Julie R. Gralow, M.D.Julie R. Gralow, M.D.

Director, Breast Medical Oncology, Seattle Director, Breast Medical Oncology, Seattle РМЖРМЖ Care Alliance Care Alliance

Professor, Medical Oncology, University of Washington School of Professor, Medical Oncology, University of Washington School of MedicineMedicine

Member, Clinical Division, Fred Hutchinson Member, Clinical Division, Fred Hutchinson РМЖРМЖ Research Center Research Center

Лечение метастаз в кости и Лечение метастаз в кости и головной мозгголовной мозг

Рецидивы при метастатическом РМЖРецидивы при метастатическом РМЖПервичная Первичная БолееБолееобластьобласть поздний поздний АутопсияАутопсиярецидиварецидива рецидиврецидив seriesseries

• КостиКости 35-45%35-45% 65-70%65-70% 49-74%49-74%• ЛегкиеЛегкие 15-25%15-25% 35-45%35-45% 55-77%55-77% ((плевральныйплевральныйPleural effusions) Pleural effusions) (50%)(50%)• ПеченьПечень 5-10%5-10% 30-40%30-40% 50-75%50-75%• ЦНСЦНС редкоредко 10-15%10-15% 20-40%20-40%

• В общем, рецидив РМЖ является системным и появляется В общем, рецидив РМЖ является системным и появляется во многих органахво многих органах

КостныеКостные метастазыметастазы припри РМЖРМЖ

• 65-75% 65-75% пациентов с пациентов с метастатическимметастатическим РМЖРМЖ имеют нарушения вимеют нарушения в костяхкостях

• 50-70% 50-70% пациентов спациентов с метастатическим метастатическим поражениемпоражением костейкостей experience SREsexperience SREs

Средняя выживаемостьСредняя выживаемость: :

• ~ 2 ~ 2 годагода, , припри 20% 5 20% 5--летн.летн. выживаемостивыживаемости (Coleman 1997)(Coleman 1997)

• ~ 4 ~ 4 годагода (Giordano (Giordano 2004, Van Poznak 2005)2004, Van Poznak 2005)

Осложнения приОсложнения при РМЖРМЖ с метастазами с метастазами в костную тканьв костную ткань

• БольБоль

• Патологические Патологические переломыпереломы

• Компрессия спинного Компрессия спинного мозгамозга

• ГиперкальциемияГиперкальциемия• Лечение Лечение SkeletalSkeletal

осложненийосложнений составляют составляют 63% 63% больничных больничных расходов, связанных с расходов, связанных с ведением больных сведением больных с advancedadvanced РМЖРМЖ (Coleman, (Coleman, РМЖРМЖ 80:1588-1594, 1997) 80:1588-1594, 1997)

Лечение РМЖ с метастазами Лечение РМЖ с метастазами в костную тканьв костную ткань

• ОбезболиваниеОбезболивание

• Системная противораковая терапияСистемная противораковая терапия

• Ортопедические вмешательстваОртопедические вмешательства

• Лучевая терапия и радиоизотопыЛучевая терапия и радиоизотопы

• Ингибиторы остеокластов Ингибиторы остеокластов OsteoclastOsteoclast inhibition inhibition

Показания для ортопедических Показания для ортопедических вмешательстввмешательств

• Коррекция патологических Коррекция патологических переломовпереломов

• Профилактика Профилактика impendingimpending переломовпереломов

– Большинство больных Большинство больных безбез переломовпереломов не не нуждаются в нуждаются в хирургических хирургических вмешательствахвмешательствах

• лечениелечение//профилактикапрофилактика компрессийкомпрессий спинного мозгаспинного мозга

ScoringScoring Система предсказания Система предсказания возникновения патологических возникновения патологических

переломов, обусловленных метастазами в переломов, обусловленных метастазами в костную тканькостную ткань

Mirels H et al, Clin Ortho 2003Mirels H et al, Clin Ortho 2003PointsPoints

VariableVariable 1 1 2 2 3 3ОбластьОбласть верхн.верхн. extext ниж.ниж. extext peri-trochantericperi-trochantericБольБоль mildmild moderatemoderate mechanicalmechanicalРадиографРадиограф blasticblastic смешан.смешан. lyticlyticРазмерРазмер (% of shaft) (% of shaft) 0-330-33 34-6734-67 68-10068-100

ScoreScore пациентыпациенты (n) (n) частота переломовчастота переломов0-60-6 1111 0%0%77 1919 5%5%88 1212 33%33%99 77 57%57%1010 1818 100%100%

Recommend surgery Recommend surgery for score for score >> 8 8

НаружнаяНаружная BeamBeam лучевая терапиялучевая терапия

• ПоказанияПоказания– Освобождение от боли иОсвобождение от боли и профилактикапрофилактика переломовпереломовss

• ПользаПольза– Обезболивание, как минимум частично уОбезболивание, как минимум частично у 80-90% 80-90% пациентовпациентов– Костные метастазы с наиболее выраженными симптомами Костные метастазы с наиболее выраженными симптомами

начинают реагировать через начинают реагировать через 10-14 10-14 днейдней– Долгосрочный обезболивающий эффектДолгосрочный обезболивающий эффект (> 6-12 (> 6-12 месяцевмесяцев))

• ЛимитацияЛимитация– Местное применениеМестное применение– Многочисленные курсы радиотерапииМногочисленные курсы радиотерапии– Кумулятивный супрессивный эффект на костный мозгКумулятивный супрессивный эффект на костный мозг

• Дебаты в области оптимальных доз и продолжительности Дебаты в области оптимальных доз и продолжительности лечениялечения

костикости-seeking Radionuclides-seeking RadionuclidesMertens WC et al, CA Mertens WC et al, CA РМЖРМЖ J Clin 48:361-374, 1998 J Clin 48:361-374, 1998

• FDA approved: FDA approved: 3232P, P, 8989Strontium, Strontium, 153153Samarium-EDTMPSamarium-EDTMP• Greater experience in prostate than in breast due to lack of other Greater experience in prostate than in breast due to lack of other

systemic systemic лечениелечениеs and less visceral involvements and less visceral involvement• StrengthsStrengths

– Systemic, addresses all sites of Systemic, addresses all sites of костикости involvement involvement– Selective absorption into Selective absorption into костикости, delivers energy locally with , delivers energy locally with

minimal systemic effectsminimal systemic effects– Single IV dose produces pain relief in the majority of Single IV dose produces pain relief in the majority of пациентыпациенты

• LimitationsLimitations– Effect shorter-lived than external beam; reEffect shorter-lived than external beam; reлечениелечение or other or other

therapy requiredtherapy required– Transient marrow suppression limits concurrent use with Transient marrow suppression limits concurrent use with

chemotherapychemotherapy– Acute leukemia risk with Acute leukemia risk with 3232PP

Osteoclast InhibitionOsteoclast Inhibition

• BisphosphonatesBisphosphonates• RANK ligand inhibitorsRANK ligand inhibitors• Gallium nitrateGallium nitrate• Under investigation:Under investigation:– Cathepsin K inhibitorsCathepsin K inhibitors– Src kinase inhibitorsSrc kinase inhibitors

Breast Breast РМЖРМЖ and Osteoclast and Osteoclast InhibitionInhibition

PTHrP, prostaglandins, PTHrP, prostaglandins, interleukins, RANK-Linterleukins, RANK-L

IGF, PDGF, TGF-BIGF, PDGF, TGF-B

breast breast РМЖРМЖ cells cells osteoclasts osteoclasts

osteoblasts, osteoblasts, macrophagesmacrophages

Bisphosphonates in Treating Bisphosphonates in Treating костикости метастазыметастазы in Breast in Breast РМЖРМЖ

• Several bisphosphonates approved throughout Several bisphosphonates approved throughout the world for reduction in skeletal-related the world for reduction in skeletal-related complications in complications in пациентыпациенты with with костикости метастазыметастазы– clodronate (po)clodronate (po)– pamidronate (IV) - USpamidronate (IV) - US– zoledronic acid (IV) - USzoledronic acid (IV) - US– ibandronate (IV, po)ibandronate (IV, po)

• To date, no improvement in To date, no improvement in выживаемостьвыживаемость has been seen in has been seen in метастатическийметастатический breast breast РМЖРМЖ

In Vitro Potency of In Vitro Potency of BisphosphonatesBisphosphonates

Non-nitrogen containingNon-nitrogen containing

etidronate (Didronel)etidronate (Didronel) 11

clodronate (clodronate (костикостиfos)fos) 1010

Nitrogen containingNitrogen containing

pamidronate (Aredia)pamidronate (Aredia) 100100

alendronate (Fosamax)alendronate (Fosamax) 1,0001,000

risedronate (Actonel)risedronate (Actonel) 5,000-10,0005,000-10,000

ibandronate (Bondronat)ibandronate (Bondronat) 10,00010,000

zoledronic acid (Zometa)zoledronic acid (Zometa) 20,00020,000

Bisphosphonates Reduce Skeletal Related Bisphosphonates Reduce Skeletal Related Events (SRE) in Breast Events (SRE) in Breast РМЖРМЖ

% pts with SRE % pts with SRE

PlaceboPlacebo 65% 24 months 65% 24 months 11

PamidronatePamidronate 46%46%

PamidronatePamidronate 49% 24 months 49% 24 months 2 2

Zoledronic AcidZoledronic Acid 46% (p = not sig) 46% (p = not sig)

PlaceboPlacebo 50% 12 months 50% 12 months 33

Zoledronic AcidZoledronic Acid 30%30%

1 1 Lipton A et al, Lipton A et al, РМЖРМЖ, 2000;, 2000; 2 2 Rosen LS et al, Rosen LS et al, РМЖРМЖ, 2003;, 2003; 33 Kohno N et al, J Clin Kohno N et al, J Clin Oncol 23, 2005Oncol 23, 2005

Zoledronic Acid vs. Placebo in Stage IV Zoledronic Acid vs. Placebo in Stage IV Breast Breast РМЖРМЖ

Pain Scores (Brief Pain Inventory)Pain Scores (Brief Pain Inventory)Kohno N et al, J Clin Oncol 23, 2005Kohno N et al, J Clin Oncol 23, 2005

First -line Denosumab for First -line Denosumab for костикости метастазыметастазыDenosumab vs. Zoledronic Acid for Denosumab vs. Zoledronic Acid for профилактикапрофилактика

of Skeletal-Related Events in Breast of Skeletal-Related Events in Breast РМЖРМЖ Stopeck et al, J Clin Oncol 28, 2010Stopeck et al, J Clin Oncol 28, 2010

RANDOMIZE

Denosumab 120 mg s.c.Denosumab 120 mg s.c.Placebo I.V.Placebo I.V.q 4 weeksq 4 weeks

Zoledronic acid 4 mg I.V.Zoledronic acid 4 mg I.V.Placebo s.c.Placebo s.c.q 4 weeksq 4 weeks

(n = 1020)

(n = 1026)

пациентыпациенты with with костикости метастазыметастазы due to breast due to breast РМЖРМЖ

Denosumab is a monoclonal antibody that inhibits Denosumab is a monoclonal antibody that inhibits osteoclasts through the RANK ligand pathway. It was FDA osteoclasts through the RANK ligand pathway. It was FDA approved in 2010approved in 2010

Denosumab vs. Zoledronic Acid for Denosumab vs. Zoledronic Acid for профилактикапрофилактика of Skeletal-Related Events of Skeletal-Related Events

in Breast in Breast РМЖРМЖ Stopeck et al, J Clin Oncol 28, 2010Stopeck et al, J Clin Oncol 28, 2010

Denosumab compared to zoledronic acid:Denosumab compared to zoledronic acid:

• Subcutaneous vs intravenousSubcutaneous vs intravenous

• EfficacyEfficacy

• 23% reduction for time to first + subsequent SRE (23% reduction for time to first + subsequent SRE (PP = .001) = .001)

• 26% reduction for time to first radiation to 26% reduction for time to first radiation to костикости ( (PP = .01) = .01)

• 13% reduction for time to moderate/severe pain (13% reduction for time to moderate/severe pain (PP = .009) = .009)

• Similar overall disease progressionSimilar overall disease progression

• ToxicityToxicity

• ONJ 20 (denosumab) vs 14 (zoledronic acid)ONJ 20 (denosumab) vs 14 (zoledronic acid)

• No renal issues with denosumab – no need for pre-creatinineNo renal issues with denosumab – no need for pre-creatinine

• Reduced first infusion myalgias/arthralgias with denosumabReduced first infusion myalgias/arthralgias with denosumab

Breast Breast РМЖРМЖ Brain Brain метастазыметастазы

Brain Brain метастазыметастазы in Breast in Breast РМЖРМЖ• Incidence of CNS Incidence of CNS метастазыметастазы in advanced breast in advanced breast РМЖРМЖ

– Clinically apparent 10-15%Clinically apparent 10-15%– Autopsy seriesAutopsy series

» Parenchymal 30%, leptomeningeal 5-16%Parenchymal 30%, leptomeningeal 5-16%– Higher in HER2+, trastuzumab treated pts?Higher in HER2+, trastuzumab treated pts?

• Factors associated with a longer life expectancy Factors associated with a longer life expectancy include either well-controlled or no include either well-controlled or no метастазыметастазы outside outside the brain, and being able to carry out daily the brain, and being able to carry out daily routines without helproutines without help

лечениелечениеs for Brain s for Brain метастазыметастазы

• лечениелечение options for CNS options for CNS метастазыметастазы– Surgical resectionSurgical resection– Radiation therapyRadiation therapy

» Whole brain Whole brain » Focal radiation (stereotactic, gamma Focal radiation (stereotactic, gamma

knife)knife)» ?Radiation sensitizers?Radiation sensitizers

– Systemic therapySystemic therapy– Supportive medsSupportive meds

» Corticosteroids, anticonvulsants, Corticosteroids, anticonvulsants, pain controlpain control

Brain SurgeryBrain Surgery

• Used for 1-2 large Used for 1-2 large метастазыметастазы (sometimes up to 4), or when (sometimes up to 4), or when метастазыметастазы are too big for radiosurgery are too big for radiosurgery

• Surgery also sometimes done to confirm the diagnosis of brain Surgery also sometimes done to confirm the diagnosis of brain metastasismetastasis

– 10% of the time the suspected brain metastasis is 10% of the time the suspected brain metastasis is something else, like a primary brain tumor, a non-something else, like a primary brain tumor, a non-РМЖРМЖous ous mass, or an infectionmass, or an infection

• Whole brain radiation often given after surgery to prevent brain Whole brain radiation often given after surgery to prevent brain метастазыметастазы from recurring from recurring

– Definitive evidence that WBRT extends life when there is a Definitive evidence that WBRT extends life when there is a single brain metastasissingle brain metastasis

• Radiosurgery after surgery can also be used as a “boost” to Radiosurgery after surgery can also be used as a “boost” to prevent recurrence at the site of surgeryprevent recurrence at the site of surgery

Whole Brain Radiation Whole Brain Radiation Therapy (WBRT)Therapy (WBRT)

• Used for the Used for the лечениелечение of multiple brain of multiple brain метастазыметастазы, delivered to the , delivered to the entire brain. entire brain.

• Shown to extend life and improvequality of lifeShown to extend life and improvequality of life

• 30-40% of 30-40% of пациентыпациенты achieve complete reversal of symptoms; 75- achieve complete reversal of symptoms; 75-85% of 85% of пациентыпациенты experience some improvement or stabilization of experience some improvement or stabilization of symptoms, especially headache and seizure symptoms, especially headache and seizure 

• Short term  side effects include memory loss, particularly verbal Short term  side effects include memory loss, particularly verbal memory, fatigue, temporary baldness, skin rash memory, fatigue, temporary baldness, skin rash

• Factors associated with a longer life expectancy include either well-Factors associated with a longer life expectancy include either well-controlled or no controlled or no метастазыметастазы outside the brain, and being able to outside the brain, and being able to carry out daily routines without helpcarry out daily routines without help

• 50% of those who receive WBRT have recurrences in the brain 50% of those who receive WBRT have recurrences in the brain within a yearwithin a year

• Use of chemotherapy as radiosensitizers is experimentalUse of chemotherapy as radiosensitizers is experimental

Stereotactic Radiosurgery Stereotactic Radiosurgery (Gammaknife, Cyberknife, X-Knife or (Gammaknife, Cyberknife, X-Knife or

Stereotactic Radiosurgery)Stereotactic Radiosurgery)• Aims high doses of radiation in a targeted manner, minimizing Aims high doses of radiation in a targeted manner, minimizing

toxicitiestoxicities

• Generally not used for more than 3 Generally not used for more than 3 метастазыметастазы at a time, or at a time, or метастазыметастазы larger than 3 centimeters larger than 3 centimeters

• Severe side effects occur in 1-2%, including seizures, edema, Severe side effects occur in 1-2%, including seizures, edema, hemorrhage, and radionecrosishemorrhage, and radionecrosis

• Can be repeated if new brain Can be repeated if new brain метастазыметастазы appear appear

• Although no direct evidence exists, radiosurgery is thought to Although no direct evidence exists, radiosurgery is thought to be as effective, and safer, than regular surgery for be as effective, and safer, than regular surgery for метастазыметастазы up to 3 centimetersup to 3 centimeters

• Can also be used after regular surgery or WBRT as a “boost” to Can also be used after regular surgery or WBRT as a “boost” to prevent brain prevent brain метастазыметастазы from recurring from recurring

• Controversial: whether WBRT is necessary after radiosurgery  Controversial: whether WBRT is necessary after radiosurgery  

Systemic Therapies in Treating Systemic Therapies in Treating Brain Brain метастазыметастазы

• ChemotherapyChemotherapy

• Not extensively studied for brain Not extensively studied for brain метастазыметастазы in breast in breast РМЖРМЖ

• Most chemo drugs not able to cross the blood-brain Most chemo drugs not able to cross the blood-brain barrierbarrier

• Evidence is emerging that as brain Evidence is emerging that as brain метастазыметастазы grow they grow they disrupt the blood-brain barrier, making it possible for disrupt the blood-brain barrier, making it possible for chemotherapeutic drugs to get into the brain chemotherapeutic drugs to get into the brain

• Brain Brain метастазыметастазы usually occur late in the course of usually occur late in the course of breast breast РМЖРМЖ when resistance to chemo is more likely  when resistance to chemo is more likely 

• Drugs with activity: capecitabine, high-dose Drugs with activity: capecitabine, high-dose mexthotrexate, carboplatin,cisplatin, doxorubicinmexthotrexate, carboplatin,cisplatin, doxorubicin

Systemic Therapies in Treating Systemic Therapies in Treating Brain Brain метастазыметастазы

• Endocrine TherapyEndocrine Therapy

• Tamoxifen, aromatase inhibitors, and megestrol acetate Tamoxifen, aromatase inhibitors, and megestrol acetate effective in treating ER-positive breast effective in treating ER-positive breast РМЖРМЖ brain brain метастазыметастазы

• Majority of women with brain Majority of women with brain метастазыметастазы have tumors that have tumors that are estrogen receptor-negative or endocrine-resistantare estrogen receptor-negative or endocrine-resistant

• Hormone status of a brain metastasis can be different from Hormone status of a brain metastasis can be different from the hormonal status of the primary tumorthe hormonal status of the primary tumor

– Preliminary evidence that in Preliminary evidence that in метастазыметастазы, including brain , including brain метастазыметастазы, estrogen receptor, progesterone receptor, , estrogen receptor, progesterone receptor, and HER2 can hange from positive to negativeand HER2 can hange from positive to negative

Lapatinib as 1st-Line Lapatinib as 1st-Line лечениелечение in HER-2+ in HER-2+ Advanced Breast Advanced Breast РМЖРМЖ

Gomez HL et al, ASCO 2005, abstract #3046Gomez HL et al, ASCO 2005, abstract #3046

Lapatinib crosses the blood-brain barrierLapatinib crosses the blood-brain barrier

Patient D: Brain Lesion Baseline and 12 WeeksPatient D: Brain Lesion Baseline and 12 Weeks

Leptomeningeal Leptomeningeal метастазыметастазы (Carcinomatous Meningitis)(Carcinomatous Meningitis)

• 2-5% of 2-5% of метастатическийметастатический breast breast РМЖРМЖ пациентыпациенты develop develop leptomeningeal leptomeningeal метастазыметастазы

– Usually occurs at a very late stageUsually occurs at a very late stage

• Difficult to treat, since many drugs unable to penetrate Difficult to treat, since many drugs unable to penetrate into the CSF into the CSF

• Often brain Often brain метастазыметастазы and leptomeningeal and leptomeningeal метастазыметастазы occur at the same timeoccur at the same time

• No agreed-upon standard No agreed-upon standard лечениелечение

– Much of the time, benefits of Much of the time, benefits of лечениелечение are offset by are offset by лечениелечение side effects side effects

Leptomeningeal Leptomeningeal метастазыметастазы (Carcinomatous Meningitis)(Carcinomatous Meningitis)

• лечениелечение depends on whether leptomeningeal depends on whether leptomeningeal метастазыметастазы are bulky or are bulky or small and diffuse small and diffuse

• Radiation given to relieve symptoms in areas of bulky disease Radiation given to relieve symptoms in areas of bulky disease 

• Chemotherapy given for diffuse disease; may extend life for several Chemotherapy given for diffuse disease; may extend life for several monthsmonths

• No direct evidence that intrathecal chemotherapy is better than No direct evidence that intrathecal chemotherapy is better than intravenousintravenous

• Intrathecal therapy generally reserved for Intrathecal therapy generally reserved for пациентыпациенты whose systemic whose systemic disease is under controldisease is under control

– Methotrexate and cytarabine commonly usedMethotrexate and cytarabine commonly used

– Important to continue to treat other Important to continue to treat other метастатическийметастатический disease disease

– Usually delivered through an Ommaya reservoirUsually delivered through an Ommaya reservoir

– In 75%, progression occurs within eight weeksIn 75%, progression occurs within eight weeks

Ommaya ReservoirOmmaya Reservoir

Quantityof

Life

Qualityof

Life

лечениелечение of of метастатическийметастатический Breast Breast РМЖРМЖ: A Balancing Act: A Balancing Act

Balancing Balancing лечениелечение efficacy and toxicity is the efficacy and toxicity is the major objectivemajor objective