Lu-DOTATATE PRRT dosimetry: - PDF Free Download

177 Lu-DOTATATE PRRT dosimetry: From theory to practice Silvano Gnesin Medical Physics department Institute of Radiation Physics, Lausanne University Hospital, Lausanne, Switzerland Gwennaëlle Marin Medical Physics and Nuclear Medicine departments Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Bruxelles, Belgique

Theranostics = Therapeutic + Diagnostic Use of the same pharmaceutic labeled with different radionuclides to be used alternatively as diagnostic and therapeutic agent Expl: Use of the same pharmaceutic labeled with one radionuclide to be used simultaneously as diagnostic and therapeutic agent We treat what we see; we see what we treat We have to Know our target Chose the agent Chose the weapon and the bullet Ga-68/Lu-177 Lu-177 only CHELATOR PEPTIDE sstr

Theranostics: weapon CHELATOR PEPTIDE sstr 68 Ga-DOTATATE = 68 Gallium-DOTA-(Tyr3)-octreotate 68 Gallium = β + emitter DOTA = chelator (Tyr 3 )-octreotate = peptide = synthetic somatostatine analogue Neuroendocrine tumors with over-expressed somatostatine receptors (sstr) 68 Ga β + emitter => PET imaging Receptor imaging Staging/selection of patients Quantification Therapy response prediction (?)

Theranostics: weapon CHELATOR PEPTIDE sstr 177 Lu-DOTATATE = 177 Lu-DOTA-(Tyr3)-octreotate 177 Lutetium = β and γ emitter DOTA = chelator (Tyr 3 )-octreotate = peptide = synthetic somatostatine analogue Neuroendocrine tumors with over-expressed somatostatine receptors (sstr) 177 Lu β - emitter => therapy (MRT) γ emitter => SPECT imaging Receptor imaging Quantification Dosimetry β - 498 kev max γ 208 kev http://www.nndc.bnl.gov/chart/

Why dosimetry? Chemotherapy wait Nuclear medicine Other solution pre-therapeutic 68 Ga-DOTATATE PET/CT A small activity of Compute absorbed dose 177 Lu-DOTATATE SPECT/CT at 24h PI

Why dosimetry? 177 Lu-DOTATATE SPECT/CT at 24h PI 177 Lu-DOTATATE SPECT/CT at 24h PI Treatment cycle 1 Treatment cycle 1 Patient profiles are similar (to the best of our knowledge): Female Intestinal (ileal) neoplasia Similar Ki67

Why dosimetry? 177 Lu-DOTATATE SPECT/CT at 24h PI 177 Lu-DOTATATE SPECT/CT at 24h PI Treatment cycle 1 Treatment cycle 4 Treatment cycle 1 Treatment cycle 4 Patient profiles are similar (to the best of our knowledge): Female Intestinal (ileal) neoplasia Similar Ki67 Different responses When do we stop the therapy?

Why dosimetry? Maximum dose limit of 23 Gy to kidneys is derived from EBRT and PRRT with 90 Y-DOTATOC 5% probability of severe kidney toxicity within 5 years Differences between molecular (MRT) and external beam radiation therapy (EBRT): -Dose rate -Fractionation Possible different biological effect -Heterogeneity of energy/dose deposition -citotoxic mechanisms EBRT dose causing 5% renal toxicity after 5 y = 23 Gy delivered by fractions of 2Gy d = 2 Gy/fraction nd = 23 Gy T1 = 0h eff 2 α/β = 2.6 Gy for kidneys T1 = 2.8 h for kidneys rep 2 = 40.7 Gy MRT Limit BED = 40 Gy Barone R. et al. J Nucl Med. 2005

Why dosimetry? EBRT dose causing 5% renal toxicity after 5 y = 23 Gy delivered by fractions of 2Gy d = 2 Gy/fraction nd = 23 Gy T1 = 0h eff 2 α/β = 2.6 Gy for kidneys T1 = 2.8 h for kidneys rep 2 = 40.7 Gy MRT Limit BED = 40 Gy BED as function of absorbed dose for healthy kidneys after PRRT with 90 Y- and 177 Lu-labeled compounds. Dotted lines denote intersection of BED of 40 Gy and corresponding cycle- and nuclide-dependent absorbed kidney doses. Vertical light blue solid line denotes normally accepted tolerable absorbed dose (23 Gy) for healthy kidneys. U. Eberlein et al., J. Nuc. Med. 58, 2017

Why dosimetry? Predictability of the dosimetry based on the fist therapy cycle Garkavij et al., Cancer 2010

Why dosimetry? N of cycles to reach a given absorbed dose to kidneys is patient specific If no risk factors Optimization by individualized dosimetry Maximize tumor dose (efficacy) Control to organ at risk (safety) n cycles >4 for 78% of patients A cycle = 7.4 GBq Data from hybrid planar+spect kidney dosimetry A. Sundlöv et al. EJNMMI 2017

A (Bq) How to perform dosimetry? In theory, in general: D r T = E(r T) m r T In theory, in nuclear medicine: D r T = A(r S ) S(r T r S ) r S r S1 r S2 = A(r S ) i r S Y ie i Φ(r T r S,E i ) m(r T ) metrology r T In practice, in nuclear medicine: Φ(r T r S, E i ) : Olinda? Voxel based? m r T : which modality? A(r S ) : which time-points? how to quantify activity? which interpolation/pharmacokinetic? A r S = A t 0 = TIAC t (hour) Bolch et al., JNM 2009

Standard dosimetry procedure Drug preparation and administration Source/target organ definition Data acquisition (Which data? When?) Activity quantification on each acquired data TAC (Time Activity Curve) computation TIAC (Time-Integrated Activity Coefficient) computation Computation of absorbed dose to organs-at-risk

Drug administration Standard 4-cyles, 7.4 GBq Cycle Cumulated activity safe for most of patients Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3] octreotate in patients with endocrine gastroenteropancreatic tumors. D.J. Kwekeboom, et al. J Clin Oncol 2005 Apr 20;23(12):2754-62 Compared to EBRT, low dose-rate PRRT potentially enable higher dose before severe toxicity appears Patient without risk factor (hypertension, diabetes) could receive up to BED = 40Gy without severe renal toxicity Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors L. Bodei et al. Eur J Nucl Med Mol Imaging (2008) 35:1847 1856 Ongoing study in Lund confirms the BED=40Gy in patient without risk factor is safe Individualized 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry A. Sundlöv et al. Eur J Nucl Med Mol Imaging (2017) 44:1480-1489)

Drug administration 177 Lu-DOTATATE should be administered by trained medical staff with supporting nursing staff with a medical physics expert available Reduced kidney dose (10-60%) is obtained by amino acid co-administration for somatostatine receptor agonist radiolabeled with 90 Y Matters to debate in 177 Lu PRRT (common practice in many centers)

Our experience Standard therapy scheme: 4 cycles of 7,4 GBq of 177 Lu-DOTATATE 4 years Institut Jules Bordet experience with 177 Lu-DOTATATE therapy 63 patients (26 part of LuMen) 186 therapy cycles (80 part of LuMen) The whole procedure is identical for all patients (routine & LuMen) LuMen: Prospective phase II clinical study «177 Lu-octreotate treatment outcome prediction using multimodality imaging in refractory neuroendocrine tumours»

Drug administration Antiemetics 1 hour before 177 Lu-DOTATATE injection Amino acids from 0,5 h before to 4 h after injection Manual intravenous 177 Lu-DOTATATE injection lasts from 10 to 20 minutes Patient s weight and size Prepared activity + measurement hour Remaining activity + measurement hour Start and end of injection => net injected activity (MBq) Standard acquisition protocol + hours

Source/target organ definition D r T = A(r S ) S(r T r S ) r S = A(r S ) i r S Y ie i Φ(r T r S,E i ) m(r T ) r S1 r S2 r T For MRT with 177 Lu-DOTATATE: Source organs: Kidneys Red marrow Liver Spleen Remainder of the body => Cumulated activity Target organs or organs-at-risk: Kidneys Red marrow => Absorbed dose Bolch et al., JNM 2009

Data acquisition Each injection is preceded by 18 FDG PET/CT, 68 Ga-DOTATATE PET/CT and MRI Each injection is followed by 3 SPECT/CT (4, 24, 168 h PI) and 5 blood samples (0.5, 1, 4, 24, 168 h PI) Previous month 18 FDG PET/CT 68 Ga-DOTATATE PET/CT MRI or CT Blood Blood SPECT/CT Blood SPECT/CT Blood SPECT/CT 177 Lu-DOTATATE injection Patient leaves hospital Siegel et al., JNM 1999; Guerriero et al., Biomed Res Int 2013

Data acquisition M: Planar imaging M2: Hybrid planar + SPECT M3: only SPECT acq. Fully planar dosimetry tends to overestimate kidney dose exposure compared to SPECT-based methods (overlapping activity with surrounding tissues) Garkavij et al., Cancer 2010

Activity quantification Activity = volume X specific activity Organ volumes on first SPECT/CT: CT contours for spleen, kidneys and liver Body weight for remainder of the body OLINDA volumes balance for patient size for red marrow Brindle et al., Cancer Biother Radiopharm 2006 Organ specific activities on each SPECT/CT and blood sample: 3 spheres for spleen, kidneys and remainder of the body Gross liver activity contour (liver + hepatic lesion) red marrow = blood (no specific uptake) Spheres in spleen and kidney Gross liver contour ROI in remainder of the body Blood activity measurement Sandström et al., EJNMMI 2015; Forrer et al., EJNMMI 2009

TAC computation SPECT 4h SPECT 24h SPECT 168h Kletting et al., Med Phys 2013; Guerriero et al., Biomed Res Int 2013

TAC computation Blood 0.5 & 1h Blood 4h Blood 24h Blood 168h Kletting et al., Med Phys 2013; Guerriero et al., Biomed Res Int 2013

TIAC computation A (Bq) Time-integrated activity coefficients (TIAC) computation for source organs T eff_early T eff_late A r S = A t 0 = TIAC t (hour) TIAC T eff_early T eff_late Mass

Absorbed dose computation Source organs TIAC Effective half-life Mass r S1 r S2 r T OLINDA/EXM software Patient specific organ mass Stabin et al., JNM 2005; Divoli et al., JNM 2009 Organ Doses (msv/7,64 GBq) Target Organs Beta Photon Total Adrenals 1,77E002 6,63E001 2,43E002 Brain 1,77E002 1,49E001 1,92E002 Breasts 1,77E002 1,46E001 1,91E002 Gallbladder Wall 1,77E002 5,67E001 2,34E002 LLI Wall 1,77E002 2,60E001 2,03E002 Small Intestine 1,77E002 3,31E001 2,10E002 Stomach Wall 1,77E002 4,18E001 2,19E002 ULI Wall 1,77E002 3,58E001 2,13E002 Heart Wall 1,77E002 3,19E001 2,09E002 Kidneys 8,69E003 1,86E002 8,87E003 Liver 1,52E003 8,07E001 1,60E003 Lungs 1,77E002 2,91E001 2,06E002 Muscle 1,77E002 2,25E001 1,99E002 Ovaries 1,77E002 2,77E001 2,05E002 Pancreas 1,77E002 6,65E001 2,43E002 Red Marrow 2,57E002 2,63E001 2,84E002 Osteogenic Cells 6,87E002 4,22E001 7,29E002 Skin 1,77E002 1,20E001 1,89E002 Spleen 1,17E004 2,38E002 1,19E004 Thymus 1,77E002 2,12E001 1,98E002 Thyroid 1,77E002 1,59E001 1,93E002 Urinary Bladder Wall 1,77E002 2,34E001 2,00E002 Uterus 1,77E002 2,64E001 2,03E002 Total Body 2,68E002 2,48E001 2,93E002

Lesion dosimetry Lesion mass definition on 68 Ga-DOTATATE PET/CT Threshold = mean SUV in inferior left kidney cortex Lesion activity quantification on 177 Lu-DOTATATE SPECT/CT Region growing from hottest voxel until reaching defined mass 4 h PI 24 h PI 168 h PI 177 Lu-DOTATATE SPECT TAC computation Measured activities are fitted with a bi-exponential function A measured /A injected Time after injection (h)

Lesion dosimetry RC (A measured /A expected ) TAC corrected for partial volume effect Phantom-based PVE correction for spheres Sphere volume (cm³) Buvat et al., JNM 2007

Dose (mgy/mbq) RC (A measured /A expected ) Dose rate (mgy/h/gbq) Lesion dosimetry Lesion TAC A measured /A injected Time after injection (h) Lesion time-dose rate curves Phantom-based PVE correction for spheres Sphere volume (cm³) Time after injection (h) 1.E+04 OLINDA sphere model for 177 Lu 1.E+03 1.E+02 1.E+01 1.E+00 1.E-01 1.E-02 0 200 400 600 800 1000 sphere mass (g)

Dosimetry results for organs-at-risk High inter-patient variability High inter-study variability Kidneys Red marrow Author Number of patients d [Gy/GBq] Del Prete et al. EJNMMI 2017 36 0.55 ± 0.2 Sandström et al. JNM 2013 200 [0.47; 0.61; 0.73] Svensson et al. EJNMMI Phys 2016 51 0.63 ± 0.2 Our results 47 [0.61; 0.77; 0.98] Wehrmann et al. Cancer Biother Radiophar 2007 61 0.9 ± 0.3 Garkavij et al. Cancer 2010 21 1.2 ± 0.3 Sandström et al. JNM 2013 200 [0.012; 0.016; 0.022] Svensson et al. EJNMMI Phys 2016 46 0.027 ± 0.007 Our results 47 [0.023; 0.028; 0.032] Forrer et al. EJNMMI 2009 15 0.034 ± 0.030 Del Prete et al. EJNMMI 2017 21 0.046 ± 0.033 Wehrmann et al. Cancer Biother Radiophar 2007 27 0.040 ± 0.02 Bergsma et al. EJNMMI 2016 23 0.067 ± 0.007

A (Bq) Dosimetry results for organs-at-risk Reduced intra-patient (inter-cycle) variability: Normalized mean = 1 (N=27) nv SD (%) nt 1/2eff SD (%) ntiac SD (%) left kidney 5 7 16 organ at risk right kidney 5 9 16 red marrow 0 9 18 liver 9 11 28 source organ spleen 15 10 23 remainder 2 19 19 T eff_early T eff_late A r S = A t 0 = TIAC t (hour)

Dosimetry results for lesions 2.7 mgy/mbq 5.4 mgy/mbq 8.1 mgy/mbq 10.8 mgy/mbq 21.6 mgy/mbq lesions Author Number of patients d [Gy/GBq] Gupta et al. Clin Nucl Med 2013 88 3.41 ± 0.68 Garkavij et al. Cancer 2010 16 [0.1; 6.7; 20] Ilan et al. JNM 2015 24 [1.4; 6.7; 22.9] Wehrmann et al. Cancer Biother Radiophar 2007 61 9.7 ± 11.1 Ilan et al., JNM 2015 Tumor dose response relationship for patients with PNETs treated with PRRT using 177 Lu-DOTATATE, including tumors larger than 2.2 cm (A) and only tumors larger than 4 cm (B) Eberlein et al., JNM 2017

Conclusion Important inter-patient variability => need for dosimetry to individualize therapy, improve patient safety and therapeutic efficacy BUT No standard dosimetry methodology proposed yet => variability of dosimetry results in different studies To improve dosimetry use and reliability, standardization, precision and accuracy are key points!