68Ga - DOTATOC

A single site experience

RicardoMoreira I have no financial interests or Declaration of Financial relationships to disclose with regard to the Interests or Relationships subject matter of this presentation. . Brief introduction on Neuroendocrine tumors Outline . Somatostatin analogues and clinical applications: SPECT/CT and PET/CT . 68Ga-DOTA-peptide: Technical Requirements . Operational Considerations . Patient Preparation and Image acquisition . Artefacts and Pitfalls . Future Perspectives Introduction

• NETs are rare tumours arising from neuroendocrine cells • Can occur anywhere in the body Source: https://www.cancerresearchuk.org/about-cancer/neuroendocrine-tumours-nets/about • Most NET occur in the lungs, appendix, small intestine, rectum and pancreas . Increasing Incidence of NETs . UK Incidence (2013/2014) is recorded at 8 per 100,000 persons . Over 4000 new diagnosis each year

Incidence

Source: Yao et al, 2008 Why the use of SST analogues?

Somatostatin receptors (SSTRs) are present on SSTR Imaging has the cell surface of been performed Neuroendocrine for several cells, providing a decades as an unique and scan specific molecular Source: Kidd et al Gastroenterol Hepatol 2015;1:131–153 target for imaging Octreotide scan

2 appointments are necessary

Further imaging is sometimes performed at 48-72 hrs to help differentiate pathologic from physiologic bowel uptake, although SPECT/CT usually obviates further delayed acquisitions Trend towards shifting from conventional imaging to PET/CT • Synthesis of 68Ga-DOTA-peptide does not require a cyclotron on site Advantages of • PET/CT imaging has an attractive approach as it PET/CT over requires less time than Octreotide (2h, instead of Coventional the 4 plus 24h acquisition) • Higher spatial Resolution of the PET/CT providing imaging better visualization of small lesions • 68Ga-DOTA-peptides have about ten-fold higher affinity for SSTRs when compared to 111In-Octreotide PET/CT imaging . 68Ga-DOTA-peptide PET/CT is used to: . Localize primary tumours and detect sites of metastatic disease (staging) . Follow-up patients with known disease to detect residual, recurrent or progressive disease Clinical (restaging) Indications . Determine SST receptor status visually as well by using semi-quantitative parameters like SUV (patients with SST receptor-positive tumors are more likely to respond to octreotide therapy) . Select patients with metastatic disease for SST receptor therapy (with 177Lu or 90Y-DOTA-peptides) Max Half Life Emax Radionuclide % decay range Production (min) (Mev) (mm)

68Ga 68 1.89 89.1 8.9 Generator

18F 110 0.635 96.7 2.4 Cyclotron

Source: www.med.harvard.edu/jpnm/physics/isotopes/pos_range.html

68 68 Ga has a shorter half life – delay of injection may lead Ga Physical to inadequate activity 68Ga has higher energy protons with a resultant longer properties range than those of 18F. 68Ga produces less positrons per unit activity than 18F

68Ga is Generator produced Radiation Protection for Patients, Carers and Staff Due to shorter half-life and lower injected activities the radiation exposure is lower then compared when using 18F Somatostatin analogues PET Imaging: Chemical Structure

Source: Johnbreck, FUTURE ONCOLOGYVOL. 10, NO. 14 Schematic Representation of 68Ga-DOTATOC

Production Final Product

20 µg DOTA in buffer + Ge-68 and metal Free Ga-68 and heating (95°C : 5-10 min) impurities impurities

Source: Rubow S. 2014. SASNM Three main 68Ga PET tracers for discussion:

Name SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 68Ga-DOTANOC >10,000 1.9 ± 0.4 4.0 ± 5.8 260 ± 74 7.2 ± 1.6 68Ga-DOTATOC >10,000 2.5 ± 0.5 613 ± 140 >1,000 73 ± 21 68Ga-DOTATATE Somatostatin >10,000 0.2 ± 0.04 >1,000 300 ± 140 377 ± 18

analogues PET Note: The smaller the number the higher the affinity for the receptor Imaging: affinities Source: Eur J Nucl Med Mol Imaging (2007) 34:982–993 for SSTRs Somatostatin analogues for PET Imaging have high affinity for SSTR2

From an image acquisition perspective, these can be assumed to be equivalent Physiologic Distribution

Source: Hofman et al (2015); 35:500-516 Pancreatic NET in a middle-aged woman with normal findings at contrast-enhanced CT. (a) Planar 111In-octreotide image demonstrates a solitary left supraclavicular nodal How does abnormality. SPECT/CT showed 68 Ga-DOTA-peptide the same finding. (b) MIP GaTate PET/CT image perform? obtained 4 days later demonstrates extensive metastatic disease

Source: Hofman et al (2015); 35:500-516 Other modalities vs Source: J Nucl Med 2007;48:508–518 68Ga-DOTATOC

A 47-y-old female patient was referred for scanning after resection of a of the ileum. Multipe liver metastases were known (A). Aditionally, 68Ga-DOTATOC showed a small lesion in right breast (arrows) (B). This finding was initially not detected with CT or (C). Ultrasound-guided fine-needle biopsy confirmed a metastasis in soft tissue derived from the NET with 7 to 4 mm diameter (D).This tumour lesion and 3 liver metastases were consecutively surgically removed A 62-y-old male was investigated after resection of a small bowel carcinoid. 68Ga-DOTATOC PET displayed multiple small liver metastases (A). These liver lesions were negative with the other 2 modalities, CT and scintigraphy (B) including SPECT (C). Other US (D) and further modalities vs follow up controls confirmed these lesions. Diameters of metastases were in the range of 1 cm. 68Ga-DOTATOC Positive PET finding initiated treatment with 177Lu- DOTATATE

Source: Gabriel et al. J Nucl Med 2007; 48:508–518 68Ga-DOTATOC vs SPECT vs CT

84 patients, prospective study 13 suspected 36 histologically proven for staging 35 post therapy Does 68Ga PET make any difference?

. 68Ga PET changed management in 36/ 51 patients (70.6%). Patients were suitable for PRRT. . 68Ga PET can identify additional lesions when 111In-DTPA-octreotide is negative or equivocal Birmingham PET Centre

68Ga-DOTATOCScanningProtocol Before Dedicated slots for 68Ga-DOTATOC imaging scanning (Tuesdays and Thursdays) day Admin team phone the patient and book the appointment a week in advance Operational Patient is informed that a last minute Considerations cancelation may occur due to production problems

68Ga-DOTATOC order form is sent to our radiopharmacy Scanning day

Patient attends 45 min prior to injection time Questionnaire performed and IV access is gained Operational 68Ga-DOTATOC is delivered by Considerations radiopharmacy staff Phone call from radiopharmacy

Patient dose drawn up

Certificate of Release is emailed to Birmingham PET Centre scanning team

Patient is injected Sandostatin – daily Short-acting Withdraw injections 1 day prior injections (2-3 times a octreotide therapy to PET/CT scan day)

Sandostatin LAR – monthly injections

Somatuline LA – Perform the PET/CT just prior to Long-acting octreotide Injections every 7-14 the scheduled monthly dose of Patient therapy days long-acting octreotide

Preparation Somatuline Autogel – monthly injections

. Patients are not required to fast . Should our patients withdraw “cold” octreotide therapy? Patient Toilet Positioned in Release IV Line Patient do Visit the scanner Patient Placement drink 600mL water during PET start uptake Scan speed: 0.7 mm/sec Time 0 60 90 (min)

150 mAs 120 kV Drink last 300 68 CT scan Ga-Dotatoc mL water Check Injection Reconstruction (1.25MB/kg)

68Ga-DOTATOC uptake (60 min) No Technical Control Within Technical Control

Physiologic Respiratory Motion

- Pancreatic uncinate process - Mismatch of PET and CT images activity - Innacurate attenuation correction Potential Pitfalls - Splenunculi Osteoblastic and Inflammatory Scatter Correction processes - Extreme hot/cold boundaries . Production of 68Ga in cyclotrons – Higher activities produced . Development of other antagonistic peptides  target more receptors than agonists receptors improvind affinity and sensitivity Future . 18F and 64Cu- labeled somatostatin receptors have not emerged into routine practice. They have an increased potential for a better resolution than 68Ga. 64Cu (half-life: 12.7hrs)  makes late imaging possible . NETs have seen a fivefold increase in incidence in last years. . The overexpression of five different subtypes of somatostatin receptors is seen in 80–100% of NETs. . PET/CT has better sensitivity and resolution compared Take home with imaging by SPECT/CT messages . 68Ga-DOTATOC, 68Ga-DOTATATE and 68Ga-DOTANOC are the most frequently used tracers for somatostatin receptor PET/CT. . Somatostatin receptor imaging should be PET based. Ricardo Moreira and Birmingham PET Centre Thank you for Queen Elizabeth Hospital Birmingham your attention! E-mail: [email protected]