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... konulu sunumlar: "AKCİĞER KANSERİ TEDAVİSİNDE GELİŞMELER KONYA 2003"— Sunum transkripti:

Prof.Dr.İsmail Savaş Ankara Üniversitesi Tıp Fakültesi Göğüs Hastalıkları Anabilim Dalı


3 Dünyada sık görülen kanserlerin sıklığı ve mortaliteleri
Erkek Kadın Akciğer Meme Kolon/rektum Mide Karaciğer Prostat Serviks Özofagus Mesane Non-Hodgkin lenfoma Based on the most recent incidence and mortality data available, Parkin and colleagues estimated that in the year 2000 there would be over 10 million new cases, 6.2 million deaths and 22.4 million people living with cancer.1 This estimate represents an increase of around 23% in incidence and mortality since the estimates for 1990. Lung cancer is the most common cancer in the world1 with the highest mortality.2 Areas with the highest incidence are Europe, North America, Australia/New Zealand and South America. The rates in China, Japan and South-East Asia are moderately high. In developing countries, the highest rates in men are seen in areas where the habit of smoking has been longest established: the Middle East, China, the Caribbean, South Africa, Zimbabwe and the Pacific.1 In the USA, the 1-year relative survival rates for lung cancer have increased from 34% in 1975 to 41% in 1997, largely as a result of improvements in surgical techniques.3 However, the 5-year relative survival rate for all stages combined is only 15%. The survival rate is 48% for cases detected when the disease is localised, but only 15% of lung cancers are detected at this early stage.2 References Parkin DM, et al. Eur J Cancer 2001; 37 (Suppl 8): S4-S66. Greenlee RT, et al. CA Cancer J Clin 2000; 50: 7-33. American Cancer Society. Cancer facts and figures, ( Slide figure reproduced from reference 1 with permission from Elsevier Science. Oral kavite Lösemi Pankreas Over Böbrek 1200 1000 800 600 400 200 Bin Parkin ve ark 2001

4 Yaşa standardize edilmiş akciğer kanseri ölüm hızları , ABD (1930-1998) ve sigara etkisi
80 Akciğer ve bronş (erkek) Akciğer ve bronş (kadın) 100,000 Kişide erkek/kadın oranı 60 40 Since about 1950, >70,000 scientific articles have left no scientific doubt that prolonged smoking is an important cause of premature mortality and disability worldwide.1 The cigarette industry in the USA experienced almost unbroken growth between 1913 and 1963,2 and changes in smoking behaviour have been linked with changes in lung cancer mortality.3 In the USA, a dramatic increase in mortality from lung cancer since the 1930s was observed. However, with increasing evidence that cigarettes cause lung cancer, cigarette consumption has declined in the USA. In the developing world, cigarette use is still increasing, at a rate of ~3.4% per year.1,2 During , US mortality from lung cancer declined significantly among men (-1.7% per year), in contrast to rates for women, which continued to increase but at a much slower pace. The increase in incidence rate among women reached a plateau in the 1990s, with incidence in 1998 being 43.4 per 100, Decreasing lung cancer incidence and mortality rates most likely result from decreased smoking rates over the previous 30 years, with decreasing smoking patterns among women lagging behind those of men.4 Estimated figures for the year 2000 indicate that 86% of lung cancer cases in men and 49% in women were due to smoking, although there was considerable regional variation in these figures.5 According to the World Health Organization, tobacco-related deaths are expected to increase from ~4 million per year in 1998 to ~10 million per year by the 2030s, with 70% of those deaths occurring in developing nations.1 This is a higher death toll than is expected from maternal and major childhood conditions, malaria and tuberculosis combined.1 References World Health Organization. The World Health Report 1999: making a difference. ( Slade J. J Psychoactive Drugs 1989; 21: Shopland DR. Environ Health Perspect 1995; 103 (Suppl 8): American Cancer Society. Surveillance research, ( Parkin DM, et al. Eur J Cancer 2001; 37 (Suppl 8): S4-S66. Source of slide figure: American Cancer Society’s Cancer Facts and Figures Reprinted with permission. 20 1930 1940 1950 1960 1970 1980 1990

5 AKCİĞER KANSERLERİ Yapılan kitle tarama çalışmaları total mortaliteyi azaltmamıştır. Her yıl akciğer kanserinden 1 milyon kişi ölmektedir. 5 yıllık sağkalım %5-10’dur. Semptomlar ortaya çıktığında hastalık genellikle ileri bir dönemdedir.

6 Dispne Öksürük Ağrı Kilo kaybı Hemoptizi
Akciğer kanserlerinde ana semptomlar 100 Hasta (yüzde) 87 86 80 81 75 60 40 41 The symptoms of non-small-cell lung cancer (NSCLC) are particularly severe and debilitating, and become worse during the final stages of the disease. Symptoms of advanced lung cancer can be more distressing than with other types of malignancy and are particularly associated with the site of the disease. In a recent study of 673 patients with NSCLC, the major presenting lung cancer symptoms at diagnosis were dyspnoea (87% of patients), cough (86%), pain (81%), loss of appetite (75%), and haemoptysis (41%).1 Although 81% of these patients had three or more of these symptoms, there were some patients who presented with only one symptom (5% of patients) or no symptoms (2%).1 Although not assessed in this study, weight loss is also a major symptom of NSCLC. Reference Hollen PJ, et al. Support Care Cancer 1999; 7: Slide figure reproduced from reference 1 with permission from Springer-Verlag. 20 Cough Pain Loss of appetite Haemoptysis Dispne Öksürük Ağrı Kilo kaybı Hemoptizi Hollen et al 1999

7 Akciğer Kanseri Tipleri
1) Küçük hücreli dışı Yassı hücreli kanser Adenokanser Büyük hücreli kanser 2) Küçük hücreli akciğer kanseri

8 Yassı hücreli kanser(~30%)
Akciğer Kanseri (Küçük hücreli dışı) Yassı hücreli kanser(~30%) Erkeklerde sık Sigarayla ilişkili (doz-bağımlı) Sıklıkla lokal olarak yayılır Balgamda malign hücre bulunabilir Yüksek düzeyde gen ekspresyonu vardır ( detoksifikasyon/antioksidan) Adenokarsinoma (30-50%) Kadınlar ve sigara içmeyenlerde daha sıktır, Lezyonlar genellikle periferaldir, Sıklığı artmaktadır K-ras mutasyonu sıktır Bronkoalveoler karsinom alt grubu vardır. About 80% of all lung cancer cases are NSCLC. The major cause of NSCLC is tobacco smoking (85% correlation) and it affects a large number of people in their productive middle years. The incidence of NSCLC is increasing as a result of ageing populations and increasing numbers of female smokers. However, tobacco smoking is by no means the only cause of lung cancer: environmental, dietary and genetic factors have all been identified as increasing the risk of the disease. There are three major types of NSCLC. Each type has a different incidence and pattern of occurrence by age, sex, race and geographical area.1 The histological type of NSCLC may affect treatment outcome. Squamous-cell carcinoma: consists of layers of epithelial cells that secrete keratin, and therefore often present as obstructing tumours in the bronchi most commonly found in men represents 30% of all cases closely correlated with smoking has a molecular profile including high expression of genes involved in cellular detoxification and antioxidation.2 Adenocarcinoma: most common type of lung cancer in women and non-smokers and the worldwide incidence is increasing characterised by high-level expression of small-airway-associated or imunologically related proteins2 and k-ras mutations are frequently reported3 a subtype of adenocarcinoma called bronchoalveolar carcinoma, which often presents at an earlier stage than other adenocarcinomas, can be less aggressive, and has been associated with better survival in some studies. Early diagnosis and surgical treatment are therefore particularly valuable in nodular bronchoalveolar carcinoma4 in contrast with other bronchial carcinomas, survival of patients with bronchoalveolar carcinoma is influenced more by the extent of lung involvement (eg presence of bilateral lesions or production of mucin by tumour cells) than by the extent of lymph node metastases5 metastatic bronchoalveolar carcinoma can be an aggressive disease, with a prognosis similar to that seen for adenocarcinoma.6 Adenocarcinoma and large-cell carcinoma: were found to recur after surgery more frequently than squamous-cell carcinomas in one study (0.088 and recurrences per patient per year, respectively), even though all cancers were the same stage (T1 N0).7 References Wingo PA, et al. J Natl Cancer Inst 1999; 91: Nacht M, et al. Proc Natl Acad Sci USA 2001; 98: Niklinski J, et al. Lung Cancer 2001; 34 (Suppl 2): S53-S58. Grover FL, Piantadosi S. Ann Surg 1989; 209: Daly RC, et al. Ann Thorac Surg 1991; 51: Feldman ER, et al. Mayo Clin Proc 1992; 67: Thomas P, Rubinstein L. Ann Thorac Surg 1990; 49: Büyük hücreli karsinom (10-25%) İndifferansiye hücrelerdir. Lezyonlar genellikle periferaldir, Metastaza meyili yüksektir.

9 Akciğer Kanseri (Küçük Hücreli)
Tüm akciğer kanserlerinin %20 sidir. Sigara içenlerde yaygındır.Kadınlarda daha sıktır. Lezyonlar genellikle santral yerleşirler. Erkenden metastaz yaparlar. Başlangıçta ilaçlara duyarlıyken daha sonra dirençli hale gelirler. Small-cell lung cancer (SCLC) accounts for approximately 20% of all lung cancer cases.1 Cellular classification small-cell carcinoma mixed small-cell/large-cell carcinoma combined small-cell carcinoma (SCLC combined with neoplastic squamous and/or glandular components). Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumour (median survival from diagnosis of 2-4 months), but is much more responsive to chemotherapy and radiotherapy than other tumour types.2 Owing to the tendency to disseminate early, SCLC is treated as a systemic disease, with chemotherapy as the cornerstone of treatment. Despite being initially chemosensitive, these carcinomas acquire drug resistance during the course of the disease. References Zöchbauer-Müller S, et al. Ann Oncol 1999; 10 (Suppl 6): PDQ Treatment Guidelines 2000.

10 Akciğer Kanseri Tanı / Evreleme
Fizik muayene Bulgular Bronkoskopi Tümörü lokalize eder,biopsi olanağı sağlar İnce iğne aspirasyonu Sitolojik inceleme Akciğer grafisi Tümörün yerleşimi , büyüklüğü , sayısı Bilgisayarlı Tomografi Göğüs duvar invazyonu, mediastinal lenfadenopati,uzak metastazlar Current standard guidelines indicate that diagnosis may be made by bronchoscopy or cytology via a fine-needle aspirate (FNA). During the initial evaluation, all patients should have their history taken and undergo physical examination, chest X-ray and chest computed tomography (CT) scans (including the adrenal glands), liver CT scan or abdominal ultrasound. Other evaluations include a complete blood count, liver function tests, measurements of electrolytes, calcium, blood urea nitrogen, and creatinine, as well as a baseline ECG. Bone scans and/or brain CT scans may be appropriate in some patients.1 The extent of the tumour, the involvement of the lymph nodes, and chest wall or mediastinal invasion can be determined with similar efficacy using either CT or magnetic resonance imaging (MRI). CT is used more commonly, although MRI may be preferable in specific situations, for example in evaluating superior sulcus tumours.2 Positron emission tomography (PET) with radiolabeled fluoro-2-deoxyglucose combined with CT was significantly more accurate than CT alone in identifying lymph node involvement in NSCLC.3 References NCCN Guidelines 2000. Webb WR, et al. Radiology 1991; 178: Vansteenkiste JF, et al. J Clin Oncol 1998; 16: PET Lenf nodülü evreleme, metastazlar Laboratuar analizler Hormon düzeyleri, hematolojik değişiklikler Mediastinoskopi Mediastinal lenf nodülü saptanması ve örneklemesi

11 Akciğer kanserinde moleküler anormallikler
Atipik alveoler hiperplazi Premalign adenom Genetik değişiklikler Eksternal sinyallere uygunsuz cevaplar Hücre döngüsü kontrolü kaybı Apopitoz yolu kaybı Kontak inhibisyon kaybı Metastaz yapabilme Anjiyogenez Ölümsüzlük Otokrin büyüme döngüsü Sigara karsinojeni Normal epitel Akciğer kanseri Bronşiyal metaplazi Carcinoma in situ Displazi

12 Küçük hücreli dışı akciğer kanseri evreler
Lenf nodülleri Göğüs duvarı invazyonu Uzak organ metastazı Ana bronş Evre IV Evre 0 Evre IA Evre IIB Evre IIIB Lung cancer is staged according to three parameters: tumour (T), lymph nodes (N), and metastatic involvement (M).1 For each of these, x indicates that the value cannot be assessed and 0 indicates that no evidence of the parameter is found. Additional stages are outlined below. Tumour stages: TIS: carcinoma in situ (confined to airway lining) T1-T4: ranging from tumour <3 cm in greatest dimension through to tumour of any size that invades the mediastinum, heart, great vessels, trachea, oesophagus, vertebral body or carina. Lymph node stages: N1: metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes involved by direct extension of primary tumour N2: metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3: metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s). Distant metastasis stages: M1: distant metastasis present. The schematic diagram shows examples of some tumour stages: Early stage 0 (carcinoma in situ): tumour is confined to the airway lining stage IA (T1 N0 M0): tumour has spread to nearby lung tissue but has not reached the main bronchus Localised stage IIB (T2 N1 M0/T3 N0 M0): tumour has reached main bronchus and local lymph nodes or direct local invasion into chest wall, diaphragm, mediastinal pleura or parietal pericardium Advanced stage IIIB (T4 Any N M0/Any T N3 M0): tumour has invaded chest wall, trachea and the contralateral lymph nodes stage IV (Any T Any N M1): distant metastasis present in the brain. Fewer than 30% of patients present with stage I or II disease.2 References Mountain CF. Chest 1997; 111: Ihde DC. N Engl J Med 1992; 327: Karşı taraf lenf bezi

13 TNM durumuna göre 5 yılllık sağkalım (Küçük hücreli dışı)
5-yıl sağkalım (%) 61 38 34 24 13 5 1 Evre IA IB IIA IIB IIIA IIIB IV TNM T1N0M0 T2N0M0 T1N1M0 T2N1M0 or T3N0M0 T1-3N2M0 orT3N1M0 T4NanyM0 or TanyN3M0 TanyNanyM1 Survival progressively declines as the stage of disease at presentation advances.1 Reference Mountain CF. Chest 1997; 111: Mountain 1997

14 Kim tedavi etmeli ? İngiltere York Shire’da 30 ayda , 240 hasta
Bunların %49’u aktif tedavi almıştır. Ekipte göğüs hastalıkları uzmanı olmadığında aktif tedavi alma oranı %21’dir. Göğüs hastalıkları uzmanlarının görmediği hastaların histolojik tanı alma sıklığı daha az. Göğüs hastalıkları uzmanları 65 yaş altı hastaların %18’ini, 65-74 yaş arası hastaların %12’sini ve 75 yaş üzerindekilerin %2’sini cerrahiye vermişlerdir. Brown ve ark;UK

15 Multidisipliner Yaklaşım
Göğüs Hastalıkları Göğüs Cerrahisi Medikal Onkoloji Radyasyon Onkolojisi Radyoloji Patoloji Yardımcı Sağlık Personeli Birimleri

Genel yaklaşım Küçük hücre dışı akciğer kanserlerinde tedavi Cerrahi tedavi Radyoterapi Kemoterapi Küçük hücreli akciğer kanserinde tedavi Palyatif tedaviler

17 Akciğer Kanseri Tedavisine Yön Veren Koşullar
1) Tümörün histopatolojik tipi 2) Hastalığın evresi 3) Hastanın performans durumu

18 (Küçük hücre dışı akciğer kanseri)
Tedavi yaklaşımları (Küçük hücre dışı akciğer kanseri) Evre II Lobektomi, pnömonektomi, segment / wedge rezeksiyon Cerrahi olanaksızsa küratif radyoterapi Adjuvant kemoterapi Adjuvant radyoterapi Evre I Lobektomi veya segment / wedge resection Cerrahi olanaksızsa küratif radyoterapi Adjuvant kemoterapi Adjuvant radyoterapi Evre IIIA Sadece cerrahi Kemoterapi + radyoterapi / neoadjuvant tedavi Post-operatife radyoterapi Sadece radyoterapi Evre IIIB Sadece kemoterapi Kemoterapi + radyoterapi Evre IV Kemoterapi ( platinli ), Yeni kemoterapi ajanları Radyoterapi (palyatif) Obstrüksiyon için endobronşiyal lazer veya brakiterapi Stage I:1 surgery is the treatment of choice and curative radiotherapy may be used in patients with contraindications to surgery many patients resected for stage I NSCLC may later develop regional or distant metastases. Investigations of adjuvant chemotherapy or radiotherapy following surgery are currently underway chemoprevention trials for second cancers in patients resected for stage I NSCLC are also underway. Stage II:1 many patients resected for stage II NSCLC may later develop regional or distant metastases. Investigations of adjuvant chemotherapy or radiotherapy following surgery are currently underway. Stage IIIA:1 surgery alone in highly selected cases chemotherapy combined with radiotherapy, chemotherapy plus radiotherapy followed by surgery, or chemotherapy after surgery (encouraging results for patients with good performance status). Optimal sequencing and scheduling have yet to be determined. Neoadjuvant chemotherapy could be considered for patients with good performance status surgery and post-operative radiotherapy (can improve local control, but there is controversy over whether it improves survival) radiotherapy (long-term survival benefit in 5-10% of patients; patients with high performance status are most likely to benefit). Stage IIIB:1 radiotherapy alone (patients with advanced disease and high performance status are most likely to benefit) chemotherapy combined with radiotherapy (modest survival benefits compared with radiotherapy alone) chemotherapy and/or radiotherapy followed by surgery chemotherapy alone (for patients with malignant pleural effusion). Stage IV:1 cisplatin-containing combination regimens produce higher response rates than single-agent chemotherapy current treatments produce modest survival benefits compared with supportive care alone, and there is no standard regimen new chemotherapy agents are being evaluated in clinical trials external radiotherapy may be used for palliation of symptoms such as compression of the trachea, oesophagus or bronchus; bone or brain metastases; local pain; vocal cord paralysis; haemoptysis; or superior vena cava syndrome endobronchial laser therapy or brachytherapy may be useful in treating lesions obstructing the proximal airways. Many patients do not receive any treatment, even first line; the proportion of patients receiving treatment reduces with the stage of the disease. Reference 1. PDQ Treatment Guidelines 2000.

19 Küçük Hücre Dışı Akciğer Kanseri
Evre I ve II hastalar rezeke edilebilen hastalar olup, olanak varsa cerrahi olarak tedavi edilmelidir. Evre IIIA cerrahi ? medikal ? Evre IIIB ve IV cerrahiye uygun olmayıp kemoterapi ? radyoterapi ? destek ?

20 Küçük Hücre Dışı Akciğer Kanseri
Hastalar öncelikle cerrahi açıdan değerlendirilmelidir. Hasta opere edilebilir mi? Rutin kardiyovasküler değerlendirme Spirometrik değerlendirme,Diffüzyon Arter kan gazı Ventilasyon / Perfüzyon sintigrafisi

21 CERRAHİ TEDAVİ Başarılı rezeksiyon akciğer kanserlerinde en iyi tedavi yöntemidir. Rezeksiyon sonrası 5 yıllık sağkalım genel olarak %40 -50 Sınırlı ve erken lezyonlarda %80’e ulaşmaktadır.

22 CERRAHİ TEDAVİ Rezektabilite :Primer tümörün ve tüm lokal yayılımının tam olarak uzaklaştırılmasıdır. Tam rezeksiyonda ; Tümör sınırları tamamen hastalıksız , Satellit nodüller incelenmeli, Mediastinal lenf bezleri değerlendirilmelidir.

Son 3 ayda MI geçirilmesi FEV1’in 1 litre altında olması (%50’den az) VO2max’ın 10 ml/kg/dk’dan az olması DLCO’nun %40’ın altında olması Sigara içimi, obezite, hipertansiyon, diabetes mellitus, kalb hastalıkları, diğer medikal problemler.

24 Cerrahi Yöntemler Segmentektomi Wedge rezeksiyon Lobektomi (önerilen)
Bilobektomi Pnömonektomi (kendisi bir hastalıktır)

EVRE pTNM 5 yıl sağkalım % I T1T2NO 65 IIA T1N1 50 IIB T2N1 50 T3N0 40 IIIA T3N1 25 N2 20 GENEL 45

26 RADYOTERAPİ Küratif ve palyatif olarak uygulanabilir.
Bölgesel tedaviyle lokal kontrolü sağlar. Erken dönemde medikal olarak cerrahiye kontrendikasyon varlığında uygulanabilir. Erken dönem tümörlerinde tek başına RT sonuçlarında bias vardır. (5 yıl %6-32) Sağkalım süresi tümör çapı, lenf bezlerinin durumu ve total radyoterapi dozuyla ilişkilidir.

27 Tümör Büyüklüğü ve Radyasyon Dozuyla İlişkili Olarak Sağkalım*
Yazar Evre I Evre I/II Evre IIIA Evre IIIB <3cm 3-5 cm < 3 cm 3-5cm 3-5 cm Morita Noorduk 22 0 Gouders Martel Sibley Armstrong Wurschmidt *5 yıllık sağkalımlar % olarak verilmiştir.

Doz Frak Hafta Gy Gün Konvansiyonel □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ Split course □□□□□ □□□□□ □□□□□ □□□□□ > Hipofrak □ □ □ □ □ □ □ □ □ □ > 2 1 <5 Hiperfrak □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ □□□□□ CHART □□□□□□□□□□□□ □□□□□□□□□□□□ HART □□□□□ □□□□□ □□ □□□□□ □□□□□ □□ (CHART: Continuous hyperfractionated accelerated radiation therapy)

29 RADYOTERAPİ Split course hasta uyumu iyidir , palyatiftir,
Hipofraksiyon palyasyon için kullanılır, Hiperfraksiyon tedavilerde toksisite artmaktadır, CHART lokal kontrolu sağlamada en iyi yöntem olmakla beraber toksisite sıkıntıları vardır. Konformal radyoterapi son yıllarda umut vericidir. Standart ışınlama primer tümör sahası ve muhtemel lenfatik drenaj bölgesidir.

İki büyük çalışmada preoperatif radyoterapinin komplikasyonların artması sonucunda sağkalımı azalttığı gösterilmiştir. Preoperatif radyoterapi süperior sulkus tümörlerinde önerilmektedir.

Yapılan çalışmalarda sağkalım süresinde anlamlı fark bulunamamıştır. Lokal nüksün azalmasını sağlamıştır. Evre I ve II hastalarda önerilmez. Evre III hastalarda sağkalım avantajı yok, lokal kontrolü sağlamaktadır.

32 PALYATİF RADYOTERAPİ Havayolu Obstrüksiyonu Hemoptizi
Vena Kava Süperior Sendromu Kemik metastazları Spinal kord kompresyonu Beyin metastazı

33 Toraks Radyoterapi Toksisitesi
Halsizlik, öksürük, balgam ve yutma güçlüğü Özofajit Pnömonitis Pulmoner fibrozis Kardiyak toksisite ( perikardit , ventrikül disfonksiyonu) Deri ve kemik toksisitesi Spinal kord toksisitesi

34 KEMOTERAPİ İleri evre hastalıkda 5-yıl sağkalım %1’in altındadır.
Hastaların çoğu kısa sürede kaybedilir. Lokal ileri hastalıkta kemoterapi sağkalımı arttırmaktadır. İleri hastalıkta hem sağkalımı hem de yaşam kalitesini arttırmaktadır.

35 Tek ilaç kemoterapi cevap oranları
 İlaç Cevap oranı (%) İrinotecan 27 İfosfamide 26 Paclitaxel 26 Docetaxel 26 Gemcitabine 21 Cisplatin Mitomycin C 20 Vinorelbine 20 Vindesine 17 Doxorubicin 13 Topotecan 13 Etoposide 11

36 KEMOTERAPİ Kemoterapi ve “best supportive care” arasında 1980 yılından bu yana birçok çalışma yapılmıştır. Yapılan 3 metaanaliz sonucunda kemoterapi kolları daha üstün bulunmuştur.

37 KEMOTERAPİ Kombine rejimlerle etkinlikle beraber toksisite de artmaktadır. MVP ile iyi sonuçlar elde edilmiştir. Cisplatin ile yapılan tüm çalışmalarda Cisplatin kolunda cevap daha iyi olunca Cisplatin temel ilaç olmuştur.

38 PROGNOSTİK KRİTERLER Hastalığın evresi ve hastanın performans durumu en önemli prognostik kriterlerdir. İyi performans Kadın olmak Tek bir metastatik bölge olması Normal Ca++ ve LDH Hemoglobinin 11 g/dL üzerinde olması Cisplatin kemoterapisi

39 KEMOTERAPİ Yeni ajanlar ve BSC karşılaştırılmıştır.
Vinorelbine yaşlı hastalarda üstün bulunmuştur. Docetaxel ve Paclitaxel BSC’e üstün bulunmuştur. Gemcitabine ile karşılaştırmada sağkalım üstünlüğü bulunmazken , hastaların yaşam kalitesinde ve palyatif radyoterapi gereksiniminde azalma bulunmuştur.

40 KEMOTERAPİ Tek ajan Cisplatin ve yeni ilaçların Cisplatinle kombinasyonları çalışılmıştır. Cisplatinin dozu ile ciddi bir ilişki bulunmasa da 100 mg/m2 ideal doz olarak saptanmıştır. Yeni ajanlarla cisplatin kombinasyonu daha iyi sonuç vermiştir.

41 KEMOTERAPİ Cisplatin Kombine Sağkalım p ( 1 yıl sağ) KT ( 1 yıl ) Wozniak 6ay +Vinorelbine 8 ay Sandler 32w+Gemcitabine 39 w Gatzemeier 35w+Paclitaxel 37 w >0.05 Von Pawel 28w+Tiripazamine 35 w 0.008

42 Kombine Kemoterapi: İleri evre Akciğer kanserinde Randomize Çalışmalar
cevap (%) * * 32.1* 28 40* * Çalışma Le Chevalier Bonomi Crino Belani 1998 Cardenal Şemalar Vindesine/cisplatin Vinorelbine/cisplatin Etoposide/cisplatin Paclitaxel (135)/cisplatin Paclitaxel (250)/cisplatin/GCSF Mitomycin/ifosfamide/cisplatin Gemcitabine/cisplatin Etoposide/cisplatin Paclitaxel/carboplatin Etoposide/cisplatin Gemcitabine/cisplatin Ortalama sağkalım (ay) * 1-yıl sağkalım (%) 28 36 - - 35 35 26 32 Data from randomised clinical trials and meta-analyses have demonstrated that platinum-based chemotherapy improves survival compared with best supportive care alone in stage IV disease. In addition, platinum-containing chemoradiotherapy results in superior survival compared with radiotherapy alone in stage III disease. Le Chevalier and colleagues found that patients treated with vinorelbine alone had a poorer survival than those treated with vinorelbine plus cisplatin.1 Recent randomised trials have demonstrated the benefit of combining cisplatin with new active agents in NSCLC, resulting in increased tumour response and prolonged median survival compared with cisplatin treatment alone,1-9 recently reviewed by Gandara et al.10 The slide outlines recent randomised trials that have compared the activity of some of the new combination regimens with older regimens such as etoposide/cisplatin. Although the trials demonstrated significant advantages for the new combinations, the significantly higher response rates do not appear to translate into equivalent improvements in survival.10 Combination therapy with three or more drugs, with new chemotherapy agents plus radiotherapy, or with newer agents in the absence of platin therapy, is also being tested in ongoing trials.11-13 References Le Chevalier T, et al. J Clin Oncol 1994; 12: Sandler A, et al. Proc ASCO 1998; 17: abstr 1747. von Pawel J, et al. Proc ASCO 1998; 17: abstr 1749. Gatzemeier U, et al. Proc ASCO 1998; 17: abstr 1748. Wozniak AJ, et al. J Clin Oncol 1998; 16: Bonomi P, et al. Proc ASCO 1996; 15: abstr 1145. Crino L, et al. Proc ASCO 1998; 17: abstr 1750. Belani CP, et al. Proc ASCO 1998; 17: abstr 1751. Cardenal F, et al. J Clin Oncol 1999; 17: Gandara DR, et al. ASCO Educational Book Spring 1999; Greco FA, Hainsworth JD. Ann Oncol 1999; 10 (Suppl 5): S63-S67. Gralla R, et al. Ann Oncol 1999; 10 (Suppl 5): S47-S51. Adjei AA, et al. Semin Oncol 1999; 26 (Suppl 16): *p<0.05;

43 Kombine Kemoterapi: İleri evre Akciğer kanserinde Randomize Çalışmalar
Tümör cevabı 28 25 - - - Çalışma Kelly 2001 Schiller 2002 Fossella 2001 Şemalar Vinorelbine (25)/cisplatin (100) Paclitaxel (225)/carboplatin (AUC 6) Paclitaxel (135)/cisplatin (75) Gemcitabine (1000)/cisplatin (100) Docetaxel (75)/cisplatin (75) Paclitaxel (225)/carboplatin (AUC 6) Docetaxel (75)/cisplatin (75) Docetaxel (75)/carboplatin (AUC 6) Vinorelbine (25)/cisplatin (100) Ortalama sağkalım (ay) 8 8 1-yıl sağkalım (%) 36 38 At present, none of the new agent/platinum combinations has been shown to be clearly superior. In two large Phase III trials, a broad range of response rates with these new combinations has been observed, but this does not translate into a significant impact on median survival.1-3 A Phase III study to compare docetaxel/cisplatin or docetaxel/carboplatin with the reference regimen vinorelbine/cisplatin in chemotherapy-naïve patients with stage IIIB/IV NSCLC has recently been reported.4 Docetaxel/cisplatin had a survival advantage over vinorelbine/cisplatin. References Kelly K, et al. Proc ASCO 1999; 18: abstr 1777. Kelly K, et al. J Clin Oncol 2001; 19: Schiller JH, et al. N Engl J Med 2002; 346: Fossella F. Eur J Cancer 2001; 37 (Suppl 6): 154 (abstr 562). Kelly et al 2001 Schiller et al 2002 Fossella 2001

44 İkinci basamak Docetaxel (İleri evre Akciğer kanseri)
1.0 Docetaxel 75 mg/m2 (n=55) Best supportive care (n=49) Docetaxel 75 mg/m2 7.5 37 Best supportive care 4.6 12 0.8 Ortalama sağkalım(ay) 1-yıl sağkalım (%) 0.6 0.4 As use of first-line therapy has increased and patients relapse following initial treatment, a need for second-line chemotherapy has emerged. Phase III trial data showed a small survival advantage for docetaxel vs best supportive care.1 Severe toxicity was observed in the highest-dose treatment arm. Current clinical guidelines state that second-line chemotherapy for advanced NSCLC can be recommended for selected patients. Although docetaxel is currently the only approved agent for second-line treatment of NSCLC, a number of other single agents have shown activity in this setting, including vinorelbine, gemcitabine, paclitaxel, OSI-774 and ZD1839 in Phase II trials. Combinations of agents are also being investigated. Reference Shepherd FA, et al. J Clin Oncol 2000: 18; Slide figure reproduced from reference 1 with permission from Lippincott, Williams & Wilkins. 0.2 Log rank: p=0.01 0.0 3 6 9 12 15 18 21 Ay Shepherd et al 2000

45 GEMCITABINE N Cevap Ort yaşam Gemcitabine 71 % ay (1000) vs Cisplatin (100)+ Etoposide(80) 75 % ay * *p > 0.05 Manegold C: Semin Oncol,1998.

46 GEMCITABINE N Cevap Ort.yaş 1 yıl sağkalım Cisplatin 262 %9 7.6 ay %28 vs Gemcitabine+ Cisplatin 260 %31 9 ay * %39* *p <0.05 Sandler A: Proc Am Soc Clin Oncol,1998.

47 ECOG 1594 ÇALIŞMASI Evre IIIB ve IV ECOG PS 0-2 Chemonaive
Önceden RT almamış Randomize

48 ECOG ÇALIŞMASI Cisplatin 75 mg/m2 D2+ Paclitaxel 175 mg/m2/24 saat D1 (21 gün) Gemcitabine 1000mg/m2 D1,8,15 + Cisplatin 100 mg/m2 D1 (28 gün) Cisplatin 75 mg/m2 D1 + Docetaxel 75 mg/m2 D1 (21 gün) Carboplatin AUC 6 D1 + Paclitaxel 225 mg/m2 /3 saat D1 (21 gün)

49 ECOG 1594 ÇALIŞMASI Cpac Cgem Cdoc CarPac Ort sağkalım 7.8ay yıllık sağkalım % Cevap oranı % Prog. sağkalım 3.5ay

50 ECOG 1594 TOKSİSİTE Cpac CGem Cdoc CarPac Nötropeni Febril Nötropeni Trombositopeni 5 48* 3 10 Anemi 13 29* Nefrotoksisite 3 9* 3 1 Hipersensitivite

51 Evre IIIA: Neoadjuvant kemoterapi
Cerrahi tedavi evre IIIA küçük hücre dışı akciğer kanserli hastaların tedavisinde başarılı değildir. Üç randomize çalışmada neoadjuvant cisplatin-bazlı kemoterapi sağkalımda başarılı sonuçlar sağlamıştır. Faz III gemcitabine/cisplatin çalışmasında hastaların %70%’den ve lenf nodüllerinin %53’den fazlasında gerileme olmuştur.(van Zandwijk 2000) Neoadjuvant docetaxel faz III çalışmalarda uzun bir sağkalım sağlamıştır. (Mattson 2001) Surgical resection alone fails to cure the majority of patients with NSCLC, due to undetected metastases at the time of surgery. Although post-operative chest radiotherapy virtually eliminates locoregional recurrences, no improvement is observed in survival. Therefore neoadjuvant chemotherapeutic approaches are warranted. At least three randomised trials have been conducted to evaluate neoadjuvant cisplatin-based chemotherapy.1 For two of these studies, statistically significant improvements in survival results were observed in those patients receiving neoadjuvant chemotherapy, compared with those receiving surgery alone. Randomised trials are in progress to determine whether triple modality regimens are superior to two modalities. In an additional trial, 47 patients with stage IIIA disease had a response rate of >70% following induction therapy with gemcitabine/cisplatin.2 Downstaging of the mediastinal lymph nodes occurred in 53% of patients. Based on proven activity and survival benefit in advanced NSCLC, docetaxel has been introduced into neoadjuvant therapy and has been evaluated in a large Phase III randomised trial.3 A total of 274 patients with stage IIIA and IIIB disease were involved. Overall 1-year survival was 59% compared with 51% in the control group. References Bunn PA, et al. Chest 2000; 117: 119S-122S. van Zandwijk N. Anticancer Drugs 2000; 11 (Suppl 1): S17-22. Mattson K. Semin Oncol 2001; 28 (3 Suppl 9):

Evre III hastalarda primer hastalık RT ile kontrol edilirken, gizli mikrometastazların KT ile kontrol altına alınma mantığı vardır. Sağkalım CT+TRT TRT Ortalama ay ay 2 yıl % %13 5 yıl % %6 7 yıl % %6 Dillman RO:J Natl Canc Inst,1996

Sağkalım KT+TRT KT Ortalama 15.2 ay 14.7 ay 2 yıl %35.5 % yıl % 9.7 % 3.1 Kubota K: J Clin Oncol,1994.

Sağkalım Eş zamanlı Ardışık Ortalama 16.5 ay 13.3 ay 1 yıl %64.1 % yıl %34.6 % yıl %22.3 % yıl %15.8 %8.9

Küçük hücreli akciğer kanseri kemoterapiyle tedavi edilir. Radyoterapi sınırlı hastalıkta uzun süreli sağkalımda önemli rol oynar. Cerrahinin rolü çok sınırlı olgularda mevcuttur.

56 Küçük Hücreli Akciğer Kanseri Evreleme
Extensive Tek bir hemitoraksın dışına çıkan, sınırlı hastalık ötesinde Uzak metastasis Limited Tek bir hemitoraksa ve/veya mediasten ve supraklavikuler nodüllere sınırlı Metastatic (extensive-stage) disease is present at diagnosis in most patients with SCLC. Thus, survival is usually not affected by small changes in the amount of locoregional tumour involvement, as it is for NSCLC. Thus, although relevant, the detailed TNM staging previously described (which is more appropriate when surgery is being considered), is not commonly employed for staging SCLC. Instead, a simplified staging system of ‘limited’ versus ‘extensive’ disease is used.1 Approximately one-third of patients with SCLC present with limited-stage disease.2 In limited-stage disease the tumour is confined to the hemithorax of origin, the mediastinum and the supraclavicular nodes, which can be encompassed within a ‘tolerable radiation’ therapy port.3 The extensive stage of SCLC encompasses any tumour too widespread to be included within the definition of limited stage and any patients with distant metastasis.3 Patients with limited disease have a median survival of 3 months without drug therapy, compared with 1.5 months for patients with extensive disease.2 References PDQ Treatment Guidelines 2000. Kelly K. Chest 2000; 117 (4 Suppl 1): 156S-162S. Zelen M. Cancer Chemother Rep ; 4:

57 Prognostik Faktörler Hastalığın evresi
Sınırlı hastalık/Yaygın hastalık Hastanın performansı Serum LDH düzeyi Plazma albümin ve sodyum düzeyi

58 Prognoz Hastalar (%) Sınırlı Yaygın *ABD verileri (1992-1997)
Based on US figures from , 5-year survival in patients with SCLC is 6.2%.1 Disease stage is one of the most important prognostic factors in SCLC. In a randomised study, in which two combination chemotherapy regimens were compared, prognostic factors were analysed in 286 patients. Disease stage was the primary pretreatment predictor of 3-year survival; 19.2% of patients with limited-stage disease survived for 3 years, compared with 3.5% with extensive-stage disease.2 The median survival duration for patients treated with combination chemotherapy is 10 to 14 months for patients with limited-stage and 7 to 11 months for those with extensive-stage, the most commonly diagnosed SCLC.3 References 1. Ries LAG, et al (eds). SEER Cancer Statistics Review, , National Cancer Institute, Bethesda, MD, 2001. 2. Kawahara M, et al. Jpn J Clin Oncol 1997; 27: 3. Zöchbauer-Müller S, et al. Ann Oncol 1999; 10 (Suppl 6): S83-S91. Sınırlı Yaygın *ABD verileri ( ) Ries et al 2001

Tedavide temel prensip; Kombinasyon Kemoterapisi ve Toraks Radyoterapisidir.

1992 yılında yapılan metaanaliz sonucunda toraksa radyoterapi alan hastalarda sağkalımın biraz daha uzun olduğu gösterilmiştir. 3 yıllık sağkalım; Kombine modalite %14.1 (1111 hasta) Sadece kemoterapi %8.9 ( 992 hasta ) (CE en sık kemoterapi şeması)

61 Sınırlı hastalık : Kombine kemoterapi ve Göğüs radyoterapisi Meta-analiz (13 çalışma)
KT + RT n=1111 Sağkalım (%) 100 sadece KT n=992 80 60 40 A meta-analysis of the 13 largest trials showed that combined chemotherapy and chest radiotherapy was more effective than chemotherapy alone. In this study, administration of thoracic radiotherapy led to a 14% reduction in mortality rate (p=0.001), which corresponded to a 5% increase in the 3-year survival rate.1 A similar result was also demonstrated in another meta-analysis of 11 randomised trials.2 Most of the benefit occurred in patients <55 years. Several randomised trials have investigated the timing of thoracic radiotherapy and, in general, have suggested that early chemoradiation is superior to late chemoradiation, with observed improvements in overall survival.3 This may be due to early control of metastases. Thus, combination chemotherapy plus chest radiotherapy is considered the standard treatment for patients with limited-stage SCLC.4 Optimal timing and sequencing of thoracic radiotherapy with both established and new agents remain to be resolved. References Pignon JP, et al. N Engl J Med 1992; 327: 2. Warde P, Payne D. J Clin Oncol 1992; 10: 3. Goto K, et al. Proc ASCO 1999; 18: abstr 1805. PDQ Treatment Guidelines 2000. Slide figure reproduced with permission from reference 1. Copyright ©1992 Massachusetts Medical Society. All rights reserved. 20 1 2 3 4 5 Yıllar p=0.001 Pignon et al 1992

Cevaplanmamış sorular; Radyoterapi ne zaman ? Alternan ? Ardışık ? Aynı anda ?

Kanada çalışması ; (308 hasta) Eş zamanlı kemoterapi ile erken (3 hafta) ve geç dönemde (15 hafta) radyoterapi Erken kolda sağkalım %40 Geç kolda sağkalım %34

Kombine kemoterapi ve eş zamanlı radyoterapi sırasında ortaya çıkan majör toksisite Akut Özofajitis

65 Sınırlı hastalık (Küçük hücreli) Kombine kemoterapi
Sık kullanılan şemalar cisplatin/etoposide (PE) cyclophosphamide/doxorubicin/vincristine (CAV) cyclophosphamide/doxorubicin/etoposide (CAE) CAV / PE PE uluslararası standart Carboplatin/etoposide daha az toksik Decade-old data indicated that multidrug, platinum-based therapy, especially in limited-stage SCLC, is superior to nonplatinum-based regimens. As a result, use of cisplatin/etoposide (PE) became the ad-hoc international standard for limited-stage SCLC. A number of combination chemotherapy regimens are currently used to treat patients with SCLC, including PE, cyclophosphamide/doxorubicin/vincristine (CAV) and cyclophosphamide/doxorubicin/etoposide (CAE).1 PE has been compared with CAV or CAV alternating with PE in 2 randomised trials.2,3 No difference in survival was observed between the treatment arms (8-9 months) for patients with extensive-stage disease. Although nausea and vomiting were considerable with PE, there was less myelosuppression, neurotoxicity and cardiac toxicity than with CAV. Based on these results, PE has become the most commonly used regimen. The combination of carboplatin/etoposide (CE) has shown activity against SCLC, with less toxicity than PE.4 The CE regimen is often used to treat patients with SCLC. The combination chemotherapy regimens commonly used in extensive-stage SCLC all appear to have similar relative effectiveness, with overall response rates of 70-85%, complete response rates of 10-40% and median survivals of 7-11 months.5 There is no compelling evidence that maintenance chemotherapy prolongs survival for patients with SCLC. In fact it may produce more toxicity and thus negatively impact on quality of life.6 References Kelly K. Chest 2000; 117 (4 Suppl 1): 156S-162S. Fukuoka M, et al. J Natl Cancer Inst 1991; 83: Roth BJ, et al. J Clin Oncol 1992; 10: Skarlos DV, et al. Ann Oncol 1994; 5: PDQ Treatment Guidelines 2000. Giaccone G, et al. J Clin Oncol 1993; 11: Kelly 2000

Sistemik kemoterapiden sonra tam remisyona giren hastalarda Gy koruyucu kafa ışınlaması beyin metastazlarını azaltmakta ve sağkalımı uzatmaktadır. Arriagada (294 hasta) ; 2 yıl sağkalım ; Koruyucu ışın alanlarda %29 Işın almayan kontrol kolunda %21

67 Sınırlı hastalık: Proflaktik kafa ışınlaması
PCI (-) n=149 PCI (+) n=145 Total beyin metastazı (%) 80 60 40 Despite the high response rates to chemotherapy, the risk of brain metastasis is 50-80% after 2 years, resulting in extremely low survival rates. This study showed that the 2-year rate of brain metastases was 67% (95% CI: 58%, 75%) in the control group compared with 40% (95% CI: 30%, 50%) in the group receiving PCI (p<10-13).1 Several randomised studies have failed to demonstrate a benefit for PCI in improving overall survival, and side effects, such as neuropsychiatric abnormalities, have been a concern. However, neurological abnormalities have been shown to exist in 30-40% of SCLC patients prior to PCI and a recent meta-analysis demonstrated an absolute 5.4% increase in 3-year survival rate in favour of PCI.2 It is now generally accepted that PCI should be administered to patients with limited-stage disease in complete remission after induction chemotherapy.2,3 Questions remain regarding optimal dose, fractionation schemes and timing or irradiation. References Arriagada R, et al. J Natl Cancer Inst 1995; 87: Auperin A, et al. N Engl J Med 1999; 341: Kotalik J, et al. Int J Radiat Oncol Biol Phys 2001; 50: Slide figure reproduced from reference 1 with permission from Oxford University Press. 20 12 24 36 48 60 Aylar Arriagada et al 1995

N Eng J Med ( Editorial) 1999 “ Sınırlı ve izole metastazlı yaygın hastalıklı küçük hücreli akciğer kanserli hastalarda tedavi sonrası hastalar tam remisyona girerlerse KORUYUCU KAFA IŞINLAMASI uygulanmalıdır “

69 YÜKSEK DOZ KEMOTERAPİ Kök hücre destekli yüksek doz kemoterapi henüz araştırma aşamasındadır. Sonuçları değerlendirmek için erkendir.

70 YÜKSEK DOZ KEMOTERAPİ 341 hastalık G-CSF destekli bir çalışma;
Cyclophosphamide 1 g/m günler Doxorubicine 50 mg/m2 Etoposide 120 mg/m2 G-CSF Günler Febril nötropeni Çalışma kolunda %28 Kontrol kolunda %57

71 YÜKSEK DOZ KEMOTERAPİ İki grupta sağkalım yönünden fark yok.
Çalışma kolunda hastanede kalış süresi daha az. Yüksek doz kemoterapiyle ilgili olarak daha yeni çalışmalara ihtiyaç var.

5 yıllık sağkalım %0.8’den %1.6’ya yükselmiştir. Çeşitli stratejiler denenmesine rağmen sonuçlar iyi değildir. Ortalama yaşam 7-9 aydır. Tedavide temel kombine kemoterapidir. Agressif tedavi yaklaşımında tam cevap ve uzun sağkalım sağlanmakla beraber, toksisite daha fazladır.

73 Yaygın hastalık (küçük hücreli) İlk seçenek Faz III çalışmalar
Cisplatin/irinotecan (CP) vs PE (Noda et al 2002) Genel cevap CP 84.4% ve PE 67.5% Median survival CP 12.8 ay ve PE 9.4 ay CP grup 70 ölüm and PE grup 74 ölüm (p=0.002) Yeni bir standart ? Tek ajan topotecan (Schiller et al 2001) Topotecan vs PE sonrası gözlem: Faz III ECOG Genel sağkalımda ve yaşam kalitesinde düzelme yok A randomised Phase III study compared cisplatin/irinotecan (CP) with cisplatin/etoposide (PE) in patients with extensive-stage SCLC.1 This study showed an overall response rate of 84.4% versus 67.5% in favour of the CP arm. The CP arm also showed significantly better survival than the standard arm (p=0.002). As expected, grade 3/4 diarrhoea was more common in the CP arm than in the PE arm (16% versus 0%, respectively; p<0.001). An ECOG trial investigated topotecan versus observation following 4 cycles of PE induction therapy.2 Progression-free survival was significantly better with topotecan compared with observation (3.6 versus 2.3 months, respectively; p<0.001), but no improvement was observed in overall survival or quality of life. In a Phase III trial of a 4-drug regimen containing cisplatin/etoposide plus cyclophosphamide and epidoxorubicin compared with cisplatin/etoposide alone, the 4-drug regimen yielded higher response rates (76% versus 61%, respectively) and better survival rates (1-year survival 40% versus 29%, respectively) in patients with extensive SCLC.3 References Noda K, et al. N Engl J Med 2002; 346: Schiller JH, et al. J Clin Oncol 2001; 19: Pujol JL, et al. J Natl Cancer Inst 2001; 93:

74 Yaygın hastalık (Küçük hücreli) İkinci basamak Faz II çalışmalar
Tedavi Irinotecan/ etoposide Paclitaxel/ carboplatin Hasta sayısı 25 32 ORR (%) 71 25 Ortalama sağkalım (ay) 9 7 Nötropenia* (%) 56 37 Trombo- sitopenia* (%) 20 9.4 The overall response rate (ORR), survival and toxicity of irinotecan/etoposide have been evaluated in refractory or relapsed SCLC.1 All patients had been pretreated with cisplatin-based combination chemotherapy. A multicentre Phase II study has evaluated the activity and toxicity of paclitaxel/carboplatin in patients with disease progression after initial chemotherapy for SCLC.2 References Masuda N, et al. J Clin Oncol 1998; 16: Kakolyris S, et al. Ann Oncol 2001; 12: *Grade 3/4 toksisite Masuda et al 1998 Kakolyris et al 2001

75 Nüks küçük hücreli hastalarda Faz III topotecan çalışması
Tedavi Topotecan CAV Cevap [sayı (%)] Sağkalım (hafta) 25 24.7 CR - 1 (1%) PR 26 (24%) 18 (18%) hasta 107 104 More than 95% of patients with SCLC relapse after initial treatment and the overall median survival expectation after failure of first-line therapy is 2-4 months.1 In a Phase III randomised comparison of second-line treatment in patients with relapsed sensitive disease (relapsed 60 days after first-line therapy) with either cyclophosphamide/doxorubicin/vincristine (CAV) or topotecan, no significant difference in response rates (24.3% and 18.3% for topotecan- and CAV-treated groups, respectively) or survival was reported.2,3 However, the results of a symptom-specific questionnaire for SCLC suggest that topotecan offers superior palliation of some symptoms.2,3 Topotecan is now licensed in the USA, Japan and Switzerland for use in the treatment of SCLC sensitive disease (progressing at least 60 days after first-line therapy). A Phase II comparator study has found oral topotecan to be similar in efficacy to intravenous topotecan in patients with relapsed SCLC, sensitive to first-line therapy, to result in less grade 4 neutropenia and have greater convenience of administration.4 References Huisman C, et al. Cancer Treat Rev 1999; 25: von Pawel J, et al. J Clin Oncol 1999; 17: Ormrod D, Spencer CM. Drugs 1999; 58: von Pawel J, et al. J Clin Oncol 2001; 19: İlk basamak tedavi,den 60 gün sonra ortaya çıkan nüks CAV, cyclophosphamide/doxorubicin/vincristine von Pawel et al 1999

Tümörün basısı ; Genel kanser etkisi (anemi, halsizlik, ağrı, anksiyete) Eşlik eden hastalıklar (KOAH, kalb yetmezliği, İnfeksiyon) İlaçsız tedavi (Fizyoterapi) Bronkodilatör tedavi Steroidler Oksijen tedavisi Fasiyel serinletme Anksiyolitik tedavi Opioid tedavi

Tümörün etkisi dışında İnfeksiyon, reflux , astım , ACE inh. Tedavide; 1) Nonopioidler, lokal anestetikler 2) Opioidler (Codein, methadon )

Analjezik (Parasetamol, Morfin) Palyatif radyoterapi Cerrahi blokaj Epidural morfin Kordotomi İntratekal yaklaşımlar

79 PALYATİF TEDAVİ (Hemoptizi)
200 ml/gün fazlası massif kanama Minör kanamalar için Tranexamic asit g/gün verilebilir. Kemoterapiye bağlı kanamalar için replasman Emboli için uygun tedavi yapılır. Endobronşiyal brakiterapi ve lazer

80 PALYATİF TEDAVİ (Postradyasyon pnömonitis)
Radyoterapiden 6-12 hafta sonra oluşur. Oral kortikosteroid 40 mg/gün birkaç hafta Fibrozis 4 ay sonra ortaya çıkar; semptomatik tedavi verilir.

81 PALYATİF TEDAVİ (Lenfanjitis karsinomatoza)
Adenokarsinomada sıktır. Ciddi dispneye neden olur. Prognoz kötüdür. Oral kortikosteroid –dexamethasone 8 mg/gün, spironolakton 100mg/gün, nebulize bronkodilatörler

Genellikle özofageal obstrüksiyona bağlıdır. Opioidlerin ağzı kurutmasına sekonder olabilir. Radyoterapi sonrası olabilir (antasidler verilebilir)

İnoperable hastalardır. Küçük hücreli dışı hastalarda acil radyoterapi gerekir. Küçük hücreli kanserde kemoterapiyle tedavi edilebilir.

84 PALYATİF TEDAVİ (Malign plevral sıvı))
İnoperabiliteyi gösterir. Sıvının boşaltılması hastanın dispnesini hafifletebilir. Küçük hücreli kanser, lenfomada kemoterapi sıvının gerilemesine neden olabilir. Plöredezis rahatlık sağlayabilir.

85 PALYATİF TEDAVİ (Kanser kaşeksisi)
Bazı sitokinler ( TNF-, IL , IFN-) bu sendroma neden olur. Tedavi genellikle başarısızdır. Bu hastaların beslenmeleri nutrisyon üniteleriyle ortaklaşa götürülmelidir. Oral kortikosteroid ve megestrol acetat kullanılabilir.

86 PALYATİF TEDAVİ Halsizlik Hastaların %50’sinde psikolojik sıkıntılar
Anksiyete Depresyon (İleri evrede %75) Uykusuzluk Panik

Uygunsuz ADH salınımı Sıvı kısıtlaması, kemoterapi Demeclocyclin Hiperkalsemi Hidrasyon Bifosfonatlar

Bulantı-kusma Antiemetik tedavi (Dopamin ve serotonin antagonistleri) Pansitopeni Saç dökülmesi Radyoterapi ( Mukozit, özofajit )

89 Akciğer Kanseri: Gelecek Tedaviler
Halen eldeki tedaviler yeterli değildir. Erken tanı Yeni moleküler temelde sınıflama Daha iyi tedavi Hedefe yönelik biyolojik ajanlar, immunolojik yaklaşımlar, gene tedavisi Daha az toksik kombinasyonlar Korunma Current treatment for NSCLC via surgery, radiotherapy and chemotherapy has had a modest impact on overall mortality rates. Median survival post-diagnosis is approximately 8 months for inoperable (stage IIIB/IV) NSCLC, the most frequently diagnosed group. Earlier diagnosis could increase the percentage of patients treated at stage I, where the outcome of treatment is often good. There is a need for new therapeutic approaches that can provide increased efficacy, both in terms of survival and symptom relief, and less toxicity. Current areas of interest are: novel targeted biological targets advances in molecular and cellular biology have allowed specific pathways involved in cancer cell growth to be pinpointed potential to produce therapies that improve efficacy with minimal adverse effects and less severe impact on quality of life. immunotherapy immunomodulators (eg interferons and interleukins) to increase the activity of the immune system passive immunisation active immunisation. gene therapy still in its infancy possible targets include oncogenes known to be associated with lung cancer (eg K-ras) or genes for powerful immunomodulators (eg interleukins). Prevention would reduce the overall burden of disease (most lung cancer is caused by environmental factors that could be avoided).

90 Erken Tanı KOAH lı hastalarda yakın takip ? Genetik risk faktörleri ?
Balgam sitolojisi Moleküler tümör belirteçleri Düşük doz spiral CT Positron emission tomography Lazer-floresan endoskop (LIFE) bronkoskopi Identification of risk factors could allow more intensive monitoring of high-risk patients, which may improve diagnosis. Risk factors include: obstructive lung disease. This increases the risk of lung cancer approximately four-fold1 genetic factors. There was a 30% increased risk of cancer in non-smoking women whose parents or siblings had a history of respiratory tract cancer.1 Sputum cytology screening can identify premalignant dysplasia in people with chronic obstructive lung disease and a history of cigarette smoking.1 The sensitivity of sputum cytology as a population-screening tool for the detection of early lung cancer may be improved by several approaches currently under development, including immunostaining to detect hnRNP A2/B1 protein as a biomarker, detection of microsatellite alterations in histological or cytological specimens and detection of p16 hypermethylation indicating inactivation.2 Additional susceptibility factors include defects in DNA repair, polymorphisms in the cytochrome P450 enzymes and the metabolising capability of glutathione S-transferase or acetylation.3 In addition to analysis of sputum samples, molecular tumour markers such as ras and p53 can be identified in tumour tissue, bronchoalveloar lavage fluids and blood components.1,2 Techniques include analysis of gene mutations, allelotyping, gene expression at RNA and protein level, molecular cytogenetics, comparative genomic hybridisation and morphometric studies. Low-dose spiral CT scanning is relatively new, and allows data to be continuously acquired, resulting in a shorter scanning time, lower radiation exposure and improved diagnostic accuracy compared with older methods.2 A review of studies using the laser-induced fluorescence endoscope (LIFE) bronchoscopy device showed improved detection rates, but further evaluation of the effect on lung cancer mortality and the health economic implications associated with this technique require further investigation.2 References 1. Edell ES. Curr Opin Pulm Med 1997; 3: 2. Hirsch FR, et al. Clin Cancer Res 2001; 7: 5-22. Wright GS, Gruidl ME. Curr Opin Oncol 2000; 12: Edell 1997 Hirsch 2001

91 Lazer floresan endoskop bronkoskopi
White-light bronchoscopy (WLB) is the most commonly used tool in the diagnosis of lung cancer. However, this technique is limited in its ability to detect premalignant lesions, as they are only a few cells thick and are rarely observed as visual abnormalities. To address this limitation, fluorescence bronchoscopy and the LIFE bronchoscopy system were developed. This system uses a helium cadmium blue laser to stimulate the lining of the bronchi in the lungs to autofluoresce. Two image-intensified cameras amplify the red and green fluorescence intensity differences between normal and abnormal tissues. As the green autofluorescence is much stronger than the red, normal tissue appears green. In dysplasia or cancer, there is a progressive decrease in green, while the red remains unchanged, thus the lesion appears brown, purplish or red. LIFE bronchoscopy allows surgeons to identify subtle changes that are difficult to visualise through conventional WLB. In this case study, a male ex-smoker presented with a persistent cough, and sputum cytology showed cells suggestive of squamous carcinoma.1 The pulmonologist was unable to localise the source of malignant cells. A second examination was carried out. In the right lower lobe it was noted, through WLB, that some thickening had occurred in bronchus RB8, but a similar thickening was also noted elsewhere. Such changes cannot readily be distinguished from inflammation or benign metaplasia. Re-examination using the LIFE system showed an area of abnormal brownish-red fluorescence in the sub-carina. This area was 2-3 mm in width and was confirmed by biopsy as carcinoma in situ, with small foci of microinvasion. Reference Slide figures reproduced from reference 1, courtesy of Xillix Technologies Corp., Beyaz ışık bronkoskopi görüntüsü LIFE Bronkoskopi görüntüsü

92 Prognostik ve prediktif faktörler
p53 , p27, p15, p16, pRb, cyclin ve CDK K-ras mutasyonu HER2/neu ve EGFR Beta tubulin Matriks metalloproteinaz and inhibitorlerinin ekspresyonu DNA topoisomeraz II ve II Tek nucleotid polimorfizm (myeloperoxidase gene) Heparin-bağlayan büyüme faktörü New prognostic markers for estimating survival outcome and monitoring treatment are helpful to select patients with poor prognosis for new therapeutic strategies.1 A recent study has demonstrated that the presence of serum p53 antibodies is an independent prognostic factor in patients with limited-stage SCLC (p=0.033). For example, the median survival was 10 or 17 months in those with or without p53 antibodies (p=0.014).2 Several other members of the p53-p21 pathway and the pRb pathway have been found to be altered in lung tumours.3 Decreased expression of tissue inhibitors of matrix metalloproteinases (TIMP-1) has been correlated with response in patients with SCLC (p=0.043).4 Increased expression of matrix metalloproteinases (MMP-3, MMP-11, and MMP-14) was also an independent negative prognostic factor for survival.4 Chromogranin A, a protein present in neuroendocrine vesicles, has also been shown to be an important prognostic factor for survival after performance status and disease stage.5 In addition, expression of topoisomerase II and  (implicated in resistance to doxorubicin and etoposide) has been shown to be predictive of poorer survival and lower response rates, respectively.6 A consistent association has been shown where lung cancer risk is decreased by a G to A polymorphism in the myeloperoxidase (MPO) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults.7 The G to A transition results in reduced expression of MPO RNA and several studies have reported a reduction in lung cancer risk for the A/A compared with the G/G genotype. Levels of pleiotrophin in blood samples from patients with SCLC (n=63) and NSCLC (n=22) were compared with levels in 41 healthy people.8 Raised levels of pleiotrophin were found in 87% of SCLC samples and 63% of NSCLC samples, compared with 2.4% of samples from healthy controls. Levels of pleiotrophin appeared to increase as the disease became more advanced. References Gandara DR, et al. Lung Cancer 2001; 34: S75-S80. Zalcman G, et al. Int J Cancer 2000; 89: Niklinski J, et al. Lung Cancer 2001; 34: S53-S58. Michael M, et al. J Clin Oncol 1999; 17: Drivsholm L, et al. Br J Cancer 1999; 81: Dinegemans AM, et al. Clin Cancer Res 1999; 5: Williams JA, et al. Carcinogenesis 2001; 22: Jäger R, et al. Br J Cancer 2002; 86:

93 Yeni Biyolojik yaklaşımlar (1)
Epidermal growth factor receptor (EGFR) inhibitörü Tyrosine kinase inhibitors ( EGFR) - ZD1839, EGFR’e monoklonal antikor - C225 HER-2’ye monoklonal antikor- trastuzumab Farnezil transferaz inhibitorleri Apoptosis indükleyicileri - COX-2 inhibitorleri, protein kinase C inhibitörleri, gen tedavisi, bcl-2 antisense oligonucleotide As a result of advances in cell and molecular biology, potential new therapeutic targets have been identified, leading to a range of novel treatment strategies for lung cancer.1 In NSCLC, epidermal growth factor (EGF) may directly stimulate tumour cell proliferation, promote cancer cell adhesion (which may be important in the development of metastases), and stimulate the development of new blood vessels in the tumour (angiogenesis). EGF acts by activating a tyrosine kinase on the intracellular domain of its receptor. This receptor is a target for anticancer therapy.2 Agents are being developed that target specific oncogene activation, such as K-ras inactivation by farnesyl transferase inhibitors.3 Inducers of apoptosis include a bcl-2 antisense oligonucleotide (oblimersen) that has shown in vivo activity against bcl-2 overexpression and disease stabilisation in a Phase I/II study.4 References Bonomi P. Semin Oncol 2001; 28 (4 Suppl 14): Raymond E, et al. Drugs 2000; 60 (Suppl 1): 15-23; discussion Rowinsky EK, et al. J Clin Oncol 1999; 17: Rudin C, et al. Proc ASCO 2001; 20: abstr 1283.

94 û û û EGFR inhibitorlerinin etkisi DNA EGF/TGFα R R Antikor
Ekstrasellüler Membran û û Intrasellüler EGFR-TKI K K EGFR-TKI û Hücrel yaşamı (anti-apoptosis) Proliferasyon Signalling EGFR is activated by the binding of a variety of ligands [eg EGF, transforming growth factor-α (TGFα)] to the extracellular domain. This results in receptor dimerisation, leading to activation of the receptor’s tyrosine kinase and subsequent intracellular signalling. EGFR activation has been implicated in the control of cell proliferation, survival and metastasis.1 There is increasing evidence that EGFR is expressed in a range of human tumours, including NSCLC, and high-level expression has been correlated in many cases with poor prognosis.2,3 Inhibitors of the EGFR in clinical development include the small molecule EGFR tyrosine kinase inhibitors ZD1839 and OSI-774, and the monoclonal antibody C A lack of EGFR positivity has been observed in SCLC.7 References Woodburn J. Pharmacol Ther 1999; 82: Salomon D, et al. Crit Rev Oncol Hematol 1995; 19: Wells A. Int J Biochem Cell Biol 1999; 31: Baselga J, Averbuch S. Drugs 2000; 60 (Suppl 1): Hidalgo M, et al. J Clin Oncol 2001; 19: Baselga J, et al. J Clin Oncol 2000; 18: Cerny T, et al. Br J Cancer 1986; 54: DNA Büyüme faktörleri Anjiyogenez Kemoterapi/ radyoterapi duyarlılığı Metastaz R, epidermal growth factor receptor

95 Tümör anjiyogenezi Tümör 1.Anjiyogenik faktörlerin sekresyonu
4. Yeni tümör damarlarının oluşumu 2. Ekstrasellüler matriksin proteolitik parçalanması 3. Endotelyal proliferasyon ve göç A tumour needs to establish new vasculature to obtain the nutrients necessary to sustain growth beyond 1-2 mm3. Angiogenesis is defined as the development of new capillaries from existing vessels. Tumours induce angiogenesis by increasing production and secretion of angiogenic factors and proteases that act in concert to promote angiogenesis. Secretion of angiogenic factors, such as vascular endothelial growth factor (VEGF) increase endothelial-cell-associated protease activity and stimulate endothelial cell migration and proliferation. Proteases secreted by tumour cells and endothelial cells degrade the extracellular matrix, allowing endothelial cell migration. Together these processes promote angiogenic sprouting and the formation of new tumour vasculature. New vessels formed during pathological angiogenesis, compared with those produced normally, are not well formed and are described as tortuous and leaky. Therapeutic inhibition of tumour angiogenesis should be effective in all solid malignancies and the biological effect should be tumour-specific, as, apart from the female reproductive system, angiogenesis is quiescent in healthy tissues. Furthermore, genetically stable endothelial cells may be less prone to developing drug resistance than tumour cells. Drug delivery is facilitated, because target tissue is in direct contact with blood. Tumour vasculature may be targeted by: preventing new blood vessel growth (angiogenesis inhibition) destroying existing tumour blood vessels (vascular targeting). Angiogenesis inhibition is potentially complementary to other antitumour strategies. Kapiller çoğalması

96 Yeni biyolojik ajanlar (2)
Antianjiyogenik ajanlar Monoklonal antikorlar - bevacizumab (rhuMab-VEGF) VEGFR tyrosine kinase inhibitorleri - ZD6474 Matriks metalloproteinaz inhibitorleri Thalidomide Vasküler hedefli ajanlar - combretastatin A4 phosphate, ZD6126 ZD6474 has demonstrated antitumour activity in human tumour xenografts, including lung.1 Metalloproteinases degrade the extracellular matrix, allowing tumour cells to invade adjacent tissues, metastasise, and develop new blood vessels. In NSCLC, metalloproteinase activity is correlated to the degree of tumour spread. Metalloproteinase inhibitors could be a new class of anticancer compounds.2 Combretastatin A4 phosphate and ZD6126 have been shown to selectively reduce tumour perfusion in adenocarcinomas in mice.3,4 ZD6126 has been shown to cause massive tumour necrosis in a range of human tumour xenografts, including lung.5 ZD6126 caused growth delay in a human lung tumour xenograft model and this activity was enhanced by combination with cisplatin.6 References Wedge SR, et al. Clin Cancer Res 2000; 6 (Suppl): abstr 268. Ferrante K, et al. Cancer Chemother Pharmacol 1999; 43 (Suppl): S61-S68. Chaplin DJ, et al. Anticancer Res 1999; 19: Evelhoch JL, et al. Proc AACR 2001; 42: abstr 580. Blakey DC, et al. Proc AACR 2000; 41: 329 (abstr 2086). Blakey DC, et al. Clin Cancer Res 2000; 6 (Suppl): abstr 283.

97 Küçük Hücre Dışı Akciğer Kanseri Evre IIIB ve IV(Faz III çalışmalar)
Şema Plasebo Plasebo Docetaxel/plasebo Cisplatin/etoposide/ radyoterapi/ docetaxel/plasebo Vinorelbine/cisplatin Sponsor NCI, NCCTG NCIC-Klinik Çalışma grubu Hücre Ağları NCI, NCCTG, NCIC-Klinik Çalışma Grubu, SWOG Ligand Pharmaceuticals Araştırılan ajan Carboxyamidotriazole OSI-774 Docetaxel/exisulind Cisplatin/etoposide/ radyoterapi/ docetaxel/ZD1839 Vinorelbine/cisplatin/bexarotene Carboxyamidotriazole is an inhibitor of angiogenesis. Exisulind is an agent that selectively induces apoptosis. A randomised trial of ZD1839 is in progress, based on the results of a recent Phase II trial in which 40% 3-year survival was observed in a group of 83 stage IIIB patients following treatment with concurrent cisplatin/etoposide/radiation followed by 4 courses of docetaxel.1 Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors. Reference Gaspar L, et al. Proc ASCO 2001; 20: abstr 1255. NCI, National Cancer Institute; NCCTG, North Central Cancer Treatment Group; SWOG, Southwest Oncology Group

98 Küçük Hücre Dışı Akciğer Kanseri Evre IIIB ve IV (Faz III çalışmalar)
Sponsor NCI, SWOG Sanofi-Synthelabo Genentech ISIS Pharmaceuticals NCI, ECOG Abgenix, Immunex AstraZeneca Araştırılan şema Paclitaxel/carboplatin/tirapazamine Cisplatin/vinorelbine/tirapazamine Paclitaxel/carboplatin/OSI-774 Paclitaxel/carboplatin/ISIS 3521 Paclitaxel/carboplatin/radyoterapi/ thalidomide Paclitaxel/carboplatin/ABX-EGF Paclitaxel/carboplatin/ZD1839 Gemcitabine/cisplatin/ZD1839 Şema Paclitaxel/carboplatin Cisplatin/vinorelbine Paclitaxel/carboplatin Paclitaxel/carboplatin/ radyoterapi Paclitaxel/carboplatin/ plasebo Gemcitabine/cisplatin/ plasebo Tirapazamine is an investigational agent that sensitises hypoxic cells and has been previously shown to enhance the activity of cisplatin in patients with advanced NSCLC.1 ISIS 3521 is an investigational antisense agent that binds to an mRNA sequence specific to protein kinase C. The combination of paclitaxel/carboplatin/radiotherapy with thalidomide, an agent with antiangiogenic properties with undefined applicability in the treatment of lung cancer, is currently being evaluated. ABX-EGF is a novel monoclonal antibody against EGFR. Reference von Pawel J, et al. J Clin Oncol 2000; 18: NCI, National Cancer Institute; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group

99 Küçük Hücre Dışı Akciğer Kanseri Evre IIIB ve IV(Faz II/III çalışmalar)
Sponsor NCI, ECOG NCIC-Clinical Trials Group NCI, Memorial Sloan-Kettering Cancer Center Şema Paclitaxel/carboplatin Paclitaxel/carboplatin/plasebo Docetaxel Araştırılan şema Paclitaxel/carboplatin/bevacizumab Paclitaxel/carboplatin/BMS Oblimersen/docetaxel A Phase II/III trial of bevacizumab (rhuMab-VEGF, anti-VEGF) is in progress, based on the results of a Phase II trial in which patients with stage IV adenocarcinoma of the lung had a median survival of 76 weeks following treatment with paclitaxel/carboplatin/bevacizumab.1 Patients with squamous histology are excluded, due to the occurrence of fatal haemoptysis in 4 patients in the Phase II trial. BMS is a novel matrix metalloprotease inhibitor. Oblimersen is a bcl-2 antisense oligodeoxynucleotide. Reference Johnson DH, et al. Proc ASCO 2001; 20: abstr 1256. NCI, National Cancer Institute; ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group;

100 Küçük Hücreli Akciğer Kanseri (Faz III çalışmalar)
Sponsor EORTC Lung Cancer Cooperative Group Vrije Universiteit Medisch Centrum Şema Birinci basamak kombine tedavi (en az iki ilaç Kemoterapisi ve göğüs radyoterapisi ) Carboplatin/paclitaxel Hastalık evre Sınırlı Yaygın Araştırılan Şema Adjuvant BCG and Monoklonal antikor BEC2 Cyclophosphamide/ doxorubicin/ etoposide BEC2 is an investigational anti-idiotypic monoclonal antibody that is designed to prevent or delay the recurrence of certain types of tumours when used with Bacillus Calmette Guerin (BCG) as an immune stimulant. EORTC, European Organization for Research and Treatment of Cancer

101 Küçük Hücreli Akciğer Kanseri (Faz III çalışmalar)
Sponsor NCI, SWOG NCI, CALGB NCI, NCCTG NCI, ECOG NCI, Uni of Michigan NCI, FCCC NCI, BRI Araştırılan şema Gemcitabine/irinotecan Paclitaxel Topotecan/paclitaxel CCI-779 Fenretinide Temozolomide Chloroquinoxaline sulfonamide Hastalık evre Tedavisiz,yaygın yaygın Nüks, dirençli Nüks Nüks, ilerleyici Yaygın,nüks CCI-779 is an ester of rapamycin that inhibits the cell cycle. Fenretinide is a synthetic analogue of retinoic acid. The cytotoxic alkylating agent temozolomide is a member of the imidazotetrazine class of compounds. Chloroquinoxaline sulfonamide is a topoisomerase II / poison. NCI, National Cancer Institute; SWOG, Southwest Oncology Group; CALGB, Cancer and Leukemia Group B; NCCTG, North Central Cancer Treatment Group; ECOG, Eastern Cooperative Oncology Group; FCCC, Fox Chase Cancer Center; Beckman Research Institute

102 Korunma Eğitim ve primer korunma Kemoproflaksi Sigarayla mücadele
retinoidler EGFR inhibitorleri selenyum COX-2 inhibitorleri Yeşil çay Up to 90% of cases of lung cancer can be attributed to the use of tobacco, and lung cancer incidence and death rates in the USA mirror patterns of cigarette smoking.1 Lung cancer incidence and death could be significantly reduced by: deterring people from beginning smoking helping people to stop smoking protecting non-smokers from environmental tobacco smoke.1 Possible strategies include reducing the availability of tobacco products to adolescents, education, increasing the cost of tobacco products, and use of tobacco tax revenue to fund mass media campaigns to reduce consumption.1 Chemoprevention - defined as the use of specific natural or pharmacological agents to reverse, suppress, or prevent the carcinogenic process and the development of invasive cancer. Development of such agents is made possible by understanding the biology of lung cancer. Retinoids, EGFR inhibitors, selenium, cyclooxygenase-2 (COX-2) inhibitors, green tea and many other possible agents are still under investigation to assess their chemopreventative action, but as yet their role is still unclear.2 The most intensively studied of these agents are the retinoids. However, in trials with lung cancer endpoints, administration of retinoids was either ineffective or, in the case of beta-carotene, led to greater lung cancer incidence and mortality.3,4 Selenium is an essential trace element that reduces certain kinds of tumours in animals and enhances immune properties in humans. Selenium may also reduce the risk of cancer in humans. Metabolites derived from COX and lipoxygenase pathways have important effects on carcinogenesis and growth-related signal transduction, respectively. Inhibition of these pathways may have a role in chemoprevention.5 References Wingo PA, et al. J Natl Cancer Inst 1999; 91: Kim ES, et al. Chest Surg Clin N Am 2000; 10: Khuri FR, Lippman SM. Semin Surg Oncol 2000; 18: Tockman MS. IARC Sci Publ 2001; 154: Cuendet M, Pezzuto JM. Drug Metabol Drug Interact 2000; 17:

103 SONUÇ Tanı ve tedavide ilerlemelere rağmen akciğer kanserli hastaların sağkalım sürelerinde sınırlı bir avantaj sağlanmıştır. Hedefe yönelik moleküler ajanlar gelecek için umut vermektedirler. Tümörlerin moleküler davranış biçimlerine göre daha mantıklı ve daha az toksik tedaviler olanaklı olacaktır.


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