Erken evre pre-perimenopozal meme kanserinin adjuvan tedavisinde LHRH analoglarının yeri
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Erken evre pre-perimenopozal meme kanserinin adjuvan tedavisinde LHRH analoglarının yeri
- 1. ERKEN EVRE PRE/PERİMENOPOZAL MEME KANSERİNİN ADJUVAN TEDAVİSİNDE LHRH ANALOGLARI’NIN YERİ Dr Nilüfer Güler 24 Şubat 2011,Ankara
- 6. Endokrin Tedavi-Tarihsel Gelişim Reference: Howell, A . et al. Reviews on Endocrine-related Cancer. 1993; 43: 5-21 İlk yayın tarihi 1896 1922 1939 1944 1951 1952 1953 1953 1971 1973 1982 1987 1993 TEDAVİ Ooferektomi Ovarian radyasyon Androjenler Sentetik östrojenler Progestinler Pituiter radyasyon Adrenalektomi Hipofizektomi Antiöstrojenler Aromataz inhibitörleri LHRH agonistleri Antiprogestinler Saf antiöstrojenler YAZAR Beatson Courmelles Ulrich Haddow Esher Douglas Huggins Luft Cole Griffiths Klijn Romieu Howell
- 8. Adjuvan İlaç Tedavisi- EBCTCG 2005 Tedavi Nüks riskinde Ölüm riskinde p değeri net azalma % net azalma % Polikemoterapi < 50 yaş 12.3 10 <0.00001 > 50 yaş 4.2 3 <0.00001 Tamoksifen 11.8 9.2 <0.00001 Over ablasyonu 4.3 3.2 0.004 veya supresyonu 194 çalışma, 200.000 hasta ; 15 yıllık net yarar Lancet 2005:365:1687-717
- 9. EBCTCG 2005 Meta-Anal iz : OA/OFS/ 15-Y ıllık Nüks ve Mortalite (7601 hasta;yaş<50;%47 ER bilinmiyor ve %61 N+) EBCTCG, Lancet 2005
- 13. Kemoterapi Rejimlerine Eşlik Ettiği Bildirilen Amenore Oranları CMF (6 ay ) CAF veya FEC (3–6 ay ) AC (3 ay ) AC-Taksan >40 yaş grubu 30–39 yaş grubu CMF = Siklofosfamid , metotreksat , 5- florourasil CAF = Siklofosfamid , doksorubisin , 5- florourasil FEC = 5- florourasil , epirubisin , siklofosfamid AC = Doksorubisin , siklofosfamid Kemoterapi Amenore gelişen kadınların yüzdesi rejimi 30–40 10–25 13 44-61 80–95 80–90 57–63 81-84 Burstein HJ, Winer EP. N Engl J Med 2000; 343: 1086–94. Walche JM, et al. J Clin Oncol,2006.
- 14. Goodwin PJ, et al. J Clin Oncol. 1999;17:2365-2370. Reprinted with permission from the American Society of Clinical Oncology. Menopoz Riski İçin Matematik Model : Tanıdan 1 Yıl Sonra 0.2 0.4 0.6 0.8 1.0 0.0 25 30 35 40 45 50 55 None Horm Only Chem Only Both Age at Diagnosis (Years) Estimated Probability İnhibin A E2 FSH LH
- 15. Adjuvan Kemoterapi Sonucu Oluşan Amenorenin (AMe) Yaşa Göre Prognostik Önemi * *Aebi et al. Lancet 2000;355:1869-1874 IBCSG I, II, V, VII çalışmaları : Yalnız kemoterapi ile tedavi ER+ AM e - ER+ AM e + ER- AM e - ER- AM e + <35 yaş (n=169) 37% 47% 59% 50% 35 yaş (n=1714) 57% 64% 65% 58% 10- yıllık OS
- 16. KT Sonrası Amenore Prognostik Önemi (NSABP B30) N Engl J Med 2010;363:2268-70 ER+; HR:0.52 p=0.002 ER+;0.51;p<0.001
- 17. CMF ’nin İndüklediği Amenore : Hastalıksız Sağkalım Üzerine Etki 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 6 7 8 9 10 Hayır Evet 36. haftada amenore n = 817 Hastalıksız sağkalım ( yıl ) Hayatta ve hastalıksız olanların oranı
- 18. ‘ LHRH Analogları’ Etki Mekanizması (1) LHRH ( hipotalamus ) Hipofiz Estrojenler Progesteron Over ’ LHRH analogları – LHRH reseptörlerinin azalması Gonadotro pinler (FSH + LH)
- 21. Metastatik meme kanserli p re-/perimenop ozal kadınlarda LHRH analoğu vs cerrahi ooferektomi Kaynak Objektit yanıt oranı (%) Ortanca sağkalım Taylor CW, et al LHRH analog* 3.6mg Cerrahi ooferektomi LHRH a. 3.6mg Cerrahi oof. J Clin Oncol ( n =29*) ( n =30*) ( n =69) ( n =67) 1998; 16: 994 – 9. 31 27 37 ay 33 ay Boccardo F, et al LHRH analog 3.6mg Cerrahi ooferektomi LHRH a 3.6mg Cerrahi oof. Ann Oncol veya over rad veya over rad 1994; 5: 337 – 42. ( n =22*) (n=15*) ( n =24) ( n =18) 27 ( + 19) 47 ( + 25) 36 ay 38 ay *Goserelin Semin Oncol,2001
- 22. LHRHa+Tamoksifen Metastatik Meme Kanseri ER+ Metastatik meme kanseri; 161 premenopozal hasta,birinci basamak hormonal tedavi Klijn JG, et al. J Natl Cancer Inst. 2000;92:903-911. Tamo ks ifen Bu serelin Kombinasyon P değeri YO % 28 % 34 % 48 0.03 PS 5.6 ay 6.3 ay 9.7 ay 0.001 G S 2.9 yıl 2.5 yıl 3.7 y ıl 0.02
- 23. Metastatik Meme Kanseri LHRHa+Tamoksifen Klijn JG, et al. J Natl Cancer Inst. 2000;92:903-911. By permission of Oxford University Press and the National Cancer Institute. 40 50 60 70 80 90 100 10 20 30 0 0 2 4 6 8 10 O N 43 54 35 53 44 54 43 11 35 23 44 16 2 11 6 1 4 0 Number of patients at risk Years Treatment LHRH-A LHRH-A + TAM TAM Percentage of Patients Overall log-rank test: P = .0114
- 25. Goserelin 3.6mg ’ın LH ve Estradiol Düzeyleri Üzerindeki Etkileri West CP, et al. Clin Endocrinol 1987; 26: 213–20. LH = luteini zan hormon 0 1 2 3 4 5 6 7 8 12 16 20 35 30 25 20 15 10 5 0 LH (mU/ml) Süre ( hafta ) ( n =7) ‘ Goserelin ’ 3.6mg depot 1 2 3 4 5 6 Estradiol (pg/ml) ‘ Goserelin ’ 3.6mg depot 1 2 3 4 5 6 0 1 2 3 4 5 6 7 8 12 16 20 Süre ( hafta ) 300 250 200 150 100 50 0 ( n =7)
- 26. Tek Başına Tamoksifen ve Tamoksifen+LHRHa Tedavileri Öncesi ve Sonrasında Plazma Estradiol Konsantrasyonları LD Mastro et al.Cancer Treat Rev,2010 Tedavi İzlem Bazal 6 hafta 12 hafta 20 hafta 28 hafta 36/44 hafta Tamoksifen Hasta sayısı 31 31 21 13 14 10 Ortanca E2 (pg/ml) 80(4-544) 256(5-1523) 212(33-1632) 482(5-1034) 346(65-890) 16(35-1438) Tam+LHRHa Hasta sayısı 34 29 30 25 24 18 Ortanca E2 (pg/ml) 68(17-750) 19(5-107) 15(5-63) 16(5-71) 16(5-56) 17(7-42)
- 29. LHRHa veya KT Çalışmaları
- 31. Erken Evre Premenopozal Meme Kanseri Major Adjuvant LHRHa Çalışmaları CMF = cyclophosphamide + methotrexate + 5-fluorouracil; CAF = cyclophosphamide + adriamycin + 5-fluorouracil; Standard therapy = ±radiotherapy, ±cytotoxic chemotherapy 1. Kaufmann M. Breast 2001; 10 (Suppl 1): S30, Abstr P53. 2. Baum M, Houghton J, Odling-Smee W, et al. Breast 2001; 10 (Suppl 1): S32–3, Abstr P64. 3. Davidson NE, O’Neill A, Vukov A, et al. Breast 1999; 8: 232–3, Abstr 069. 4. Jakesz R, Hausmaninger H, Samonigg H, et al. Breast 2001; 10 (Suppl 1): S10, Abstr S26. 5. Boccardo F, Rubagotti A, Amoroso D, et al. J Clin Oncol 2000; 18: 2718–27. 6. Castiglione-Gertsch M, Gelber RD, O’Neill A, et al. Eur J Cancer 2000; 36: 549–50.
- 32. ZEBRA (Zoladex Early Breast Cancer Association) Çalışması Cerrahi ± Radyoterapi ‘ Goserelin ’ 3.6mg 28 günde bir, 2 yıl 1,6 14(%73,7 ER+) pre-/perimenop ozal hastalar, nod-positi f , erken meme kanseri , yaş 50 İzlem CMF 28- gün 6 siklus Randomi zasyon 1:1 ( açık,çok merkezli ) Nüks Ölüm Ölüm CMF = Cyclophosphamide, methotrexate, 5-fluorouracil
- 34. ZEBRA Son Analiz Sonuçları : ER+ Hastalarda Kaplan-Meier HS eğrisi ‘ Zoladex’ 3.6mg CMF 1.0 0 Hayatta ve hastalıksız olanların oranı Süre (yıl) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8 9 10 Kaufmann M, et al. Eur J Cancer 2003; 39: 1711–7.
- 35. ZEBRA Son Analiz Sonuçları : ER+ Hastalarda Kaplan-Meier Genel Sağkalım Eğrisi Süre (yıl) 1.0 0 Hayatta olanların oranı 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8 9 10 ‘ Zoladex’ 3.6mg CMF Ortanca izlem süresi 7.3 yıl Kaufmann M, et al. Eur J Cancer 2003; 39: 1711–7.
- 38. IBCSG VIII Çalışması : ER+ Hastalarda Kaplan–Meier HS Eğrileri 100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 Süre (yıl) Hayatta ve hastalıksız olanların yüzdesi ‘ Goserelin ’ 3.6mg ( n =229; 50 olay ) CMF ( n =247; 55 olay ) IBCSG. J Natl Cancer Inst 2003; 95: 1833–46. ( Nispi risk = 0.97; % 95 CI 0.66–1.42; p =0.86)
- 40. TABLE Çalışması
- 44. ABCSG AC05: Sonuçlar Nükssüz sağkalım (NS) RR=1.35; % 95 CI 1.02–1.79; p =0.0374 Lokal nükssüz sağkalım RR=1.86; % 95 CI 1.13–3.08; p =0.0150 Genel sağkalım RR=1.32; % 95 CI 0.87–1.99; p =0.1948 Ortanca izlem dönemi: 5 yıl RR = Nispi risk ; RR>1.00 , ‘ Goserelin ’ 3.6mg + tamoksifen lehinedir Ortanca 6 yıllık izlem sonucun da da NS yararı aynı şekilde devam etmektedir ( %73’7’ye karşılık % 78.1 ; p =0.045) CMF ile ‘ Goserelin ’ 3.6mg + tamoksifenin karşılaştırılması Jakesz R, et al. J Clin Oncol 2002; 20: 4621–7. Jakesz R. EJC Suppl 2003; 1(4): 1, Abstr O–3.
- 45. ABCSG AC05: Kaplan-Meier Nükssüz Sağkalım (RFS) Eğrileri Jakesz R, et al. J Clin Oncol 2002; 20: 4621–7. ‘ Goserelin ’ 3.6mg + tamoksifen CMF 100 90 80 70 0 60 48 36 24 12 0 Nükssüz sağkalım (%) Süre (ay)
- 46. ABCSG AC05: Kaplan-Meier Genel Sağkalım Eğrileri Jakesz R, et al. J Clin Oncol 2002; 20: 4621–7. 100 90 80 70 0 60 48 36 24 12 0 Genel sağkalım (%) Süre (ay) ‘ Zoladex’ 3.6mg + tamoksifen CMF
- 53. ZIPP-Çalışma Tasarımı Baum M. Eur J Cancer, 2006
- 54. Baum M. Eur J Cancer, 2006 ZIPP-Olaysız Sağkalım
- 55. Baum M. Eur J Cancer, 2006 ZIPP-Genel Sağkalım
- 57. ZIPP(Zoladex In Premenopausal Patients) Çalışması (J Natl Cancer Inst 2009;101:341-49) 20-40 mg-2 yıl 3,6 mg,ayda bir,2 yıl
- 58. ZIPP Çalışması (Ortanca izlem 12 yıl)
- 59. ZIPP Çalışması
- 62. INT-0101 Çalışmasının Sonuçları J Clin Oncol 2005;23:5973-82
- 65. Mam-1 GOCSI Çalışması : Sonuçlar Nispi Risk antrasiklin (+) vs antrasiklin (–) Nispi Risk yalnızca kemoterapi vs kemoterapi + endokrin tedavi Nüks 0.86 0.63 ( p =0.42) ( p =0.01) Sağkalım 0.79 0.86 ( p =0.31) ( p =0.52) Ortanca izlem süresi 5 yıl GS---- KET vs KT ( %82 vs %80 HR:0.84) Ortanca izlem 72 ay HS---- KET vs KT ( %64 vs %53 p=0.04) Ant vs Non ant HS %65 vs %54 ;GS %83 vs %79 ‘ Bu veriler erken meme kanserli premenopozal kadınlarda adjuvan kemoterapiden sonra kombine endokrin tedavi kullanılmasının yararlı olduğunu göstermektedir ’ Costanzo R, et al. Ann Oncol 2001; 12 (Suppl 4): 55, Abstr E19 De Placido S,et al. Br J Cancer 2005;92:467-74.
- 68. LHRHa Metaanaliz-Ana Sonuçlar Del Mastro L, Cancer Treat Rev,2010 Cuzick et al.Lancet,2007; Parton et al.J Clin Oncol 2008 Karşılaştırma n Nüks riskinde değişme P değeri Nüks sonrası ölüm riskinde değişme P değeri LHRHa vs Nonsistemik tedavi 338 -28.4 .08 -17.8 .49 (LHRHa+Tam) vs Nonsistemik tedavi 407 -58,4 <0.0001 -46,6 0.04 LHRHa+KT vs KT 2376 -12 .07 -13 .11 (LHRHa+Tam)+KT vs KT 1210 -27 .001 -24 .01 LHRHa+Tam vs Tam 1013 -14.5 .20 -15.9 .33 LHRHa+(KT ± Tam) vs (KT ± Tam) 2741 -12.2 .04 -15 .04 KT vs LHRHa 3184 +3.9 .52 -6.7 .40 LHRHa +(KT+Tam) vs (KT+Tam) 365 -16 0.37 -33 .14 LHRHa+Tam vs KT 1577 -10.1 .25 -11.1 .37
- 69. LHRHa veya Sistemik Tedavi Yok Klinik Yarar Cuzick J, et al. SABCS 2006. Abstract 15. Death After Recurrence Recurrence HR: 0.72; 95% CI: 0.50-1.03; P = .08 (n = 338) No systemic therapy LHRH agonist HR: 0.82; 95% CI: 0.47-1.43; P = .49 (n = 338) 9.2% vs 5.8% 3.4% reduction 33.7% vs 24.1% 9.6% reduction 0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization No systemic therapy LHRH agonist 0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization Recurrence (%) Death After Recurrence (%)
- 70. LHRH a Kemoterapi Kadar Etkilidir HR: 0.93; 95% CI: 0.79-1.10; P = .40 (n = 3184) HR: 1.04; 95% CI: 0.92-1.17; P = .52 (n = 3184) 29.8% vs 27.6% 2.2% increase 13.0% vs 12.1% 0.9% reduction Chemotherapy LHRH agonist Chemotherapy LHRH agonist 0 10 20 30 40 50 Recurrence (%) 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization 0 10 20 30 40 50 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization Death After Recurrence Recurrence Death After Recurrence (%) Cuzick J, et al. SABCS 2006. Abstract 15.
- 71. Tamoksifen’e LHRHa Eklenmesi ile Küçük, Önemli Olmayan Yarar Tamoxifen LHRH + tamoxifen HR: 0.86; 95% CI: 0.61-1.19; P = .33 (n = 1013) 8.8% vs 7.3% 1.5% reduction HR: 0.85; 95% CI: 0.67-1.09; P = .20 (n = 1013) Tamoxifen LHRH + tamoxifen 22.8% vs 18.2% 4.6% reduction 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization 0 10 20 30 40 50 Recurrence (%) 0 10 20 30 40 50 Death After Recurrence (%) Cuzick J, et al. SABCS 2006. Abstract 15. Death After Recurrence Recurrence
- 72. Kemoterapiye LHRHa Eklenmesiyle Önemli Klinik Yarar Chemotherapy ± tamoxifen LHRH addition HR: 0.85; 95% CI: 0.73-0.97; P = .04 (n = 3307) 13.1% vs 11.3% 1.8% reduction HR: 0.88; 95% CI: 0.73-0.93; P = .04 (n = 3307) Chemotherapy ± tamoxifen LHRH addition 29.4% vs 24.0% 5.4% reduction 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization 0 10 20 30 40 50 Recurrence (%) 0 10 20 30 40 50 Death After Recurrence (%) Death After Recurrence Recurrence Cuzick J, et al. SABCS 2006. Abstract 15.
- 75. LHRHa vs Diğer Tedaviler Çalışma LHRHa vs Tam (1400 hasta) Hasta No %ER+ LHRHa vs KT >3000 hasta Hasta No %ER+ Soreide 2002 (Goserelin) X 2 yıl T 320;ER? ZBSCG Trial B(Japonya) (Goserelin) X 2 yıl T 187;ER? ZIPP( Goserelin) X 2 yıl T 900; %68 GABG IV-A-93 (Goserelin) X 3 siklus CMF 771; %100 IBCSG VIII (Goserelin) X 6 siklus CMF 1111; %68 TABLE (Leuprolid) X 6 siklus CMF 599; ER? ZEBRA (Goserelin) X 6 siklus CMF 1189; %73.7
- 77. LHRHa+Tamoksifen vs Başka Tedavi Çalışma Vs Tamoksifen Vs LHRHa Vs Kemoterapi 1367 hasta LHRHa+AI vs LHRHa+Tam 1803 hasta ZBCSG Trial B (Goserelin) X (sonuç yok) X (sonuç yok) ZIPP (Goserelin) X X ECOG 5188 INT-0101 (Goserelin) X ABCSG 5 (Goserelin) X 6 CMF FASG 06 (Triptorelin) X FEC50 ABCSG-12 (Goserelin) X
- 79. SOFT(Supression Of Ovarian Function) ve TEXT(Tamoxifen and Exemestane Trial) Çalışmaları
- 82. LHRHa+Kemoterapi vs Başka Tedavi Çalışma Vs LHRHa Vs Kemoterapi IBCSG VIII (CMF) (Goserelin) X X CMF ECOG 5188 INT-0101 (CAF) (Goserelin) X CAF ZIPP (CMF-FEC) (Goserelin) X CMF-FEC GABG IV-B-93 (CMF) (Goserelin) X CMF CMF-EC Pretoria (CMF) (Buserelin) X CMF
- 84. LHRHa+KT+Tamoksifen vs KT Çalışma Vs Kemoterapi ECOG 5188 INT-0101 (Goserelin) X CAF ZIPP (Goserelin) X CMF-FEC MAM 01 GOCSI (Goserelin) X CMF veya A-CMF
- 87. LHRH-Early Breast Cancer Overview Group 2007+ Cochrane Metaanalizi 2009 Karşılaştırma Nüks riskini azaltma P değeri Nüks sonrası ölüm riskini azaltma P değeri Tüm ölümler P değeri Nüks veya ölüm P değeri LHRHa vs Tedavi yok %28 P=0.08 %17,5 P=0.11 ----- ----- LHRHa vs KT 1,04 P=0.52 0,93 P=0.40 -%9,4 P=0.27 %3 P=0.63 LHRHa+Tam vs KT 0,90 P=0.25 0,89 P=0.37 %12,8 P=0.27 %11,3 P=0.18 LHRHa+Tam vs Tam 0,85 P=0.20 0,84 P=0.33 -%13,7 P=0.39 -%13,9 P=0.21 KT vs KT+LHRHa ---- ----- -%11,5 P=0.14 -%11 P=0.08 KT vs KT+Tam+LHRH ---- ---- -%19,8 P=0.03 -%23,8 P=0.002
- 90. ZEBRA: Yaşam Kalitesi (2) Genel Yaşam Kalitesi ( başlangıca kıyasla pozitif değişiklik, düzelme anlamındadır ) de Haes H, et al. J Clin Oncol 2003; 21: 4510–6. NS = istatistik anlamlı değil 14 12 10 8 6 4 2 0 -2 3 . ay 2 . yıl 3 . yıl Vi z it Yaşam Kalitesi Puanı ‘ Goserelin ’ 3.6mg CMF Tedavi 1 . yıl 6 . ay p <0.0001 p <0.0001 NS NS NS
- 96. LHRHa-Yaş
- 99. INT 0101-YAŞ
- 100. J Natl Cancer Inst 2007;99:516-25 2144 kadın;5 yıl tamoksifen ± KT
- 105. h TEŞEKKÜR EDERİM
Notas del editor
- In 1996, it was exactly 100 years since George Beatson first published details of a favourable response of patients with advanced breast cancer to oophorectomy Endocrine drug treatment for advanced breast cancer assumed greater importance with the launch of the first antioestrogen, tamoxifen, in 1970 Although aromatase inhibitors were first used in the 1970s, it is only very recently that selective aromatase inhibitors have become available. Oral formulations and improved tolerability of this class of drug have brought new treatment strategy options to clinicians In the early 1980s, the potential benefits of LHRH agonists in premenopausal women with advanced breast cancer were established ‘ Pure’ (non-agonist) antioestrogens are still currently under development
- Surgical oophorectomy , results in immediate and permanent reduction in ovarian steroid production. The current laparoscopic surgical techniques are associated with less operative morbidity and are the usual means of removing the ovaries in the standard surgical situation. However, women who have a genetic predisposition to ovarian cancer—for example, women who carry mutations in the BRCA1 or BRCA2 genes—require open surgery with removal of the uterus. Node sampling and peritoneal washing are often recommended at the time of surgery for these women. Women who choose to have their uterus removed at the time of surgery would also have an open procedure. The removal of the ovaries permanently prevents the production of ovarian steroids such as estrogen and alleviates the burden of continued, expensive monthly injections (ie, with GnRH agonists). One of the difficult aspects of treatment in women who have received chemotherapy is the need for continued injections throughout the duration of their hormone therapy in order to reduce and prevent the production of estrogen by the ovaries. The use of a surgical oophorectomy can prevent the need for continued intervention. However, surgery induces early menopause and renders the recovery of ovarian estrogen production impossible. Therefore, this procedure is a difficult decision for most young women facing a diagnosis of breast cancer and the implications of early menopause.
- In this slide, a mathematical model of the risk of menopause based on age in the first year after diagnosis and related to the type of treatment given to a woman in the adjuvant setting can be viewed. It can be used as an assessment guideline for risk of menopause based on type of treatment. The first line on the graph shows that women younger than 40 years of age who received both chemotherapy and hormone therapy had < 50% chance of entering menopause in the first year of treatment. Many women who became menopausal in the first year of combined treatment recovered their ovarian function over time, and it should be noted that the menopause seen here was not permanent. The chance that women older than 40 years of age will become menopausal is much greater, roughly 80% or higher between 40 and 50 years of age and older. In women who received hormone therapy only, represented by the red x on lower curve of the slide, it is apparent that very few women achieve menopause. This is an important fact because many women in this population mistakenly believe that hormonal therapy such as tamoxifen can cause menopause. Hormonal agents may trigger an earlier (in terms of age) menopause, but they do not cause women to become menopausal.
- Q1: Yes/No for amenorrhoea at 36 weeks. Correct? A. Yes Q2: Is this the total CMF group, i.e. n = 817? A. Yes (not coming from P3)
- Gonadotropinlerin (FSH ve LH) salgılanmasını sağlayan normal uyaran, hipotalamustan pulsasyonlar şeklinde salınan LHRH’dır Premenopozal kadınlarda LH, overlerden estradiol salgılanmasını başlatır ‘ Zoladex’ , hipotalamus-hipofiz ekseni üzerinde LHRH reseptörlerini azaltarak etki eder
- ‘ Zoladex’ 3.6mg depo t’un ilk dozunun ardından goserelin, hipofiz hücresinin yüzeyindeki bütün LHRH reseptörlerine bağlanmıştır (Şekil A) Serum LH düzeyleri, bunun sonucunda geçici olarak artmış; ancak goserelinin bağlandığı LHRH reseptörleri kümeler oluşturarak yavaş yavaş hücre içerisine doğru çekilmiş, önce LH’nın, ardından da estradiolün güçlü bir şekilde supresyonuna neden olmuştur Devamlı olarak sentez edilen yeni LHRH reseptörleri de, ‘Zoladex’ 3.6mg depot’tan aralıksız salgılanan goserelin tarafından bağlanmıştır Böylece goserelinin sürekli varlığı, LHRH reseptörünün uyarılmasını engeller ve estrojen yapımının postmenopozal düzeylere inmesi, ‘medikal kastrasyon’ meydana gelmesiyle sonuçlanır (Şekil B) Kaynak Furr BJA. Hormone Res 1989; 32 (Suppl1): 86–92.
- A third, popular way to cause ovarian suppression in premenopausal women with early‑stage breast cancer is through the use of GnRH analogues, or GnRH agonists. These agents suppress ovarian function through agonist properties. High doses of GnRH agonists flood the body with hormone-releasing agent and prompt suppression of ovarian function. These agents are given as monthly or every-3-month injections and were first used in the treatment of metastatic prostate cancer. Available GnRH agonists include goserelin, leuprolide, and triptorelin. Monthly injection is the most appropriate administration schedule because data indicate it is more effective than injection every 3 months. When GnRH agonists are discontinued, particularly in young women, the effects are generally reversible, and menses may restart. This reversibility is likely to be age related: Suppression of menses is less likely to be reversible in women older than 40 years of age compared with women younger than 40 years of age. The duration of GnRH agonist therapy and its relationship to recoverability of ovarian function in not fully understood. Most studies have investigated 2 years of therapy and recovery. Whether 5 years of therapy affects the recoverability of ovarian function or not is unknown. The extent to which fertility is preserved in women receiving long-term ovarian suppression with GnRH agonists is also unknown. Isolated reports of breakthrough ovarian function in women who have substantial residual ovarian function (eg, in women younger than 35 years of age) have been reported. Breakthrough ovarian function in these women is managed through the regular monitoring of estradiol levels, which can help ensure continued ovarian suppression, as opposed to assuming that an amenorrhea state is equivalent to full ovarian suppression. Gonadotropin‑releasing hormone agonists possess fairly modest side effects that are similar to the effects of menopause. All individual side effects from GnRH agonists are associated with suppression of ovarian function. This can benefit patients by allowing them to experience the effects of menopause while still retaining a chance that ovarian function will return once treatment is stopped, in contrast to the immediate and final ovarian suppression with surgery. Although patients treated with GnRH agonists will not require surgery, it is necessary that they return to clinic monthly for injections during a long treatment course.
- The results of the studies by Taylor et al and Boccardo et al show that ‘Zoladex’ 3.6mg is an effective alternative to oophorectomy for the treatment of advanced breast cancer in premenopausal women with ER+ve/unknown tumours The study reported by Boccardo et al was extended to include two more arms: ‘ Zoladex’ 3.6mg + tamoxifen Oophorectomy (or ovarian irradiation) + tamoxifen
- An interesting data set comes from the metastatic or advanced disease setting and from investigators in the European Cooperative Oncology Group. Klijn and colleagues published these data in 2000 along with a subsequent meta‑analysis from several different trials. The researchers investigated 161 premenopausal women with metastatic hormone receptor–positive breast cancer who had not received prior tamoxifen . The women were randomized to receive tamoxifen , ovarian suppression with the gonadotropin‑releasing hormone (GnRH ) analogue goserelin, or the combination of the 2 agents. This slide shows that the response rate was significantly higher in patients receiving combination therapy, and this resulted in a longer duration of progression‑free survival as well as a prolongation of overall survival.
- This slide shows the effect of the addition of the GnRH agonist goserelin to tamoxifen given to patients in the Klijn and colleagues study. The solid line at the top represents the improvement in survival seen in patients receiving combination therapy. These data, along with other evidence in the metastatic setting, led to increased interest in exploring the role of ovarian suppression along with chemotherapy and hormone therapy in women with early stage premenopausal breast cancer who still potentially could be cured with the addition of such therapies as ovarian suppression.
- Kadın gönüllülere ‘Zoladex’ 3.6mg verilmesi (n=7), LH ve estradiol düzeylerinin azalmasıyla sonuçlanmıştır Üretilen LH miktarının azalması, estradiol düzeylerinin postmenopozal kadınlardaki değerlere yaklaşacak şekilde baskı altına girmesine (azalmasına) neden olmuştur
- LHRH, luteinizing hormone-releasing hormone. This slide displays the trials that were included in this meta-analysis. One potentially significant point to make is that for many of these studies, the LHRH analogue is being given for only 2 years, whereas in North America, most of the trials have used this agent administered for 5 years.
- ZEBRA = ‘ Z oladex’ 3.6mg E arly B reast Cancer R esearch A ssociation. ABCSG = A ustrian B reast & C olorectal Cancer S tudy G roup. GROCTA = Italian Breast Cancer Adjuvant Study Group.
- Kaplan–Meier eğrileri, ‘Zoladex’ 3.6 mg ve CMF kemoterapisinin, ER+ hastalarda DFS bakımından eşdeğerliliklerini devam ettirdiğini açıkça göstermektedir
- Bu eğriler ER+ hastalarda ‘Zoladex’ 3.6 mg’ın genel sağkalım bakımından CMF kemoterapisiyle eşdeğer olduğunu açıkça göstermektedir
- IBCSG = International Breast Cancer Study Group
- Nispi riskin <1 olması ‘Zoladex’ 3.6mg lehinedir ‘ Zoladex’ 3. 6mg’ın ER+, nod-negatif hastalarda CMF kemoterapisine benzer etkinliğe sahip olduğunu gösteren bu veriler; ‘Zoladex’ 3.6mg ’ın ER+, nod-pozitif hastalarda CMF kemoterapisine eşdeğer etkinliğe sahip olduğunu ortaya koyan ZEBRA çalışması verilerini desteklemektedir
- Bu eğriler ‘Zoladex’ 3.6mg ve CMF kemoterapisinin, ER+, nod-negatif erken evre meme kanserli premenopozal kadınlarda DFS bakımından benzer etkinliğe sahip olduğunu açıkça göstermektedir
- Bu çalışma, ‘Zoladex’ 3.6mg + tamoksifen kombinasyonunun, HR+ erken evre meme kanserli premenopozal kadınlarda etkinliğini, CMF kemoterapisiyle karşılaştırmak üzere 1990’da başlatıldı ABCSG = Austrian Breast and Colorectal Cancer Study Group
- Kaplan–Meier eğrileri, ‘Zoladex’ 3.6mg + tamoksifen kombinasyonunun nükssüz sağkalım bakımından CMF kemoterapisinden üstün olduğunu açıkça göstermektedir
- Kaplan–Meier eğrileri ‘Zoladex’ 3.6mg + tamoksifen kombinasyonunun genel sağkalım bakımından CMF kemoterapisine üstün olma eğilimi taşıdığını açıkça göstermektedir
- There was no difference in clinical outcome of patients treated with oophorectomy or ovarian irradiation compared with those treated with ‘Zoladex’ 3.6mg. The results of the small GROCTA 02 trial support those from the ABCSG AC05 trial. Both trials demonstrate the efficacy of ‘Zoladex’ 3.6mg plus tamoxifen in premenopausal women with hormone-sensitive, early breast cancer.
- This trial was set up to compare the combination of medical ‘ovarian ablation’ with an LHRHa (triptorelin) plus tamoxifen versus an anthracycline-based chemotherapy regimen, in premenopausal patients with hormone receptor+ve, node+ve (1–3 nodes), early breast cancer.
- Reseptör: At the time of trial design (1985) ER status was not routinely recorded among European patients. However, it became known subsequently that many ER negative cases were included in the study, providing an internal check on the plausibility of the results and emphasising the importance of routine measurement of this biological predictive factor.
- ZIPP analizinin sonuçları, ± radyoterapi ± kemoterapi ± tamoksifen şeklinde olabilen standart adjuvan tedaviye ‘Zoladex’ 3.6mg ilave edilmesinin, erken evre meme kanserli premenopozal kadınlarda hastalıksız sağkalımı ve genel sağkalımı anlamlı şekilde artırdığını gösterdi
- ECOG = Eastern Co-operative Oncology Group SWOG = South Western Oncology Group CALGB = Cancer and Leukemia Group B CAF = Siklofosfamid, doksorubisin, 5-florourasil
- GOCSI – Gruppo Oncologico Centro-Sud-Isole Bu çalışma, Önce adriamisin, daha sonra CMF kullanılmasının, tek başına CMF kemoterapisinden üstün olup olmadığının Kemoterapiden sonra 2 yıl boyunca endokrin tedavi ( ‘Zoladex’ 3.6mg + tamoksifen) kullanılmasının, yalnızca kemoterapi kullanılmasından daha üstün olup olmadığının araştırılması amacıyla yapılmıştır
- Sonuçlar; tümör büyüklüğüne, metastatik lenf nodu sayısına ve estrojen reseptörü durumuna göre düzeltilmiştir Nispi riskin <1.0 olması, antrasiklin kullanılması lehinedir Nispi riskin <1.0 olması, kemoterapi – endokrin tedavi kombinasyonu lehinedir
- LHRH, luteinizing hormone-releasing hormone. This slide displays the trials that were included in this meta-analysis. One potentially significant point to make is that for many of these studies, the LHRH analogue is being given for only 2 years, whereas in North America, most of the trials have used this agent administered for 5 years.
- CCO would like to thank the LHRH Agonists in Early Breast Cancer Overview Group for permission to use this figure. LHRH, luteinizing hormone-releasing hormone. Shown on this slide and the next few slides are comparisons of the effects of treatment on disease recurrence and death after recurrence. When comparing treatment with LHRH analogue with no systemic therapy, there is a trend toward an improvement in the risk of recurrence (HR = 0.72; P = .08) and an improvement in mortality (HR = 0.82; P = .49). This is really not a meta-analysis. This analysis includes data from only 1 trial, and in this trial, the LHRH analog was only given for 2 years. So the effect of LHRH analogue treatment is not as beneficial compared with what one might observe for tamoxifen treatment of younger patients. The LHRH analogues may have been used in a suboptimal way in this study.
- CCO would like to thank the LHRH Agonists in Early Breast Cancer Overview Group for permission to use this figure. LHRH, luteinizing hormone-releasing hormone. Shown on this slide are results of studies that suggest LHRH agonist therapy is as effective as chemotherapy. The recurrence of disease and mortality curves are essentially identical for these 2 treatments. It does not appear that one of these treatments would be favored over the other. Although this may be interesting news in Europe, I think these data are probably not as exciting in North America. I believe in North America, the usual treatment decision for almost all patients is whether to administer a hormonal therapy or a hormonal therapy plus chemotherapy. The idea that hormonal therapy is equivalent to chemotherapy is not the most important comparison. The most important comparison is whether or not hormonal therapy adds to chemotherapy.
- CCO would like to thank the LHRH Agonists in Early Breast Cancer Overview Group for permission to use this figure. LHRH, luteinizing hormone-releasing hormone. On this slide, the impact of adding LHRH agonists to tamoxifen is shown. The results demonstrate a slight trend for improvement in recurrence and also in mortality when patients are given the combination therapy. Again, this analysis is based on only 2 trials, and in these 2 trials the LHRH agonist was used for only a 2‑year duration.
- CCO would like to thank the LHRH Agonists in Early Breast Cancer Overview Group for permission to use this figure. LHRH, luteinizing hormone-releasing hormone. On this slide, the impact of adding an LHRH agonist to chemotherapy is shown. When the LHRH agon ist is added to chemotherapy, there is a statistically significant improvement in recurrence risk (HR = 0.88; P = .04) and in death after recurrence (HR= 0.85; P = .04) . I question this result being presented in this way. I would not expect a significant benefit to be seen in all age groups. In fact, in the question and answer period, the presenter was asked whether or not they performed a subset analysis by age. This initial benefit of adding a LHRH agonist to chemotherapy was only observed in the younger patients, presumably the patients who are still menstruating after chemotherapy.
- HR, hormone receptor; LHRH, luteinizing hormone-releasing hormone. The conclusions from this study were that the adjuvant use of LHRH agonists were effective in premenopausal women with hormone receptor – positive early breast cancer, were as effective as chemotherapy, and have some additional benefit when combined with tamoxifen. I would add to these conclusions that I think it is very important to stratify these analyses by patient age, particularly when considering the effectiveness of LHRH agonists compared with chemotherapy or in combination with chemotherapy. In terms of the effectiveness of LHRH agonists in combination with tamoxifen, we are conducting a large randomized study (the Suppression of Ovarian Function [SOFT] trial) evaluating whether or not that particular combination is effective.
- ‘ Zoladex’ 3.6mg , tedavinin ilk 6 ayında yaşam kalitesinin genel olarak yükselmesini sağladı