Neoadjuvan 5-fluorourasil bazlı kemoterapi alan baş ve boyun kanserli hastalarda tümöral timidilat sentetaz ekspresyonunun kemoterapi yanıtı ve sağkalıma olan etkisinin araştırılması
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Date
2007
Authors
Aydın, Hasan
Journal Title
Journal ISSN
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Publisher
Uludağ Üniversitesi
Abstract
Baş ve boyun kanserleri dünyada beşinci en sık, orta asyada ise en sık görülen kanser türünü oluşturmaktadır. Bu kanserlerin standart tedavisinde cerrahi ve radyoterapi sıklıkla kullanılmaktadır. Ancak bu tedavi yöntemleri sonucunda genellikle önlenemeyen estetik ve fonksiyonel bozukluklar oluşmakta ve hastanın yaşam kalitesi önemli ölçüde bozulmaktadır. Öte yandan organ koruyucu amaçlı diğer tedavi yöntemleri sayesinde total larenjektomi gerektiren cerrahi uygulamalar, bir grup hastada sağkalıma olumsuz etki göstermeksizin gereksiz kılınabilmiştir. Organ koruyucu protokollerde en sık uygulanan şemalardan birisi hastaya öncelikle 2-3 siklus gibi belirli bir sayıda kemoterapiyi uygulamak ve sonrasında cevap araştırması yaparak cevaplı hastalarda küratif radyoterapi/kemoradyoterpi uygulamak şeklindedir. Kemoterapide kullanılan antikanser ajanların başında 5-fluorourasil (5FU) gelmektedir. 5-FU baş ve boyun kanserleri, gastrointestinal sistem kanserleri başta olmak üzere birçok kansere karşı etkilidir ve etkisini öncelikle DNA sentezi için hız kısıtlaycı enzim olan timidilat sentetaz’a bağlanmak yoluyla gerçekleştirmektedir. Baş ve boyun kanserlerinde 5-FU’in cisplatinle veya cisplatin ve dosetaksel kombinasyonu ile birlikte kullanımı lokal ileri ve metastatik hastalarda en sık kullanılan tedavi rejimini oluşturmaktadır. Bu tedavilerle öncesinde tedavi almamış hastalarda %70’e varan patolojik tam cevap ve %90’a varan tümör regresyonu oranları elde edilebilmektedir. Organ koruyucu protokollerde de ilacın sık olarak kombinasyonlara dahil edildiği bilinmektedir. Bu nedenle organ koruyucu yaklaşımlardan daha fazla yarar görebilecek hastaların seçimi, ilaca daha çok cevap verebilecek grupla paralel görülmektedir. Ancak henüz literatürde indüksiyon tedavisine cevapla hastaya ait klinikopatolojik verilerin ilişkisi tam bir netliğe kavuşmamıştır. Literatüre bakıldığında timidilat sentetaz enzim düzeyi ile kanserlerin metastaz durumu, evresi, prognostik önemi, tedaviye yanıtları, progresyon zamanı, genel sağkalım ve hastalıksız sağkalım arasındaki ilişkiyi araştıran birçok çalışma göze çarpmaktadır. Genel olarak çoğu kolorektal kanserlerde yapılan bu çalışmalarda yüksek timidilat sentetaz ekspiresyonu ile kötü prognostik bir ilişki saptanmıştır. Ancak baş ve boyun kanserlerinde çalışmalar oldukça sınırlıdır. Bu nedenle çalışmamızda retrospektif olarak neoadjuvan 5fluorourasil bazlı kemoterapi alan yassı epitel hücreli baş ve boyun kanserlerinde tümör dokusu timidilat sentetaz ekspresyonu ile kemoterapiye yanıt, progresyonsuz sağkalım ve genel sağkalım arasındaki ilişki araştırılmıştır. Çalışmaya 22 hasta dahil edilmiş ve bu hastalara ait biyopsilerin parafin bloklarından kesitler alınarak immünohistokimyasal yöntemlerle timidilat sentetaz ekspresyonu belirlenmiştir. Elde edilen veriler, hastaya ait demografik özellikler, tedavi yanıtı, progresyonsuz sağkalım ve genel sağkalım verileri göz önünde tutularak karşılaştırılmıştır. Çalışma sonucunda timidilat sentetaz ekspresyonu negatif olan grupta progresyonsuz sağkalımın daha uzun olduğu, fakat genel sağkalım açısından timidilat sentetaz negatif grupla elde edilen daha uzun sağkalım süresinin (129,62 haftaya 84,78 hafta) istatistiksel olarak sınırda anlamlılık gösterdiği (p=0,062) saptandı. Timidilat sentetaz ekspresyonu ile kemoterapi yanıtı arasında ilişki ise saptanmadı. Sonuç olarak yassı epitel hücreli baş ve boyun kanserlerinde timidilat sentetaz over ekspresyonu progresyonsuz sağkalımı azaltmakta, timidilat sentetaz over ekspresyonunun genel sağkalımı olumsuz yönde etkileyebileceğine ilişkin dolaylı veriler elde edilmiştir, ancak bu konuda kesin sonuçlara varmak için çok merkezli, geniş kapsamlı ve daha büyük hasta grupları ile yapılacak çalışmalara ihtiyaç vardır.
Head and neck cancers are fifth most common among the cancers worldwide and most common in Central Asia. Surgery and radiotherapy are frequently used as standard treatments for head and neck cancers. But these treatments produce inevitable functional and esthetic abnormalities and quality of life deteriorates significantly. On the other hand, surgical procedures including total laryngectomy have become inessential in a group of patients without negative survival effects, by the use of organ preservation treatments. One of the most used schemes of organ-sparing protocols is, to administer 2 or 3 course of chemotherapies and after evaluation of response to the therapy, to perform curative radiotherapy/chemotherapy in selected responsive patients. 5-fluorouracil (5-FU) is the leading chemotherapeutic agent among the others in use. 5-FU is efficient against many cancers including gastrointestinal system and head and neck cancers, and mechanism of action is inhibiting the rate-determining step of DNA synthesis by binding timidilate synthetase. The combination of 5-FU with cisplatin or docetaxel and cisplatin is the treatment of choice for local advanced and metastatic head and neck cancers. Complete histopathological response rates of 70% and tumor regression rates of 90% may be achieved in previously untreated patients by these treatments. It is known that medical therapies are frequently included in organ-sparing protocols. Selection of patients that will receive more benefits from organsparing approaches is parallel with the group of patients which may response medical therapy. But the relationship between response to induction therapy and patient related clinicopathological data has not been clearly elucidated in the literature yet. In the literature, there are lots of studies drawing attention that investigates the relationship between thymidylate synthase enzyme levels and metastasis, disease stage, prognosis, response to therapy, progression time, general survival and disease-free survival. Generally, in these studies which were mostly conducted on colorectal cancers, a relationship between high thymidylate synthase expression and bad prognosis was suggested. But there is limited data about head and neck cancers. Therefore, in our study we evaluate the relationship between thymidylate synthase expression in tumoral tissue and response to chemotherapy, progression-free survival and general survival in patients with squamose cell head and neck cancer, receiving neoadjuvant 5fluorouracil based chemotherapy, retrospectively. 22 patients were included in the study and sections from paraffin blocks of the biopsies of these patients were investigated using immunohistochemical techniques to determine thymidylate synthase expression. The obtained data was compared according to demographic properties, treatment reponses, progression-free survival and general survival of the patients. We concluded that in the group with negative thymidylate synthase expression, progression-free survival was longer but general survival benefit (129,62 weeks vs 84.78 weeks) was statistically borderline significant (p=0.062). There was no relationship between thymidylate synthase expression and response to chemotherapy. In conclusion, presence of thymidylate synthase expression in patients with squamose cell head and neck cancer. To conclude with certain results, there is a need for comprehensive, multicentered studies with larger patient populations. In conclusion, timidilate synthetase over expression decreases progression-free survival rates in patients with squamose cell head and neck cancer. We also obtained indirect data that thymidylate synthase over expression may negatively impact on general survival rates. But there is a need for multicentered, comprehensive studies with larger patient populations to have certain conclusions.
Head and neck cancers are fifth most common among the cancers worldwide and most common in Central Asia. Surgery and radiotherapy are frequently used as standard treatments for head and neck cancers. But these treatments produce inevitable functional and esthetic abnormalities and quality of life deteriorates significantly. On the other hand, surgical procedures including total laryngectomy have become inessential in a group of patients without negative survival effects, by the use of organ preservation treatments. One of the most used schemes of organ-sparing protocols is, to administer 2 or 3 course of chemotherapies and after evaluation of response to the therapy, to perform curative radiotherapy/chemotherapy in selected responsive patients. 5-fluorouracil (5-FU) is the leading chemotherapeutic agent among the others in use. 5-FU is efficient against many cancers including gastrointestinal system and head and neck cancers, and mechanism of action is inhibiting the rate-determining step of DNA synthesis by binding timidilate synthetase. The combination of 5-FU with cisplatin or docetaxel and cisplatin is the treatment of choice for local advanced and metastatic head and neck cancers. Complete histopathological response rates of 70% and tumor regression rates of 90% may be achieved in previously untreated patients by these treatments. It is known that medical therapies are frequently included in organ-sparing protocols. Selection of patients that will receive more benefits from organsparing approaches is parallel with the group of patients which may response medical therapy. But the relationship between response to induction therapy and patient related clinicopathological data has not been clearly elucidated in the literature yet. In the literature, there are lots of studies drawing attention that investigates the relationship between thymidylate synthase enzyme levels and metastasis, disease stage, prognosis, response to therapy, progression time, general survival and disease-free survival. Generally, in these studies which were mostly conducted on colorectal cancers, a relationship between high thymidylate synthase expression and bad prognosis was suggested. But there is limited data about head and neck cancers. Therefore, in our study we evaluate the relationship between thymidylate synthase expression in tumoral tissue and response to chemotherapy, progression-free survival and general survival in patients with squamose cell head and neck cancer, receiving neoadjuvant 5fluorouracil based chemotherapy, retrospectively. 22 patients were included in the study and sections from paraffin blocks of the biopsies of these patients were investigated using immunohistochemical techniques to determine thymidylate synthase expression. The obtained data was compared according to demographic properties, treatment reponses, progression-free survival and general survival of the patients. We concluded that in the group with negative thymidylate synthase expression, progression-free survival was longer but general survival benefit (129,62 weeks vs 84.78 weeks) was statistically borderline significant (p=0.062). There was no relationship between thymidylate synthase expression and response to chemotherapy. In conclusion, presence of thymidylate synthase expression in patients with squamose cell head and neck cancer. To conclude with certain results, there is a need for comprehensive, multicentered studies with larger patient populations. In conclusion, timidilate synthetase over expression decreases progression-free survival rates in patients with squamose cell head and neck cancer. We also obtained indirect data that thymidylate synthase over expression may negatively impact on general survival rates. But there is a need for multicentered, comprehensive studies with larger patient populations to have certain conclusions.
Description
Keywords
Baş ve boyun kanserleri, Timidilat sentetaz, Neoadjuvan kemoterapi, 5-fluorourasil, Head and neck cancers, Thymidylate synthase, Neoadjuvant chemotherapy, 5- fluorouracil
Citation
Aydın, H. (2007). Neoadjuvan 5-fluorourasil bazlı kemoterapi alan baş ve boyun kanserli hastalarda tümöral timidilat sentetaz ekspresyonunun kemoterapi yanıtı ve sağkalıma olan etkisinin araştırılması. Yayınlanmamış uzmanlık tezi. Uludağ Üniversitesi Tıp Fakültesi.