Ga68 and FDG PET have been increasingly utilised in the investigation of neuroenclocrine tumours (NETs) to aid prognostication and guide management FDG PET avidity is associated with poor prognosis, and FDG positive but Ga68 negative areas may signal the presence of high grade disease.

1. ANZNET

2. N
A retrospective study of dual
18F-fluorodeoxyglucose/
68Gallium (FDG/Ga68)
positron emission
tomography (PET) grading
and its prognostic value in
metastatic pancreatic
neuroendocrine tumours
(PNET)
David L Chan
Dale L Bailey
Geoffrey P Schembri
Elizabeth J Bernard
Nick Pavlakis
Paul J Roach
Departments of Nuclear Medicine & Medical Oncology  Royal North Shore Hospital
Faculty of Health Sciences & Sydney Medical School  University of Sydney
Sydney Vital (Northern Translational Cancer Research Centre)
Sydney  AUSTRALIA

3. COMBINED SSR & FDG PET
SCANNING IN NETs
[68Ga]-DOTA-Octreotate
(“DOTATATE”)
[18F]-FDG

4. SSR (DOTATATE) +VE IMAGING
• Reflects well-differentiated disease
• Well suited to targetting with radiolabelled
SSR therapy
• What is the significance of the degree of
uptake (e.g., SUVmax)?
• What is the reproducibility of uptake?
• Is uptake affected by competing agents?
• Role in reflecting likely rate of disease
progression?
FDG +VE IMAGING
• Reflects degree of de-differentiation / Ki67
• Often invoked when Ki67 from the primary
lesion or a biopsy exceeds a threshold (3%,
5%, 10%, 20%, etc) – based on NET Grading
(G1, G2, G3)
• High FDG uptake with low SSR uptake
indicates disease may be less amenable to
radiolabelled SSR therapy - chemo/biologics
may be more suitable
• Represents more aggressive disease & poorer
prognosis
• Pathology may not reflect varying disease
differentiation throughout the body
COMBINED SSR & FDG IMAGING

5. DOTATATEFDG
Dual DOTATATE/FDG reporting
• The two scans need to be
reported together
• In the top diagram, there is good
overlap of DOTATATE and FDG
uptake, ?G2 disease
• In the bottom one – there are
actually two NET areas. One low-
grade/indolent, one high-
grade/aggressive; Treatments
such as Lutate would treat only
the low-grade component!
DOTATATE FDG

6. The NETPET Grading Scheme - AIMS
› To grade the scans by spatial concordance and relative uptake;
› To recognise the complementary intrinsic biological signals present in each
scan;
› To summarise the results of the two scans in a single score which captures
the joint information available – especially to assist referrers;
› To see whether the grading scheme has a role in prognosis.
› To allow further data analysis in translational research;

7. NETPET Grading Scheme*
P0 P1 P2 P3 P4 P5
SSR -ve
FDG -ve
SSR +ve
FDG -ve
SSR -ve
FDG +ve
SSR +ve
FDG +ve
FDG uptake < SSR uptake
FDG uptake  SSR uptake
FDG uptake > SSR uptake
SSR +ve
FDG +ve
SSR +ve
FDG +ve
*With image display thresholds set at: SUVmax(DOTATATE) = 15
SUVmax(FDG) = 7

8. DOTA FDG
+ve? +ve?P0NO
P1
NO
YES YES
What is the most FDG>DOTA* lesion?
FDG +ve DOTA -ve
how many?
P5
2+
2+
P4b
1-2 1
P2bP2a
NETPET Grading
Flowchart – D1.1
More likely to benefit
from Lutate Rx
Less likely to benefit
from Lutate Rx
3+
FDG<DOTA
how many?
1-2
P3bP3a
3+
FDG≡DOTA
how many?
1-2
P4a
P4a
3+
FDG>DOTA
how many?
How many
FDG>DOTA
lesions?
P4b P5
0 1
* Functionally discordant
P5
FDG>DOTA
FDG+DOTA-
FDG≡DOTA
FDG<DOTA

9. METHODS
› In the period 2011-2015 we performed n=186 [68Ga]-DOTATATE and [18F]-
FDG scans on the same individuals (n=125) within 28 days;
› All scans acquired on Siemens Biograph mCT with Time-of-Flight capability
and resolution recovery software using an iterative OSEM reconstruction;
› A cohort of subjects diagnosed as having primary pancreatic NET (pNET)
were selected for pilot evaluation (n=30):
- these are the results being presented today;
› Two experienced NM physicians independently scored the DOTATATE/FDG
scan pairs, with all clinical information available, & graded them according
to the flowchart;
› After the scans were read independently the two reporters conferred to
check each other’s grading.

10. [68Ga]-DOTA-Octreotate
[18F]-FDG
P1 P2 P3 P4 P5P0
SSR -ve
FDG -ve
No residual disease
after surgery
Well 2 years out

11. DOTA FDG
+ve? +ve?P0NO
P1
NO
YES YES
What is the most FDG>DOTA* lesion?
FDG+DOTA-
how many?
P5
2+
2+
P4b
1-2 1
P2bP2a
NETPET Grading
Flowchart – D1.1
More likely to benefit
from Lutate Rx
Less likely to benefit
from Lutate Rx
3+
FDG<DOTA
how many?
1-2
P3bP3a
3+
FDG≡DOTA
how many?
1-2
P4a
P4a
3+
FDG>DOTA
how many?
How many
FDG>DOTA
lesions?
P4b P5
0 1
* Functionally discordant
P5
FDG>DOTA
FDG+DOTA-
FDG≡DOTA
FDG<DOTA
There is both FDG+ and DOTA+ disease

12. [68Ga]-DOTA-Octreotate [18F]-FDG
Alive with stable disease – 2 years
P1 P2 P3 P4 P5P0
SSR +ve
FDG -ve
[68Ga]-DOTA-Octreotate [18F]-FDG
Died 5 mo after diagnosis
SSR -ve
FDG +ve
“Well-differentiated” “Poorly-differentiated”

13. DOTA FDG
+ve? +ve?P0NO
P1
NO
YES YES
What is the most FDG>DOTA* lesion?
FDG+DOTA-
how many?
P5
2+
2+
P4b
1-2 1
P2bP2a
NETPET Grading
Flowchart – D1.1
More likely to benefit
from Lutate Rx
Less likely to benefit
from Lutate Rx
3+
FDG<DOTA
how many?
1-2
P3bP3a
3+
FDG≡DOTA
how many?
1-2
P4a
P4a
3+
FDG>DOTA
how many?
How many
FDG>DOTA
lesions?
P4b P5
0 1
* Functionally discordant
P5
FDG>DOTA
FDG+DOTA-
FDG≡DOTA
FDG<DOTA
There is both FDG+ and DOTA+ disease

14. [68Ga]-DOTA-Octreotate [18F]-FDG
P3b
P1 P2 P3 P4 P5P0
FDG uptake  SSR uptake
SSR scan +ve
FDG scan +ve
No lesions
FDG +ve
SSR -ve
“Moderately-
differentiated”
– G2
Alive – stable disease

15. [68Ga]-DOTA-Octreotate [18F]-FDG
P1 P2 P3 P4 P5P0
P4a
FDG uptake > SSR uptake
SSR scan +ve
FDG scan +ve
No lesions
FDG +ve
SSR -ve
Given lutate with
good effect
Primary
subsequently
resected

16. DOTA FDG
+ve? +ve?P0NO
P1
NO
YES YES
What is the most FDG>DOTA* lesion?
FDG+DOTA-
how many?
P5
2+
2+
P4b
1-2 1
P2bP2a
NETPET Grading
Flowchart – D1.1
More likely to benefit
from Lutate Rx
Less likely to benefit
from Lutate Rx
3+
FDG<DOTA
how many?
1-2
P3bP3a
3+
FDG≡DOTA
how many?
1-2
P4a
P4a
3+
FDG>DOTA
how many?
How many
FDG>DOTA
lesions?
P4b P5
0 1
* Functionally discordant
P5
FDG>DOTA
FDG+DOTA-
FDG≡DOTA
FDG<DOTA
There is both FDG+ and DOTA+ disease

17. [68Ga]-DOTA-Octreotate [18F]-FDG
P1 P2 P3 P4 P5P0
Died 11 months
Lesions present
FDG +ve
DOTA -ve
P5
“Poorly-differentiated”
Grade 3

18. RESULTS – pNETs ONLY
Grade Number Lutate Rx?
P0 4 0
P1 3 0
P2a 2 0
P2b 9 1
P3a 2 1
P3b 1 1
P4a 3 2
P4b 2 1
P5 4 0
TOTAL 30 6
(XW)

19. RESULTS – pNETs ONLY
n=4
n=22
n=4
Survival (months)
0 16 32 48
P=0.014 by logrank test
for trend (Bland JM & Altman DG.
The logrank test. BMJ. 2004;328:1073)

20. Grade Changing
[68Ga]-DOTA-Octreotate [18F]-FDG [68Ga]-DOTA-Octreotate [18F]-FDG
Mar 2015 - P4a Jul 2015 - P2a 2  cycles Lutate 

21. DISCUSSION
› Only small numbers to date and limited follow-up period;
› Does the grading scheme adequately reflect the burden of disease?;
› Do we know the significance of SUV (or uptake level) for SSR imaging?:
- for the present should [68Ga]-DOTATATE be graded with a binary score (Y/N)?;
› Do we need to add more information regarding the bulk of disease for the primary
lesion? Or perhaps include a TNM system?
ACKNOWLEDGEMENTS
• David Chan is a research fellow funded in part by Sydney Vital (Cancer Institute NSW)
• Nick Pavlakis & Dale Bailey are co-leaders of the “NETwork” flagship project of Sydney Vital which receives funding from Cancer Institute NSW
FDG
DOTATATE
› How to deal with intra-lesional heterogeneity;
› Does the classification scheme predict for Lutate efficacy?
› Will the classification scheme have prognostic value?
› How will the classification compare with other grading schema?
GM 1062450

22. Thank you!
Any questions?