UK PET-CT Guidelines Current status and future directions Prof Sally Barrington and Dr Andrew Scarsbrook PET-CT in England

• Framework for Development of PET Services published by Department of Health/RCR in 2005

• PET-CT provision expanded in 2008 with independent sector provided mobile PET-CT at multiple sites http://www.credo-group.com/downloads/PETCT%20Whitepaper.pdf PET-CT in England

• Phase I National PET-CT re-procurement in 2015 accounting for 50% activity in England • Phase II procurement will commence May 2017 for remaining 50% of PET-CT scanning services and PET-CT ‘standard’ tracers to be delivered 1 April 2018 Indications for PET-CT

• Wide range of indications for PET-CT have good evidence that patients benefit from improved disease assessment resulting in altered management and/or improved outcomes

• Comprehensive list of oncological and non-oncological PET-CT applications and key evidence is available in Guidelines produced by the Intercollegiate Standing Committee on (Latest version published June 2016)

Scarsbrook A and Barrington SF https://www.rcr.ac.uk/sites/default/files/publication/bfcr163_pethttps://www.rcr.ac.uk/publication/evidence-based- -ct.pdf indications-use-pet-ct-united-kingdom-2016 Head and neck: Staging, Brain: Characterise lesions, grade tumours, Find the primary, response assessment, guide biopsy, relapse, response assessment Relapse Thyroid: rising markers, recurrence? Thymus: characterise, stage Parathyroid: find gland (hyperPTH) Breast : disease extent (bone), brachial plexopathy, recurrence, response Oesophagus , Stomach : Staging, recurrence Lung and pleura: Characterise lesions , Liver & biliary: Guide biopsy, Staging, response assessment, Staging selected ? operable Relapse, Tumours, Recurrence Colorectal Staging, restaging, recurrence, Ovary, uterus & cervix : Presacral masses Staging prior to pelvic NETs exenteration , recurrence, rising Urological: Stage, response markers Staging selected renal tumours, Prostate recurrence Lymphoma: Testicular recurrence, residual Staging, response, recurrence masses Myeloma relapse in non secretory Skin & connective tissue: disease extent plasmacytoma Staging of disseminated melanoma, Response, Sarcoma staging and response Whole body: Find primary assessment The BIG FIVE

• Lymphoma • Lung • Colorectal • Head and neck • Oesophageal

Scarsbrook and Barrington, Clin Radiol. 2016 ;71: 673-90 Hillner BE et al J Clin Oncol 2008 Clinical Commissioning Policy statement PET-CT

NHS England will commission ‘as expressed in 2013 Evidence based guidelines PET-CT using FDG and non FDG tracers and Non-oncology indications’

Including : Selected cases of & PUO Large vessel vasculitis Sarcoidosis Cardiac and neurological conditions Amyloid imaging will NOT be commissioned New Oncological FDG PET-CT Applications Lung cancer

• Characterisation of a solid pulmonary nodule with an initial risk of malignancy of > 10% (Brock model) where the nodule size is greater than local PET-CT detection threshold (8- 10mm) below which the influence of the partial volume effect is substantial and precludes adequate sensitivity

Baldwin et al Thorax 2015; 70(8): 794-798 Lung cancer

Treatment response largely assessed with CT but 2 recent studies suggest FDG PET-CT has a higher NPV for responding nodes and may guide optimal patient selection for curative resection Assessment of response to chemotherapy and /or radiation treatment in selected patients who have had an apparently very good response on conventional imaging and surgery is being considered

Kremer et al. Ann Nucl Med 2016; 30: 114 Kim et al. Medicine (Baltimore) 2015; 94: e955 Complete Metabolic Response

Pre-treatment

Post-treatment

Kremer et al. Ann Nucl Med 2016; 30: 114 Partial Metabolic Response

Pre-treatment

Post-treatment

Kremer et al. Ann Nucl Med 2016; 30: 114 Response Assessment in rectal cancer • MRI is mainly used for staging of rectal cancer, but has limited value in response assessment following CRT 1

• Several studies have indicated a correlation between metabolic and pathologic response and demonstrated a superior NPV (up to 96%) for pathologic CR compared to MRI

• A recent systematic review combining results of over 1500 patients found a high pooled accuracy for early PET restaging post CRT for LARC 2

Assessment of treatment response in patients with rectal carcinoma post (chemo)radiotherapy with indeterminate findings on other imaging

1Van der Paardt et al. Radiology 2013; 269: 101 2Maffione et al. Am J Roentgenol 2015; 204: 1261 Monitoring Therapy of Liver Metastases

Patients not suitable for liver resection may have systemic or regional therapy to the liver: Radiofrequency ablation Cryo-therapy Selective internal radiotherapy (SIRT) with 90Yttrium microspheres FDG PET-CT can be used to assess response in patients with liver metastases earlier than anatomical changes FDG negative lesions following therapy are associated with longer disease-free periods Residual FDG uptake is predictive of early recurrence and can help guide further treatment Sabet et al. Eur J Nucl Med Mol Imaging 2015; 42: 370 Zheng et al. Nucl Med Commun 2014; 35: 339 Colorectal

• Restaging of patients with recurrence being considered for radical treatment and/or invasive targeted techniques (e.g. metastatectomy/SIRT).

• Assessment of treatment response following targeted therapy (ablative techniques for liver or lung metastases, selective internal radiotherapy for liver metastases) in metastatic colorectal carcinoma when findings on other imaging are inconclusive

1Van der Paardt et al. Radiology 2013; 269: 101 2Maffione et al. Am J Roentgenol 2015; 204: 1261 Response to radiofrequency ablation (RFA)

Recurrent metastasis : pre-RFA Response to radiofrequency ablation (RFA)

6 weeks after RFA: complete ablation 2 hepatic metastases, 6 weeks after RFA

incomplete ablation

complete ablation PET-CT is useful in assessment of therapy success post-ablation

Sainani et al. Am J Roentgenol 2013; 200: 184 Response to Selective Internal (SIRT)

Pre-treatment

Post-treatment Evaluating response in cervical cancer

• Decline in SUVmax predicts tumour response earlier than tumour volume • Post-therapy PET is able to detect residual disease and predict tumour recurrence and overall survival • Complete metabolic response on post-therapy FDG-PET is a powerful predictor for survival after chemo-radiotherapy

Response assessment of locally advanced cervical cancer after chemoradiotherapy

Schwarz et al. Int J Radiat Oncol Biol Phys 2012; 83: 185 Partial Metabolic Response

A B

Pre-treatment 3-months post-therapy 7-months post-treatment

40 yr old female with stage 2b node positive cervical cancer treated with chemo-radiotherapy Progressive Disease • 40 year old with stage 2B disease

• Primary SUVmax 16.1

• PET-CT 78 days after completion of CRT – CMR in pelvis but new left humeral lesion

• Treated with radiotherapy but patient had progressive metastatic disease and died 18 months post initial diagnosis Lymphomas • Staging of FDG-avid lymphomas • Remission assessment of FDG-avid lymphomas after completion of treatment using the five-point scale (Deauville criteria) for response assessment. If there has been a complete metabolic response (CMR) on an interim scan, an end of treatment scan is not required • Interim assessment to guide response adapted treatment in selected patients with Hodgkin Lymphoma • Interim assessment to monitor treatment if mid- therapy imaging is performed and to exclude progression in patients with aggressive non-Hodgkin Lymphoma

Barrington et al JCO 2014; 32: 3048, Cheson et al JCO 2014 32: 3059 Radford et al NEJM 2015; 372: 1598, Raemaekers et al JCO 2014;32:1188,Johnson et al NEJM 2016; 374: 2419 MR, CT, PET-CT replace XR to assess bone disease

Imaging identifies smouldering/asymptomatic myeloma with high risk of progression

Rajkumar et al Lancet Oncol 2015: 15: e538-48 Repeat MR recommended for diffuse or 1 focal lesion Myeloma

To identify patients with smouldering myeloma at high risk of progression to symptomatic disease requiring initiation of treatment in line with revised International Myeloma Working Group Criteria Response Assessment in Myeloma

1. PET assesses response better than MR because it can differentiate between active and inactive lesions especially useful with oligo-secretory or non-secretory myeloma with minimal or no paraproteins or light chains in blood, urine or bone marrow 2. Several studies show PET detects additional lesions in 30-50% of cases with apparent solitary plasmacytoma 3. PET better at predicting remission post ASCT than conventional defined CR using blood and bone marrow due to increased sensitivity for extramedullary & non-secretory disease

Caldarella et al Int Journal of Mol Imaging 2012 Nanni et al 2008 In Vivo 22: 513, Yi et al 2013 Annals of Hematology, 92: 1421 Bartel et al 2009 Blood 114: 2068 Zamagni et al 2011 Blood 118: 5989, Lapa et al 2014a Oncotarget 15: 7381 Myeloma • Baseline assessment in patients with non-secretory and oligo- secretory myeloma as a baseline for subsequent response assessment. • Assessment of patients with apparently solitary plasmacytoma to exclude other sites of disease. • To assess response or suspected relapse in patients with oligo- secretory or non-secretory myeloma, patients with predominantly extra-medullary disease, patients with solitary plasmacytoma. • Remission assessment post stem-cell transplantation in patients with absence of para-proteins or light chains in blood, urine and bone marrow in selected cases. • Assessment of patients with monoclonal gammopathy associated neuropathies (MGAN) to identify plasmacytomas which may be amenable to radiotherapy. Active vs inactive lesions post tx Pre-treatment 3 months post-treatment Response assessment in Myeloma 59 yo man 2009 solitary plasmacytoma Pretreatment

Post RT

CMR Skin tumours

• In the assessment of selected patients with Merkel Cell Carcinoma to more accurately stage disease extent where this would alter intended management and for assessment of treatment response and/or suspected recurrence when conventional imaging is inconclusive

• To exclude systemic involvement in skin lymphomas and exclude large cell transformation in Mycosis Fungoides.

George et al Nucl Med Commun 2014; 34: 282 Byrne et al J Nucl Med 2015; 56: 1328 Feeney et al Am J Roentgenol 2010; 195: 333-340. Neuroendocrine tumours

• Assessment of selected patients with adrenocortical carcinoma being considered for invasive treatment where cross-sectional imaging is inconclusive.

Takeuchi et al Eur J Nucl Med Mol Imaging 2014; 41: 2066 Rare tumours in children and young adults

• Rhabdomyosarcoma

Norman et al BMJ Open 2015 8: e006030 New Non-Oncological FDG PET-CT Applications Cardiac sarcoidosis

1. Increased uptake of FDG occurs in macrophages at site of in cardiac sarcoidosis and has high sensitivity 2. Need to suppress glucose uptake in normal myocardium With >12h fast +/- high fat low CHO diet 3. FDG imaging often accompanied by perfusion imaging as advanced disease may show scarring Suppression of cardiac uptake

Standard Fast Overnight Fast/Adkins diet

Coulden et al. Eur Radiol 2012; 22: 2221 FDG for Cardiac Sarcoid

• Sensitivity 89% (95CI 79-96%) • Specificity 78% (95 CI 68 -86%)

FDG

Ammonia

Youssef et al JNM 2012 Implantable cardiac electronic device (ICED) infection

British Cardiovascular Society guidelines for ICED infection (2014)

“At the present time there is insufficient evidence of what FDG PET-CT adds to a clinical diagnosis, and this investigation cannot be recommended as a routine clinical test but may be useful in selected cases where there is diagnostic uncertainty”

Sandoe et al. J Antimicrob Chemother 2015; 70: 325 58 M. Suspected pacing lead related infection

Pacing lead–related sepsis Cardiac imaging

• Assessment of activity and distribution of disease at baseline in highly selected cases where there is diagnostic uncertainty using conventional imaging (e.g. suspected cardiac sarcoidosis. May be used in combination with perfusion imaging to assess known or suspected cardiac inflammation in patients with known or suspected sarcoidosis after prolonged fasting). • Evaluation of vascular graft or cardiac implantable device related infection in selected cases provided sufficient time has elapsed since surgery. New Non-FDG PET-CT Applications Gallium-68 prostate specific membrane antigen

 Gallium-68 PSMA has rapidly emerged into routine clinical practice in mainland Europe and Australia as agent for imaging prostate cancer

 Various PSMA-based ligands have been developed Gallium-68 PSMA PET-CT

• 68Ga-PSMA PET-CT shows high detection rates in recurrent prostate cancer at low PSA values

• Superior sensitivity compared to Choline PET-CT

• 68Ga-PSMA PET-CT might replace other tracers in future clinical practice but currently is not funded in the UK

68Gallium-PSMA (Prostate Specific Membrane Antigen) is a rapidly emerging alternative tracer for assessment of prostate malignancy with superior diagnostic accuracy compared to Choline. Choline v Gallium-68 PSMA PET-CT

Afshar-Oromieh et al. EJNMMI 2014; 4: 11 Amino Acid PET-CT in brain tumours

1. Amino acid tracers have higher tumour-to-background ratio in brain tumours than FDG PET 2. A recent systematic review has confirmed FET is more accurate than FDG 2 and a number of reports suggest it is cost-effective

11C-Methionine and 18F-FET are superior at defining the extent of tumour in low and intermediate grade gliomas compared to FDG, which has limited use because of high uptake in normal brain.

Fink et al. J Nucl Med 2015; 56: 1554 Dunet et al. Neuro-Oncology 2016; 18: 426 High uptake with FET in recurrent temporal low grade glioma

Coronal Axial Sagittal Conclusions

• Evidence supporting a wide range of FDG PET-CT indications continues to expand year-on-year • Recent studies have demonstrated new applications in the assessment of therapy response in selected patients with lung, colorectal, cervical and haematological malignancies • Non-oncological uses of FDG PET-CT continue to grow • Non-FDG PET-CT indications are expanding and underpinned by a rapidly expanding literature • Revised Intercollegiate Guidelines encompassing new literature from the past 2 years provide a comprehensive list of PET-CT indications for routine clinical use Thanks for your attention