1. Peptide Receptor Radionuclide Therapy PRRT
Sofia N. Chatziioannou, MD
Associate Professor of Nuclear Medicine
University of Athens, School of Medicine
Director of PET/CT, BRFAA

2. Lu-177 imaging
18m follow-up
177 LUTETIUM

3. Imaging ΝΕΤs Well differentiated NETs
OCTREOSCAN (111 In-DTPA, DPhe1 octreotide)
Good sensitivity for well differentiated NETs
Staging
Selection of patients for PRRT
Follow-up

4. Imaging ΝΕΤs Well differentiated NETs Poorly differentiated NETs
68 Ga-DOTA- (TOC, TATE, NOC) PET/CT
Better sensitivity and specificity than Octreoscan
Correlation of SUV to response to SUVmax PRRT
Not available in Greece yet
Poorly differentiated NETs
18 F-FDG PET/CT
Usually the octreoscan is negative when FDG PET is positive
Staging
Follow up
Response to treatment

7. Ga-68 tracers

8. Gallium-68-DOTA-TOC PET scan

9. 68Ga-DOTATATE PET/CT

16. ΘΕΡΑΠΕΥΤΙΚΕΣ ΜΕΘΟΔΟΙ NETs
Surgery
Local liver treatments: RFA, embolization, SIRT
Chemotherapy, somatostatin analogues, a-interferone, m-TOR, VEGFR inhibitors)
PRRT

17. PRRT-NCCN Guidelines Version 1.2012
Treatment with radiolabelled somatostatin analogues has been reported to result in tumor responses in patients with advanced carcinoid tumors. This approach remains investigational, and randomized trials to further evaluate the relative benefit and potential toxicities of radiopeptide therapy in advanced carcinoid are needed.

18. ESMO GUIDELINES 2012
Öberg K. et al, Annals of Oncology 23 (Supplement 7)

19. Radiopharmaceuticals
Y90- DOTA—Phe-tyr3-octreotide
Lu177-DOTA-Tyr3-Thre8-octreotide

20. Mechanism

21. Characteristics of Radionuclides
Characteristics of 111In, 90Y and 177Lu therapeutic radionuclides
used in PRRT
Radionuclide
Half life (days)
Radiation
Mean Energy (keV)
Maximum tissue penetration
111Indium (111In)
2.8 γ
171 and 245
Auger e-
3.6 and 19
10 µm
90Yttrium (90Y)
2.7 β
934
12 mm
177Lutetium (177Lu)
6.7
149
2 mm
208

22. Y90 DOTATOC For larger tumors and bigger range
Only β radiation = no imaging
By-stander effect
Renal toxicity (due to reabsortion). Administration of solution of aminoacids to decrease renal toxicity

23. 177 Lu DOTATATE Smaller tumors and smaller range
β and γ radiation = imaging
= 3 days hospital stay (?)
= need for more radiation protection measures (?)

24. Treatment Criteria Histopathological proof
Positive Octreoscan within the last 2 months
Karnofski >50%-60%
Life expectancy >6 months
No pregnancy

25. Treatment Criteria Normal renal and liver function GFR ≥ 60mL/min
Serum creatinine<1.3 mg/dl
AST/SGOT ή ALT/SGPT ≤ 2.5 x ULN
AST/SGOT ή ALT/SGPT ≤ 5 x ULN (for liver metastase)
ALP < 2 x ULN (for liver metastases)
Normal hematological profile
Ηbg > 0.9gr/dl
WBC > 2.500/dl
Absolute neutrophil count ≥ 1.5x109/L
PLT > /dl

26. Treatment Criteria Prior Surgery ≥ 2 months SSA LAR ≥ 2 months
Somatulin LA ≥ 1 month
SSA subcutaneously ≥ 12 hours
Chemo/radiation therapy ≥ 2 μήνες

27. Side Effects Immediate/Early Late Nausea Vomiting Fatigue Diarrhea
Thrombocytopenia
Anemia
Neutropenia
Renal toxicity (Y 90)
Liver toxicity
Hair loss (Lu 177)
Myelodysplastic syndrome

28. Side Effects
Bushnell et al, J Clin Oncol 2010,April 1;28(10):1652-9

29. FOLLOW UP 3-6 following treatment and every 6 months afterwards
Hematologic status
Tumor markers
Renal function
Imaging (octreoscan, CT, PET/CT)
Quality of life

30. Υ90-DOTATOC Protocol . 90Y-DOTATOC 120 mCi i.v.
Amino acid infusion
90Y-DOTATOC 120 mCi i.v.
8 weeks
90Y-DOTATOC 120mCi i.v. .

31. TREATMENT WITH 90Y-DOTATOC
STUDY
NR OF PATIENTS
M.O.S (YEARS)
CONTROL OF DISEASE
CLINICAL
RESPONSE
HEMATOLOGIC TOXICITY
(GRADE 3 OR 4)
RENAL TOXICITY
Imhof et al
(1-10cycles)
1109
(NETs)
3.8
CR O.6%
PR 34%
SD 5.2%
30%
12.8%
transient grade 3 or 4
9.2%
permanent grade 4 or 5
Cwikla et al
(2-3cycles) 60
(GEP-NETs)
2.2
23% PR
50% SD
72% 5%
persistent
grade 3 or 4
10%
grade 2 or 3
Imhof et al Journal of Clinical Oncology 2011, Jun 10;29(17):
Cwikla et al, Annals of Oncology 21: 787–794, 2010

32. RESPONSE, SURVIVAL& LONG-TERM TOXICITY
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17):

33. Imhof A, et al. JCO 2011;29:

34. TUMOR UPTAKE IN PRETREATMENT OCTREOSCAN-RESPONSE
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17): Epub 2011 May 9.

35. RENAL UPTAKE IN PRETREATMENT OCTREOSCAN-RENAL TOXICITY
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17): Epub 2011 May 9.

36. TREATMENT WITH 177Lu-DOTATATE
STUDY
NR OF PATIENTS
M.O.S
(YEARS)
CONTROL OF DISEASE
HEMATOLOGICAL TOXICITY
RENAL TOXICITY
HAIR
LOSS
Kwekkeboom et al
(4 cycles)
504
(NETs) 3
2% CR
28% PR
16% MR
35% SD
(GEP NETs)
9.5%
transient grade 3 or 4
Few and mild
62%
grade 1
temporary
Kwekkeboom et al, JNM, Vol. 26 Nr13 May

37. Combination Protocol 486 patients Mean survival 5,5 years
Villard L, et al. J Clin Oncol Apr 1;30(10):

38. TREATMENT WITH 90Y-DOTATOC+177Lu-DOTATATE
STUDY
NR OF PATIENTS
M.O.S
(YEARS)
CONTROL OF DISEASE
CLINICAL RESPONSE
HEMATOLOGICAL TOXICITY
(GRADE 3 OR 4)
RENAL TOXICITY
Villard et al
(until tumor progression or permanent toxicity)
249
(NETs)
5.5
46%
2% CR
20% PR
24% SD
29.7% 5%
transient
grade 3 or 4
11.2%
permanent grade 4 or 5
Villard L et al, J Clin Oncol Apr 1;30(10): Epub 2012 Mar 5

39. Renal toxicity in combination protocol
486 patients
Villard L, et al. J Clin Oncol Apr 1;30(10):

40. RENAL TOXICITY PRRT DECLINE IN CREATININE CLEARANCE (%/year)
MEDIAN FOLLOW UP (years)
28 pts. with metastatic NET
90Y-DOTATOC (1-5cycles)
7.3%
2.9
37 pts. with metastatic NET
177Lu-DOTATATE (3-7cycles)
3.8%
Vakelma et al, J Nucl Med 2005; 46:83S–91S

42. Pre-treatment
18m follow-up

46. Lu-177 imaging
18m follow-up
177 LUTETIUM

47. Conclusions
PRRT has demonstrated benefit in anatomical evaluation, clinical symptomatology, and survival in patients with NET tumors.
Vision: Potential in imaging and treating with the same agent (with the most uptake) for optimal results and personalized treatment.