Julie R. Gralow, MD Director, Breast Medical Oncology, Seattle

Лечение метастаз в кости и
головной мозг
Julie R. Gralow, M.D.
Director, Breast Medical Oncology, Seattle РМЖ Care Alliance
Professor, Medical Oncology, University of Washington School of
Medicine
Member, Clinical Division, Fred Hutchinson РМЖ Research Center
Рецидивы при метастатическом РМЖ
Первичная
область
рецидива
Более
поздний
рецидив
• Кости
35-45%
65-70%
• Легкие
15-25%
35-45%
(плевральныйPleural effusions)
• Печень
5-10%
30-40%
• ЦНС
редко
10-15%
Аутопсия
series
49-74%
55-77%
(50%)
50-75%
20-40%
• В общем, рецидив РМЖ является системным и
появляется во многих органах
Костные метастазы при РМЖ
• 65-75% пациентов с
метастатическим РМЖ
имеют нарушения в
костях
• 50-70% пациентов с
метастатическим
поражением костей
experience SREs
Средняя выживаемость:
• ~ 2 года, при 20% 5летн. выживаемости
(Coleman 1997)
• ~ 4 года (Giordano
2004, Van Poznak
2005)
Осложнения при РМЖ с метастазами
в костную ткань
•
•
•
•
•
Боль
Патологические
переломы
Компрессия спинного
мозга
Гиперкальциемия
Лечение Skeletal
осложнений составляют
63% больничных
расходов, связанных с
ведением больных с
advanced РМЖ (Coleman,
РМЖ 80:1588-1594, 1997)
Лечение РМЖ с метастазами
в костную ткань
•
•
•
•
•
Обезболивание
Системная противораковая терапия
Ортопедические вмешательства
Лучевая терапия и радиоизотопы
Ингибиторы остеокластов Osteoclast
inhibition
Показания для ортопедических
вмешательств
• Коррекция патологических
переломов
• Профилактика impending
переломов
– Большинство больных
без переломов не
нуждаются в
хирургических
вмешательствах
• лечение/профилактика
компрессий спинного мозга
Scoring Система предсказания
возникновения патологических
переломов, обусловленных метастазами в
костную ткань
Mirels H et al, Clin Ortho 2003
Variable
Область
Боль
Радиограф
Размер
(% of shaft)
Score
0-6
7
8
9
10
Points
1
2
3
верхн. ext
ниж. ext
peri-trochanteric
mild
moderate
mechanical
blastic
смешан.
lytic
0-33
пациенты (n)
11
19
12
7
18
34-67
68-100
частота переломов
0%
5%
Recommend surgery
33%
for score > 8
57%
100%
Наружная Beam лучевая терапия
• Показания
– Освобождение от боли и профилактика переломовs
• Польза
– Обезболивание, как минимум частично у 80-90%
пациентов
– Костные метастазы с наиболее выраженными
симптомами начинают реагировать через 10-14 дней
– Долгосрочный обезболивающий эффект (> 6-12
месяцев)
• Лимитация
– Местное применение
– Многочисленные курсы радиотерапии
– Кумулятивный супрессивный эффект на костный мозг
• Дебаты в области оптимальных доз и продолжительности
лечения
кости-seeking Radionuclides
Mertens WC et al, CA РМЖ J Clin 48:361-374, 1998
• FDA approved: 32P, 89Strontium, 153Samarium-EDTMP
• Greater experience in prostate than in breast due to lack of
other systemic лечениеs and less visceral involvement
• Strengths
– Systemic, addresses all sites of кости involvement
– Selective absorption into кости, delivers energy locally
with minimal systemic effects
– Single IV dose produces pain relief in the majority of
пациенты
• Limitations
– Effect shorter-lived than external beam; reлечение or
other therapy required
– Transient marrow suppression limits concurrent use
with chemotherapy
– Acute leukemia risk with 32P
Osteoclast Inhibition
•
•
•
•
Bisphosphonates
RANK ligand inhibitors
Gallium nitrate
Under investigation:
– Cathepsin K inhibitors
– Src kinase inhibitors
Breast РМЖ and Osteoclast
Inhibition
PTHrP, prostaglandins,
interleukins, RANK-L
osteoblasts,
macrophages
breast РМЖ cells
osteoclasts
IGF, PDGF, TGF-B
Bisphosphonates in Treating
кости метастазы in Breast РМЖ
• Several bisphosphonates approved
throughout the world for reduction in skeletalrelated complications in пациенты with кости
метастазы
– clodronate (po)
– pamidronate (IV) - US
– zoledronic acid (IV) - US
– ibandronate (IV, po)
• To date, no improvement in выживаемость
has been seen in метастатический breast
РМЖ
In Vitro Potency of
Bisphosphonates
Non-nitrogen containing
etidronate (Didronel)
clodronate (костиfos)
Nitrogen containing
pamidronate (Aredia)
alendronate (Fosamax)
risedronate (Actonel)
ibandronate (Bondronat)
zoledronic acid (Zometa)
1
10
100
1,000
5,000-10,000
10,000
20,000
Bisphosphonates Reduce Skeletal Related
Events (SRE) in Breast РМЖ
% pts with SRE
Placebo
65% 24 months 1
Pamidronate
46%
Pamidronate
49% 24 months 2
Zoledronic Acid
46%
Placebo
50% 12 months 3
Zoledronic Acid
30%
(p = not sig)
A et al, РМЖ, 2000; 2 Rosen LS et al, РМЖ, 2003; 3 Kohno N et al, J Clin
Oncol 23, 2005
1 Lipton
Zoledronic Acid vs. Placebo in Stage IV
Breast РМЖ
Pain Scores (Brief Pain Inventory)
Kohno N et al, J Clin Oncol 23, 2005
First -line Denosumab for кости метастазы
Denosumab vs. Zoledronic Acid for профилактика
of Skeletal-Related Events in Breast РМЖ
Stopeck et al, J Clin Oncol 28, 2010
пациенты with
кости метастазы
due to breast
РМЖ
R
A
N
D
O
M
I
Z
E
Denosumab 120 mg s.c.
Placebo I.V.
q 4 weeks
(n = 1026)
Zoledronic acid 4 mg I.V.
Placebo s.c.
q 4 weeks
(n = 1020)
Denosumab is a monoclonal antibody that inhibits
osteoclasts through the RANK ligand pathway. It was FDA
approved in 2010
Denosumab vs. Zoledronic Acid for
профилактика of Skeletal-Related Events
in Breast РМЖ
Stopeck et al, J Clin Oncol 28, 2010
Denosumab compared to zoledronic acid:
• Subcutaneous vs intravenous
• Efficacy
• 23% reduction for time to first + subsequent SRE (P = .001)
• 26% reduction for time to first radiation to кости (P = .01)
• 13% reduction for time to moderate/severe pain (P = .009)
• Similar overall disease progression
• Toxicity
• ONJ 20 (denosumab) vs 14 (zoledronic acid)
• No renal issues with denosumab – no need for pre-creatinine
• Reduced first infusion myalgias/arthralgias with denosumab
Breast РМЖ Brain метастазы
Brain метастазы in Breast РМЖ
• Incidence of CNS метастазы in advanced breast РМЖ
– Clinically apparent 10-15%
– Autopsy series
» Parenchymal 30%, leptomeningeal 5-16%
– Higher in HER2+, trastuzumab treated pts?
• Factors associated with a longer life expectancy
include either well-controlled or no метастазы outside
the brain, and being able to carry out daily
routines without help
лечениеs for Brain
метастазы
• лечение options for CNS метастазы
– Surgical resection
– Radiation therapy
» Whole brain
» Focal radiation (stereotactic, gamma
knife)
» ?Radiation sensitizers
– Systemic therapy
– Supportive meds
» Corticosteroids, anticonvulsants,
pain control
Brain Surgery
• Used for 1-2 large метастазы (sometimes up to 4), or
when метастазы are too big for radiosurgery
• Surgery also sometimes done to confirm the diagnosis of
brain metastasis
– 10% of the time the suspected brain metastasis is
something else, like a primary brain tumor, a nonРМЖous mass, or an infection
• Whole brain radiation often given after surgery to prevent
brain метастазы from recurring
– Definitive evidence that WBRT extends life when there
is a single brain metastasis
• Radiosurgery after surgery can also be used as a “boost”
to prevent recurrence at the site of surgery
Whole Brain Radiation
Therapy (WBRT)
• Used for the лечение of multiple brain метастазы,
delivered to the entire brain.
• Shown to extend life and improvequality of life
• 30-40% of пациенты achieve complete reversal of
symptoms; 75-85% of пациенты experience some
improvement or stabilization of symptoms, especially
headache and seizure
• Short term side effects include memory loss, particularly
verbal memory, fatigue, temporary baldness, skin rash
• Factors associated with a longer life expectancy
include either well-controlled or no метастазы outside
the brain, and being able to carry out daily
routines without help
• 50% of those who receive WBRT have recurrences in the
Stereotactic Radiosurgery
(Gammaknife, Cyberknife, X-Knife or
Stereotactic Radiosurgery)
• Aims high doses of radiation in a targeted manner,
minimizing toxicities
• Generally not used for more than 3 метастазы at a time,
or метастазы larger than 3 centimeters
• Severe side effects occur in 1-2%, including seizures,
edema, hemorrhage, and radionecrosis
• Can be repeated if new brain метастазы appear
• Although no direct evidence exists, radiosurgery is
thought to be as effective, and safer, than regular surgery
for метастазы up to 3 centimeters
• Can also be used after regular surgery or WBRT as a
“boost” to prevent brain метастазы from recurring
• Controversial: whether WBRT is necessary after
radiosurgery
Systemic Therapies in Treating
Brain метастазы
• Chemotherapy
• Not extensively studied for brain метастазы in breast
РМЖ
• Most chemo drugs not able to cross the blood-brain
barrier
• Evidence is emerging that as brain метастазы grow they
disrupt the blood-brain barrier, making it possible for
chemotherapeutic drugs to get into the brain
• Brain метастазы usually occur late in the course of
breast РМЖ when resistance to chemo is more likely
• Drugs with activity: capecitabine, high-dose
mexthotrexate, carboplatin,cisplatin, doxorubicin
Systemic Therapies in Treating
Brain метастазы
• Endocrine Therapy
• Tamoxifen, aromatase inhibitors, and megestrol acetate
effective in treating ER-positive breast РМЖ brain
метастазы
• Majority of women with brain метастазы have tumors
that are estrogen receptor-negative or endocrineresistant
• Hormone status of a brain metastasis can be different
from the hormonal status of the primary tumor
– Preliminary evidence that in метастазы, including
brain метастазы, estrogen receptor, progesterone
receptor, and HER2 can hange from positive to
negative
Lapatinib as 1st-Line лечение in HER-2+
Advanced Breast РМЖ
Gomez HL et al, ASCO 2005, abstract #3046
Lapatinib crosses the blood-brain barrier
Patient D: Brain Lesion Baseline and 12 Weeks
Leptomeningeal метастазы
(Carcinomatous Meningitis)
• 2-5% of метастатический breast РМЖ пациенты develop
leptomeningeal метастазы
– Usually occurs at a very late stage
• Difficult to treat, since many drugs unable to penetrate
into the CSF
• Often brain метастазы and leptomeningeal метастазы
occur at the same time
• No agreed-upon standard лечение
– Much of the time, benefits of лечение are offset by
лечение side effects
Leptomeningeal метастазы
(Carcinomatous Meningitis)
• лечение depends on whether leptomeningeal метастазы are
bulky or small and diffuse
• Radiation given to relieve symptoms in areas of bulky
disease
• Chemotherapy given for diffuse disease; may extend life for
several months
• No direct evidence that intrathecal chemotherapy is better
than intravenous
• Intrathecal therapy generally reserved for пациенты whose
systemic disease is under control
– Methotrexate and cytarabine commonly used
– Important to continue to treat other метастатический
disease
– Usually delivered through an Ommaya reservoir
Ommaya Reservoir
лечение of метастатический
Breast РМЖ: A Balancing Act
Balancing лечение efficacy and toxicity is the
major objective
Quantity
of
Life
Quality
of
Life