JOURNAL TRANSCRIPT

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FLUCICLOVINE: 1ST FDA APPROVED F-18 PET IMAGING AGENT FOR RECURRENT PROSTATE CANCER KEVIN P BANKS, MD SAN ANTONIO MILITARY MEDICAL CENTER ASSISTANT PROFESSOR OF RADIOLOGY, USU

I HAVE NO FINANCIAL DISCLOSURES.

GOALS AND OBJECTIVES 1. Review characteristics and clinical pharmacology of Fluciclovine F-18. 2. Discuss role of Fluciclovine F-18 in management of prostate cancer and research supporting its efficacy. 3. Contrast administration & image acquisition of Fluciclovine F-18 to commonly utilized FDG. 4. Review interpretation criteria for Fluciclovine F-18 images in setting of suspected recurrent prostate cancer.

Anti-1-Amino-3-18F-Fluorocyclobutane-1-Carboxylic Acid (FACBC) v L-Leucine Amino Acid Analogue

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LEUCINE: essential amino acid for protein synthesis and cell growth Taken up via LAT & ASCT systems LAT & ASCT systems up regulated in many carcinomas – LAT1 and ASCT2 associated with more aggressive disease FACBC does not undergo metabolism Uptake in prostate-specific membrane antigen (PSMA) expressing and nonexpressing tumor cells

PERFORMANCE OF F-18 FACBC •

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Efficacy initially evaluated by Emory University 105 F18-FACBC PET/CT scans compared to histopathology Interpreted by 3 blinded independent readers Detection rate 60% PSA 1.78 blood pool. èFocal median lobe uptake has high likelihood of FP. • Diffuse uptake >> bone marrow is moderately suspicious for recurrence Manufacturer recommends review of PET only coronal images to aid interpretation.

PATHOLOGIC UPTAKE PROSTATE BED, PROSTATECTOMY 66 YO S/P PROSTATECOMY WITH BCR

▸ FOCAL UPTAKE ▸ ≥ 1 CM IN SIZE ▸ VISUALLY ≥ BONE MARROW ✓ SUSPICIOUS FOR CANCER RECURRENCE

PATHOLOGIC UPTAKE NON-PROSTATECTOMY 62 YO S/P XRT WITH BIOCHEMICAL RECURRENCE (BCR)

▸ FOCAL ASYMMETRIC UPTAKE ▸ ≥ 1 CM IN SIZE ▸ VISUALLY ≥ BONE MARROW ✓ SUSPICIOUS FOR CANCER RECURRENCE

DIFFUSE UPTAKE NON-PROSTATECTOMY 66 YO S/P XRT WITH BCR

▸ DIFFUSE UPTAKE ▸ VISUALLY >> BONE MARROW ✓ SUSPICIOUS FOR CANCER RECURRENCE

HETEROGENOUS OR MULTIFOCAL UPTAKE 58 YO S/P XRT WITH BCR

NON-PROSTATECTOMY

▸ HETEROGENOUS UPTAKE ▸ VISUALLY ≥ BONE MARROW ✓ SUSPICIOUS FOR CANCER RECURRENCE

18F-FLUCICLOVINE PET-CT FOR PRIMARY PROSTATE CANCER? Schuster, AJNMMI 2013

Turkbey, Radiology 2014

• Correlated uptake of anti-3-[18F] • Compared FACBC PET to MRI and FACBC with histology of prostatectomy Histology specimens • 21 patients with tumors > 0.5 cm • 10 patients • Average SUVmax tumor 4.5 +/- 0.6 • Average SUVmax tumor 4.0 +/- 1.3 • 2.8 +/- 0.5 normal prostate • BUT nonmalignant 3.4 +/- 0.9 • BUT 4.3 +/- 0.7 BPH

à SIGNIFICANT OVERLAP OF AVIDITY FOR PCa VS NONMALIGNANT TISSUE

T2-weighted MR Sensitivity 73% Specificity 79% PPV 66% NPV 87%

à NO DIFFERENCE PCa VS BPH

ADC maps of DW MR Sensitivity 73% Specificity 80% PPV 68% NPV 87%

18F FACBC PET/CT

Sensitivity 67% Specificity 66% PPV 50% NPV 78%

INTERPRETATION CRITERIA LYMPH NODES Avidity of pathologic FACBC uptake assessed visually Sites Typical for Prostate Cancer Recurrence • Avidity ≥ bone marrow considered suspicious. o BUT if node is small (> than blood pool Atypical Sites (inguinal, distal external iliac, hilar, and axillary nodes) • Mild, symmetric uptake is typically physiologic o BUT if uptake present in context of other clear malignant disease, it may be considered suspicious for cancer recurrence.

SUSPICIOUS NODAL UPTAKE ASYMMETRIC LYMPH NODE AVIDITY 69 YO WITH HISTORY OF PROSTATE CANCER

▸ NODES TYPICAL FOR PROSTATE CANCER SPREAD ▸ ≥ 1 CM IN SIZE ▸ VISUALLY ≥ BONE MARROW ✓ SUSPICIOUS FOR CANCER RECURRENCE

BENIGN NODAL UPTAKE MILD LYMPH NODE AVIDITY ▸ NODES TYPICAL FOR PROSTATE CANCER SPREAD ▸ >= 1 CM IN SIZE ▸ VISUALLY < BONE MARROW ✘ NOT SUSPICIOUS FOR CANCER RECURRENCE

IF < 1 CM IN SIZE ▸ NODES TYPICAL FOR PROSTATE CANCER SPREAD ▸ VISUALLY NOT >> BLOOD POOL & NOT APPROACHING BONE MARROW ✘ SUSPICIOUS FOR CANCER RECURRENCE

BENIGN NODAL UPTAKE ATYPICAL SYMMETRIC LYMPH NODE AVIDITY

▸ ATYPICAL LN SITES FOR RECURRENCE INGUINAL DISTAL EXTERNAL ILIAC HILAR AXILLARY ▸ MILD TO MODERATE SYMMETRIC UPTAKE ✘ NOT SUSPICIOUS FOR CANCER RECURRENCE

MODERATE PHYSIOLOGIC FACBC ACTIVITY IN BLADDER IS ATYPICAL. OCCURS IN 10-15% OF PATIENTS. MAY THEORETICALLY BE REDUCED BY NOT HAVING PATIENT VOID WITHIN 30 MIN BEFORE ADMINISTERING RADIOTRACER.

SUSPICIOUS NODAL UPTAKE ISOLATED ASYMMETRIC LYMPH NODE AVIDITY 65 YO WITH PRIOR PROSTATECTOMY AND BCR

▸ ATYPICAL NODAL SITE FOR RECURRENCE: DISTAL EXTERNAL ILIAC ▸ ASYMMETRIC UPTAKE (INTENSITY DEPENDENT UPON SIZE) ▸ CAUSES OF FALSE POSITIVITY EXCLUDED: RECENT PROCEDURE OR IPSILATERAL HARDWARE/GRAFTS ✓ MODERATLEY SUSPICIOUS FOR CANCER RECURRENCE

INTERPRETATION CRITERIA BONE Focal uptake CLEARLY visualized on Maximum Intensity Projection (MIP) or PET-only images, can be considered suspicious for cancer. o Lytic metastases typically show intense FACBC avidity o Mixed bony lesions most commonly show moderate uptake o Dense sclerotic abnormality on CT without uptake does not exclude metastasis F Alternative imaging should be considered

BONE UPTAKE SUSPICIOUS LESIONS 73 YO S/P PROSTATECOMY WITH BCR

▸ FOCAL UPTAKE CLEARLY VISUALIZED ON MIP OR PET-ONLY IMAGES SUSPICIOUS ▸ LYTIC LESIONS MOST INTENSE ▸ MIXED LESIONS MODERATELY INTENSE ▸ DENSE SCLEROTIC METS MAY BE FALSELY NEGATIVE

INDETERMINATE SCLEROTIC BONE LESION 58 YO S/P PROSTATECOMY WITH BCR • 9 MM SCLEROTIC LESION IN RIGHT FEMUR • REMAINDER OF EXAM NEGATIVE

INDETERMINATE SCLEROTIC BONE LESION ▸ FOCAL UPTAKE CLEARLY VISUALIZED ON MIP OR PET-ONLY IMAGES SUSPICIOUS ▸ LYTIC LESIONS MOST INTENSE ▸ MIXED LESIONS MODERATELY INTENSE ▸ DENSE SCLEROTIC METS MAY BE FALSELY NEGATIVE

INDETERMINATE SCLEROTIC BONE LESION ▸ DENSE SCLEROTIC ABNORMALITY ON CT WITHOUT UPTAKE DOES NOT EXCLUDE METASTASIS F ALTERNATIVE IMAGING SHOULD BE CONSIDERED

ADDITIONAL FOCI OF NAF AVIDITY SEEN ON MIP CORRESPONDED TO BENIGN DEGENERATIVE ACTIVITY.

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES POTENTIAL SOURCES OF FALSE POSITIVES

18F-FACBC has elevated uptake in numerous malignancies: • Breast cancer • Lung carcinoma • Malignant and premalignant colonic neoplasia • Squamous cell carcinoma of scalp • Follicular lymphoma • Multiple myeloma • Primary and metastatic brain tumors 18F-FACBC also shows elevated uptake in benign tumors: • Pituitary adenoma, meningioma, osteoid osteoma, and adrenal adenoma have been described. Schuster, JNM, 2014

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES POTENTIAL SOURCES OF FALSE POSITIVES 18F-FACBC also shows elevated uptake in inflammation: • Mild to moderate linear esophageal uptake in >50% of patients • Other acute and chronic inflammation and infection: • Hilar, axillary, and inguinal lymph nodes • Inflammatory skin lesions, ringworm infection, and muscle inflammation • Mild uptake in degenerative facet disease à intensity generally < than 18F-FDG.

Schuster, JNM, 2014

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES XRT CHANGES TO MARROW UPTAKE OF FACBC 59 YO S/P XRT FOR CAP WITH BCR

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES BENIGN INCREASED MUSCLE UPTAKE OF FACBC SECONDARY TO EXERCISE 59 YO S/P PROSTATECTOMY FOR CAP WITH BCR ▸ MILD DIFFUSE HOMOGENEOUS MUSCLE UPTAKE IS NORMAL & INCREASES WITH TIME AFTER INJECTION ▸ MODERATE TO INTENSE UPTAKE IS OFTEN SEEN IN SOFT TISSUE INFLAMMATION

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES FACBC UPTAKE SECONDARY TO SOFT TISSUE INFLAMMATION RELATED TO INSULIN INJECTIONS 55 YO S/P PROSTATECTOMY FOR CAP WITH BCR ▸ MODERATE TO INTENSE UPTAKE IS OFTEN SEEN IN SOFT TISSUE INFLAMMATION

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES FACBC UPTAKE SECONDARY TO PNEUMONIA 62 YO S/P PROSTATECTOMY FOR CAP WITH BCR MODERATE TO INTENSE UPTAKE IS OFTEN SEEN IN INFLAMMATION

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES BENIGN INCREASED UPTAKE OF FACBC RELATED TO ADRENAL ADENOMA 62 YO S/P PROSTATECTOMY FOR CAP WITH BCR • 18F-FACBC PET SHOWS SMALL FOCUS OF MILD INCREASED RADIOTRACER JUST POSTERIOR TO LIVER (ARROWHEAD). • AXIAL CT IMAGE SHOWS AVIDITY LOCALIZES TO ADRENAL NODULE WITH ATTENUATION AND LONG TERM STABILITY CONSISTENT WITH BENIGN ADENOMA • CONTRALATERAL NORMAL ADRENAL WITHOUT UPTAKE

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES INTENSE FACBC UPTAKE SECONDARY TO BENIGN BONE LESION 69 YO WITH PRIMARY CAP ▸ FOCAL UPTAKE CLEARLY VISUALIZED ON MIP OR PETONLY IMAGES SUSPICIOUS w CT IMAGE SHOWS AVIDITY LOCALIZES TO SUBCHONDRAL GLENOID LESION

INCIDENTAL FOCUS OF UPTAKE ON AXIAL FUSED IMAGE (ARROWHEAD) RELATED TO ROTATOR CUFF INJURY RELATED INFLAMMATORY FACBC AVIDITY.

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES INTENSE FACBC UPTAKE SECONDARY TO BENIGN BONE LESION w MDP BONE SCAN SHOWS OSTEOBLASTIC ACTIVITY AT SITE OF LESION IN ADDITION TO OTHER AREAS OF DEGENERATIVE UPTAKE w NO FEATURES OF BONY METASTASES ▸ MILD FOCAL UPTAKE MAY BE SEEN IN DEGENERATIVE DISEASE, BUT USUALLY NOT TO SAME DEGREE AS WITH FDG.

NORMAL VARIANTS, ARTIFACTS, AND NONMALIGNANT PROCESSES BENIGN FOCAL AVIDITY FROM NORMAL PITUITARY GLAND UPTAKE 59 YO S/P XRT FOR CAP WITH BCR ▸ MODERATE PITUITARY GLAND UPTAKE IS PART OF THE NORMAL FACBC BIODISTRIBUTION

FUTURE DIRECTIONS STAGING PRIMARY DZ 59 YO S/P WITH HIGH GRADE PROSTATE CANCER ON MULTIPLE BIOPSY SPECIMENS

CONCLUSION vIn May of 2016, Fluciclovine F-18 was first FDA approved F-18 PET imaging agent for use in patients with suspected recurrent prostate cancer. vShows better accuracy than C-11 choline and In-111 Prostascint, only other radiotracers currently FDA approved for imaging recurrent prostate cancer vDetection rate increases with increasing PSA vFamiliarization with novel imaging protocol and proper interpretation criteria key to success

REFERENCES • • • • •

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Miller M. Axumin Fluciclovine F18 Injection Image Acquisition Training. Blue Earth Diagnostics Inc. July 2016. Axumin (fluciclovine F18) Imaging & Interpretation Manual. Blue Earth Diagnostics Inc. Version 1.0; July 2016. Furlong L. NDA 208054 Axumin/fluciclovine F18. Application Number: 208054Orig1s000. Center for Drug Evaluation and Research. May 25, 2016. Schuster DM, Nanni C, Fanti S, et al. Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid: Physiologic uptake patterns, incidental findings, and variants that may simulate disease. JNM 2014;55:1986-92. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)Incapromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014 May;191(5):1446-53 Nanni C, Schiavina R, Boschi S, et al. Comparison of 18F-FACBC and 11C-choline PET/CT in patients with radically treated prostate cancer and biochemical relapse: preliminary results. Eur J Nucl Med Mol Imaging 2013;40:S11-7. Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F FACBC PET/CT: Comparison with MR imaging and histopathologic analysis. Radiology 2013;270(3):849-856. Schuster DM, Taleghani PA, Nieh PT, et al. Characterization of primary prostate carcinoma by anti-1-amino-2-[(18)f]-fluorcyclobutane1-carboxylic acid (anti-3-[(18)F] FACBC) uptake. Am J Nucl Med Mol Imaging 2013;3(1):85-96. Akin-Akintayo OO, Jani AB, Odewole O, et al. Change in salvage radiotherapy management based on guidance with FACBC (Fluciclovine) PET/CT in postprostatectomy recurrent prostate cancer. Clin Nucl Med 2016;00(00):1-7. Schreibmann E, Schuster DM, Rossi PJ, et al. Image guided planning for prostate carcinomas with incorporation of anti-3-[18F]FACBC (Fluciclovine) positron emission tomography: Workflow and initial findings from a randomized trial. Int J Radiation Oncol Biol Phys 2016;96(1):206-13. Jadvar H. Positron emission tomography in imaging evaluation of staging, restaging, treatment response, and prognosis in prostate cancer. Abdom Radiol 2016;41:889-898. Vargas HA, Wassberg C, Fox JJ, et al. Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology. 2014 Apr;271(1):220-9 Sah B-R, Burger IA, Schibli R, et al. Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer. J Nucl Med. 2015;56:372–378

CONTACT

Dr. Kevin P Banks Department of Radiology and Nuclear Medicine San Antonio Military Medical Center Assistant Professor, Uniformed Services University [email protected]