Moleküler Hedeflenmiş Tedaviler

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1 Moleküler Hedeflenmiş Tedaviler
Biological Therapies Moleküler Hedeflenmiş Tedaviler Uz.Hem.Hümeyra ZENGİN 20 Nisan 2007 Antalya

2 HÜCRENİN BİYOLOJİSİ Genler mRNA Proteinler Hücrenin kaderi

3 HÜCRENİN BİYOLOJİSİNDE ROL ALAN FAKTÖRLER
Reseptörler Sinyal Molekülleri Transkripsiyon Faktörleri Hücre Siklusu Düzenleyicileri Adezyon Molekülleri Kromotin Düzenleyicileri

4 Hücre büyümesi ve bölünmesi yani hücre döngüsünü düzenleyen mekanizmalardaki bozukluk sonucu ortaya çıkan patolojik durum KANSER Standart Tedaviler Remisyon/Relaps

5 Kanser hücresi oluşumu, gelişimi, invazyonu ve metaztazları moleküler düzeyde tanımlanmaktadır.

6 Moleküler hedeflenmiş tedaviler
Sitotoksik ajanlar Moleküler hedeflenmiş tedaviler Ağırlı olarak genel hücre çoğalma mekanizmalarını hedef alarak yan etki profili yüksek tümör regresyonu sağlar Hedeflenmiş ajanlar kanser hücresine etki ederek seçici ve normal dokulara daha az etkili bir tedavi şeklidir

7 Literatür adı:Hedef moleküler veya smart bombs=akıllı bombalar
Kanser hücrelerinde hedeflenmiş tedavide hedeflenecek yapılar; Hücrelerin membran reseptörleri Sinyal iletim yolları Anjiogenez inhibitörleri Hücre matriks/protein reseptörleri Hücre siklusu ajanları Hücre ölümü ve hücre komponentleri ile reaksiyona giren nitelikler taşırlar

8 Moleküler Hedeflenmiş Tedaviler
Biological Therapies Moleküler Hedeflenmiş Tedaviler Tirozin Kinaz İnhibitörleri Proteasom Inhibitörleri Monoklonal Antikorlar (MoAbs) Slide 29 These are chemical molecules developed to act at the cellular level. They interact with various receptors or enzymes within cells to affect cellular function. MoAbs may be viewed as both biological and molecular targeted therapies. Reference: Grabenstein, 2004

9 Tyrosine Kinase Inhibitors (TKI)
Biological Therapies Tyrosine Kinase Inhibitors (TKI) Imatinib Mesylate (Gleevec®), Novartis Gefitinib (Iressa®), AstraZeneca Hücre içi trozin kinaz aktivesini bloke ederek hücre içi sinyal mekanizmalarını ve KML hücrelerinin büyümesini ve çoğalmasını engellemektedir. Slide 31 Because phosphorylation triggers the cell-growth signaling cascade, researchers have developed tyrosine kinase inhibitors in an attempt to turn cell growth "off." These inhibitors cause rapid cell death when the cancerous survival mechanism is deactivated. Thus, for tumors that use tyrosine kinase signals to maintain constant proliferation, these inhibitors are promising therapeutic agents. They are being tested in many types of cancer: leukemias, breast (HER2 positive), prostate, ovary, bladder, liver, and lung. Two have received FDA approval: Imatinib mesylate and gefitinib. Reference: Grabenstein, 2004; Novartis, 2004; AstraZeneca, 2003

10 Imatinib Mesylate (Gleevec®)
Biological Therapies Imatinib Mesylate (Gleevec®) İmatinib mesylate (Gleevec) philadelphia kromozomu pozitif olan KML hastalarında (ilk seçenek ve relaps) ve gastrointestinal stromal tümörlerde (GIST) kullanım endikasyonu vardır. Ağızdan alınabilen küçük organik bir moleküldür Slide 32 Imatinib mesylate also inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF- mediated cellular events. These actions are responsible for its efficacy in GIST. In clinical trials, imatinib mesylate as a single agent demonstrated longer progression-free survival in patients with chronic myeloid leukemia than did the combination of interferon-alpha plus cytarabine. Seventy percent of the interferon-treated patients crossed over to the imatinib mesylate arm during the trial or dropped out of therapy because of the high toxicity of the interferon therapy. Ninety percent of the imatinib mesylate patients remained on therapy for the duration of the study, and reported no toxicities severe enough to warrant stopping therapy. Effectiveness (hematologic response) has varied with dosage, and response rates have been higher in patients who have not been previously treated with another therapy. Overall, imatinib appears to lengthen time to progression and overall survival in patients with CML In patients with GIST – kit-positive unresectable and/or metastatic malignant – between 33% and 43% of patients demonstrated a partial response. References: Novartis, 2004 Gleevec® (Novartis)

11 Imatinib Mesylate: Uygulama
Biological Therapies Imatinib Mesylate: Uygulama Dozu: 100 mg ya da 400 mg oral tabletleri bulunmaktadır KML de: kronik fazda 400 mg/gün; akselere ya da blast krizi için 600 mg/gün GIST: 400 mg ya da 600 mg / gün Gastrointestinal sistem rahatsızlığını azaltmak için yiyeceklerle birlikte alınmalıdır Slide 33 Patients appreciate the convenience of oral administration in the out-patient setting. Because patients take the medication at home, they must be educated about monitoring for adverse events and reporting any significant changes. They should be seen in the clinic at regular intervals. References: Novartis, 2004 Neumega® (Wyeth-Ayerst)

12 Imatinib Mesylate: Yan etkiler
Biological Therapies Imatinib Mesylate: Yan etkiler En yaygın yan etkiler: Hafif orta ödem, Bulantı, kusma, Kas krampları, Kemik ağrısı, İshal, Döküntü Daha az görülen yan etkiler: Anemi, Nötropeni, Trombositopeni, Karaciğer toksisitesi, İlaç etkileşimleri Slide 34 Patients should be weighed and monitored regularly for signs of fluid retention. It can most often be managed with diuretics. Imatinib mesylate should be taken with food to minimize GI irritation. Imatinib mesylate has been associated with anemia, neutropenia, and thrombocytopenia, and complete blood counts should be performed weekly for the first month, biweekly in the second month, and periodically thereafter. Liver toxicity, sometimes severe, has occurred with imatinib mesylate. Patients should be monitored and dosage reduced or stopped if abnormalities appear. There are several known drug interactions with imatinib: physicians and nurses should be aware of patient usage of any other substance. Reference: Novartis, 2004 Neumega® (Wyeth-Ayerst)

13 Biological Therapies Gefitinib (IRESSA®) Bir aniloquinozol olup HER 1-EGFR (epidermal büyüme faktör reseptörü) nü içeren transmembran reseptörleri ile ilişkili hücre içi trozin kinaz fosforilizasyonunu bloke ederek tümör hücresinin büyümesini ve çoğalmasını engeller. Slide 35 Gefitinib was approved for use in patients with non-small cell lung cancer as third-line therapy. Patients had previously been treated with at least two other regimens; 25% had undergone four or more. The overall response rate at either 250 or 500 mg per day was about 10%. There appeared to be substantial differences in response rates in subsets of patients, with higher response rates for women (about 17%) and patients with adenocarcinoma, and with lower response rates seen in men (about 5%) and smokers. In combination with platinum-based chemotherapy, gefitinib did not demonstrate any increase in tumor response rate, time to progression, or overall survival. Gefitinib was approved on the FDA’s accelerated program that permits patients with very severe conditions to receive therapies prior to the usual extent of testing. Thus, it continues in clinical trials. While gefitinib has been approved as third-line therapy in non-small cell lung cancer, it remains in investigational trials in NSCLC as well as other forms of cancer. Reference: AstraZeneca, 2003 IRESSA® (AstraZeneca)

14 Gefitinib (Iressa) Gefitinib (Iressa) ileri evre küçük hücreli olmayan akciğer kanseri olan ve platin ve doksotaksel içeren kemoterapi rejimine cevap vermeyen hastalarda kullanım endikasyonu vardır

15 Biological Therapies Gefitinib: Uygulama Dozu: oral tabletler (250 mg tablet yiyecekle birlikte ya da yiyeceksiz alınabilir) Pulmoner distres belirti ve bulguları yönünden izlem Slide 36 Gefitinib is orally available, permitting outpatient administration. Reference: AstraZeneca, 2003 IRESSA® (AstraZeneca)

16 Gefitinib: Yan Etkiler
Biological Therapies Gefitinib: Yan Etkiler En yaygın yan etkiler: Hafif orta derecede ishal, Akne benzeri döküntü Cilt reaksiyonları Bulantı ve kusma Daha az yaygın ancak ciddi ve ölümcül olabilen yan etki: intestisyel akciğer hastalığı Slide 37 Common side effects reported with gefitinib in clinical trials were nausea, vomiting, diarrhea, rash, acne, and dry skin. Gefitinib may cause fetal harm when administered to pregnant women. A significant safety concern associated with gefitinib did emerge during the approval process. Reports from Japan described the occurrence of serious and sometimes fatal interstitial lung disease (ILD) in patients treated with it. The FDA extended its review of gefitinib by three months to review these reports. After careful review of information from all sources, including a comprehensive analysis of updated toxicity information from clinical trials and the gefitinib expanded access program, involving approximately 23,000 patients, FDA determined that the incidence of ILD was approximately 2% in the Japanese experience and approximately 0.3% in the United States expanded access program, with about 1/3 of affected patients dying from this toxicity. FDA believes that this rare but serious toxicity of gefitinib does not outweigh the benefits demonstrated in patients with advanced NCSLC. Reference: AstraZeneca, 2003; FDA, 2003 IRESSA® (AstraZeneca)

17 Proteazom İnhibitörleri
Biological Therapies Proteazom İnhibitörleri Proteazom (hücre işlevi ve büyümesini düzenlemede önemli bir rol oynayan enzim) aktivitesini engelleyen protezom inhibitörüdür Proteasomlar hücre siklusu, yeni kan damarı oluşumu, hücre adhezyonu, sitokin üretimi ve apopitoz da rol oynar Bloke edildiğinde/engellendiğinde kanserli hücre ölümü meydana gelir Slide 38 Proteasomes are enzymes that “chop” proteins into smaller pieces inside a cell. Once a protein has been chopped up, the pieces can be transported to the cell surface for “recognition” by ligands or receptors. Several different cell cycle processes are regulated through this proteasome mediation. Evidence suggests that it serves both as a disposal system for damaged cellular proteins and as a mechanism for degrading short-lived regulatory proteins that govern cellular functions such as the cell cycle, cell growth, and differentiation. Because these processes or their dysregulation are crucial steps in tumor formation, the proteasome pathway is a logical target for therapeutic intervention. Proteasome inhibition appears to: - Impede cancer cell proliferation by preventing the breakdown of certain valuable proteins and transcription factors that are known to hinder cancer cell growth. - Reduce the survivability of cancer cells by inactivating certain genes and proteins that help cancer cells survive chemotherapy. - Cause cancer cell death by producing extreme cellular stress in tumor cells through disruption of cell proliferation. References: Sompayrac, 1999; Millennium, 2004

18 Bortezomib (Velcade™): Endikasyonları ve Dozu
Biological Therapies Bortezomib (Velcade™): Endikasyonları ve Dozu Bortezomib (Valcade) tedaviye yanıt vermeyen ve ilerleme gösteren multiple myelom hastalarında kullanım endikasyonu vardır. Dozu: IV injeksiyon 1.3 mg/m2 iki hafta için 1,4,8 ve 11. günlerde IV puşe sonrasında 10 günlük dinlenme dönemi Slide 39 Selective inhibition of proteasome activity has numerous effects that can be relevant in cancer treatment, including attenuating the activity of NF-kB, the transcription factor that controls cellular inflammatory response, and inhibiting the activity of bcl-2, a gene involved in cell survival. Elevated NF-kB and bcl-2 activities allow cancer cells to defend themselves against treatment with standard chemotherapy agents. By blocking the normal function of NF-kB and bcl-2, a proteasome inhibitor can cause the death of cancer cells. References: Millennium, 2003; Millennium, 2004 Velcade™ (Millennium Pharmaceuticals, Inc.)

19 Bortezomib (Velcade™): Yan etkiler
Genellikle geri dönüşümlü olarak gelişen periferik nöropati Doz ayarlaması gerektirebilecek trombositopeni Nötropeni Gastrotoksisite Nadiren de DVT

20 Monoklonal Antikorlar
Biological Therapies Monoklonal Antikorlar Hedeflediği antikora özel etki gösterir Ana etkisi kompleman bağımlı sitotoksisite, antikor bağımlı hücresel sitotoksisite ve/ya da apopitoz (programlı hücre ölümü) uyarma yoluyla immün sistem aktivasyonu Slide 41

21 Monoklonal Antikor Türleri
Biological Therapies Monoklonal Antikor Türleri İnsan -umab Fare -momab Özdeş (Chimeric) -ximab İnsanlaştırılmış -zumab Slide 43 Murine monoclonal antibodies are derived from mice. Mouse antibodies have a very short half-life in the human body, are not as effective as human antibodies in eliciting an effector response from the CDC and ADCC systems, and can cause the development of human anti-mouse antibodies (HAMA) that neutralize and render the mouse antibodies ineffective against the tumor. Mouse antibodies are usually named with the suffix “-momab.” An example of a mouse antibody is ibritumomab tiuxetan (Zevalin®). To overcome the limitations of mouse monoclonal antibody, scientists have engineered antibodies that have more human and fewer murine components. This allows better interaction with human effector cells and thus better cell killing, fewer side effects, and a longer serum half-life. Three types of “engineered antibodies” are described in this slide. Chimeric antibodies: The Fc portion of the human antibody is fused to the Fab portion of the mouse monoclonal antibody. The mouse portion recognizes the antigen and the human portion recruits the immune system. Chimeric antibodies are usually named with the suffix “-ximab.” An example of a chimeric antibody is rituximab (Rituxan®). Humanized antibodies: Only a very small part of the Fab portion of the mouse antibody is fused to a human antibody, making the antibody primarily human (95-98%). The monoclonal antibody retains its ability to recognize and bind to the target antigen (through the mouse portion), provides effective CDC/ADCC activation (through the human portion), and limits the potential neutralizing response to the antibody. Humanized antibodies are usually named with the suffix “-zumab.” Examples of humanized antibodies are trastuzumab (Herceptin®) and alemtuzumab (Campath®). In fully human antibodies, the entire antibody has been engineered to contain only human antibody gene sequences. Many of these types of antibodies are still in developmental stages. Human antibodies are usually named with the suffix “-umab.” An example of a fully human antibody is adalimumab (Humira™), used in treating rheumatoid arthritis. References: Cheng et al., 2000; LoBuglio et al., 1992; Rieger, 2001; Yarbro et al., 2000; Cheson, 2001.

22 Kanser Tedavisi İçin Kullanımı Onaylanmış MoAbs
Biological Therapies Kanser Tedavisi İçin Kullanımı Onaylanmış MoAbs Monoklonal Antikor Fonksiyonu Endikasyonu Alemtuzumab (Campath®), Berlex CD52 B- hücreli lenfositik lösemi Bevacizumab (Avastin™), Genentech VEGF (vasküler endotelyal büyüme faktörü) hedef alır , anjiogenezi önler Metastatic kolorektal kanser, ilk seçenek Cetuximab (Erbitux™), Imclone/Bristol-Meyers Squibb EGFR reseptörünü hedef alır Relaps, Metastatik kolorektal kanser Gemtuzumab ozogamicin (Mylotarg®), Wyeth-Ayerst CD33 antijeni; calicheamicin (antibiyotik) ile konjuge Akut myeloid lösemi, relaps Slide 46 More monoclonal antibodies have received FDA approval. Their uses range from treating rheumatoid arthritis to preventing allograft rejection to preventing acute cardiac ischemic complications from PCI. Some are used to deliver radioactive substances that permit the diagnosis of metastases from colorectal cancer, lung, ovarian, prostate, or breast cancers or the discovery of damage from heart attack. Reference: Grabenstein, 2004

23 Kanser Tedavisi için Kullanımı onaylanmış MoAbs
Biological Therapies Kanser Tedavisi için Kullanımı onaylanmış MoAbs Monoklonal Antikor Fonksiyonu Endikasyonu Ibritumomab tiuxetan (Zevalin®), IDEC CD20 antigen; Y-90 ile konjuge Relaps lenfoma Trastuzumab (Herceptin™), Genentech HER2 reseptörünü hedef alır Metastatik meme kanseri Rituximab (Rituxan™), IDEC CD20 B hücrelerini hedef alır; apopitozu uyarır B-hücreli NHL Tositumomab (Bexxar®), Corixa CD20 B hücrelerini hedef alır; Iodine I 131 ile konjuge B-hücreli non-Hodgkin lenfoma (NHL) Slide 47

24 Rituximab: Etki Mekanizması
Biological Therapies Rituximab: Etki Mekanizması B-Cell non-Hodgkins Lymphoma Targets CD20 Antigen Slide 49 B-cell lymphomas have well-defined surface antigens known as CDs (clusters of differentiation). CDs, such as CD20, play a role in normal B-cell maturation and survival, which makes them ideal candidates for monoclonal antibody therapy. The CD20 antigen is an ideal target antigen for monoclonal antibody therapy for several reasons: CD20 is present on greater than 90% of B-cell lymphomas. CD20 is found on normal B-cell precursors and mature B cells, but not on stem cells, normal plasma cells, or other nonlymphoid normal tissues. This allows for normal immunoglobulin production and B-cell repopulation. CD20 may play a role in regulating tumor cell growth. References: Genentech, 2002a; Wood, 2001; Alas, 2001 Rituxan™ (Genentech)

25 (MaBthera®,Rituximab) Uygulama
Biological Therapies (MaBthera®,Rituximab) Uygulama 375 mg/m2 yavaş IV infüzyon şeklinde haftada bir kez, toplam 4 doz olarak kullanılmaktadır Kesinlikle IV puşe veya bolus şeklinde uygulanmamalıdır 50 mg/saat şeklinde başlanır; tolere ediliyorsa 30 dakikada bir verilme hızı 50 mg/ saat artırılır (maksimum 400 mg/saat) Sonraki infüzyona 100 mg/saat olarak başlanır ve 30 dakikada bir verilme hızı 100 mg/ saat artırılır (maksimum 400 mg/saat) Reaksiyon meydana gelirse; infüzyon durdurulur ve semptomlar ilerlemeye devam ederse reaksiyon öncesi verilme hızı %50 azaltılarak yeniden başlanır A Rituximab dose is typically 375 mg/m2/week for 4 doses. Doses are scheduled on days 1, 8, 15, and 22. Rituximab preparation consists of a single-use vial of either 100 mg/10 mL or 500 mg/50 mL (the concentration is 10 mg/mL). The maximum concentration of solution for administration is 4 mg/mL. The final solution of 1:1 may ease the administration-rate calculation and decrease infusion-rate errors.

26 (MaBthera®, Rituximab) İnfüzyonla İlişkili Yan Etkiler
Biological Therapies (MaBthera®, Rituximab) İnfüzyonla İlişkili Yan Etkiler Hafif-Orta Ciddi Gecikmiş Ateş Bronkospazm Hafif lökopeni Titreme/ katılık Hipotansiyon Hafif trombositopeni Bulantı Anjiyo-ödem Hafif nötropeni Halsizlik Aritmi Hafif anemi Baş ağrısı Kaşıntı, döküntü, ürtiker Burun akıntısı Myalji/atralji Rituximab side effects are generally mild to moderate, most occurring during the first infusion, especially the first 1 to 3 hours of the first infusion. Therefore, close observation of the patient during the first 1 to 3 hours is necessary. The frequency and severity of the infusion-related effects are affected by the rate of infusion, by the health and concomitant illnesses of the patient, and possibly by the presence of tumor cells in circulation. Infusion-related effects include temperatures >38ŞC, chills, rigors, urticaria, rhinitis, nausea, diarrhea, and myalgia/arthralgia. Uncommon but potentially more severe events have included bronchospasm, hypotension, and angioedema. Arrhythmia has recurred in patients with a history of this disorder. Potential allergic reactions and anaphylaxis have not been reported, but patients should be assessed and treated for these life-threatening events. The treatment of infusion-related effects is to stop the infusion and restart it when the side effects have been successfully treated. Subsequent doses are usually well tolerated without major side effects.

27

28 Trastuzumab (Herceptin)
İnsan epidermal büyüme faktör reseptörü (HER-2)” ne karşı hedeflenmiş monoklonal bir antikordur. HER-2 meme kanserlerinin % 25-30’ unda çok fazla üretilmektedir. HER2/neu proteini pozitif olan metastatik meme kanseri için kullanılmaktadır

29 Yaygın Görülen Yan Etkiler
İnfüzyonla ilişkili semptomlar (ateş, titreme, katılık) ilk infüzyonda daha sık görülür; sonraki infüzyonlarda şiddeti ve görülme sıklığı azalır Daha az görülen yan etkiler: bulantı, kusma, ağrı (tümör bölgesinde), baş ağrısı, baş dönmesi, dispne, hipotansiyon, döküntü; özellikle yaşlı ve doksorubucin ve siklofosfamid ile birlikte trastuzumab alan hastalarda kardiyotoksisite meydana gelebilir;

30 Dikkat Edilmesi Gereken Önemli Noktalar
Premedikasyon önerilmemektedir Daima infüzyon şeklinde uygulanmalı; kesinlikle IV puşe veya bolus şeklinde uygulanmamalıdır Dozu:4mg/kg yükleme dozunu takiben 2mg/kg haftalık doz İlk infüzyon 90 dakikada, sonraki infüzyonları 30 dakikada uygulanır. Kardiyak değerlendirme tedavi öncesi yapılmalı ve periyodik olarak tekrarlanmalıdır İnfüzyonla ilişkili reaksiyonlarda yukarıdaki önlemler alınmalıdır.

31 ANJİOGENEZ İNHİBİTÖRLERİ

32 VEGF Yolunun inhibisyonu
Biological Therapies VEGF Yolunun inhibisyonu Slide 62 Anti-VEGF and anti-VEGF receptor therapies target the abnormal blood vessels that tumors develop. Many human tumors express VEGF. The rationale for blocking the binding of VEGF is derived from our knowledge that: Tumor survival and growth depend on an adequate blood supply, oxygen, and nutrients. VEGF is the primary angiogenic factor produced by tumor cells. Tumor blood vessels are abnormal and depend on a constant supply of VEGF for maintenance. Disruption of VEGF can prevent tumor growth and may even cause the tumor to regress. References: Chen, Kitson, & Goldbarb, 2002; Dvorak, Brown, & Detmar, 1995; Melder, Koenig, Witwer, et al., 1996; Unemori, Ferrara, Bauer, et al., 1992; Nagy et al., 2002 Somatik mutasyon Küçük damarsız tümör Tümörden VEGF salınımı anjiogenezi uyarır Anjiogenez inhibitörleri bu süreci tersine döndürebilir Hızlı tümör büyümesi ve matastaz

33 Bevacizumab (Avastin™)
Biological Therapies Bevacizumab (Avastin™) % 93 insan, %7 fare VEGF bağlanır VEGF ve reseptörlerine bağlanarak VEGF yoluyla oluşan anjiojenezisi engeller Slide 60 Bevacizumab is a recombinant humanized monoclonal antibody against the VEGF molecule. It is 93% human and 7% murine. Because humanized antibodies contain a much smaller percentage of mouse protein than chimerized antibodies, they are thought to be less likely to trigger an unwanted immune response. Bevacizumab recognizes all forms of VEGF and binds to the VEGF molecule with high affinity. The antibody prevents VEGF from binding to its natural receptors, thus inhibiting VEGF-induced angiogenesis. This image depicts the binding of VEGF with bevacizumab thereby minimizing the amount of circulating VEGF available to bind to its receptors and activate the angiogenesis process. The terminal half-life of bevacizumab is days. Bevacizumab, in combination with IV 5-fluorouracil chemotherapy, has been approved for first-line treatment of patients with metastatic carcinoma of the colon and rectum. Reference: Hurwitz, Fehrenbacher, Cartwright, et al., 2003 Avastin™ (Genentech)

34 Bevacizumab (Avastin™)
Endikasyonu:Metastatik kolon ya da rektum kanserinin ilk seçenek tedavisi için 5-FU ile kombine kullanımı onaylanmıştır. Doz Özellikleri: 5mg/kg IV infüzyon Hazırlanması: 100 ml %0.9 sodyum klorür içinde dilüe edilmelidir. Dekstroz solüsyonları ile birlikte verilmemeli ve karıştırılmamalıdır. Ugulanması: Başlangıç dozu 90 dakikada verilmeli; tolere ediyorsa ikinci tedavi 60 dk da uygulanabilir. 60 dakikalık infüzyon tolere edildi ise bir sonraki ilaç infüzyonu 30 dk da uygulanabilir. Yan Etkiler: Hemoraji, hipertansiyon, proteinüri, konjestif kalp yetmezliği, ishal, halsizlik, lökopeni, tromboembolizm, hiponatremi

35 Cetuximab: Endikasyonlar ve Uygulama
Biological Therapies Cetuximab: Endikasyonlar ve Uygulama İrinotecan içeren KT nin 3 ayı içerisinde ya da progrese olan metastatik kolorektal hastaların 2. seçenek tedavisi için onaylanmıştır Cetuximab ın irinotecan ile birlikte elde edilen yanıt oranı tek başına kullanımından daha iyi ve uzun sürer Cetuximab (400 mg/m2 ilk infüzyon 120 dakikanın üzerinde daha sonra 250 mg/m2 ( haftalık, 60 dakikanın üzerinde IV infüzyon) Diphenhydramine ile premedikasyon. Irinotecan aynı dozda infüze edilir Slide 68 The EMR study was a phase II trial of cetuximab with irinotecan, or as a single agent, in patients with EGFR+ metastatic, irinotecan-refractory colorectal cancer. Patients were eligible if they progressed during or within three months after irinotecan-based chemotherapy. Patients were randomized into two study arms: Arm A: Irinotecan plus cetuximab (218 patients), and Arm B: Cetuximab as a single agent (111 patients). Patients in Arm B were allowed to switch to combination therapy after failure of cetuximab as a single agent. The primary end point of this study was overall response rate. Secondary end points included time to progression and survival time. Cetuximab was given in an initial dose of 400 mg/m2 infusion, then 250 mg/m2 weekly thereafter. Irinotecan was administered at the same dose and on the same schedule that patients had been on previously, or were on when their disease progressed. Reference: Cunningham, 2003; Imclone/Bristol-Meyers Squibb, 2004 Erbitux™ (Imclone/Bristol-Meyers Squibb)

36 Cetuximab: Yan Etkiler
İnfizyonla ilişkili reaksiyonlar; bronkospazm, ürtiker, hipotansiyon, ses kısıklığı, pulmoner toksisite, döküntü, ciltte kuruluk ve çatlak, ateş Diğer yan etkiler: ishal, halsizlik, güçsüzlük, bulantı, kusma, anoreksi, lökopeni, akne benzeri döküntü

37 Dikkat Edilmesi Gereken Önemli Noktalar
Güneş ışınlarına maruziyeti sınırlaması ve koruyucu faktörlü ürünler kullanması yönünde bilgilendirme H1 antagonistleri ile premedikasyon 0.22 mikron luk filtreli setler ile uygulama yapılmalı İnfüzyon sonrası set SF ile yıkanmalı Buzdolabında saklanmalı, kesinlikle dondurulmamalı Çalkalanmamalı Dilüe edilmemeli Kullanılmayan ilaç buzdolabında 12 saat, oda ısısında 8 saat bekletilebilir

38 Alemtuzumab (Anti CD52, Campath)
CD52 antikoruna bağlanır B hücreli kronik lenfositik lösemi nedeniyle daha önce alkilleyici ajanlar ve fludarabine ile tedavi edilmiş ancak tedaviye yanıt alınamamış bireylerde kullanımı onaylanmıştır

39 Alemtuzumab (Anti CD52, Campath)
30 mg tek doz ya da haftalık 90 mg kümülatif dozun üzerinde uygulanmamalıdır 2 saatlik infüzyon şeklinde uygulanmalı; kesinlikle IV puşe veya bolus şeklinde uygulanmamalıdır Asetominofen ve diphenhydramine ile premedikasyon Yan etkiler:Trombositopeni, anemi, nötropeni, hipotansiyon, ateş, yorgunluk, döküntü, ürtiker, bulantı, kusma, ishal, katılık, dispne

40 Moleküler hedeflenmiş tedavilerde Hemşirelik Bakımı
Hasta ve aile eğitimi (yazılı ve görsel olarak) ilaçların etkileri ve yan etkileri oral tabletlerin evde kullanımı İlaçların kullanımına yönelik yazılı politikalar ve prosedürler oluşturmak Yan etkilerin yönetimi Döküntü için önerilen dermatolojik retinoidler, kortikositoreidler, Vitamin A ve D içeren preparatlar İshal İçin loperomide kullanımı (günde 3-4-kez 2,5 mg), gerektiğinde İV. Hidrasyon ve TKI dozunun azaltılması Bulantı-kusma, yorgunluk ve karaciğer enzimlerinin izlenmesine yönelik uygulanabilecek standart tedaviler

41 Özet… Hedeflenmiş tedaviler özelilikle tümör hücresini hedef alırlar; normal hücrelere yan etkisi azdır. İlaç direnci olasılığı düşüktür. Standart kanser tedavilerine göre daha az toksiktir. Oral kullanımı nedeniyle doz sınırlaması yan etkileri azdır. Ve artık kanser tedavisinde sıklıkla kullanılmaktadır.

42 ONKOLOJİ HEMŞİRELİĞİ DERNEĞİ
HEMŞİRELER İÇİN KEMOTERAPİ VE BİYOTERAPİ İLAÇ BİLGİLERİ EL KİTABI Hazırlayanlar Sultan KAV Fatma GÜNDOĞDU Nisan 2007 Ankara Fiyatı:10 YTL