Download Choline PET/CT

Robert S. Bridwell MD MBA
Founder and CMO
Appian 360
Medical Advisor to Zevacor Pharma, Inc.
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.
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FDG
NAF
Choline/Amino Acid imaging
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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
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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
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NAF PET/CT revealed multifocal osteoblastic
metastatic disease
Not one of the lesions was noted on the CT
study
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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
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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
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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
Tc99m MDP
F-Choline
NAF
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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
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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)
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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 0.5-40.2
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
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Primary Gleason score
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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
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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
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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
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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
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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
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Relatively poor sensitivity for prostate cancer
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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
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Pros
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A better, faster bone scan
Higher diagnostic accuracy to assess osteoblastic
metastatic disease
Cons
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Cost
Cannot assess soft tissue metastatic disease
 Prostate bed recurrence
 Nodal disease
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Interpreters’ false positive rate
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20 minute half-life
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Indication for patient restaging
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Logistically and technically different patient flow
when compared to FDG/NAF
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
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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
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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 10-15 mCi
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 Depends on equipment
 Depends on PSA value and anticipation for delayed
imaging
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Fasting for at least six hours - similar to FDG
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Collect clinical history prostate cancer
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Clinical history other tumor types
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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?
Type of cancer
Any prior therapy-surgery/radiation
Contrast considerations
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Oral and iv
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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
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Blinded interpretation
Assess quantitatively which study provided
the highest sensitivity and specificity
Histologic confirmation in all positive lesions
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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
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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
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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
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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
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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
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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.
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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
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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
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C-11 choline was positive in 28.4% of patients.
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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
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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
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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
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Positive choline finding disease within normal
sized lymph nodes in the pelvis in a multifocal
pattern
Hilar nodes are inflammatory in etiology
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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
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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 Ffluoride, respectively.
No significant differences were found between
the sensitivity and specificity of C-choline or Fcholine and F-fluoride.
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Giovacchini G et al. C-11 choline PET/CT
predicts cancer specific survival in patients
with biochemical failure during androgendeprivation 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
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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
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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
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C-11 Choline PET/CT revealed multifocal
metastatic disease both within soft tissue
lymph nodes and osseous metastatic disease
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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
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12 treated with brachytherapy
34 with external beam radiation therapy
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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
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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
0.2-1.5). C-11 choline was used as the first imaging
examination at the time of PSA detection
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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
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C-11 Choline was positive in 29-102 patients
(28%). Choline detected local relapse in 7
patients, bone metastases in 13 patients and
lymph node metastases in 9 patients.
Performance
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Sensitivity 93%
Specificity 74%
PPV 60%
NPV 96%
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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
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Choline PET/CT revealed increased uptake the
prostate bed consistent with local recurrence
No distant nodal or osseous disease is noted
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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
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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
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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.
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Chondrogiannis S et al. Is the detection rate of
18-F-Choline PET/CT influenced by androgendeprivation therapy? Eur J Nucl Med Mol
Imaging July 2014
Retrospective study of 325 consecutive patients
with biochemical relapse after definitive
therapy
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Two groups
 PSA trigger between 0.1 and 80 ng/ml
 PSA trigger between .5 ng/ml and 5 ng/ml
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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
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In group B only trigger PSA was correlated
with the detection rate
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History - PSA level, PSA doubling time, Type
of initial treatment, current therapy (ADT or
not),
Acquisition
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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
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The potential impact of ADT
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Hormone naïve prostate CA
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If the ADT was just started and the PSA is dropping
it may have a negative impact on Choline sensitivity
Patient progressing through ADT
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If the patient’s PSA is rising on ADT therapy suggest
a de-differentiated prostate ca. Choline PET/CT will
show a higher sensitivity.
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Up front clinical training
Educating your market
After deployment support
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Competitive product pipeline
Blue Earth Diagnostics
 F18-Fluciclovine-Currently in Phase 3
 Synthetic amino acid
 Indication is the same as Choline
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 Restaging of prostate cancer with biochemical failure
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Accuracy
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For disease in the prostate bed
 Sensitivity 90% and specificity 40%
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For extraprostatic disease
 Sensitivity of 55% and specificity of 96.7%
 Compared to ProstaScint 25.7% of patients were upstaged
Small molecule PSMA inhibitor
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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
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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
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On a patient basis
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F-fluciclovine was superior to C-choline P>0.000001
 Lymph nodes, bone, and local relapses
 There was no significant difference in terms of target to
background between C-choline and F-Flucicclovine
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When patients were divided into groups with
different PSA
 F-fluciclovine had superior detection rate for low,
intermediate and high PSA levels.
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Szabo Z, et al., Initial Evaluation of
[18F]DCFPyL for Prostate-Specific Membrane
Antigen (PSMA)-Targeted PET Imaging of
Prostate Cancer. Mol Imaging Biol. 2015 Apr 21
9 patients with prostate cancer
Radiation dose similar to that of other PET/CT
tracers
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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 2015 17:575-584.
14 patients with biochemical relapse of prostate
cancer
Patients had both studies
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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
F-18 DCFPyl
Ga-68-PSMA-HBED-CC
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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 0.01-116.
The patients had both studies within 30 days
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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 62-78
lesions-tumor to background was higher in 7478 lesions
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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
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Amino acid molecules-F-18 labeled
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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
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Specific imaging of the PSMA found on prostate CA
More accurate than GA labelled PSMA compounds
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Ga68 labeled PSMA compounds
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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
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Distribution
Interpretive confidence
Cost
Availability
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