Common Procedures in Metabolic Therapy in Nuclear Medicine Departments

Transcription

1 Common Procedures in Metabolic Therapy in Nuclear Medicine Departments Elisa Caballero Calabuig Medicina Nuclear Hospital U. Dr. Peset Valencia Junio 2016

2 THERAPY IN NUCLEAR MEDICINE Nuclear Medicine and Metabolic Therapy Molecular Image Radiophysics and Radiochemistry: the radiopharmaceutical Detectors and Images References and Information Systems Processes en Nuclear Medicine Metabolic Therapy procedures: Bq = Gy Patient adjusted vs fixed activities? Individual dosimetry? Things to be done to improve and expand metabolic therapy

3 Functional, clinical Patient Many factors of variability Diagnostic 90%, therapy 10% Therapy >10% Medicine Physics, Chemistry, Image Nuclear Medicine, molecular image and therapy 99m Tc, low E Highly dependant of technology Tracer activities, No toxicity 177 Lu, 90 Y, α Therapeutic effect Toxicity

4 DETECTORS AND IMAGES: opportunities and challenges Dosimetry packages for Radioisotope Therapy planning

5 REFERENCES IN NM: standarisation

6 REFERENCES IN NM: process

7 REFERENCES IN NM: multidisciplinary teams And the Patient

8 PLANNING AND DOSIMETRY IN (non)-targeted THERAPY External RT Metabolic therapy Systemic administration: how much dose reaches the tumour? Systemic disease, often pre-terminal: outcome assessment Survival, time to relapse, tumour size change? How to measure toxicity: peripheral blood? Bone marrow G0? GI?

9 PLANNING AND DOSIMETRY IN (non)-targeted THERAPY So far, individual dose planning and dosimetry haven t been common procedures in the clinical practice. Calculation of the (approximated) absorbed dose for RIT in NM: Uses the distribution of the activity through images over time Too many assumptions from anatomical or mathematical models, non reproducible. standard anatomy. uniform radiopharmaceutical distribution (body, tumour volume) Complex and time-consuming procedures for doctors and patients Interpersonal variability Difficulty on assessing effects and toxicity No evident effect on clinical outcomes We work with data from scientific evidence (clinical trials on survival and toxicity)

10 PLANNING AND DOSIMETRY IN (non)-targeted THERAPY Conclusion: As radionuclide therapy enters an era where patient-specific dosimetry is used to guide treatments, accurate bone-marrow and whole-body dosimetry will become an essential element of treatment planning. We hope that these guidelines will provide a basis for the optimization and standardization of the treatment of cancer with radiopharmaceuticals, which will facilitate single- and multicentre radionuclide therapy studies.

11 METABOLIC THERAPY: why not (so far) and what for? 131 I for Hiperthyroidism 131 I in Differentiated Thyroid cancer 90 Y-microspheres to liver 177 Lu-DOTATATE in neuroendocrine tumours 90 Y-Ibritumumab-tiuxetan for Lymphoma 223 Ra-Dichloride for blastic bone metastases

12 METABOLIC THERAPY Prescription reviewed Multidisciplinary team Other exams / lab Other image as needed; non futile exams Informed and written consent Patient preparation Daily life activities survey Activity, dose ratio (microsv/h) and recommendations to patient s chart RP recommendations to relatives and environement Follow-up

13 131 I for HYPERTHYROIDISM Diffuse hyperthyroidism: Gy Hyperfunctioning nodules: Gy More cure rates with fixed activities (90 % cure -60 % hypothyroidism-) Less hypothyroidism with calculated activities Fixed activities: mci Radiation sensitivity of the gland Estimated weight of the gland Out patient Function dynamics Aim: to cure hyperthyroidism

14 131 I for HYPERTHYROIDISM 15 mci Apr 2015 Jan 2016 Response to TRAK and TSH levels Evolving functional changes

15 131 I for DIFFERENTIATED THYROID CANCER Fixed modulated activities Long experience Good clinical results, low toxicity Aim: Survival??

16 131 I in THYROID CANCER Ablación Adyuvancia Terapia Tras tiroidectomía Células tiroides Obligatoria? Tras cirugía LR o de metástasis Micrometástasis Células tumor Metástasis Ablación Dx 1 año M1 pulmón

17 131 I for DIFFERENTIATED THYROID CANCER Different dose to tumour, remnant, lymph nodes or metastases Uncertain clinical evolution, usually long survival Outcome difficult to be verified (survival or long term toxicity) 2014 Mujer de 32 años Papilar T3 N1 (11/24 gg) E I 120 mci 131 I M1

18 131 I for DIFFERENTIATED THYROID CANCER Tumour kinetics Uptake measures difficult due to TSHr-e or deprivation Stunning Er

19 131 I for DIFFERENTIATED THYROID CANCER Usually, planar images No measurable tumour volume

20 131 I for DIFFERENTIATED THYROID CANCER The goals of 131 I in thyroid cancer are: To kill thyroid cells (normal or tumoral) To avoid futile treatments in refractary patients Different kinetics mci a. CPT T3 N1a M0. E III

21 100 pacientes I y FDG - Tratamiento 131 I I vs 131 I Objetivo - Evitar ttos 131 I - - Dosimetría 124 I 124 I FDG Kist. Cancer 2014

22 131 I for DIFFERENTIATED THYROID CANCER

23 131 I for DIFFERENTIATED THYROID CANCER We are still debating about the benefit of 131I on survival

24 131 I for HIPERTHYROIDISM and DTC: external dosimetry for RP Daily life activities survey microsv/h 24 h, 7, 15 d or as needed RP recommendation of permitted activities

25 131 HOSPITAL I for HIPERTHYROIDISM and DR. PESET, VALENCIA DTC: personalised instructions MEDICINA NUCLEAR TEL: INSTRUCCIONES PERSONALIZADAS DESPUÉS DEL TRATAMIENTO CON 131I Recomendaciones Debe volver a Medicina Nuclear para nueva medición el día:

26 90 Y to LIVER: Hepatocellular carcinoma and colorectal metastases Hepatocellular carcinoma and colorectal metastases Well tolerated Favorable dosimetry to medical staff Survival increased by 5-10 m Not fully integrated in the therapeutic algorithm because radiation and procedure fears

27 90 Y to LIVER: Hepatocellular carcinoma and colorectal metastases Hepatic tumours nourrised by hepatic artery Activity according to tumor density, volume, shunt and clinical situation, related to survival All these are key points for strong variability Braat J Nucl Med 2015; 15

28 90 Y to LIVER: Hepatocellular carcinoma and colorectal metastases Tumor/liver= 250 Gy/100 Gy Non established threshold values for liver toxicity: uniform liver: 30 Gy. BUT Tumors: Gy Wide range of absorbed doses Braat J Nucl Med 2015; 56

29 90 Y to LIVER: Hepatocellular carcinoma and colorectal metastases MAA scan to know 90 Y extrahepatic passage Assessed by planar, SPECT, SPECT-CT? Tumour size and volume, sometimes difficult to assess: SPECT-CT Inhomogeneity of tumours, liver and lung Number and intralesional spheres distribution for tumor volume Are planning techniques able to predict therapeutic efficacity and toxicity? Options for combined therapy with QT Lambert, EJNMMI 2010

30 90 Y to LIVER: Hepatocellular carcinoma Braat. J Nucl Med 2015; 56

31 90 Y to LIVER: colorectal metastases Braat. J Nucl Med 2015; 56

32 177 Lu-DOTATATE for NEUROENDOCRINE TUMOURS NETs are different kind of tumours Expression of somatostatin receptors when well differentiated 90 Y, 177 Lu - Somatostatin analogues are high affinity and specific target to SR Metastatic or inoperable Neoadjuvant use Benefit on survival!! New treatment, to be clearly positioned

33 33 Objective Responses Currently evaluable patients 177-Lu-Dotatate (n=101)* Sandostatin LAR 60 mg (n=100)* Complete Response (n) 1 0 Partial Response (n) 17 3 Objective Response Rate (*) 18% 3% Confidence Interval (95%) 10% - 25% 0% - 6% Statistical Significance p = All patients (n=116) (n=113) Progressive Disease 6 (5%) 27 (24%) Stable Disease 77 (66%) 70 (62%) (*) Exclude patients with no post-baseline scans or central response available

34 34 Summary and Conclusions Final analysis : In this first prospective randomized study in patients with progressive metastatic midgut NETs, 177 Lu-Dotatate was superior to Octreotide 60 mg in terms of: PFS (Not Reached vs 8.4 months, p<0.0001) ORR (18% vs 3%, p=0.0008) Interim analysis suggests increased OS (13 vs 22 deaths), to be confirmed by final analysis 177 Lu-Dotatate demonstrates a favorable safety profile, with no clinically relevant findings especially regarding hematological, renal and hepatic parameters While few treatment options are available for patients progressing under SSAs, 177 Lu-Dotatate has a major therapeutic benefit for this patient population

35 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS Lu-DOTA-TATE 90 Y-DOTA-TOC TÁNDEM ( 177 Lu / 90 Y) Kidney protection with infused AA Variable absorbed dose to kidney 200 mci /6-8 s (4 ciclos) Response assessment now Prospective studies are lacking Toxicity not well understood yet Kam, EJNMMI 2012

36 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS CICLO 1 CICLO 3 Imágenes cedidas por el H.U.P. La Fe de Valencia

37 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS 111 In-Octreótido 99m Tc-Octreótido 68 Ga-DOTATATE 2-3 DÍAS 4 HORAS S: 60% S: 80% E: 94% Acc: 82.9% S > 90%

38 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS 111 In-Octreótido 18 F-FDG Imágenes cedidas por el Servicio MN del C.H.Provincial de Castellón

39 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS Not only RECIST!

40 177 Lu-DOTATATE in NEUROENDOCRINE TUMOURS 2016

41 90 Y-IBRITUMOMAB TIUXETAN for LYMPHOMA CD20+ F-NHL (B-cell L), indolent subtypes Low-grade or follicular B-cell NHL that has relapsed during or after treatment with other anticancer drugs 2008: Newly diagnosed follicular NHL following a response to initial anticancer therapy Exclusion criteria: bone marrow supression MBq/kg Potential severe toxicity, but manageable Currently, not frequently prescribed

42 90 Y-IBRITUMOMAB TIUXETAN for LYMPHOMA

43 90 Y-IBRITUMOMAB TIUXETAN for LYMPHOMA 111 In-Zevalin after Rituximab 250 mg/m2 Planar Images and blood samples at 8 points MIRDOSE3 software program Individual patient dosimetry non predictive for 90Y Zevalin toxicity with current methods

44 90 Y-IBRITUMOMAB TIUXETAN for LYMPHOMA

45 223 Ra for BONE METASTASES Activity / kg Aim: Survival Individual efficacy has to be shown

46 223 Ra for BONE METASTASES 50 kbq/kg, other schemes are under study The first pass is to check proper distribution with multichannel detector

47 223 Ra for BONE METASTASES Peak 82, 154, 269, 351 KeV Window 10% HE 4 cm/min 10 min 4 h. post administration

48 Valor FA (UI/l) 223 Ra for BONE METASTASES Efficacy: ALP change from abnormal basal ALP FA basal normal ( UI/l) FA basal aumentada n: 6 n: 7 Reducción FA 85.7 % Basal pre-2ºc pre-3ºc pre-4ºc pre-5ºc pre-6ºc fin de tto Pac 2 Pac 4 Pac 6 Pac 8 Pac 9 Pac 10 Pac 13

49 EVA 223 Ra for BONE METASTASES Pain relief: Visual Analogue Scale (VAS) Pacientes analizados EVA EVA estable EVA n: 11 8 (73 %) 2 (18 %) 1 (9 %) pre-1º pre-2º pre-3º pre-4º pre-5º pre-6º fin tto Título del eje Pac 1 Pac 2 Pac 3 Pac 4 Pac 6 Pac 7 Pac 8 Pac 9 Pac 10 Pac 11 Pac 12

50 223 Ra for BONE METASTASES Toxicidad hematológica y no hematológica 223 Ra toxicity per patient (n: 12) Todos los grados G3 Anemia 6 (50 %) 1 (8.3 %) - Trombocitopenia 2 (16.7 %) 1 (8.3 %) - Neutropenia 1 (8.3 %) - - Náuseas 2 (16.7 %) - - Vómitos Diarrea 3 (25 %) - - Estreñimiento Disgeusia 1 (8.3 %) - - G4

51 223 Ra for BONE METASTASES Improvement/worsening pattern after 3 cycles (some kind of response: 86 %) Baseline HDP bone scan HDP After 3 cycles 223 Ra

52 OTHER

53 WORK IN PROGRESS: dose planning and dosimetry Necessarily multidisciplinar: clinical specialist, NM, radiopharmacist, physicist Collaborative, non competitive Challenging complex systems: from planar images to Tumor: genetic profile, vascular, angiogenesis, heterogeneity Vector: improved systems AG-AB, devices, administration ways RF: other more precise and selective Sinergias: RT, ChT, AA Detectores: enfermedad mínima Imagen: SPECT-CT, PET-CT Paciente: factores clínicos Método: modelos matemáticos, planning helpers, 3D Comprensión de micro-nanodosimetría Metrología: datos

54 ACTIONS: dose planning and dosimetry Dosimetry procedures should be included on the list of activities of a NM department, and time and economic valuation should be assigned Integrating projects: Clinicians - Nuclear Medicine - Physicists - Radiopharmacists Processes design for diagnosis and therapy Data Information Patient selection Outcome selection and assessment (max dose to tumor or min dose for toxicity?)

55 Gracias