PET / CT in lymphoma Dr Bhuey Sharma Consultant Radiologist The Royal Marsden Hospital Lymphoma Masterclass 2016

More questions than answers

PET negative DOES NOT = no lymphoma PET positive DOES NOT = active lymphoma PET negative DOES NOT = no lymphoma

Timeline oncological imaging Sharma B, Martin A, Stanway S, Johnston SR, Constantinidou A. Imaging in Oncology- over a century of advances. Nat Rev Clin Oncol. 2012; 9(12):728-737

Timeline oncological imaging Sharma B, Martin A, Stanway S, Johnston SR, Constantinidou A. Imaging in Oncology- over a century of advances. Nat Rev Clin Oncol. 2012; 9(12):728-737

Timeline: the development of lymphoma staging and response assessment guidelines 1965 Rye Classification 1971 Ann Arbor Hodgkin’s disease. Contiguous spread; extended field radiotherapy; chemotherapy advanced disease. Localised extranodal disease related to adjacent lymph node disease does not adversely affect survival, E; laparotomy and splenectomy. Two systems of classification, clinical staging (CS) and pathological staging (PS). 1989 Cotswolds Meeting Hodgkin’s disease. 1. Computed tomography for nodes 2. spleen and liver involvement includes focal defects on 2 imaging techniques 3. bulky disease concept (>10cm) X 4. CR(u) ‘uncertain/unconfirmed’ new category, to accommodate difficulty persistent radiological abnormalities of uncertain significance. 1999 International Working Group Criteria Non-Hodgkin’s lymphomas. Standardised response guidelines. Anatomic definition response, normal lymph node size after treatment 1.5 cm largest transverse diameter CT. CRu (unconfirmed) >75% reduction tumour size with residual mass. Gallium scans encourage valuable adjunct, but such scans require appropriate expertise. 2007 International Harmonization Project PET for response assessment in Hodgkin’s disease and non-Hodgkin’s lymphoma. PET after therapy completion at least 3 weeks, preferably 6-8 weeks post chemo/chemoimmunotherapy, 8-12 weeks post radiation. Visual assessment adequate. Residual mass > 2 cm, reference mediastinal blood pool activity; smaller or normal sized node (< 1 x 1 cm) surrounding background. Liver, spleen, lung, bone marrow criteria. Use of PET response assessment during therapy part of clinical trial or prospective registry. 2014 The Lugano Classification Hodgkin’s disease and non-Hodgkin’s lymphoma. PET staging (BMB HD & NHL). 5-point scale for PET response. Modification of Ann Arbor descriptive terminology and CT response. Routine surveillance imaging discouraged.

Having (high-grade) lymphoma was bad for you Even if you were treated Once upon a time…. Having (high-grade) lymphoma was bad for you Even if you were treated Standard Staging Investigations: CXR + lymphography + Splenectomy Standard treatment: Mantle field radiotherapy Standard outcome: not very good 7

Evolution of clinical PET imaging Sharma B, Martin A, Stanway S, Johnston SR, Constantinidou A. Imaging in Oncology- over a century of advances. Nat Rev Clin Oncol. 2012; 9(12):728-737

Staging Accuracy PET > CT per lesion PET and CT discordant up to ^ 30% patients Stage migration up to ^ 30% patients Treatment change up to circa 15% patients No evidence improvement patient outcome

Presented in June 2004 with back and groin pain Presented in June 2004 with back and groin pain. MRI from December 2004 and February 2005 demonstrated disease in the vertebral body between T2 and T4. A PET scan confirmed uptake in these areas as well as the 4th rib. Core biopsy from T3 confirmed follicular lymphoma final staging 1AE. He received a total of 30Gy in 20# from T1 to T5 completed in July 2005. An MRI scan performed at Barnet Hospital in November 2005 was reported to have shown a new lesion at L4 of 1.5cm in size. A subsequent PET scan showed no activity in the lumbar spine but low grade uptake in the right 4th rib at the lower end of the sternum and in the lower thoracic vertebra which was felt to constitute evidence of disease relapse. He was seen in September 2007 with a 2 month history of increasing cervical and lumbar pain which was poorly controlled.  Radiology Review: An MRI scan shows suspicious lesions at T4 toT6 but these are likely to represent radiotherapy change. PET scan performed 1st November - FDG uptake in the left transverse process of T4 and the left pedicle of T7. There is also abnormal uptake in the right 4th rib.  11

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FEBRUARY 2008 15

Deauville criteria No uptake Uptake < mediastinum Uptake > mediastinum but < liver Uptake moderately higher than liver Uptake markedly higher than liver and / or new lesions New areas of uptake unlikely to be related to lymphoma Interim and end of treatment Good inter observer agreement reported in HL, DLBCL, FL Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on interim PET scan in lymphoma. Leuk Lymphoma. 2009; 50(8):1257-1260

PET ‘post therapy assessment’ Terasawa T, Nihashi T, Hotta T, et al. 18F-FDG PET for posttherapy assessment of Hodgkin’s disease and aggressive non-Hodgkin’s lymphoma: a systematic review. J Nucl Med. 2008;49(1):13-21 Advanced stage Hodgkin’s disease, HD15 trial The negative predictive value for PET at 12 months was 94.1% (95% CI 92.1-96.1); and 225 (11%) of 2126 patients received additional radiotherapy. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799 EORTC H10 trial Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014; 32(12):1188-1194 RAPID trial Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015; 372(17):1598-1607 Estimated dependence of lifetime radiation induced risk of cancer on age at exposure Brenner DJ, Hall EJ. Computed Tomography – an increasing source of radiation exposure. N Engl J Med. 2007; 357(22):2277-2284

Diagnostic improvements Clear national/international guidelines Haemato-oncology specialist radiologists Network (regional) MDTs National (mandatory) training program E-learning (haematology/NIHR) national program Template approach Education/training (e-journal approach)

Staging – The future 25

NATURE REVIEWS | CLINICAL ONCOLOGY Imaging in oncology—over a century of advances Bhuey Sharma, Axel Martin, Susannah Stanway, Stephen R. D. Johnston and Anastasia Constantinidou Abstract | Over the past 120 years, the discipline of oncology has evolved so that a multitude of anatomical and increasingly complex functional imaging techniques are now applicable in both clinical and research platforms. This Timeline article revisits the achievements of the pioneer techniques in cancer imaging, discusses how these techniques have changed over time, provides some examples of clinical importance, and ventures to explain how imaging will remodel the future of modern oncology. Sharma, B. et al. Nat. Rev. Clin. Oncol. advance online publication 13 November 2012; doi:10.1038/nrclinonc.2012.195

Conclusions Lymphoma tremendous development over 50 years Complex imaging landscape across clinical and research platforms Persistent challenge assessment ‘as close as possible to the truth’ Understanding imaging science to provide ‘appropriate’ and ‘optimal’ patient care Appropriate and efficient use of health care tests, resources Future multiparametric anatomolecular / functional imaging; more-accurate diagnosis, detection of minimal disease, prognostication, early response evaluation and treatment guidance More questions than answers