[ 18 F]-FDG PET/CT in the Staging and Management of Indolent Lymphoma: A Prospective Multicenter PET Registry Study

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1 [ 18 F]-FDG PET/CT in the Staging and Management of Indolent Lymphoma: A Prospective Multicenter PET Registry Study Ur Metser, MD, FRCPC 1 ; Jill Dudebout, MD, FRCPC 2 ; Tara Baetz, MD, FRCPC 2 ; David C. Hodgson, MD, MPH, FRCPC 3 ; Deanna L. Langer, PhD 4 ; Pamela MacCrostie, HBSc, CCPE 4 ; Victor Mak, MSc 5 ; and Noam Tau, MD 1 BACKGROUND: To measure the clinical impact of pretreatment fludeoxyglucose positron emission tomography/computed tomography (PET/CT) on the staging and management of apparent limited stage indolent lymphoma being considered for curative radiation therapy. METHODS: We conducted a prospective multicenter registry study that included 197 patients accrued between May 1, 2012, and December 31, Pre-PET/CT stage, determined by clinical and CT data, was documented. If pre-pet/ct stage was indeterminate, a stage was assigned to the patient by the referring oncologist according to best clinical judgment and treatment intent. After PET/CT, revised stage and planned management were recorded and compared with data on actual treatment received available through provincial databases (n 5 155). RESULTS: PET/CT resulted in the upstaging of 47 (23.9%) patients with presumed limited stage disease (stage I-II) to advanced stage disease (stage III-IV) (P <.0001). Ten (5.1%) patients were downstaged by PET/CT, 4 of whom migrated from advanced to limited stage disease. Twenty-eight (14.2%) patients with a specific pre-pet/ct stage had equivocal PET/CT findings that required further evaluation to confirm disease extent. After PET/CT, 95 (61.3%) patients were planned to receive active treatment. Of the 59 patients planned for radiotherapy alone post-pet/ct, 34 (57.6%) received this treatment (P 5.002), and nearly 80% of them (n 5 27) had confirmed limited stage disease. CONCLUSION: PET/CT has a significant impact on staging and management in patients with apparent limited stage indolent lymphoma who are being considered for curative radiotherapy. PET/CT should be routinely incorporated into the workup of these patients. Cancer 2017;123: VC 2017 American Cancer Society. KEYWORDS: lymphoma, B-cell, follicular lymphoma, low-grade lymphoma, positron emission tomography computed tomography, registries, chemoradiotherapy, radiotherapy. INTRODUCTION Non-Hodgkin B-cell lymphomas (NHLs) are a heterogeneous group of diseases, each with its own histology, biology, and clinical course. More than 35 different subtypes have been described by the World Health Organization, and these can be further clinically classified as aggressive or indolent. 1 Follicular lymphoma accounts for the majority of indolent NHLs, with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), mantle cell lymphoma, and splenic and nodal marginal zone lymphomas accounting for the remainder. 2 NHLs are staged according to the Ann Arbor system and its later Cotswolds modification, with the majority of patients presenting with advanced stage disease (Table 1). 3 selection is prescribed by disease stage and clinical symptoms, and options include locoregional radiotherapy for localized disease, watchful waiting in asymptomatic advanced stage patients, and systemic therapy for symptomatic patients and specific types of indolent NHLs. 4-6 Staging of indolent lymphoma includes clinical, imaging, and histological data. The role of positron emission tomography (PET) in the workup of patients with indolent lymphoma has been a controversial topic. Although highgrade lymphomas are mostly fludeoxyglucose (FDG)-avid and can be readily staged and surveilled with FDG-PET/computed tomography (CT), conflicting data have been published regarding the FDG avidity of different low-grade lymphoma subtypes. 7 Although some subtypes of indolent lymphoma (eg, small lymphocytic lymphoma) may not be FDG-avid, most indolent NHLs and nearly all follicular lymphomas (the most common indolent subtype) are FDG-avid. 7-9 Corresponding author: Ur Metser, MD, FRCPC, 610 University Avenue, Suite 3-960, Toronto, ON M5G 2M9, Canada; Fax: (416) ; ur.metser@uhn.ca 1 Joint Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada; 2 Department of Oncology, Cancer Centre of Southeastern Ontario, Queen s University, Kingston, Ontario, Canada; 3 Department of Radiation Oncology, University of Toronto, and Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada; 4 Cancer Imaging, Clinical Programs and Quality Initiatives, Cancer Care Ontario, Toronto, Ontario, Canada; 5 Cancer Analytics, Cancer Care Ontario, Toronto, Ontario, Canada The analyses, conclusion, opinions, and statements expressed in this article are those of the authors and do not necessarily represent those of Cancer Care Ontario or the Ontario Ministry of Health and Long-Term Care. DOI: /cncr.30672, Received: January 24, 2017; Revised: February 15, 2017; Accepted: February 18, 2017, Published online March 13, 2017 in Wiley Online Library (wileyonlinelibrary.com) 2860 Cancer August 1, 2017

2 PET/CT in Indolent Lymphoma/Metser et al TABLE 1. Cotswalds Classification Stage I II III IV Features Involvement of a single lymph node region or lymphoid structure (eg, spleen, thymus, Waldeyer s ring) Involvement of 2 or more lymph node regions on the same side of the diaphragm Involvement of lymph regions or structures on both sides of the diaphragm Involvement of extranodal sites beyond that designated E For all stages, A 5 no symptoms and B 5 symptomatic (fever [388C], drenching sweats, and weight loss [10% body weight over 6 months]). For stages I-III, E 5 involvement of a single, extranodal site contiguous or proximal to the known nodal site. In recent years, researchers have attempted to assess the impact of FDG-PET/CT on staging of patients with indolent lymphoma and on the ability of PET/CT to predict patient outcome. Most studies were retrospective and were performed in a single center. In a prospective multicenter study including 74 patients with indolent lymphoma, Scott et al 10 reported that PET (with or without fused CT data) upstaged presumed limited stage disease in 28% of patients and had an impact on patient management in 34% of cases. Other retrospective studies on follicular and other indolent lymphomas have shown disease upstage after PET in 10.6%-46.8% of patients, with approximately 10%-31% of patients being upstaged from limited to advanced stage disease A recent systematic review on the role of PET in staging of follicular lymphoma, including 7 studies with a total of 349 patients, suggested that overall methodological quality of available studies was poor. This review found a pooled proportion of patients upstaged by PET of 18.7%. 19 Based on existing data, a consensus statement of the International Conference on Malignant Lymphomas Imaging Working Group (MLIWG) published in 2014 recommended the use of PET/CT in staging of all FDG-avid lymphomas, including FDG-avid indolent subtypes. 20,21 The purpose of this multicenter prospective study was to measure the clinical impact of pretreatment FDG- PET/CT on the staging and management of untreated, apparent limited stage indolent lymphoma patients who are being considered for curative radiation therapy. PATIENTS AND METHODS Study Design and Data Sources The Ontario PET Registry (OPR) for indolent lymphomas was a multicenter prospective registry study funded by the Ontario Ministry of Health and Long-Term Care. Registry data was collected by Cancer Care Ontario (CCO) as a continuation of studies initiated by the Ontario Steering Committee for Positron Emission Tomography Evaluation (also known as the PET Steering Committee). The drive behind the launch of this registry was the need to strengthen existing evidence for the use of PET/CT in the staging and management of patients with indolent lymphoma, as an adjunct to the standard staging procedures which include clinical and conventional radiologic investigations. The registry was designed to prospectively measure the clinical impact of PET/CT performed in this patient population in multiple centers across the province. PET/CT was interpreted locally at each participating center. Similarly, the decision of whether to treat or observe a patient was made by the local oncologist, with all available clinical and imaging data including PET/CT staging. The outcome measures included comparison of disease stage and intended treatment modality before and after PET/CT, as well as change in actual treatment received compared with planned treatment after PET/CT. Analyses were performed for the cohort as a whole, and to more specifically characterize the impact of PET/CT for more homogeneous histology for the subset of patients with the dominant indolent lymphoma subtype, follicular lymphoma. The inclusion criteria for this registry were (1) histological confirmation of nodal follicular or other indolent NHLs; (2) apparent or possible limited stage disease as per conventional clinical and radiological staging procedures (CT); and (3) consideration for curative radiation therapy if limited stage is confirmed. As a prerequisite for inclusion in the registry, referring physicians were required to document the specific histologic subtype, pre- PET/CT stage as per available clinical and CT data; and pre-pet/ct planned treatment. Patients with indeterminate findings for limited or advanced stage on conventional workup before PET/CT who were candidates for curative therapy if limited stage disease was confirmed were included in this registry. For these patients, a specific stage (I-IV) was assigned by the referring oncologist according to the best clinical judgment and treatment plan, as if PET/CT was not available. To avoid selection bias, all patients from all centers who were eligible and were referred for PET/CT were included in the registry. Patients were scanned in 1 of 10 PET/CT centers across the Canadian province of Ontario between May 1, 2012, and December 31, After PET/CT was performed, the revised post-pet/ct stage was recorded by the reporting nuclear medicine physician according to the Ann Arbor classification (Cotswolds modification) or as equivocal if PET/CT identified an indeterminate lesion Cancer August 1,

3 TABLE 2. Pre- and Post-PET/CT Stage Post-PET/CT Stage (n 5 197) Equivocal Stage I Stage II Stage III Stage IV Total Pre-PET/CT stage Stage I (66) Stage II (22.3) Stage III (6.1) Stage IV (5.6) Total 28 (14.2) 69 (35.0) 39 (19.8) 42 (21.3) 19 (9.6) that if proven positive for lymphoma on further workup would upstage the patient. In addition, a revised treatment plan was documented by the referring oncologist with the PET/CT results (ie, post-pet/ct treatment intent). To evaluate the actual impact of PET/CT to patient management, we performed a data linkage of OPR data to provincial administrative databases using health insurance numbers. To obtain patient demographic data, OPR was linked to the Ontario Cancer Registry (OCR), which includes information on all newly diagnosed cases of lymphoma in Ontario. To retrieve treatment data, OPR was also linked to CCO s Activity Level Report database, which contains patient-level activity data from Ontario s Integrated Cancer Programs. This data was available for all activities occurring before August 31, Data collection, analysis, and presentation of these results was conducted in accordance with CCO s designation as a prescribed entity for the purposes of section 45(1) of the Personal Health Information Protection Act (2004). As a prescribed entity, CCO is able to collect personal health information for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to, or planning for all or part of the health system, including the delivery of services. CCO s information management practices are reviewed on a triennial basis by the Information and Privacy Commissioner of Ontario. [ 18 F]FDG-PET/CT Imaging Procedure PET/CT scans were performed in 10 participating Ontario centers using local departmental oncology protocols, with a non contrast-enhanced low-dose CT preceding PET acquisition and whole-body PET/CT scanning in the supine position from the skull base to the upper thighs. All scans were interpreted locally by the nuclear medicine physician with knowledge of the clinical history and access to correlative imaging studies. Statistical Analysis Differences in proportions of patients were assessed for significance using chi-square tests, where P <.05 was considered significant. All tests were 2-tailed except for the proportion of patients planned to receive treatment before and after PET/CT, where a 1-tailed test was used. Confidence intervals of the difference in ratios are also given. Statistical analysis was performed using R statistical software version (2014). RESULTS Study Population The registry included a total of 197 patients (104 men and 93 women) with newly diagnosed indolent lymphoma with a median age of 63 years (range, years). There were 150 (79.1%) patients with follicular lymphoma, 21 (10.7%) patients with marginal zone lymphoma, and 26 (13.2%) patients with other subtypes of indolent lymphoma. Stage Migration After [ 18 F]-FDG-PET/CT Entire cohort After PET/CT, there was a change in disease stage in 110 (55.8%) patients; for 51 (25.9%) patients, this was stage migration from either limited stage to advanced stage or vice versa (Tables 2 and 3). Specifically, of the 72 (36.5%) patients who were upstaged post-pet/ct, there was migration to advanced stage disease (stage III-IV) in nearly two thirds of cases (47 of 72 [65.3%] patients), whereas the other 25 patients were either upstaged from stage I to II or from stage III to IV. Of the 10 (5.1%) patients who were downstaged post-pet/ct, 4 (40%) were migrated from advanced to limited stage disease (stage I-II). Additionally, there were 28 (14.2%) patients with a specific 2862 Cancer August 1, 2017

4 PET/CT in Indolent Lymphoma/Metser et al TABLE 3. Pre- and Post-PET/CT Limited Versus Advanced Disease Stage Post-PET/CT stage (n 5 197) Equivocal Limited Stage (I or II) Advanced Stage (III or IV) Total Pre-PET/CT stage Limited disease (stage I or II) 23 (11.7) 104 (52.8) 47 (23.8) 174 (88.3) Advanced disease (stage III or IV) 5 (2.5) 4 (2.0) 14 (7.1) 23 (11.7) Total 28 (14.2) 108 (54.8) 61 (30.9) pre-pet/ct stage who had equivocal PET/CT findings requiring further evaluation to confirm disease extent. Overall, there was a significant difference in proportion of patients assessed as having limited stage disease before versus after PET/CT (174 of 197 [88.3%] patients and 108 of 169 [63.9%] patients, respectively; 95% confidence interval [CI], ; P <.0001). Follicular lymphoma cohort For the subset of 150 patients with follicular lymphoma, there was stage migration from either limited to advanced stage or vice versa in 49 (32.7%) patients. Specifically, of the 61 (40.7%) patients who were upstaged post-pet/ CT, there was migration from limited to advanced stage disease in nearly three quarters of cases (45 of 61 [73.8%] patients). Overall, there was a significant difference in the proportion of patients with limited stage disease before and after PET/CT (133 of 150 [88.7%] patients and 77 of 133 [57.9%] patients, respectively (95% CI, ; P <.0001). Post-PET/CT Intent and Actual Management Entire cohort As per the registry criteria, the pre-pet/ct treatment plan for all patients was radiation therapy. Post-PET/CT data linkage to treatment data available through CCO s Activity Level Report was available for patients treated until August 31, 2015 (155 of 197 [78.7%] patients). The post-pet/ct treatment plan, as documented by referring physicians after receiving the PET/CT stage, was compared with the actual treatment delivered and is presented in Table 4. The distribution of received treatment by post-pet/ct disease stage is detailed in Table 5. The change in proportion of patients planned for active treatment before PET/CT (radiation therapy, as per inclusion criteria) versus after PET/CT was significant, with only 95 of 155 (61.3%) patients planned to receive active treatment post-pet/ct (95% CI, 21.0 to 20.32; P <.0001); however, only 66 of 155 (42.6%) patients were TABLE 4. Planned Versus Actual Received by Patients Type Post-PET/CT Intent Actual Received All indolent lymphoma (n 5 155) Chemotherapy only 30 (19.3) 28 (18.1) Radiation only 59 (38.1) 34 (21.9) Combined modality 6 (3.9) 4 (2.6) No treatment 60 (38.7) 89 (57.4) Follicular lymphoma only (n 5 121) Chemotherapy only 26 (21.5) 28 (23.1) Radiation only 43 (35.5) 34 (28.1) Combined modality 2 (1.6) 4 (3.3) No treatment 50 (41.3) 55 (45.5) actually treated, all of whom had follicular lymphoma (95% CI, ; P ). The greatest variance between planned post-pet/ct treatment and actual treatment was in the group of patients being considered for radiotherapy as a single treatment modality. Fifty-nine of 155 patients (38.1%) were planned for radiotherapy as a single treatment modality after PET/CT; however, only 34 of the entire cohort ultimately received radiotherapy (95% CI, ; P 5.002). Of the patients who received radiotherapy, most had confirmed limited stage follicular lymphoma stage post-pet/ct (27 of 34 [79.4%] patients). Follicular lymphoma cohort Post-PET/CT data linkage was available for 121 of 150 (80.1%) patients with follicular lymphoma. There were 71 of 121 (58.7%) patients who were planned to receive treatment after PET/CT (95% CI, 21.0 to 20.34; P <.0001), and most of them were ultimately treated (66 of 71 [92.9%] patients). Consistent with the findings for the entire cohort, the greatest discrepancy between post-pet/ CT treatment intent and actual treatment delivered for the subset of patients with follicular lymphoma was in the Cancer August 1,

5 TABLE 5. Actual Received by Post-PET/CT Disease Stage for All Indolent Lymphomas Actual Post-PET/CT Stage Chemotherapy Radiation Combined Modality No / Other a Equivocal (n 5 19) 1 (0.6) 3 (1.9) 2 (1.3) 13 (8.4) Stage I (n 5 57) 2 (1.3) 20 (12.9) 1 (0.6) 34 (21.9) Stage II (n 5 30) 3 (1.9) 7 (4.5) 0 (0.0) 20 (12.9) Stage III (n 5 34) 15 (9.7) 3 (1.9) 0 (0.0) 16 (10.3) Stage IV (n 5 15) 7 (4.5) 1 (0.6) 1 (0.6) 6 (3.9) Total (n 5 155) 28 (18.1) 34 (21.9) 4 (2.6) 89 (57.4) a Other 5 other procedure (eg, biopsy) needed before defining management. TABLE 6. Actual Received by Post-PET/CT Disease Stage for Follicular Lymphoma Actual Post-PET/CT Stage Chemotherapy Radiation Combined Modality No / Other a Equivocal (n 5 11) 1 (0.8) 3 (2.5) 2 (2.5) 5 (4.1) Stage I (n 5 43) 2 (1.6) 20 (16.5) 1 (0.8) 20 (16.5) Stage II (n 5 22) 3 (2.5) 7 (5.8) 0 (0.0) 12 (9.9) Stage III (n 5 33) 15 (12.4) 3 (2.5) 0 (0.0) 15 (12.4) Stage IV (n 5 12) 7 (5.8) 1 (0.8) 1 (0.8) 3 (2.5) Total (n 5 121) 28 (23.1) 34 (28.1) 4 (3.3) 55 (45.5) a Other 5 other procedure (eg, biopsy) needed before defining management. group planned for single-modality radiotherapy (Table 4); however, when assessing this cohort independently, this change was no longer statistically significant. Forty-three of 121 (35.5%) patients were planned for radiotherapy as a single treatment modality after PET/CT, and 34 of 121 (28.1%) patients ultimately received treatment (95% CI, to 0.20; P 5.214), as detailed in Table 6. DISCUSSION Therapy choice for patients diagnosed with indolent lymphoma is dependent on accurate disease staging. In this prospective study, we were able to demonstrate the impact of PET/CT on the initial staging and management of patients with indolent lymphoma. Our data show that 1 in 4 patients with apparent limited stage disease, as determined through clinical and CT assessment, were shown to have advanced disease on PET/CT, which is consistent with previously published data Although our study did not target patients with overt advanced stage disease, referring physicians could assign an advanced stage pre- PET/CT if this reflected intended treatment (<12% of the entire patient cohort). This facilitated PET/CT scans for patients with equivocal CT for advanced stage when the patient would be a candidate for curative radiotherapy if assigned a limited stage post-pet/ct. The actual rate of downstaging is therefore difficult to determine with our data, although from the small number of patients with possible advanced disease pre-pet/ct (n 5 23), nearly 1 in 6 patients (n 5 4) were downstaged to limited disease after PET/CT. Stage migration after PET/CT resulted in a change in treatment intent and actual therapy received in a large proportion of patients. Although planned radiotherapy was one of the criterion for inclusion in the registry, this remained the plan after the PET/CT scan for only 41.9% of patients. Furthermore, only 24.5% of the patients in the cohort ultimately received radiation, either as a single modality or in conjunction with chemotherapy, and a majority of patients (57.4%) did not receive any treatment and were clinically surveilled. The impact on patient management suggested by the results of the current study may be greater than that suggested previously (31% as reported by Scott et al 10 ). When considering the relapse rate of patients who receive radiotherapy (up to 50% after 2864 Cancer August 1, 2017

6 PET/CT in Indolent Lymphoma/Metser et al 10 years in patients with follicular lymphoma) and the potential morbidity associated with this treatment, it is evident that pretreatment PET/CT plays an important role in the appropriate selection of patients for this mode of management. 22 Staging PET/CT is likely to have further impact on patient management, which was not captured in this registry. Even for patients in whom disease stage was not altered post-pet/ct, actual treatment delivery such as the definition of radiation fields may have changed. Therefore, the overall impact of PET/CT on patient management is likely underestimated in the current study. There are a few additional observations from this study. First, 14.2% of patients who were assigned a specific disease stage pre-pet/ct were found to have equivocal findings on PET/CT that would potentially impact management decision necessitating further investigation, such as biopsy. The relatively high number of equivocal cases post-pet/ct may be due to the inherent limitation of PET/CT in confirming malignant nodal involvement in locations where reactive nodes are commonly encountered, such as jugulodigastric, axillary,orgroinlymphnodes.whenmetabolicallyactive, histological evaluation may be needed to confirm or exclude a further site of disease, although the registry study design prevented us from capturing patient-specific biopsy data. However, given the rate of change in management plan after PET/ CT, the benefit of performing PET/CT in indolent lymphoma staging may still be substantial. A further interesting observation from our results is that approximately 20% of patients underwent a watchful waiting approach compared with the post-pet/ct management plan (38.7% pre-pet/ct versus 57.4% post-pet/ct). Given the design of the study, which did not mandate a specific mode of management, we can only suggest potential explanations for this finding. First, because there are similar outcomes for various treatment strategies, there may be patient or physician preference for a specific approach. 23 Furthermore, radiotherapy may be deferred after weighing in the potential specific treatment toxicity (for example, bowel toxicity related to radiotherapy directed at abdominal lymphadenopathy) and associated patient comorbidities. In our cohort, approximately 43% of patients with early stage follicular lymphoma were treated with radiotherapy, similar to the results of the National LymphCare Study. 23 This study has a few major strengths. Study design was prospective, and to date represents the largest cohort in published literature assessing the impact of staging with PET/CT as well as the downstream impact to treatment decisions for patients with indolent lymphoma. This was also extended to demonstrate actual treatment received by patients. It thus solidifies the evidence for current recommendations of the MLIWG on the use of PET/CT in the staging of patients with FDG-avid indolent lymphomas, and documents the impact on patient management, especially when radiotherapy is being considered as a sole modality of treatment. Moreover, because the study was designed as a multicenter, multireader prospective study with PET/CT interpreted locally, the results likely reflect actual clinical impact of PET/CT on staging and management of this patient population in routine practice. In addition, unlike previous studies that included either PET or mixed PET and PET/CT data, our study was performed using only integrated PET/CT. There are several limitations to this study. Because of the limitations of administrative databases, actual treatment received was available for most but not all patients; however, the findings where data were available is compelling. Additionally, follicular lymphoma comprised the majority of histological subtypes of indolent lymphoma in this study; therefore, although we were able to comment on the impact of PET/CT overall and for the subset of patients with follicular lymphoma, conclusions regarding other subtypes may not be as robust. Of note, in our cohort, all patients who ultimately received treatment had follicular lymphoma. This is likely due to its prevalence compared with other indolent subtypes, as well as due to underrepresentation of non FDG-avid indolent lymphomas (eg, small lymphocytic lymphoma) and other subtypes not primarily treated with radiotherapy (eg, mucosa-associated lymphoid tissue lymphoma). Furthermore, our study did not compare patient outcome, including rate of remission, or disease control after radiotherapywhenpet/ctorctwereusedforpatientselection and treatment planning. However, given migration to advanced stage after PET/CT in a significant proportion of patients, PET/CT is likely to better select patients for radiotherapywithcurativeintentandmayimproveoveralloutcome in the treated cohort. Finally, the cost-effectiveness of adding PET/CT to the workup of patients with indolent lymphoma being considered for curative intent radiotherapy was not addressed in this study, but may be taken into consideration when designing future prospective trials. In conclusion, PET/CT has a significant impact on staging and management of patients with apparent limited stage indolent lymphoma being considered for curative radiotherapy. Routine PET/CT should be routinely incorporated into the workup of these patients. FUNDING SUPPORT The Ontario PET Cancer Registry was funded by the Ontario Ministry of Health and Long-Term Care. Parts of this material are based Cancer August 1,

7 on data and information compiled and provided by Cancer Care Ontario. CONFLICT OF INTEREST DISCLOSURES Tara Baetz has received personal fees from Novartis, Roche, Merck, Bristol Myers Squibb, Gilead, and Lundbeck. AUTHOR CONTRIBUTIONS Conceptualization: Ur Metser (lead), David C. Hodgson, Deanna L. Langer. Methodology: Ur Metser, Jill Dudebout, Tara Baetz, David C. Hodgson, Deanna L. Langer. Investigation: Ur Metser, Deanna L. Langer, Pamela MacCrostie. Data curation: Pamela MacCrostie. Formal analysis: Ur Metser, Jill Dudebout, Tara Baetz, Deanna L. Langer, Victor Mak, Noam Tau. Writing (original draft): Ur Metser, Noam Tau. Writing (review and editing): Ur Metser, Jill Dudebout, Tara Baetz, David C. Hodgson, Deanna L. Langer, Pamela MacCrostie, Noam Tau. Supervision: Ur Metser. Project administration: Deanna L. Langer, Pamela MacCrostie. Final review and approval of the article: Ur Metser, Deanna L. Langer, Noam Tau. REFERENCES 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, et al., eds. SEER Cancer Statistics Review, Accessed November 30, Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin s disease: Cotswolds meeting. J Clin Oncol. 1989;7: Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127: Thieblemont C, Molina T, Davi F. Optimizing therapy for nodal marginal zone lymphoma. Blood. 2016;127: Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127: Weiler-Sagie M, Bushelev O, Epelbaum R, et al. (18)F-FDG avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med. 2010;51: 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: Perry C, Herishanu Y, Metzer U, et al. Diagnostic accuracy of PET/ CT in patients with extranodal marginal zone MALT lymphoma. Eur J Haematol. 2007;79: Scott AM, Gunawardana DH, Wong J, et al. Positron emission tomography changes management, improves prognostic stratification and is superior to gallium scintigraphy in patients with low-grade lymphoma: results of a multicentre prospective study. Eur J Nucl Med Mol Imaging. 2009;36: Karam M, Novak L, Cyriac J, Ali A, Nazeer T, Nugent F. Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas. Cancer. 2006;107: Beal KP, Yeung HW, Yahalom J. FDG-PET scanning for detection and staging of extranodal marginal zone lymphomas of the MALT type: a report of 42 cases. Ann Oncol. 2005;16: Carrillo-Cruz E, Marın-Oyaga VA, de la Cruz Vicente F, et al. Role of 18F-FDG-PET/CT in the management of marginal zone B cell lymphoma. Hematol Oncol. 2015;33: Le Dortz L, De Guibert S, Bayat S, et al. Diagnostic and prognostic impact of 18F-FDG PET/CT in follicular lymphoma. Eur J Nucl Med Mol Imaging. 2010;37: Wirth A, Foo M, Seymour JF, Macmanus MP, Hicks RJ. Impact of [18f] fluorodeoxyglucose positron emission tomography on staging and management of early-stage follicular non-hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2008;71: Janikova A, Bolcak K, Pavlik T, Mayer J, Kral Z. Value of [18F] fluorodeoxyglucose positron emission tomography in the management of follicular lymphoma: the end of a dilemma? Clin Lymphoma Myeloma. 2008;8: Cho SF, Chang CC, Liu YC, et al. Utilization of 18F-FDG PET/ CT as a staging tool in patients with newly diagnosed lymphoma. Kaohsiung J Med Sci. 2015;31: Luminari S, Biasoli I, Arcaini L, et al. The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi. Ann Oncol. 2013;24: Adams HJ, Nievelstein RA, Kwee TC. Systematic review on the additional value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography in staging follicular lymphoma. J Comput Assist Tomogr. 2017;41: Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32: Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32: Tsang RW, Gospodarowicz MK. Radiation therapy for localized lowgrade non-hodgkin s lymphomas. Hematol Oncol. 2005;23: Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol. 2012;30: Cancer August 1, 2017