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
Lu-177 imaging 18m follow-up
177 LUTETIUM
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
Imaging ΝΕΤs
• Well 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
Ga-68 tracers
Gallium-68-DOTA-TOC PET scan
68Ga-DOTATATE PET/CT
ΘΕΡΑΠΕΥΤΙΚΕΣ ΜΕΘΟΔΟΙ NETs
• Surgery
• Local liver treatments: RFA, embolization, SIRT
• Chemotherapy, somatostatin analogues, a-interferone,
m-TOR, VEGFR inhibitors)
• PRRT
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.
ESMO GUIDELINES 2012
Öberg K. et al, Annals of Oncology 23 (Supplement 7)
Radiopharmaceuticals
Y90- DOTA—Phe-tyr3-
octreotide
Lu177-DOTA-Tyr3-Thre8-
octreotide
Mechanism
Characteristics of Radionuclides
Characteristics of 111In, 90Y and 177Lu therapeutic radionuclides
used in PRRT
Radionuclide Half life Radiation Mean Energy Maximum tissue
(days) (keV) penetration
111
Indium (111In) 2.8 γ 171 and 245
Auger e- 3.6 and 19 10 µm
90
Yttrium (90Y) 2.7 β 934 12 mm
177
Lutetium (177Lu) 6.7 β 149 2 mm
γ 208
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
177 Lu DOTATATE
Smaller tumors and smaller range
β and γ radiation = imaging
= 3 days hospital stay (?)
= need for more radiation protection
measures (?)
Treatment Criteria
• Histopathological proof
• Positive Octreoscan within the last 2 months
• Karnofski >50%-60%
• Life expectancy >6 months
• No pregnancy
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 > 100.000/dl
Treatment Criteria
• Prior Surgery ≥ 2 months
• SSA LAR ≥ 2 months
• Somatulin LA ≥ 1 month
• SSA subcutaneously ≥ 12 hours
• Chemo/radiation therapy ≥ 2 μήνες
Side Effects
Immediate/Early Late
• Nausea •Renal toxicity (Y 90)
• Vomiting •Liver toxicity
• Fatigue •Hair loss (Lu 177)
•Myelodysplastic syndrome
• Diarrhea
• Thrombocytopenia
• Anemia
• Neutropenia
Side Effects
Bushnell et al, J Clin Oncol 2010,April 1;28(10):1652-9
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
Υ90-DOTATOC Protocol
Amino acid infusion Amino acid infusion Amino acid infusion
8 weeks 8 weeks
90
Y-DOTATOC 120 mCi i.v. 90
Y-DOTATOC 120 mCi i.v. 90
. 120mCi i.v.
Y-DOTATOC
TREATMENT WITH 90Y-DOTATOC
STUDY NR OF M.O.S CONTROL OF CLINICAL HEMATOLOGIC RENAL
PATIENTS (YEARS) DISEASE RESPONSE TOXICITY TOXICITY
(GRADE 3 OR 4)
Imhof et 1109 3.8 CR O.6% 30% 12.8% 9.2%
al (NETs) PR 34% transient permanent
(1-10cycles) SD 5.2% grade 3 or 4 grade 4 or
5
Cwikla et 60 2.2 23% PR 72% 5% 10%
al (GEP- 50% SD persistent grade 2 or
(2-3cycles) NETs) grade 3 or 4 3
Imhof et al Journal of Clinical Oncology 2011, Jun 10;29(17):2416-23.
Cwikla et al, Annals of Oncology 21: 787–794, 2010
RESPONSE, SURVIVAL& LONG-TERM TOXICITY
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17):2416-23
Imhof A, et al. JCO 2011;29:2016-23
TUMOR UPTAKE IN PRETREATMENT
OCTREOSCAN-RESPONSE
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17):2416-23. Epub 2011 May 9.
RENAL UPTAKE IN PRETREATMENT
OCTREOSCAN-RENAL TOXICITY
Imhof et al, Journal of Clinical Oncology 2011, Jun 10;29(17):2416-23. Epub 2011 May 9.
TREATMENT WITH 177Lu-DOTATATE
STUDY NR OF M.O.S CONTROL OF HEMATOLOGICAL RENAL HAIR
PATIENT (YEARS DISEASE TOXICITY TOXICITY LOSS
S )
Kwekkeboom 504 3 2% CR 9.5% Few and 62%
et al (NETs) 28% PR transient grade 3 mild grade 1
16% MR or 4 temporary
(4 cycles) 35% SD
(GEP NETs) (NETs) (NETs)
Kwekkeboom et al, JNM, Vol. 26 Nr13 May 1 2008
Combination Protocol
• 486 patients
• Mean survival 5,5 years
Villard L, et al. J Clin Oncol. 2012 Apr 1;30(10):1100-6.
TREATMENT WITH 90Y-DOTATOC+177Lu-
DOTATATE
STUDY NR OF M.O.S CONTROL OF CLINICAL HEMATOLOGICAL RENAL
PATIENTS (YEARS) DISEASE RESPONSE TOXICITY TOXICITY
(GRADE 3 OR 4)
Villard 249 5.5 46% 29.7% 5% 11.2%
et al (NETs) 2% CR transient permanent
(until tumor
progression or
20% PR grade 3 or 4 grade 4 or
permanent 24% SD 5
toxicity)
Villard L et al, J Clin Oncol. 2012 Apr 1;30(10):1100-6. Epub 2012 Mar 5
Renal toxicity in combination protocol
486 patients
Villard L, et al. J Clin Oncol. 2012 Apr 1;30(10):1100-6.
RENAL TOXICITY
PRRT DECLINE IN MEDIAN FOLLOW UP
CREATININE (years)
CLEARANCE (%/year)
28 pts. with 90Y-DOTATOC (1- 7.3% 2.9
metastatic NET 5cycles)
37 pts. with 177Lu-DOTATATE (3- 3.8% 2.9
metastatic NET 7cycles)
Vakelma et al, J Nucl Med 2005; 46:83S–91S
Pre-treatment 18m follow-up
Lu-177 imaging 18m follow-up
177 LUTETIUM
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.
