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 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

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 (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

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 Vomiting Fatigue Diarrhea Thrombocytopenia Anemia Neutropenia Renal toxicity (Y 90) Liver toxicity Hair loss (Lu 177) Myelodysplastic syndrome

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

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):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 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 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 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. 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 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

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.