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Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle РМЖ Care Alliance

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.

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Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle РМЖ Care Alliance

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  1. Лечение метастаз в кости и головной мозг Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle РМЖCare Alliance Professor, Medical Oncology, University of Washington School of Medicine Member, Clinical Division, Fred Hutchinson РМЖResearch Center

  2. Рецидивы при метастатическом РМЖ Первичная Более область поздний Аутопсия рецидиварецидивseries • Кости 35-45% 65-70% 49-74% • Легкие 15-25% 35-45% 55-77% (плевральныйPleural effusions) (50%) • Печень 5-10% 30-40% 50-75% • ЦНСредко 10-15% 20-40% • В общем, рецидив РМЖ является системным и появляется во многих органах

  3. КостныеметастазыприРМЖ • 65-75% пациентов с метастатическимРМЖимеют нарушения вкостях • 50-70% пациентов сметастатическим поражениемкостейexperience SREs Средняя выживаемость: • ~ 2 года, при 20% 5-летн.выживаемости(Coleman 1997) • ~ 4 года(Giordano 2004, Van Poznak 2005)

  4. Боль Патологические переломы Компрессия спинного мозга Гиперкальциемия Лечение Skeletalосложненийсоставляют 63% больничных расходов, связанных с ведением больных сadvancedРМЖ(Coleman, РМЖ80:1588-1594, 1997) Осложнения приРМЖс метастазами в костную ткань

  5. Лечение РМЖ с метастазами в костную ткань • Обезболивание • Системная противораковая терапия • Ортопедические вмешательства • Лучевая терапия и радиоизотопы • Ингибиторы остеокластов Osteoclast inhibition

  6. Коррекция патологических переломов Профилактика impendingпереломов Большинство больных безпереломовне нуждаются в хирургических вмешательствах лечение/профилактикакомпрессийспинного мозга Показания для ортопедических вмешательств

  7. ScoringСистема предсказания возникновения патологических переломов, обусловленных метастазами в костную тканьMirels H et al, Clin Ortho 2003 Points Variable 1 2 3 Областьверхн.extниж.extperi-trochanteric Боль mild moderate mechanical Радиографblasticсмешан.lytic Размер (% of shaft) 0-33 34-67 68-100 Scoreпациенты(n) частота переломов 0-6 11 0% 7 19 5% 8 12 33% 9 7 57% 10 18 100% Recommend surgery for score > 8

  8. НаружнаяBeamлучевая терапия • Показания • Освобождение от боли ипрофилактикапереломовs • Польза • Обезболивание, как минимум частично у80-90% 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

  9. кости-seeking RadionuclidesMertens WC et al, CA РМЖJ 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 костиinvolvement • 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; reлечениеor other therapy required • Transient marrow suppression limits concurrent use with chemotherapy • Acute leukemia risk with 32P

  10. Osteoclast Inhibition • Bisphosphonates • RANK ligand inhibitors • Gallium nitrate • Under investigation: • Cathepsin K inhibitors • Src kinase inhibitors

  11. Breast РМЖand Osteoclast Inhibition PTHrP, prostaglandins, interleukins, RANK-L osteoblasts, macrophages breast РМЖcells osteoclasts IGF, PDGF, TGF-B

  12. Bisphosphonates in Treating костиметастазы in Breast РМЖ • Several bisphosphonates approved throughout the world for reduction in skeletal-related complications in пациенты with костиметастазы • 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

  13. In Vitro Potency of Bisphosphonates Non-nitrogen containing etidronate (Didronel) 1 clodronate(костиfos) 10 Nitrogen containing pamidronate (Aredia) 100 alendronate (Fosamax) 1,000 risedronate (Actonel) 5,000-10,000 ibandronate (Bondronat) 10,000 zoledronic acid (Zometa) 20,000

  14. % pts with SRE Placebo 65% 24 months 1 Pamidronate 46% Pamidronate 49% 24 months 2 Zoledronic Acid 46% (p = not sig) Placebo 50% 12 months 3 Zoledronic Acid 30% Bisphosphonates Reduce Skeletal Related Events (SRE) in Breast РМЖ 1 Lipton A et al, РМЖ, 2000; 2 Rosen LS et al, РМЖ, 2003;3Kohno N et al, J ClinOncol 23, 2005

  15. Zoledronic Acid vs. Placebo in Stage IV Breast РМЖPain Scores (Brief Pain Inventory) Kohno N et al, J ClinOncol 23, 2005

  16. First -line Denosumab for костиметастазыDenosumab vs. Zoledronic Acid for профилактика of Skeletal-Related Events in Breast РМЖStopeck et al, J ClinOncol 28, 2010 Denosumab 120 mg s.c. Placebo I.V. q 4 weeks RANDOMI ZE пациентыwith костиметастазыdue to breast РМЖ (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

  17. Denosumab vs. Zoledronic Acid for профилактика of Skeletal-Related Events in Breast РМЖStopeck et al, J ClinOncol 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

  18. Breast РМЖ Brain метастазы

  19. Brain метастазыin Breast РМЖ • Incidence of CNS метастазыin advanced breast РМЖ • Clinically apparent 10-15% • Autopsy series • Parenchymal 30%, leptomeningeal 5-16% • Higher in HER2+, trastuzumabtreated 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

  20. 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

  21. 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 non-РМЖous 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

  22. 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 brain within a year • Use of chemotherapy as radiosensitizers is experimental

  23. 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

  24. 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

  25. 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 endocrine-resistant • 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

  26. Lapatinib as 1st-Line лечениеin HER-2+ Advanced Breast РМЖGomez HL et al, ASCO 2005, abstract #3046Lapatinib crosses the blood-brain barrierPatient D: Brain Lesion Baseline and 12 Weeks

  27. Leptomeningealметастазы (Carcinomatous Meningitis) • 2-5% of метастатический breast РМЖпациенты develop leptomeningealметастазы • Usually occurs at a very late stage • Difficult to treat, since many drugs unable to penetrate into the CSF • Often brain метастазы and leptomeningealметастазы occur at the same time • No agreed-upon standard лечение • Much of the time, benefits of лечение are offset by лечение side effects

  28. Leptomeningealметастазы (Carcinomatous Meningitis) • лечение depends on whether leptomeningealметастазы 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 • In 75%, progression occurs within eight weeks

  29. Ommaya Reservoir

  30. лечение of метастатический Breast РМЖ: A Balancing ActBalancing лечениеefficacy and toxicity is the major objective Quantity of Life Quality of Life

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