Radyoterapiyle Eşzamanlı Tedavilerin Uygulanışı

... konulu sunumlar: "Radyoterapiyle Eşzamanlı Tedavilerin Uygulanışı"— Sunum transkripti:

1 Radyoterapiyle Eşzamanlı Tedavilerin Uygulanışı
Dr Pervin HÜRMÜZ

2 Kombine Tedavinin Klinik Endikasyonları
KT radyasyona duyarlılığı arttırarak lokal kontrolü arttırabilir. Radyorezistan klonları öldürerek sağkalımı artırabilir. Eş zamanlı KT sistemik olarak etki gösterebilir ve mikrometastazları eradike eder. KemoRT organ koruyucu yaklaşım olarak kullanılabilir. KT cerrahi ve RT öncesi tümör yükünü ↓ için kullanılabilir.

3 Kombine Tedavi Dr Mine Genç

4 Kombine Tedavi

5 Etkileşim Total hücre ölümü fazla RT alanında toksisite artışı yok
Toksisite çeşitlerinde artış Erken evre Hodgkin Hastalığında ardışık uygulama

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7 Hodgkin Hastalığı

8 Bağımsız Etkiler

9 Hücresel ve Moleküler Etkileşme

10 Hücresel ve Moleküler Etkileşme

11 Doz Modifiye Edici Faktör

12 RADYO-KEMOTERAPİ ETKİLEŞİMİNİN MEKANİZMALARI

13 Radyo-kemoterapi etkileşiminin mekanizmaları
Kısa dönem etkileşim: Sağkalım eğrisinin şeklinde değiştirme Örnek: Tamir inhibisyonu, hipoksik hücre duyarlaştırılması Orta dönem etkileşim: Tümör repopulasyonu veya fizyolojisini değiştirme Örnek: Oksijenizasyon veya pH durumu. Diğer modaliteye dirençli hücrelerin öldürülmesi

14 Kısa dönem etkileşim Sağkalım eğrisinde değişiklik
Artmış radyasyon hasarı Mekanizma: DNA/RNA’ya bağlanma Örnek: 5FU, sisplatin DNA tamirinin inhibisyonu Mekanizma: RT sonrası DNA tamir prosesi ile etkileşir. Örnek: Halojenli pirimidinler, Nükleozid analoglar, Sisplatin, Metotreksat, Etoposid ,Doksorubisin, Hidroksiüre, BCNU, Carmustine, Lomustine

15 Kısa dönem etkileşim Hipoksiye bağlı radyoresistansın kırılması Mekanizma: -Hipoksik hücrelerin radyasyona duyarlaştırılması, Nitroimidazol (misonidazol, nimorazol) -Hipoksik hücrelerin selektif öldürülmesi Tirapazamin Mitomisin C

16 Kısa dönem etkileşim Sitokinetik kooperasyon ve senkronizasyon
Mekanizma Hücre siklusu spesifik: Çoğu ajan Hücrelerin radyosensitif G2 ve M fazlarında birikmesi: Taksan, Vinka alkolodi, Cisplatin, Etoposide, Bleomisin Radyoresistan S fazındaki hücrelerin eliminasyonu: 5FU, Cisplatin, Vinca alkaloidleri, Methotrexate

17 Hücre Döngüsüne Özgü Toksisite

18 Hücre Döngüsü Senkronizasyonu

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20 Orta-dönem etkileşim Mekanizmalar: Reoksijenizasyon Çoğu ajan
Pro-survival sinyallerin inhibisyonuHedef tedavileri Hiperradyosensitivite Taksanlar

21 Toksisite

22 Tedavi Ajanları

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24 Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.79
Figure 2 Combination strategies to augment the biological effects of radiotherapy Figure 2 | Combination strategies to augment the biological effects of radiotherapy. Irradiation of the tumour causes a variety of biological consequences, which can be exploited by combining radiotherapy with novel agents that target the relevant pathways123. ATR, ataxia telangiectasia and Rad3-related protein; CA9, carbonic anhydrase 9; Chk1, checkpoint kinase 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DDR, DNA damage response; DNA-PK, DNA-dependent protein kinase; HIF-1-α, hypoxia-inducible factor 1-alpha; MCT 1, monocarboxylate transporter 1; MCT 4, monocarboxylate transporter 4; mTOR, mechanistic target of rapamycin ; PARP, poly(ADP-ribose) polymerase; PD-1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase; NF-κB, nuclear factor-kappa-B; UPR, unfolded protein response. Sharma, R. A. et. al. (2016) Clinical development of new drug–radiotherapy combinations Nat. Rev. Clin. Oncol. doi: /nrclinonc

25 Sisplatin Cisplatin DNA’ya bağlanarak
Replikasyon ve transkripsiyonu bloke eder; Tamir mekanizmalarını etkiler; Hücre ölümüne neden olur.

26 Direkt DNA hasarı Zincir kırığı Adducts İntercalation
Radyasyona bağlı DNA kırığını ↑ Selektif antitumör etkisi yok FRAKSİYONE RT İLE DAHA ETKİLİ

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29 Toksisite Erken Geç Oral mukozit Cilt reaksiyonu Özefajit Proktit
Kemik iliği deplesyonu Matür hücre kaybıKök hücre ve öncü hücrelerin yenilenmesi Tüm dokularda Latent dönem Kalıcı Spesifik yan etki radyasyon alanına giren dokularda varsa!!! Bleomisin AC Doksorubisin Kalp Cisplatin Böbrek, İşitme

30 Terapötik oran/kazanç

31 Terapötik oran/kazanç
RT dozunu↑ yerine KT eklenmesi ile mukoza 4.3 Gy eşdeğeri korunmuş olur! Kemoradyoterapi > Radyasyon doz artırımı Eş zamanlı KT ile 12 Gy doz artışına eşit etki artışı sağlanır. Standart veya modifiye fraksiyone RT ile aynı doz artışı yan etkileri ↑↑ (Kasibhatla et al IJROBP 2007)

32 Sonuçlar Serviks Ca Anal Kanal Ca Eşzamanlı sisplatin
%10 sağkalımda artış Hematolojik ve GİS erken yan etkilerde ↑ Haftalık >25 mg cisplatin Eş zamanlı 5 florourasil, mitomisin %18 lokal kontrolde %32 kolostomi free survivalda artış

33 Sonuçlar Lokal İleri Evre Baş-Boyun Ca Özefagus Ca
Metaanaliz Pignon et al 2000 Önce ve sonra %1-2 artış Eşzamanlıda 5 yıllık sağkalım artışı %8 1 yıllık sağkalımda %9 artış 2 yıllık sağkalımda %4 artış Toksitede ↑↑

34 Sonuçlar Rektum Ca Akciğer Ca Postop KRT ile lokal kontrolde artış
Sağkalım avantajı yok. Preop KRT>RT sağkalım avantajı yok. KHDAK: %14 ölüm riskinde azalma Akut toksitede belirgin artma KHAK: %5 sağkalım avantajı

35 Moleküler Hedefe Yönelik Biyolojik Ajanlar

36 Biyolojik Ajanlar

37 Biyolojik Ajanlar Oldukça spesifik Düşük toksisite RT ile etkileşir
Radyosensitivite Hipoksi Proliferasyon İmmünaktivasyon Terapötik indeksi yüksek

38 Therapeutic Targeting of the Hallmarks of Cancer
PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs).The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Ov Therapeutic Targeting of the Hallmarks of Cancer

39 EGFR Yolağı

40 EGFR EGFR Durumu-Baş&Boyun Ca DAHANCA 6-7

41 Cetuximab (c225)

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43 Gereç-Yöntem Orofarenks, hipofarenks, larenks

44 Sonuç

45 Adverse Etkiler

46 Acneiform rash tedaviye yanıtla ilişkili mi?!

47 Acneiform rash= Daha iyi sağkalım

48 KemoRT+Cetuximab RTOG0522 Faz 3 , randomize çalışma
Evre 3-4 Baş&Boyun Ca Eşzamanlı akselere RT+KT± Cetuximab ( ) Toksisite artmıştır

49 KemoRT+Cetuximab Tedaviye Yanıt Toksisite

50 Diğer CONCERT-1 CONCERT-2 Faz 2 RCT Evre 3-4 Baş&Boyun Ca
KemoRT (63) vs. KemoRT+Panitumumab (87) FARK YOK Faz 2 RCT Evre 3-4 Baş&Boyun Ca KemoRT (61) vs. RT+ Panitumumab (90) STANDART TEDAVİNİN YERİNİ ALAMAZ

51 İmmun-modülasyon RT’nin etkisi Geleneksel: Lokal etki (hücre ölümü)
Alan dışı etkiler RT tm mikroçevresini düzenleyen bir etki yapar

52 Radiotherapy combination opportunities leveraging immunity for the next oncology practice
Immune Mechanisms Triggered by Tumor Irradiation. (a) Exposure of tumor antigen and activation of antigen‐presenting cells. RT induces immunogenic cell stress or immunogenic cell death in cancer cells, exposing CRT on their plasma membrane, and releasing ATP and HMGB1, which bind to CD91, P2RX7, and TLR4, respectively, and facilitate the recruitment of DCs into the tumor bed (by ATP), the engulfment of tumor antigens by DCs (enhanced by CRT), and optimal antigen presentation to T cells (stimulated by CRT and HMGB1). TLR4 activates the MyD88 pathway, leading to the nuclear translocation of NF‐κB, a transcription factor that favors DCs maturation with upregulation of MHC molecules and costimulatory ligands. C3a and/or C5a, released as a result of complement activation through the alternative pathway, are also critically important for stimulation of DC maturation. Altogether, these processes result in a potent inflammatory cytokine response promoting DC maturation, upregulation of co‐stimulatory signals facilitating cross‐priming of CTLs and upregulation of appropriate chemokine receptors promoting DC migration to the draining lymph nodes. (b) T‐cell priming in lymph nodes. DCs migrate to the lymph nodes and present tumor antigen peptides lodged in the MHC molecule to T cells, which recognize specific peptides through the TCR. Interaction of the peptide‐MHC complex and TCR is insufficient to cause T‐cell proliferation in the absence of costimulatory signals and appropriate cytokines released by DCs, and may result in T‐cell tolerance. Costimulatory ligands CD80 and CD86 expressed by mature DCs bind to the costimulatory receptor CD28 on T cells triggering the production of cytokines including interleukin 2, which is important for T‐cell proliferation, but also bind to the coinhibitory receptor CTLA‐4, which attenuates T cell activation. Additional costimulatory ligands are upregulated in properly matured DCs, including ICAM‐1, which binds to LFA‐1 on T cells, and the CD40 ligand (CD40L), which plays a key role in activating CD4+ T‐helper cells through CD40, “licensing” them to provide help to CD8+ cells. CD40L is required for the optimal activation of CD8+ T cells by DC, revealing an important synergy between CD4+ and CD8+ T cells and DC. (c) Effector T cells exit the lymph nodes and home to tumors: Antigen‐educated T cells exit the lymph node and patrol the body for tumor antigen. They can home into the irradiated but also non‐irradiated tumor deposits, and may cause regression of distant tumors, promoting the so‐called abscopal responses reported in cancer patients. RT indicates radiation therapy; ATP, adenosine triphosphate; CRT, calreticulin; CTL, cytotoxic CD8+ T lymphocyte; DC, dendritic cell; HMGB1, high‐mobility group box 1; P2X7, purinogenic receptor; IL, interleukin; TLR, Toll‐like receptor; MHC: major histocompatibility complex; NF‐κB, nuclear factor‐kappa B; MyD88, Myeloid differentiation primary response gene 88; C3a ‐ C5a, complement component 3a and 5a receptor; TCR, T cell receptor; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. CA: A Cancer Journal for Clinicians Volume 67, Issue 1, pages 65-85, 29 AUG 2016 DOI: /caac

53 Tm mikroçevresini düzenler
Radiotherapy combination opportunities leveraging immunity for the next oncology practice Tm mikroçevresini düzenler Radiotherapy Reprograms the Tumor Microenvironment. (a) Tumors have developed multiple mechanisms to effectively inhibit antitumor immune response. Some tumors lack the appropriate inflammatory mediators necessary for effective antigen presentation and generation of tumor‐reactive T cells. In addition, reduced production of appropriate T‐cell–recruiting chemokines fails to attract T cells to the tumor site. The tumor vasculature establishes a further barrier to tumor‐reactive T cells through the down‐regulation of adhesion molecules necessary for T‐cell arrest and transmigration as well as the expression of immunosuppressive ligands that act to inhibit T‐cell function or of death ligands that induce T‐cell apoptosis, resulting in poorly inflamed tumors (immune desert). Under the influence of tumor‐derived and stromal‐derived, immunosuppressive, soluble factors (eg, transforming growth factor β [TGFβ], interleukin 10 [IL‐10], prostaglandin E2 [PGE2]), the tumor endothelium upregulates coinhibitory ligands (T‐cell immunoglobulin and mucin‐domain containing 3 [TIM‐3], programmed cell death ligand 1 [PDL‐1], and/or PD‐L2) and immunosuppressive molecules like indoleamine 2,3‐dioxygenase (IDO1) or PGE2, which limit effector T‐cell activation. T cells that manage to transmigrate farther into the tumor stroma may encounter inhibitory immune cells, such as alternatively activated (M2) macrophages (MΦ2), myeloid‐derived suppressor cells (MDSCs), and T‐regulatory cells (Treg) or stroma fibroblasts, which, through different mechanisms, can drive T‐cell anergy, exhaustion, or apoptosis. Finally, the encounter with target tumor cells may not lead to efficient lysis because of the down‐regulation of major histocompatibility complex (MHC) or specific tumor‐associated antigens on tumor cells and increased expression of immunosuppressive proteins by the tumor cells, such as PD‐L1, which act to inhibit T‐cell function. (b) RT promotes an inflammatory response in tumors as it induces expression of inflammatory mediators, interferons (IFNs), and appropriate chemokines that attract T cells. Radiation reprograms tumor macrophages to inducible nitric oxide synthase (iNOS)‐expressing M1 cells, which increase the expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) in the tumor endothelium, enabling T‐cell homing. The upregulation of MHC‐I in tumor cells by RT allows recognition by incoming T cells with subsequent release of effector cytokines and killing of tumor targets. APC indicates antigen‐presenting cells; CD31; cluster of differentiation 31 (platelet endothelial cell adhesion molecule); CXCL9; chemokine [C‐X‐C motif] ligand 9; ICAM1, intercellular adhesion molecule 1; LFA1, lymphocyte function‐associated antigen 1 (αLβ2 integrin); MDSCs, myeloid‐derived suppressor cells; NK cells, natural killer cells; NKG2D, natural‐killer group 2, member D; TAAs, tumor‐associated antigens; TLR, Toll‐like receptor; VCAM1, vascular cell adhesion molecule 1; VLA2, integrin α2β1. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. CA: A Cancer Journal for Clinicians Volume 67, Issue 1, pages 65-85, 29 AUG 2016 DOI: /caac

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55 Radyoimmünoterapi Kombinasyonları
IT+hipofraksiyone RT DF azaltmak İnsitu vaksinasyon etkisi+ IT’nin lokal ve sistemik etkisi IT+kemoRT KemoRT’nin lokal etkisini arttırmak ve DF azaltmak RT ve IT arasındaki sinerji RT+IT IT’nin lokal etkisini arttırmak RT=biyolojik yanıt düzenleyici

56 Radiotherapy combination opportunities leveraging immunity for the next oncology practice
Opportunities for Radioimmunotherapy Combinations. (a) Immunotherapy can complement different radiotherapy (RT) doses and fractionations to help overcome tumor‐induced immune suppression. Although RT induces the release of immunogenic tumor antigens, the in situ vaccination effect could be potentiated by drugs enhancing the maturation of dendritic cells, such as CD40 agonists or Toll‐like receptor (TLR) agonists or type‐I interferon (IFN). In addition, cancer vaccines could provide opportunities for further boosting the radiation‐mediated in situ vaccination effect. (b) Different RT doses and fractionations can be combined with agonistic antibodies directed against costimulatory molecules on T cells (eg, tumor necrosis factor receptor superfamily member 4 [OX‐40], cluster of differentiation 137 [CD137], CD27) and/or blocking antibodies against coinhibitory molecules (eg, cytotoxic T‐lymphocyte‐associated protein 4 [CTLA‐4], programmed cell death 1 [PD‐1]), to increase T‐cell function. (c) The immunomodulatory effects of RT at different doses and schedules on the tumor microenvironment could be harnessed to enhance the therapeutic efficacy of immunotherapy approaches that aim to activate T cells, such as antibodies against coinhibitory T‐cell receptors (eg, PD‐1, PD‐1 ligand [PD‐L1], T‐cell immunoglobulin and mucin‐domain containing 3 [TIM‐3], lymphocyte activation gene 3 protein [LAG‐3], etc) or transforming growth factor β (TGF‐β)–blocking drugs. Finally, low‐dose RT could increase the homing capacity of activated T cells and could be useful particularly in the context of adoptive T‐cell therapy or cancer vaccines. BTLA/HVEM, indicates B‐lymphocyte and T‐lymphocyte attenuator/herpes virus entry mediator; Gy, grays; IDO, indoleamine 2,3‐dioxygenase CD134 (tumor necrosis factor receptor superfamily member 4 [OX‐40]). IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. CA: A Cancer Journal for Clinicians Volume 67, Issue 1, pages 65-85, 29 AUG 2016 DOI: /caac

57 Sorular IT ile maksimum etkileşim için uygun RT doz ve fraksinasyonu
Eşzamanlı KT ve kombine edilecek İT şeması Parçacık radyasyon ve radyonüklid tedavinin etkileri

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59 IT Birçok ajan var Preklinik klinik çalışmalar
IT+RT+/- KT çalışmalar artıyor

60 Sonuç RT ile eşzamanlı tedaviler artmakta Etkinlik artmakta
Toksisite artmakta Yeni ajanlar var Takip gerekli

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