combined therapies for bone metastases · 2016-08-09 · pain from bone metastasis •effective...
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Combined Therapies for Bone Combined Therapies for Bone MetastasesMetastases
Giuliano MarianiRegional Center of Nuclear Medicine, University of Pisa Medical School, Pisa
(Italy)
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Most Common Skeletal Metastasis
•• Breast (70%)Breast (70%) ⇒ 40% osteoblastic•• Prostate (70%)Prostate (70%) ⇒ 80% osteoblastic•• Lung (30%) Lung (30%) ⇒ 10% osteoblastic•• Thyroid (50%)Thyroid (50%)•• KidneyKidney--Bladder (25%)Bladder (25%)•• StomachStomach•• OvaryOvaryUsually a late manifestation of cancer spread, more common in slow growing cancers.
45-50%of alltums.
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Bone metastases• 85% axial skeleton
– 40% spine– 30% ribs and sternum– 10% pelvis – 10% scalp
• 15% long bones
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InflammationInflammation⇒⇒ painpain
Tumorproliferation
Disruption of normal boneremodeling
JP Vuillez, Grenoble
The The ““vicious loopvicious loop””
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Full-Blown Skeletal Metastases
•• Source of considerable morbidity: pain, hypercalcemia, Source of considerable morbidity: pain, hypercalcemia, compression of spinal cord, pathologic fracture, bone compression of spinal cord, pathologic fracture, bone marrow infiltration.marrow infiltration.
•• Pain initially mild to moderate, progresPain initially mild to moderate, progres--sively increasing, sively increasing, becoming multifocal and refractory to various treatments.becoming multifocal and refractory to various treatments.
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Excruciating painMobility restrictionSleep reduction
Worsening patient’s quality of life.
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Pain from Bone Metastasis•• Effective antiEffective anti--tumor therapies:tumor therapies:
- chemotherapy- hormonal therapy- anti-tumor radiopharmaceuticals
• Bisfosfonates• Bone-seeking radiopharmaceuticals
•• Palliation therapies:Palliation therapies:- external beam radiation therapy- surgery- pain-killing medications
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Pain from Bone Metastasis
•• Multidisciplinary approach!Multidisciplinary approach!
•• Most therapies are compleMost therapies are comple--mentary rather than compementary rather than compe--titive!titive!
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Bone-Seeking Radionuclides• Simultaneous treatment of multiple sites.
• Ease of administration.• Repeatability.• Low cost.• Integration with the other therapies.
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Bone seeking radiopharmaceuticalsBone seeking radiopharmaceuticals
BisphosphonatesBisphosphonatesCompetition in Competition in bone uptake???bone uptake???
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•• Combined treatment with Combined treatment with ZoledronicZoledronic acid and acid and 153153SmSm--EDTMP is feasible and safe.EDTMP is feasible and safe.
•• Competition was not found in lesion uptake of the Competition was not found in lesion uptake of the bonebone--seeking agent.seeking agent.
Lam et al. Eur J Nucl Med Mol Imaging 2008
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rhTSH-stimulated 123I-WBS: multiple bone metastases from follicular thyroid cancer (serum Tg: 3810 ng/mL)
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Simultaneous whole-body 99mTc-HDP scan for better localization of the 123I-avid lesions
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Post-therapy WBS after 3.7 GBq131I, following prior surgical debulking of the two major skull lesions.
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Three-year follow-up: 0.1 ng/mL serum Tg with suppressed TSH, 0.7 ng/mL after rhTSH stimulation.
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Palliation therapy with bone-seeking radionuclides can be combined with external beam radiation on selected
site(s) at risk of impending fracture
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Beyond Palliation of Bone Pain
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Emax (MeV)Maxim
um ra
nge o
f β-pa
rticles
in wa
ter (m
m)Because of their path-length in tissues, β- particles emitted
at the osteoid layer hit all cells within the bone marrow (including metastatic tumor cells)
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osteoclastsosteoclasts
osteoblastsosteoblasts
d
TumorTumor cellscells
InflammatoryInflammatorycellscells
JP Vuillez, Grenoble
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Biochemical Response to Therapy with Bone-Seeking Radionuclides
• Sciuto et al. J Nucl Med 2000:- reduced serum levels of tumormarkers (PSA, Ca15.3) after 186Re-
HEDP.
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Response to 153Sm-EDTMP
BaselineBaseline bonebone scanscan BoneBone scanscan afterafter 33 cyclescycles
0102030405060708090
I cyc
le
II cy
cle
III cy
cle
Ca 15.3
0 1 2 3 4 5 Months
Courtesy of L. Bodei, EIO, Milan
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Prolonged survival with high doses (2.5 Prolonged survival with high doses (2.5 mCimCi/kg) of /kg) of 153153SmSm--EDTMP (but higher EDTMP (but higher myelotoxicitymyelotoxicity).).
(Collins et al. J Nucl Med 1993)
Metastatic Prostate Cancer
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8989Sr slows down bone resorption up to at least 6 months Sr slows down bone resorption up to at least 6 months after palliation (urinary pyridinium collagen crossafter palliation (urinary pyridinium collagen cross--links).links).
Papatheofanis FJ. J Nucl Med 1997; 38: 1175-9.
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A: Doxorubicin + A: Doxorubicin + 8989SrSr 27.7 months27.7 monthsB: DoxorubicinB: Doxorubicinalonealone 16.8 months16.8 monthsC: Non randomisedC: Non randomised 11.1 months11.1 months
Tu S-M, et al. Lancet 2001; 357: 336-341.
p=0.0014
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Zyskowski A, et al. Australas Radiol2001; 45: 39-42.
SimilarSimilar resultsresults reportedreported independentlyindependently byby Windsor Windsor (Clin Oncol - R Coll Radiol 2001) and and byby Van Van derderPel Pel etet al. al. (Urol Int 2006)
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FollowFollow--up, monthsup, months
Prob
abilit
y of S
urviv
ingPr
obab
ility o
f Sur
viving
1.0
0.8
0.6
0.4
0.2
0.0 706050403020100
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)
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………………………………………………………………………………………………………………
D = Docetaxel 75 mg/m2
Sm = 153Sm-EDTMP 37 MBq/kg (15 to 6 hours before Docetaxel)…… = Prednisone 10 mg/day (from Day-1 of cycle 1 to Day-21 of cycle 9)
65 7 8 93 4
3 weeks
Sm Sm SmD DD
1 2
D D D D DD
Sm
A Phase I Study of 153Sm-EDTMP + Docetaxel inPatients with Hormone-Resistant Prostate Cancer
(Morris et al. J Clin Oncol 2009)
Sm
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PSA Response by Cohort(Morris et al. J Clin Oncol 2009)
All pts Taxane-naive disease
Taxane pretreated pts Taxane-refractory disease