PRRT in Management of NETs Ioannis Karfis, MD PhD Assistant Head of Clinic Nuclear Medicine Dept IJB, Brussels
THERAPEUTIC TARGETS in NENs Pavel M: Neuroendocrinology 2013;97:99-112
THERAPEUTIC ARENA in NENs locoregional treatments (surgery/rfa/tace/tare) GRADE 1 SSAs INF α-2b sunitinib (pnets) everolimus GRADE 2 SSAs Chemo (STZ / 5FU / TMZ / CAP) INF α-2b sunitinib (pnets) everolimus GRADE 3 Chemo (cisplatin/etoposi de, temozolamide/ca pecitabine, topotecan, CAF) 177 Lu- / 90 Y- PRRT
KEY ROLE OF NM IN MGMT OF NETs MOLECULAR IMAGING / DIAGNOSIS 68 Gallium-DOTA-peptide (β+) [ 68 Ga-DOTA-OCTREOTATE] Receptor imaging Staging/Sélection of patients (cold and hot SSAs) Quantification PEPTIDE RECEPTOR RADIONUCLIDE THERAPY 177 Lutetium-DOTA-peptide (β-, γ) [ 177 Lu-DOTA-OCTREOTATE] Therapy Dosimetry AGONIST CHELATOR PEPTIDE SS receptor
THERANOSTIC TWINS 68 Ga-DOTATATE PET MIP 177 Lu-DOTATATE SPECT MIP WE SEE WHAT WE TREAT & WE TREAT WHAT WE SEE...
HISTORICAL BACKGROUND PRRT isotopes: t 1/2 phys emissions energy particule tissue penetration max 111 In 2,8d γ Auger e - IC e - 0,5-25KeV 218-245KeV 0,02-10μm 200-550μm 90 Y 2,7d β 2,2MeV 12mm 177 Lu 6,7d γ β 497KeV 2mm 177 Lu: third generation radionuclide β-emission >>>>> therapy / reduced radiation dose to OaRs γ-radiation >>>>> imaging / quantification / dosimetry Kwekkeboom DJ et al, Endocr-Rel Cancer 2010;17(1):R53-73
PRRT PRINCIPLE 111 In 90 Y 177 Lu Octr Octr Octr internalization
Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines). EJNMMI 2013
PRRT INDICATIONS The ideal candidates are those with well-differentiated NET G1/G2 (metastatic or inoperable NET with positive expression of sstr2) patients with gastroenteropancreatic/bronchial NETs, but also patients with phaeochromocytoma, paraganglioma, neuroblastoma or medullary thyroid carcinoma. Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines). EJNMMI 2013
ABSOLUTE: PRRT CONTRAINDICATIONS Pregnancy Acute/Severe concomitant disease Acute psychiatric disease RELATIVE: Lactation Compromised renal fonction [<60% NV adjusted for age] Compromised bone marrow fonction [WBC: <3,000/μL with neutros<1,000/μl] PLT: <75,000/μL RBC: <3,000,000/μL] Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines. EJNMMI 2013)
Tx MODALITIES ( 177 Lu-PRRT) One injection iv every 6-12 weeks Administered activity: 5.5-7.4GBq (150-200mCi)/cycle Number of cycles: 3-5 0 1 2 3 4 5 6h AE AA 177 Lu START AA END AA Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines). EJNMMI 2013
HOSPITALISATION Hospitalised in dedicated rooms / isolation Duration according national regulations Urine/faeces should be disposed to according national regulations Hydration/Urination as much as possible during the process
POST-Tx RECOMMENDATIONS Released if radiation rate <20µSv/h @1m Oral/Written practical radioprotection instructions Release Card to carry for up to 10x t 1/2 biol Avoid close contacts (<1m) for up to 2 weeks 3 weeks if children <10y/pregnant women Hydration as much as possible
EFFICACY: OR(CR+PR) Valkema et al, 2002 (Rotterdam) Anthony et al, 2002 (New Orleans) Limouris et al, 2008 (Athens) Delpassand et al, 2012 (Houston) Waldherr et al, 2002 (Basel) Bodei et al, 2004 (Milan) Valkema et al, 2006 -multicentric- Imhof et al, 2010 (Basel) Cwikla et al, 2010 (Warsaw) Pfeifer et al, 2011 (Copengahen) Kweekeboom et al, 2008 (Rotterdam) Sward et al, 2010 (Gothenberg) Garkavij et al, 2010 (Lund) Bodei et al, 2011 (Milan) Ezziddin et al, 2014 (Bonn) 111 In-DTPAOC 90 Y-DOTATOC 177 Lu-DOTATATE 0 5 10 15 20 25 30 35 %
EFFICACY: PFS/OS Trial Therapeutic Agent pts PFS (m) OS (m) Valkema et al, 2002 111 In-DTPA-OC 32-12 Delpassand et al, 2012 111 In-DTPA-OC 40-22 Valkema et al, 2006 90 Y-DOTA-TOC 58 29 37 Bushnell et al, 2010 90 Y-DOTA-TOC 90 16 27 Cwikla et al, 2010 90 Y-DOTA-TOC 58 17 22 Pfeifer et al, 2011 90 Y-DOTA-TOC 53 29 - Kwekkeboom et al, 2008 177 Lu-DOTATATE 310 33 46 Bodei et al, 2011 177 Lu-DOTATATE 42-36 Ezziddin et al, 2014 177 Lu-DOTATATE 74 26 55 Kouvaraki et al, 2004 STZ+5-FU+DOXORUBICIN 84 39 18/37 Kulke et al, 2009 TMZ 53 34 14/35 Chan et al, 2013 TMZ+BEVACIZUMAB 15 33 14/42 Chan et al, 2013 TMZ+EVEROLIMUS 43 40 15/- Yao et al, 2011 EVEROLIMUS 207 5 11/- Raymond et al, 2011 SUNITINIB 86 9 11/-
NETTER-1 multicentric (41 centers/8 countries), prospective, randomized, phase III sponsor: Advanced Accelerator Applications (Lutathera ) unresectable progressive SSTR+ midgut NETs Sandostatine LAR 60mg vs 177 Lu-DOTATATE c.a. 229 patients were randomized on the 2 arms study start date: 11/2012, estimated study completion 12/2019 Strosberg J et al.: NEJM 2017;376:125-35
NETTER-1: DESIGN RECIST 1.1 assessments every 12±1w from the first treatment date until EOS
NETTER-1: EFFICACY - PFS/OS (n: 229) 177 Lu-DOTATATE Median PFS: NR Octreotide LAR 60 mg Median PFS: 8.4 m mpfs has not been reached in the 177 Lu-DOTATATE arm trial has not yet reached the point at which the mos can be calculated interim analysis results suggest a longer mos on the PRRT arm Strosberg J et al.: NEJM 2017;376:125-35
NETTER-1: EFFICACY - OR (n: 229) PRRT (n=101) SSA (n=100) Complete Response (n) 1 0 Partial Response (n) 18 3 Objective Response (n, %) 19% 3% Progressive Disease (n, %) 5 (4%) 27 (24%) Stable Disease (n, %) 77 (66%) 70 (62%) Strosberg J et al.: NEJM 2017;376:125-35
DOSE DEPENDENT TOXICITY? ACUTE >nausea, vomiting >fatigue (first 10d post-injection) >abdominal pain/disconfort >carcinoid crisis, <1% (6/479 pts) SUBACUTE/CHRONIC > G3/G4 hematological: <11% (BM: critical organ, nadir: 6-8w PI) > G1 alopecia: 65% CHRONIC > G4 renal: <3.5% (kidneys: critical organ) de Keizer B et al.: EJNMMI 2008;35:749-55, Bodei L et al.: Sem NM 2016;46:225-238 Sabet A et al.: Nuclearmedizin 2014;53:54-59, Kwekkeboom DJ et al.: JCO 2008;26:2124-30
DOSE INDEPENDENT TOXICITY? MDS/AL > rare: MDS (3%) / AL (1.1%) > median interval btw last PRRT - MDS: 3.7y > stochastic event: unidentified individual susceptibilities > no correlation with administered activities > consequence of mutational events induced by sequentional cytotoxic therapies: prenious alkylating chemotherapy >NETTER1: 1pt in the PRRT arm/229pts >Kwekkeboom D et al: n: 504 MDS/ALL: 3 Sabet A et al: n: 203 MDS/ALL: 3 Bodei L et al: n: 807 MDS/ALL: 8 Strosberg J et al.: NEJM 2017;376:125-35, Bodei L et al.: EJNMMI 2015;42:5-19 Sabet A et al.: JNM 2013;54:1857-61, Kwekkeboom DJ et al.: JCO 2008;26:2124-30
PLACE OF PRRT (sinets)? Pavel M et al.: Neuroendocrinology 2016;103:172-185
PLACE OF PRRT (pnets)? Pavel M et al.: Neuroendocrinology 2016;103:172-185
PLACE OF PRRT? ideally, second line treatment, after failure of SSAs outstanding results of NETTER1 effective treatments must be given earlier at the course of the disease
PRRT: THE IJB EXPERIENCE OF ~4y IJB: one of the two PRRT centers in Belgium 63 pts: GEP-NETs: 46pts (1 insulinoma, 1 gastrinoma, 2 rectal) mammary NET: 2pts NET pulmonaire: 5 pt paragangliome/pheochromocytome: 6pts kidney NET: 1pt CUPS: 3pts 186 injections iv so far
PRRT: THE IJB EXPERIENCE OF ~4y LuMEn: 177 Lu-octreotate treatment outcome prediction using Multimodality imaging in refractory neuroendocrine tumours [NCT01842165] ongoing φii, non-randomised trial GEP-NETs to be bicentric soon (+UZL) objectives: evaluate the predictive value of the following imaging biomarkers: 68 Ga-DOTATATE and 18 FDG uptake, tumor absorbed dose > to identify non responding lesions / non responding patients. endpoints: lb-ttp, pb-pfs, efficacy & safety
PRRT: THE IJB EXPERIENCE OF ~4y LuMEn: main inclusion criteria: Disease progression defined as follows: - Radiological progression (RECIST 1.1) over the last 12m - Progression on SSTR imaging, over the last 12m - Clinical progression + significant increase in tumoral markers Adequate renal function: GFR 50 ml/min/1.73m 2 Adequate bone marrow function: Hg 9 g/dl; WBC 2 10 3 /μl; PLTs 100 10 3 /μl. Adequate liver function
UNMET NEEDS IN PRRT REGISTRATION APPROVAL UPON AUTHORITIES ACCURATE DOSIMETRY TO GUIDE THERAPY? cycles of PRRT STANDARDISATION optimal nephroprotection scheme optimal interval between injections optimal administered activity (cumulative, /cycle: standard vs tailored) PREDICTIVE BIOMARKERS
PREDICTIVE BIOMARKERS? OF RESPONSE: High uptake on receptor imaging [Rotterdam visual 5 scale: >liver uptake or spleen uptake] [ 68 Ga-DOTA-peptide uptake correlates with sst 2 R expression] OF NON RESPONSE: Bulky hepatic metastases Karnofsky performance score<70 Significant weight loss Kwekkeboom DJ et al.: JCO 2008;26:2124-30 Boy C et al.: EJNMMI 2011;38:1224-36
STRATEGIES TO IMPROVE PRRT EFFICACY combination with chemotherapy (5FU, Cap/Tem) intra-arterial PRRT for liver only / dominant disease α-emittors as novel therapeutic isotopes re-tx after progressive disease following PRRT neo-adjuvant PRRT Kashyap R et al.: EJNMMI 2014, Claringbold PG et al.: EJNMMI 2011, Limouris GS et al.: Clin Nucl Med 2016, Kratochwil C et al.: EJNMMI 2014, Sabet A et al.: EJNMMI 2014, van Vliet EI et al.: JNM 2015
TAKE HOME MESSAGES PRRT IS EFFICIENT high tumor response rates (80%: OR+SD) PFS that may reach 40m according to NETTER1 SAFE PROFILE excellent tolerance mild acute AEs <10% late AEs ideally: second line Tx after failure of SSAs
MULTIDISCIPLINARITY IN NET MGMT NUCLEAR MEDICINE ONCOLOGY GASTRO- ENTEROLOGY PATIENT SURGERY ENDOCRINO- LOGY PATHOLOGY RADIOLOGY
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