eur J Nucl Med 1988;13:527 –9. [41] Sehweil AM, McKillop JH, Milroy R, Wilson R, Abdel-Dayem HM, Omar YT. Mechanism of 201Tl uptake in tumors. Eur J Nucl Med 1989;15:376–9. [42] Sehweil AM, McKillop JH, Milroy R, et al. 201Tl scintigraphy in the staging of lung cancer, breast cancer and lymphoma. Nucl Med Commun 1990;11:263–9. [43] Sisson JC. Selection of the optimal scanning agent for thyroid cancer. Thyroid 1997;7:295–302. [44] Sluyser M, Hoefnagel CA. Breast carcinomas detected by thallium201 scintigraphy. Cancer Lett 1988;40:161– 8. [45] Stuschke M, Hoederath A, Sack H, et al. Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic–centrocytic lymphomas: results of a prospective multicenter study. Study Group NHL-fruhe Studien. Cancer 1997;80: 2273–84. [46] Sutcliffe SB, Gospodarowicz MK, Bush RS, et al. Role of radiation therapy in localized non-Hodgkin’s lymphoma. Radiother Oncol 1985;4:211–23. [47] Van Amsterdam JA, Kluin-Nelemans JC, van Eck-Smit BL, Pauwels EK. Role of 67Ga scintigraphy in localization of lymphoma. Ann Hematol 1996;72:202–7. [48] Waxman AD, Eller D, Ashook G, et al. Comparison of gallium-67citrate and thallium-201 scintigraphy in peripheral and intrathoracic lymphoma. J Nucl Med 1996;37:46–50.