Combined Therapies for Bone Combined Therapies for Bone MetastasesMetastases

Giuliano MarianiRegional Center of Nuclear Medicine, University of Pisa Medical School, Pisa

(Italy)

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.

Bone metastases• 85% axial skeleton

– 40% spine– 30% ribs and sternum– 10% pelvis – 10% scalp

• 15% long bones

InflammationInflammation⇒⇒ painpain

Tumorproliferation

Disruption of normal boneremodeling

JP Vuillez, Grenoble

The The ““vicious loopvicious loop””

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.

Excruciating painMobility restrictionSleep reduction

Worsening patient’s quality of life.

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

Pain from Bone Metastasis

•• Multidisciplinary approach!Multidisciplinary approach!

•• Most therapies are compleMost therapies are comple--mentary rather than compementary rather than compe--titive!titive!

Bone-Seeking Radionuclides• Simultaneous treatment of multiple sites.

• Ease of administration.• Repeatability.• Low cost.• Integration with the other therapies.

Bone seeking radiopharmaceuticalsBone seeking radiopharmaceuticals

BisphosphonatesBisphosphonatesCompetition in Competition in bone uptake???bone uptake???

•• 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

rhTSH-stimulated 123I-WBS: multiple bone metastases from follicular thyroid cancer (serum Tg: 3810 ng/mL)

Simultaneous whole-body 99mTc-HDP scan for better localization of the 123I-avid lesions

Post-therapy WBS after 3.7 GBq131I, following prior surgical debulking of the two major skull lesions.

Three-year follow-up: 0.1 ng/mL serum Tg with suppressed TSH, 0.7 ng/mL after rhTSH stimulation.

Palliation therapy with bone-seeking radionuclides can be combined with external beam radiation on selected

site(s) at risk of impending fracture

Beyond Palliation of Bone Pain

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)

osteoclastsosteoclasts

osteoblastsosteoblasts

d

TumorTumor cellscells

InflammatoryInflammatorycellscells

JP Vuillez, Grenoble

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.

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

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

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.

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

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)

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)

………………………………………………………………………………………………………………

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

PSA Response by Cohort(Morris et al. J Clin Oncol 2009)

All pts Taxane-naive disease

Taxane pretreated pts Taxane-refractory disease