terapéutica con radiofármacos...external beam radiation vs radioimmunotherapy for low-grade nhl...
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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
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