1. Choline PET/CT Robert S. Bridwell MD MBA Founder and CMO Appian 360
Medical Advisor to Zevacor Pharma, Inc.

2. Disclosure/Disclaimer
This presentation has been prepared and delivered at the request of Zevacor Pharma, Inc. for which the author/speaker has received an honorarium. Any opinions, findings, conclusions or recommendations expressed in this presentation are those of the author. The information is designed for educational purposes only and is not engaged in rendering medical advice or professional services.

3. Prostate cancer as a target

5. Three PET isotopes to target prostate CA
FDG
NAF
Choline/Amino Acid imaging

6. Prostate Cancer 65yo male with history of 8/10 Gleason Prostate Cancer
The patient presents one year after initial treatment with elevated ALK, bone pain and elevated PSA
Bone scan and FDG PET/CT ordered to restage the patient

8. FDG PET/CT

9. Case study 69yo male with a history of prostate cancer,
Gleason 8/10 initially treated with radiation therapy
Now presenting with rapidly elevated PSA, asymptomatic
NAF PET/CT ordered for assessment of osseous involvement

12. Impact of NAF PET/CT
NAF PET/CT revealed multifocal osteoblastic metastatic disease
Not one of the lesions was noted on the CT study

13. NAF PET/CT for Prostate Cancer
Kjolhede et al. Combined F-fluorocholine and NAF PET/CT imaging for staging of high risk prostate cancer. BJU Apr 2012
90 patients with initial staging evaluation, negative planar bone scan and PSA between 20-99ng/ml and/or Gleason score 8-10 tumors
Patients initially considered for curative therapy
Compared clinical impact of PET/CT in patients with a negative or equivocal bone scan

14. NAF PET/CT Prostate Cancer
For 50/90 patients one or both PET/CT scans indicated metastases
F-Fluorocholine PET/CT indicated lymph node and/or bone metastases in 35 (39%) of patients
NAF PET/CT was consistent with bone mets in 41% of patients
In 20% of cases NAF found diffuse metastatic disease and changed therapy from curative to non curative

16. NAF PET/CT
Of the patients with a positive scan 74% had a Gleason score 8-10
All patients with boney metastatic disease on the F choline study were detected on the NAF PET/CT

17. Tc99m MDP F-Choline NAF

18. Case study 68yo male with a history of prostate cancer
He now presents with rapid increase in PSA
The patient is asymptomatic
A CT and bone scan (NAF PET/CT), along with FDG PET/CT was ordered

19. NAF FDG

20. Impact of PET/CT
NAF PET/CT revealed multiple areas of increased osteoblastic activity consistent with widespread osseous metastatic disease
Every site of abnormal uptake is FDG negative
This illustrates that FDG PET/CT has limited impact (sensitivity) in some patients compared to bone scanning (NAF PET/CT)

21. FDG versus NAF for Prostate Cancer
Jadav et al. Prospective evaluation of NAF and FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer. Clin Nuc Med Jul 2012
37 med with PSA relapse (range ng/ml, median 3.2 ng/ml) after definitive therapy with negative conventional imaging underwent FDG and NAF imaging
Reference standard imaging and clinical follow up

22. FDG vs. NAF Primary Gleason score
Less than 7 in 7 patients
7 or higher in 27 patients
Unattainable in 3
Patients with a positive NAF PET/CT PSA range was 1.9 to 5.8 ng/ml

23. FDG vs. NAF FDG PET/CT positive in 2 patients for nodal disease
True positive detection rate for NAF imaging was 16.2%
NAF positivity tends to associated with increasing PSA level

25. Case study 65yo male with high risk prostate cancer
The patient was staged with CT and bone scan which were negative for regional or distant disease
NAF PET/CT was performed prior to definitive management to improve the sensitivity of bone scintigraphy

26. Case study

28. Impact of NAF PET/CT
NAF PET/CT revealed multifocal uptake in the axial skeleton, which was undetected on conventional bone imaging
Findings were consistent with metastatic disease
Patient management decision, therefore, was based on more accurate information

29. Case study
72yo male with a history of prostate cancer treated with definitive radiation therapy
Now the patient presents with elevated PSA and hip pain
Bone scan ordered to assess for metastatic disease

30. Case study

31. Case study

33. FDG PET/CT Relatively poor sensitivity for prostate cancer
Low metabolic rate
High false negative rate
Sensitivity dependent on the PSA doubling time and or absolute PSA
Only reimbursed for restaging by CMS
Limited clinical utilization due to poor sensitivity

34. NAF PET/CT Pros Cons A better, faster bone scan
Higher diagnostic accuracy to assess osteoblastic metastatic disease
Cons
Cost
Cannot assess soft tissue metastatic disease
Prostate bed recurrence
Nodal disease
Interpreters’ false positive rate

35. C-11Choline 20 minute half-life Indication for patient restaging
Logistically and technically different patient flow when compared to FDG/NAF
Indication for patient restaging
Biochemical failure after definitive therapy for prostate cancer
Sensitive for early PSA failure PSA< 1.5 ng/ml
There is data for staging (off label indication)
Mechanism of action parallels choline metabolism

36. Choline metabolism

37. Value of Choline PET
Different physiologic mechanism compared to FDG and NAF
Higher diagnostic accuracy to assess soft tissue than CT or MRI - finding disease within normal sized structures
Power of fusion to minimize false positives
Sensitivity may be preserved for low PSA recurrences-PSA <1.0
Already in the NCCN guidelines for restaging

38. NCCN

41. C-11 Choline Technical considerations 20 minute half-life
Early imaging of the pelvis to avoid urine excretion into the bladder
Late imaging to improve sensitivity (especially if the PSA is low)
Injection between mCi
Depends on equipment
Depends on PSA value and anticipation for delayed imaging
Fasting for at least six hours - similar to FDG

42. C-11 Choline Collect clinical history prostate cancer
Prior definitive therapy
PSA value at the time of the study
PSA values over time
What type of therapy is the patient on? ADT? When did it start?
Clinical history other tumor types
Type of cancer
Any prior therapy-surgery/radiation
Contrast considerations
Oral and iv

43. Acquisition
Massaro et al. Optimizing F-18 Choline PET/CT acquisition protocol in prostate cancer. N Am J Med Sci Sep 2012
30 patients with biochemical relapse of prostate cancer
Five scan protocols
Early dynamic
Early static scan pelvis
Early whole body scan
Delayed static scan of the pelvis
Delayed whole body scan

44. Acquisition Blinded interpretation
Assess quantitatively which study provided the highest sensitivity and specificity
Histologic confirmation in all positive lesions

45. Acquisition
One hour delayed scan provided the highest diagnostic accuracy about prostate bed, local nodal recurrences and distant metastatic disease
The early static scan provided important information regarding urine from loco regional recurrence

48. Choline PET/CT

49. Case 3
72yo male with a history of prostate cancer. He was definitively treated with external beam radiation therapy 3 years ago. The patient has had a recent rise in his PSA over the last year
12 months ago 0.5ng/ml
6 months ago 0.8 ng/ml
2 months ago 2.2 ng/ml
The patient is asymptomatic and has had negative CT of the abdomen and pelvis and bone scan

53. Impact of Choline PET/CT
PET/CT with choline revealed two areas of abnormal focal accumulation consistent with recurrent disease
Choline PET/CT improved the sensitivity of anatomical and other functional imaging modalities

54. Review article
Evangelista L et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nuc Med May 2013
53 complete articles - 19 articles met criteria for inclusion
A total of 1555 patients
Pooled sensitivity-85.6%, specificity 92.6% for all sites

55. Review article
Pooled sensitivity of 75.4% (95% CI: 66.9%-82.6%) and pooled specificity of 82% (95% CI: 68.6%-91.4%) for prostatic fossa recurrence
Pooled sensitivity of 100% (95% CI: 90.5%-100%) and pooled specificity of 81.8% (95% CI: 48.2%-97.7%) for lymph node metastases.

56. Restaging prostate cancer
Castellucci P et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients from a restaging C-11 Choline PET/CT scan before salvage radiation therapy? J Nucl Med Sep 2014
605 patients treated for cure and a biochemical relapse being considered for S-RT
PSA values were > 0.2 ng/ml and < 2.0 ng/ml
All patients classified as N0 after RP

57. Restaging Prostate Cancer
17/605 received adjuvant RT
148/605 were receiving ADT at the time of the PET/CT
PSA, PSA kinetics, Gleason score, age, time to biochemical relapse, ADT and tumor stage were correlated with positive study on C-11 Choline

58. Restaging Prostate Cancer
C-11 choline was positive in 28.4% of patients.
83/605 positive only in the pelvis
72/605-positive for distant metastatic disease
17/605 positive for both local and distant disease
At multivariate analysis, PSA, PSA doubling time (PSAdt), and ongoing ADT were significant predictors for positive scan results

59. Case Study
72yo male with prior history of prostate cancer s/p prostatectomy
The patient is now asymptomatic and presents with biochemical failure
PSA 12 months ago 0.1ng/ml
PSA 6 months ago 0.5 ng/ml
PSA now 1.0 ng/ml
Prior CT and bone scan negative for evidence of recurrence
C-11 Choline ordered to improve the sensitivity of anatomical based imaging and bone scan

65. Impact of PET/CT with Choline
Positive choline finding disease within normal sized lymph nodes in the pelvis in a multifocal pattern
Hilar nodes are inflammatory in etiology

66. Literature review
Wondergen M et al. A literature review of 18F fluoride PET/CT and 18F-choline or C-11 choline PET/CT for detection of bone metastases in patients with prostate cancer Nucl Med Commun Oct 2013
13 articles

67. On a lesion basis, we found a sensitivity and specificity of 84
On a lesion basis, we found a sensitivity and specificity of 84.0 and 97.7% for C-choline and F-choline and 88.6 and 90.7% for F-fluoride, respectively.
On a patient basis, the sensitivity and specificity were 85.2 and 96.5% for C-choline and F-choline and 86.9 and 79.9% for F-fluoride, respectively.
No significant differences were found between the sensitivity and specificity of C-choline or F-choline and F-fluoride.

68. Choline Predicts Survival
Giovacchini G et al. C-11 choline PET/CT predicts cancer specific survival in patients with biochemical failure during androgen-deprivation therapy. J Nucl Med Feb 2014
Retrospective study of 195 patients s/p RP with biochemical failure (PSA> 0.2ng/ml) on ADT.
Disease specific survival was correlated with positive or negative Choline study

69. Survival C-11 choline was positive in 57% of the patients
The median PCa specific survival was 16.4y in patients with a negative C-11 choline study
The median PCa specific survival was 11.2 years in patients with a positive C-11 choline study
Patients with disease in the nodes had a longer survival than those with skeletal metastatic disease

72. Case Study 75yo male with a history of prostate cancer
He has had a prior prostatectomy and now presents two years after surgery with an elevated PSA of 15 ng/ml
The patient is asymptomatic and has had a negative CT and bone scan
C-11 Choline PET/CT ordered to improve the sensitivity of anatomical based imaging

78. Impact of Choline PET/CT
C-11 Choline PET/CT revealed multifocal metastatic disease both within soft tissue lymph nodes and osseous metastatic disease

79. Choline for Restaging Prostate Cancer
Chondrogiannis S et al. Role of F-choline PET/CT in suspicion of relapse following definitive radiotherapy for prostate cancer. Eur J Nucl Med Mol Imaging. Sep 2013
46 patients previously treated by definitive radiotherapy presenting with biochemical failure
12 treated with brachytherapy
34 with external beam radiation therapy

80. Restaging Prostate Cancer
Overall positive detection rate was 80.4%
The detection rate increased with increasing trigger PSA
There was no statistical difference between those on ADT and those not
Detection
59% of the patient had local relapse only
22% of the patients had distant relapse only
19% showed local and distant disease

81. C-11 Choline PET/CT Performance
Castellucci P et al. Is there a role for C-11 Choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase < 1.5ng/ml. Eur J Nucl Med Mol Imaging Jan 2011;38(1):55-63
102 patients previously treated with RP and who presented during FU with a mild increase of PSA serum level <1.5ng/ml (mean 0.86 ng/ml, range ). C-11 choline was used as the first imaging examination at the time of PSA detection

82. C-11 PET/CT Performance
86 patients were not receiving any pharmaceutical intervention and 16 were under anti-androgenic therapy
Gold standard was tissue or follow up for at least 12 months or alternative imaging

83. C-11 PET/CT Performance
C-11 Choline was positive in patients (28%). Choline detected local relapse in 7 patients, bone metastases in 13 patients and lymph node metastases in 9 patients.
Performance
Sensitivity 93%
Specificity 74%
PPV 60%
NPV 96%

84. Case Study
64yo male with prostate cancer s/p definitive therapy with radioactive seed implantation. The patient has an asymptomatic biochemical failure with PSA of 2.0 ng/ml
Anatomical imaging negative for recurrent disease
C-11 Choline ordered to improve the sensitivity of CT

89. Impact of Choline PET/CT
Choline PET/CT revealed increased uptake the prostate bed consistent with local recurrence
No distant nodal or osseous disease is noted

90. Restaging of Prostate Cancer
Beheshti M et al. Impact of 18F-choline PET/CT in prostate cancer patients with biochemical relapse: influence of androgen deprivation therapy and correlation with PSA kinetics. J Nucl Med Jun 2013.
Prospective study 250 patients
Mean PSA was 46.9 ng/ml and 55 % of patients were receiving ADT
Histopathology or consensus was the gold standard

91. Restaging Prostate Cancer
F-18 choline was able to correctly detect malignant lesions in 74%
The sensitivity of the (18)F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%-91%) than in patients without ADT (59.5%; confidence interval, 50%-69%)
(18)F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively

92. Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001).
Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings.

93. ADT and Choline Imaging
Chondrogiannis S et al. Is the detection rate of 18-F-Choline PET/CT influenced by androgen-deprivation therapy? Eur J Nucl Med Mol Imaging July 2014
Retrospective study of 325 consecutive patients with biochemical relapse after definitive therapy
Two groups
PSA trigger between 0.1 and 80 ng/ml
PSA trigger between .5 ng/ml and 5 ng/ml

94. ADT and Choline imaging
Overall detection rate of Choline was 58.2%
In group A
Trigger PSA and ADT were significantly correlated with detection rate.
The detection rate was higher in patients under ADT compared to those not under ADT
In group B only trigger PSA was correlated with the detection rate

95. Choline imaging
History - PSA level, PSA doubling time, Type of initial treatment, current therapy (ADT or not),
Acquisition
Delayed imaging may improve sensitivity
Acquisition consideration given your equipment
Sensitivity tied to PSA trigger level and PSA doubling time-know what you are looking for

96. ADT The potential impact of ADT Hormone naïve prostate CA
If the ADT was just started and the PSA is dropping it may have a negative impact on Choline sensitivity
Patient progressing through ADT
If the patient’s PSA is rising on ADT therapy suggest a de-differentiated prostate ca. Choline PET/CT will show a higher sensitivity.

97. Training and support Up front clinical training Educating your market
After deployment support

98. The future Competitive product pipeline Accuracy
Blue Earth Diagnostics
F18-Fluciclovine-Currently in Phase 3
Synthetic amino acid
Indication is the same as Choline
Restaging of prostate cancer with biochemical failure
Accuracy
For disease in the prostate bed
Sensitivity 90% and specificity 40%
For extraprostatic disease
Sensitivity of 55% and specificity of 96.7%
Compared to ProstaScint 25.7% of patients were upstaged

99. [F18]DCFPyl (DCFPyl)
Small molecule PSMA inhibitor

101. Regional distribution of Fluciclovine
Sorensen et al. Regional distribution and kinetics of F-18 fluciclovine, a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nuclear Med Dec 2012
Six patients with biopsy proven prostate CA
PET/CT performed between 1-15 minutes and sequentially to 120 minutes post injection

103. Comparison
Nanni C et al., 18F-Fluciclovine PET/CT for the detection of prostate cancer relapse: A comparison to C-11-Choline PET/CT. Clin Nucl Med Aug 2015
50 patients previously treated for prostate cancer and presenting with biochemical failure
All patients were off of hormonal therapy
Both Choline and Fluciclovine obtained within a week

104. On a patient basis
F-fluciclovine was superior to C-choline P>
Lymph nodes, bone, and local relapses
There was no significant difference in terms of target to background between C-choline and F-Flucicclovine
When patients were divided into groups with different PSA
F-fluciclovine had superior detection rate for low, intermediate and high PSA levels.

105. First clinical study
Szabo Z, et al., Initial Evaluation of [18F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol Imaging Biol Apr 21
9 patients with prostate cancer
Radiation dose similar to that of other PET/CT tracers

108. Comparison PSMA imaging
Dietlein et al. Comparison of F-18 DCFPyl and Ga68-PSMA-HBED-CC for PSMA PET imaging in patients with relapsed prostate cancer. Mol Imaging Biol :
14 patients with biochemical relapse of prostate cancer
Patients had both studies

109. Comparison
All suspicious lesions identified by the galliun tracer were also detected by FDCFPyl.
In three patients F18-DCFPyl detected additional lesions
The SUVmax was higher with the F-18 DCFPyl tracer
Higher target to background was also noted

110. F-18 DCFPyl Ga-68-PSMA-HBED-CC

112. Choline versus PSMA
Afshar-Oromieh et al. Comparison of PET imaging with Ga68-labelled PSMA ligand and F-18 choline based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2013
37 patients with biochemical relapse of prostate cancer. Mean PSA 11.1 range of
The patients had both studies within 30 days

113. Choline versus PSMA
78 lesions characteristic for prostate cancer were detected in 32 patients with Ga68 PSMA imaging
56 lesions in 26 patients were detected with choline imaging
Higher detection rate of PSMA was statistically significant p=0.04
GA68 PSMA uptake was >10% higher in lesions-tumor to background was higher in lesions

114. Conclusion Choline PET/CT Well researched
First PET/CT agent approved to assess for soft tissue metastatic disease in restaging prostate CA
Already in NCCN guidelines
Competitive to NAF market for restaging prostate CA
Non specific for prostate CA
Challenge will be 20 minute half-life
There is a learning curve for interpretation

115. Competitive pipeline Amino acid molecules-F-18 labeled
FABC - will be here first
PETNet
In limited studies appears more accurate than choline
F-18 distribution and workflow
Not specific for prostate CA
F-labelled PSMA PET/CT molecules
Specific imaging of the PSMA found on prostate CA
More accurate than GA labelled PSMA compounds

116. Competitive products Ga68 labeled PSMA compounds Specific imaging
Long half-life/wide distribution
Maybe less accurate than F-labeled PSMA product in limited comparison studies
PSMA more accurate than Choline in comparable studies

117. Utilization
Distribution
Interpretive confidence
Cost
Availability

118. Questions? This activity is approved for credit by the ASRT
American Society of Radiologic Technologists
Technologists are eligible for 1.0 hr CE credit
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