common procedures in metabolic therapy in nuclear medicine ... › new › ... › 2016 ›...

Elisa Caballero Calabuig

Medicina Nuclear Hospital U. Dr. Peset Valencia

Junio 2016

Common Procedures in Metabolic Therapyin Nuclear Medicine Departments

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

Functional, clinical

Diagnostic90%, therapy

10%

99mTc, low E

Traceractivities,

No toxicity

Highlydependant of

technology

Physics, Chemistry,

Image

Many factorsof variability

Nuclear Medicine, molecular image

and therapy

Patient

Medicine

Therapy >10%

177Lu, 90Y, α

Therapeutic effectToxicity

DETECTORS AND IMAGES: opportunities and challenges

Dosimetry packages forRadioisotope Therapy planning

REFERENCES IN NM: standarisation

REFERENCES IN NM: process

REFERENCES IN NM: multidisciplinary teams

And the Patient

PLANNING AND DOSIMETRY IN (non)-TARGETED 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?

External RT Metabolic 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 variabilityDifficulty on assessing effects and toxicity

No evident effect on clinical outcomes

We work with data from scientific evidence (clinical trials on survival and toxicity)

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 multi-centre radionuclide therapy studies.

PLANNING AND DOSIMETRY IN (non)-TARGETED THERAPY

• 131I for Hiperthyroidism

• 131I in Differentiated Thyroid cancer

• 90Y-microspheres to liver

• 177Lu-DOTATATE in neuroendocrine tumours

• 90Y-Ibritumumab-tiuxetan for Lymphoma

• 223Ra-Dichloride for blastic bone metastases

• …

METABOLIC THERAPY: why not (so far) and what for?

METABOLIC THERAPY

Prescription reviewed

Other exams / lab

Informed and writtenconsent

Patient preparation

Daily life activities survey

RP recommendations to relatives and environement

Follow-up

• Activity, dose ratio (microSV/h) andrecommendations to patient’s chart

• Other image as needed; non futile exams

• Multidisciplinary team

131I for HYPERTHYROIDISM

• Diffuse hyperthyroidism: 100-150 Gy• Hyperfunctioning nodules: 300-400 Gy• More cure rates with fixed activities

(90 % cure -60 % hypothyroidism-)• Less hypothyroidism with calculated activities

Fixed activities: 10 – 15 – 20 mCi Radiation sensitivity of the gland Estimated weight of the gland Out patient Function dynamics Aim: to cure hyperthyroidism

131I for HYPERTHYROIDISM

Response to TRAK and TSH levels Evolving functional changes

15 mCi Apr 2015 Jan 2016

131I for DIFFERENTIATED THYROID CANCER

• Fixed modulated activities• Long experience• Good clinical results, low toxicity• Aim: Survival??

131I 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

2014 Mujer de 32 años• Papilar T3 N1 (11/24 gg) E I• 120 mCi 131I M1

131I 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)

131I for DIFFERENTIATED THYROID CANCER

Tumour kinetics Uptake measures difficult due

to TSHr-e or deprivation Stunning

Er

131I for DIFFERENTIATED THYROID CANCER

No measurable tumour volume Usually, planar images

2012

131I for DIFFERENTIATED THYROID CANCER

The goals of 131I in thyroid cancer are: • To kill thyroid cells (normal or tumoral)• To avoid futile treatments in refractary patients

• Different kinetics 1- 100 mCi

71 a. CPT T3 N1a M0. E III2012

Kist. Cancer 2014

100 pacientes- 124I y FDG- Tratamiento 131I- 124I vs 131I

Objetivo- Evitar ttos 131I -- Dosimetría 124I

124I FDG

131I for DIFFERENTIATED THYROID CANCER

131I for DIFFERENTIATED THYROID CANCER

We are still debatingabout the benefit of 131I on survival

131I 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

131I for HIPERTHYROIDISM and DTC: personalised instructionsHOSPITAL DR. PESET, VALENCIA MEDICINA NUCLEAR TEL: 96 162 25 00

INSTRUCCIONES PERSONALIZADAS DESPUÉS DEL TRATAMIENTO CON 131I

Recomendaciones

Debe volver a Medicina Nuclear para nueva medición el día:______________

90Y 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 algorithmbecause radiation and procedure fears

Braat J Nucl Med 2015; 15

90Y 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; 56

Tumor/liver= 250 Gy/100 Gy

90Y to LIVER: Hepatocellular carcinoma and colorectal metastases

• Non established threshold values for liver toxicity: uniform liver: 30 Gy. BUT Tumors: 100-200 Gy

• Wide range of absorbed doses

• MAA scan to know 90Y extrahepatic passage

• Assessed by planar, SPECT, SPECT-CT?

Lambert, EJNMMI 2010

90Y to LIVER: Hepatocellular carcinoma and colorectal metastases

• 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

Braat. J Nucl Med 2015; 56

90Y to LIVER: Hepatocellular carcinoma

Braat. J Nucl Med 2015; 56

90Y to LIVER: colorectal metastases

177Lu-DOTATATE for NEUROENDOCRINE TUMOURS

• NETs are different kind of tumours• Expression of somatostatin receptors

when well differentiated• 90Y, 177Lu - 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

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 = 0.0008

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

Objective ResponsesCurrently evaluable patients

Summary and Conclusions

34

• Final analysis : In this first prospective randomized study in patients with progressive

metastatic midgut NETs, 177Lu-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

• 177Lu-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, 177Lu-Dotatate has a major therapeutic benefit for this patient population

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

2013

Response assessment now Prospective studies are lacking Toxicity not well understood yet

177Lu-DOTA-TATE 90Y-DOTA-TOC TÁNDEM (177Lu / 90Y)

• Kidney protection with infused AA • Variable absorbed dose to kidney• 200 mCi /6-8 s (4 ciclos)

Kam, EJNMMI 2012

CICLO 1 CICLO 3

Imágenes cedidas por el H.U.P. La Fe de Valencia

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

111In-Octreótido 99mTc-Octreótido 68Ga-DOTATATE2-3 DÍAS 4 HORAS

S > 90% S: 60% S: 80% E: 94% Acc: 82.9%

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

Imágenes cedidas por el Servicio MN del C.H.Provincial de Castellón

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

111In-Octreótido 18F-FDG

Not only RECIST!

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

177Lu-DOTATATE in NEUROENDOCRINE TUMOURS

2016

90Y-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• 11-15 MBq/kg• Potential severe toxicity, but manageable• Currently, not frequently prescribed

90Y-IBRITUMOMAB TIUXETAN for LYMPHOMA

90Y-IBRITUMOMAB TIUXETAN for LYMPHOMA

• 111In-Zevalin after Rituximab 250 mg/m2• Planar Images and blood samples at 8 points• MIRDOSE3 software program

• Individual patient dosimetry non predictivefor 90Y Zevalin toxicity with current methods

90Y-IBRITUMOMAB TIUXETAN for LYMPHOMA

223Ra for BONE METASTASES

• Activity / kg• Aim:

• Survival• Individual efficacy

has to be shown

223Ra for BONE METASTASES

• 50 kBq/Kg, other schemes are under study

• The first pass is to check proper distribution with multichannel detector

• Peak 82, 154, 269, 351 KeV• Window 10%• HE• 4 cm/min 10 min• 4 h. post administration

223Ra for BONE METASTASES

0

400

800

1200

1600

2000

Basal pre-2ºc pre-3ºc pre-4ºc pre-5ºc pre-6ºc fin de tto

Va

lor

FA

(U

I/l)

Pac 2 Pac 4 Pac 6 Pac 8 Pac 9 Pac 10 Pac 13

Efficacy: ALP change from abnormal basal ALP

FA basal normal

(40-150 UI/l)

n: 6

FA basal

aumentada

n: 7

Reducción FA 85.7 %

223Ra for BONE METASTASES

Pain relief: Visual Analogue Scale (VAS)

0

1

2

3

4

5

6

7

8

9

10

pre-1º pre-2º pre-3º pre-4º pre-5º pre-6º fin tto

EV

A

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

Pacientes

analizados

↓ EVA EVA

estable

↑ EVA

n: 11 8 (73 %) 2 (18 %) 1 (9 %)

223Ra for BONE METASTASES

223Ra toxicity per patient (n: 12)

Toxicidad

hematológica y no

hematológica

Todos los

grados

G3 G4

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 %) - -

223Ra for BONE METASTASES

Improvement/worsening pattern after 3 cycles (some kind of response: 86 %)

223Ra for BONE METASTASES

Baseline HDP bone scan HDP After 3 cycles 223Ra

OTHER

2008

2003

• Necessarily multidisciplinar: clinical specialist, NM, radiopharmacist, physicistCollaborative, non competitive

WORK IN PROGRESS: dose planning and dosimetry

• 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

• 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?)

ACTIONS: dose planning and dosimetry

Gracias