Pr Francesco GIAMMARILE

CHLS Lyon

Faculté de Lyon Sud

« Aut tace aut loquere meliora silentio »

Situación y perspectivas:

el punto de vista del medico nuclear

Terapéutica con radiofármacos

External Beam Radiation vs

Radioimmunotherapy for Low-Grade NHL

R/immunotherapyExternal

beam radiation

Método:

- Radiación (daño en el ADN)

Objetivo:

- irradiación máxima de las células tumorales

- mínima toxicidad para las células sanas

Método:

- (Radio)fármaco trópico del tumor administrado

por vía sistémica o localmente

Objetivo:

- Medidas específicas en el tumor primario y

sus metástasis (macro- y micro-scópicas)

Una radioterapia dirigida

Un tratamiento anti-tumoral

puede adaptarse a un determinado tipo de

cáncer y un paciente individualmente

- Molécula vector: captación específica

- Radioelemento: diferentes propiedades físicas

(transición, energía, vida media)

En la teoría toda radiación ionizante puede ser

usada para fines terapéuticos, en la práctica se usan los emisores de partículas: •- (distancia máxima 0,3/12 mm: irradiación del tejido)

• (distancia máxima 50/80 µm: irradiación de células)

• e- (CE o CI, distancia máxima 10 nm: irradiación de núcleos)

Una radioterapia molecular

Una radioterapia modular

EFECTO BYSTANDER

Mitosis

INESTABILIDAD GENÓMICA TRANSMISIBLE

IRRADIACIÓN DIRECTA Y « FUEGO CRUZADO »

Vecinidad

Distancia depende

del radioelemento

- Aumenta el efecto

tumoricida Y toxicidad

Baja tasa de dosis

- continua y prolongada

Destrucción

de células

adyacentes

Muerte difería

Respuesta al estrés

- Función del ambiente

y de la inmunidad

Radiofármaco

Modeles

dosimétricos

Dosis?

Efecto?

Radioelemento Vector Propiedades

biológicas

Propiedades

físicas

OBJETIVO Natura del tumor,

situación, tamaño...

Biodistribución?

Propiedades

biológicas

y químicas

Distancia

depende del tipo y la energía de la

partícula

Transferencia lineal de energía

(TEL)

determina la citotoxicidad

Periodo de semidesintegración

Adaptado a la semivida de

eliminación

Objetivo tumoral

- Vascularización rica

- Actividad metabólica

- Reacción del tejido sano adyacente

Captaciones

- Intracelular

(mIBG, iodo, análogos de SMS)

- Superficie celular

(AcM)

- Extracelular

(óseo)

- Intracapilar

(hígado)

Radiofármacos

- Objetivo:

- captación intensa y selectiva

- retención prolongada

- Tejidos normales:

- captación baja

- eliminación rápida

Dosimetria

Actividad:

La cantidad de

radiación

administrada, en MBq

Dosis:

La energía impartida por

la radiación por unidad

de masa, en Gray

Condiciones de tratamiento

AD

AP

TA

CIO

N

TO

XIC

IDA

D

DIF

ICU

LTA

DE

S

Actividad (dosis) fija

administraciones únicas o múltiples (GBq)

Actividad (dosis) adaptada a las características

del paciente

• Rudimentario

Peso (GBq por kg)

Área de superficie corporal (GBq por m²)

• Más preciso

(por ejemplo implicación de médula ósea)

Evaluación dosimétrica

• Propósito: calcular la actividad administrada para

obtener una dosis efectiva dada (GBq por cGy)

dosis al cuerpo entero

dosis al tumor

Pr Francesco GIAMMARILE

CHLS Lyon

Faculté de Lyon Sud

« Aut tace aut loquere meliora silentio »

TRATAMIENTO DEL DOLOR ÓSEO:

El presente: tratamiento paliativo

Terapéutica con radiofármacos

Nuclear Medicine

Bone scans

Gamma imaging: 99mTc-DP

+

PET : 18F-NaF

PET-CT SPECT-CT

Bone uptake specific

for bone lesion NOT

for metastasis

Osteolytic lesion + arthrosis

Bone metabolic reaction

Bone scan reflects new-

bone formation

(osteoblastic activity)

2

3

4

1

Even-Sapir, JNM 2005

Advantages

• complete exam

(soft tissue lesions)

• more specific

• follow-up

• prognosis

Metastases

detection

1) medullary

2) lytic

3) mix

4) blastic

FDG PET in Bone Malignancies

(Coleman RE, Cancer, 1997)

Skeletal Metastasis

Primary Bone metastasis Osteoblastic

Breast 65-75% 40%

Prostate 65-75% 80%

Lung 30-40% 10%

Thyroid 50%

Urinary bladder 40%

Kidney 20-25%

Melanoma 14-45%

45-50%

of all

tumours

Frequency

85% axial skeleton

40% spine

30% ribs and sternum

10% pelvis

10% scalp

15% long bones

Severe pain

Pathological fractures Spinal-cord compression

Hypercalcemia

Bone marrow infiltration

Mobility restriction

Sleep reduction

→ Worsening patient’s quality of life.

Complication of Skeletal Metastasis

Pathogenesis of bone pain

Experienced by <30-60% of patients, during the development of their disease

Krishnamurthy GT&S J Nucl Med 2000

Inflammation

pain

Tumor

proliferation

Disruption of

normal bone

remodeling

JP Vuillez, Grenoble

The “vicious loop”

Effective anti-tumor therapies

Chemotherapy

Hormonal therapy

Bisphosphonates

Palliation therapies

Pain-killing medications (analgesics, ...)

External beam radiotherapy

Surgery

Bone-seeking radiopharmaceuticals

Simultaneous treatment of multiple sites

Ease of administration

Repeatability

Potential integration with the other treatments

Bone pain: treatment options

Aim Palliation of patients with painful metastases is of primary

importance in the clinical management of advanced cancer.

Internal therapy with radionuclides - concentrate at sites of increased bone turnover

(radiation dose to the lesions while selectively sparring healthy

bone and associated bone marrow)

- control metastatic bone pain and improve quality of life as an

effective alternative treatment to conventional therapies

(analgesics, external beam radiotherapy)

- early treatments: literature data show the greatest benefit

- Prejudices: myelosuppression, high costs

Palliation of Bone Metastases

Krishnamurthy & Krishnamurthy. J Nucl Med 2000

Mechanisms of Bone Pain Palliation

by Ionizing Radiations

Bone-seeking radiopharmaceuticals

Radiopharmaceutical T1/2

(d)

Eβ (MeV) Range (mm) Eγ

(keV)

Dose (cGy/MBq)

nuclide labelled Max Ave Max Ave Lesion Bone

32P Phosphate 14.3 1.71 0.695 7.9 1.85 - 5 0.6

33P Phosphate 25.3 0.077 0.06

85Sr Chloride 64 0.015 (eA) 10 nm 514 8.2 1.4

89Sr Chloride 50.5 1.49 0.583 6.7 1.75 - 23 1

153Sm EDTMP 1.95 0.81 0.224 3.4 0.53 103 67 15

186Re HEDP 3.77 1.08 0.349 4.7 0.92 137 2 0.1

186Re HEDP 0.71 2.12 0.760 10.8 2.43 155 NA NA

117mSn DTPA 13.6 0.152 (eA) 0.15 158.6 5.4-8 0.1-0.2

- Short blood clearance - Low non-osseous uptake - Specific bone lesions uptake (bone scan)

Characteristics:

Emax (MeV)

Ma

xim

um

ran

ge o

f β

- p

art

icle

s

in w

ate

r (m

m)

Because of their path-length in tissues, β- particles

emitted at the osteoid layer hit all cells in the bone

marrow (including metastatic tumor cells)

osteoclasts

osteoblasts

d

Tumor cells

Inflammatory

cells

JP Vuillez, Grenoble

Choice of Radionuclide

1. Physical characteristics of the radionuclide

Half life Long: low activities, long dose delivery, long responses

Short: higher dose-rate (quick responses), treatment repetition (faster bone

marrow recovery, lower bone marrow toxicity), radioprotection (urine)

Path length of the emitted radiation in tissue Long: cross-fire

Short: lower non-target irradiation

Associated emission Present: external detection (quantification, dosimetry)

Absent: radioprotection (irradiation)

2. Bone marrow reserve

3. Availability of the radiopharmaceutical in single countries (different approvals in different countries)

Characteristics - Low cost, availability

- Not employed in EU

- Orthophosphate binds to hydroxyapatite crystals

- Severe bone marrow depression (also employed for the

treatment of polycitemia vera)

- 33P isotope can also be used (25.34d – 0.07 MeV – 0.06 mm)

Results Patients 500 prostate 350 breast

Activity 150-900 MBq

Response 77% (50% complete) 84% (20% complete)

Duration 5 months (+/-2.6)

Silberstein, Semin Oncol 1993, 20: 10-21

32P Orthophosphate

Characteristics - No more available

- Strontium exchanges with bone calcium (chemical analogue)

- Formerly used for bone scan detection, decays by electron

capture

- The associated X emissions (10 to 15 keV) allow effective

internal radiotherapy

Results Patients 119 prostate

Activity 335 MBq

Response 72% (49% complete)

Duration 4.3 months

Giammarile, J Nucl Med 1999, 40: 585-90

85Sr Chloride

Characteristics - Strontium exchanges with bone calcium (chemical analogue)

- First radionuclide employed for prostatic osteoblastic

metastases (Pecher, 1941) and most widely used

Results Patients 500 prostate

Activity 150 MBq

Responder 80% (30% complete)

Duration 3-6 months

Robinson, Cancer 1993, 72: 3433-5

89Sr Chloride (Metastron®)

Characteristics - Ethylenediamine tetramethylene phosphonate binds to

hydroxyapatite crystals

- Allows detection

- The most employed in EU

Results Patients 200 prostate

Activity 3.7 MBq/Kg

Responder 70% (20% complete)

Duration >2 months

Serafini, J Clin Oncol 1998, 16: 1574-81

153Sm EDTMP (Quadramet®)

Characteristics - Hydroxyethylidenediphosphonate binds to hydroxyapatite

crystals

- Allows detection

Results Patients 12 prostate 16 breast

Activity 1.3 GBq

Responder 67% 36%

Duration 45d 24d

Gauthier, J Nucl Med 2000

186Re HEDP

Characteristics - Hydroxyethylidenediphosphonate binds to hydroxyapatite

crystals

- Allows detection

- 188Re can be eluted from 188W/188Re generator (useful shelf-

life of several months)

Results Patients 27 prostate

Activity 2.7-3.5 GBq (depending on platelets count)

Responder 76% (20% complete)

Duration > 2 months

Liepe K, Br J Cancer. 2003

188Re HEDP

Characteristics - Tin exchanges with bone calcium (bone affinity)

- Good results in trials

- Allows detection

- Very short range of emission (Auger electron)

Results (phase I / II study) Patients 47 (30 prostate)

Activity 2.64-10.58 MBq/kg

Responder 75%

Srivastava, J Nucl Med 1999 (abstract)

117mSn DTPA

Procedure

1. Indications

Treatment of bone pain due to: - osteoblastic metastases or mixed osteoblastic lesions

- from prostate or breast carcinomas (established indications)

Any other primary or secondary bone tumour presenting osteoblastic lesions seen as areas of intense uptake at bone scan

(matching painful areas)

2. Absolute contraindications Pregnancy

Breastfeeding

Risk of acute spinal cord compression

Pathological fractures

No uptake on bone scan

Life expectancy < 4 weeks

This is the limit, but BSR are more beneficial in patients with relatively long

life expectancy !

Relative contraindications

Haematological disorders

(max in patients heavily pre-treated or in extensive bone marrow

involvement: “superscan”) Low blood cell count:

Hb <90 g/l

WBC <3.5×109/l

PLT <100×109/l

In selected situations lower values can be considered e.g. WBC ≥2.4×109/l, consider blood stem cell support

PLT≥60×109/l, exclude chronic DIC

Poor renal function

if GFR <50 ml/min: halve the dose

if GFR <30 ml/min (creatinine >180 μmol/l): exclude

“Chronic” spinal cord compression Corticosteroids

Bone pain limiting normal activities not easily controlled by analgesics

Recent bone scan (<4 weeks)

Exclude: neurogenic pain pathological fractures

Wait: ≥3 mo after wide-field RT ≥ 4 weeks after chemo

Recent full haematological and biochemical profile (<7 days) clotting tests if DIC suspected

Patient preparation

Slow intravenous infusion, followed by saline flush, of

89Sr-chloride: = 150 MBq

153Sm-lexidronam = 37 MBq/kg,

186Re-etidronate = 1,295 MBq

The amount of activity to be administered should be checked with an isotope calibrator ( emission)

Recommended activities

Whole body distribution Matches closely that of 99mTc-phosphonates: - Avidly concentrated by areas of high osteoblastic activity in the bone mineral matrix - Deposited in the mineral structure of newly synthesised bone

Bone lesions targeting Precise - Selective uptake and prolonged retention at sites of increased bone mineral turnover (especially those adjacent to metastatic lesions)

Whole-body retention Proportional to metastatic burden - Evaluated by the urinary excretion: from 11% to 88% (depending on the skeletal involvement)

Bone Uptake

“Flare” phenomena, usually within 72 hrs, in 10% of pts

Myelotoxicity: decrease in PLT and WBC (15-50%)

3-5 weeks nadir for 153Sm or 186Re

12-16 weeks nadir for 89Sr

Reversible in patient with normal haematological parameters (bone marrow reserve)

Blood monitoring (weekly basis) until baseline recovery (1-2m)

Calcium-like flush sensations

slow infusion!

Side effects

50

100

150

200

250

300

350

0 2 4 6 8 10 12 14 16

Placebo

0.5 mCi/kg

1.0 mCi/kg

Pla

tele

ts (×

10

3/μ

L)

Week Number

Dose-finding study for 153Sm-EDTMP

Highly predictable pattern of mild and

reversible hematologic toxicity

Efficacy of Therapy (Pain Palliation)

Radio-

pharmaceutical

Activity Partial

(%)

Complete

(%)

Begin (w) Duration

(w)

89SrCl2 148 MBq 50-65 20-25 2-4 12-26

153Sm-EDTMP 1.3 GBq 65-75 30 1-3 8-12

186°-HEDP 37 MBq/kg 60-75 18-20 1-2 8-10

Improved pain control and reduction of analgesic consumption:

- unlikely immediately after therapy

- more probable 2 weeks after therapy

- delayed even to 4 weeks, especially with 89Sr

- earlier with the shorter-lived radionuclides (higher dose-rate)

Typically at least 50% of the patients have a clinical benefit (significant

reduction of pain and analgesic requirements, better quality of life and

reduction of management costs) of which 20 to 30% became effectively pain

free

Variable duration of response (even for as long as 18 months).

(McQuay et al. Cochrane Database Syst Rev 2000; CD001793)

Efficacy of Therapy (physical

properties)

The mechanism of pain relief is controversial, probably, but not only, related to the absorbed dose in tumour and bone

Differences in physical T1/2 and energy of /γ emission

89Sr-chloride

prolonged onset of benefit

prolonged duration of response: up to 12 months

153Sm-lexidronam and 186Re-etidronate

rapid onset of benefit

shorter duration of response: up to 5-9 months

post-therapy scintigraphy: imaging and dosimetry

• Wide diffusion

• Short life expectancy

• Limited number of metastases

• Long life expectancy

Efficacy of Therapy (retreatment)

In responding patients when pain recurs

Quality of response may decrease

Haematological parameters must be recovered:

8 weeks for 153Sm-lexidronam

6-8 weeks for 186Re-etidronate

12 weeks for 89Sr-chloride

Basal bone scan Bone scan after 3 cycles

0 10 20 30 40 50 60 70 80 90

I c

yc

le

II c

yc

le

III c

yc

le

Ca 15.3

0 1 2 3 4 5 Months

Response after repeated 153Sm-

EDTMP treatments

Efficacy of Therapy (beyond

palliation)

Stabilization and reduction of tumour markers

Delayed occurrence of new painful sites and new metastases

Better response in patients with few metastases

Less brilliant results in patients with wide metastatic diffusion

Zyskowski A, et al. Australas Radiol 2001; 45: 39-42.

Open questions

Rationale - Palliative:

Evident (but difficult to evaluate: placebo)

- Anti-tumoral ?

Probably slow down the progression of metastatic lesions

(fewer new metastases with BSRn compared with external beam radiotherapy)

Dosimetry - Whole body dosimetry (depending on the renal function and tumour load):

patient specific whole body dose (rather than fixed or weight based activity) to

prevent bone marrow depletion ensuring the highest possible activities

- No clinical evidence of clear dose-response relationship

Efficacy of the treatment - Early prophylactic therapy of small metastases

- Improve dose uniformity using a radionuclide cocktail

- Repeated therapy at less toxic activities

- Randomized trials (competition with chemotherapy)

- Combination with other treatment modalities

Combined treatments

Effects of low-dose cisplatin on 89-Sr therapy for painful bone

metastases from prostate cancer Sciuto J Nucl Med 2002

Advanced androgen-indipendent prostate cancer bone-targeted

therapy Tu Lancet 2001

Bone seeking radiopharmaceuticals and Chemotherapy

A: Doxorubicin + 89Sr 27.7 months

B: Doxorubicin alone 16.8 months

C: Non randomised 11.1 months

Tu S-M, et al. Lancet 2001; 357: 336-341.

p=0.0014

Follow-up, months

Pro

bab

ilit

y o

f S

urv

ivin

g

1.0

0.8

0.6

0.4

0.2

0.0 70 60 50 40 30 20 10 0

153Sm-EDTMP alone (10 months)

153Sm-EDTMP + chemo 3-5 month apart

(11 months)

153Sm-EDTMP + chemo <1 month apart

(30 months)

P=0.008

P=0.023

(Ricci S, et al. Eur J Nucl Med Mol Imaging, 2007)

Semiquantitative assessment of uptake and retention of 153Sm-EDTMP

on the scintigraphic images showed maximum concentration in bone

metastases at 8 hours post-injection.

Optimizing the time of co-administration of docetaxel and samarium-

153 for advanced androgen-independent carcinoma of the prostate

Widmark et al. Proc Am Soc Clin Oncol 2003; 22: abstr. 1739

Optimal interval

between administration

of 153Sm-EDTMP and

docetaxel to obtain

maximal radiosen-

sitizing effect on tumor

while protecting normal

tissue: 8-24 hours.

Combined treatments

Other Randomized Trials

Palliation therapy with bone-seeking radionuclides

can be combined with external beam radiation on

selected site(s) at risk of impending fracture

Combined treatments

Bone seeking radiopharmaceuticals and Bisphosphonates

• Combined therapy with 153Sm-EDTMP and

Zoledronic acid is feasible

and safe.

• Competition was not found

in uptake of the bone-

seeking agent at the lesion

sites.

Lam et al. Eur J Nucl Med Mol Imaging 2008 153Sm-EDTMP 99mTc-DP

Conclusions

• Systemic radionuclide therapy is a feasible, safe, effective, well tolerated

and cost-effective palliative treatment in patients with refractory bone pain

• Patients at an early stage of metastatic disease benefit the most from

treatment. Only patients with a reasonably good general condition should

be candidated for this treatment (radioprotection rules)

• Treatment of bone metastases should be performed with a multidisciplinary

approach for better benefit of patients

• Most of the available therapies are synergistic rather than competitive

• In addition to bone pain palliation, bone-seeking radiopharmaceuticals may

have an anti-tumor effect per se, especially if combined with chemotherapy

• However,

• the evaluation of the pain relief is difficult (subjectivity, placebo), the

dosimetric calculations are not evident

• the competition with chemotherapy/bisphosphonates is important