Učinkovitost elektrokemoterapije v zdravljenju raka glave in vratu

Grošelj, Aleš (author), Strojan, Primož (mentor), Serša, Gregor (co-mentor)

Znanstveno izhodišče: Elektrokemoterapija je inovativen način zdravljenja raka, vendar je malo raziskav, ki bi bile osredotočene na njeno vlogo v zdravljenju sluzničnega in kožnega raka glave in vratu. Za ugotavljanje učinkovitosti in varnosti zdravljenja tudi pri tej skupini bolnikov so nujne pravilno zasnovane in izvedene prospektivne klinične raziskave. Z izboljšanjem tehnoloških postopkov zdravljenja z elektrokemoterapijo lahko zdravimo tudi globoko ležeče tumorje glave in vratu. Pri zdravljenju z elektrokemoterapijo se najpogosteje uporablja bleomicin. Vendar lahko sistemsko zdravljenje z bleomicinom izzove stranske učinke, predvsem pljučno fibrozo in razjede na mestih zdravljenja. Da bi bilo zdravljenje z elektrokemoterapijo kar najbolj učinkovito in varno, je poleg ostalega potrebno določiti tudi parametre farmakokinetike bleomicina. Prav tako je potrebno razjasniti vpliv tumorskega mikrookolja na porazdelitev bleomicina v tumorju in posledično na učinkovitost zdravljenja z elektrokemoterapijo. Namen dela: Namen doktorskega dela je bil ovrednotiti učinkovitost in varnost elektrokemoterapije z bleomicinom v zdravljenju raka glave in vratu. Specifični cilji so bili: (i) določitev optimalnega časovnega okvirja od časa injiciranja bleomicina do elektroporacije in optimalne koncentracije bleomicina, ki je potrebna za učinkovito elektrokemoterapijo, (ii) izboljšanje tehnološkega postopka zdravljenja globoko ležečih tumorjev v področju glave in vratu, (iii) določitev napovednih dejavnikov za uspešnost elektrokemoterapije. Hipoteza: Elektrokemoterapija je učinkovita in varna metoda zdravljenja raka v področju glave in vratu. Metode: V doktorski disertaciji smo spremljali učinek in varnost elektrokemoterapije pri bolnikih s kožnim in sluzničnim rakom glave in vratu. S sklopitvijo načrta zdravljenja in navigacijskega sistema smo poskušali izboljšati postopek zdravljenja globoko ležečih tumorjev v področju glave in vratu. Parametre farmakokinetike bleomicina smo določili tako pri bolnikih kot in vivo pri miših s tekočinsko kromatografijo sklopljeno z masno spektrometrijo. Tumorsko mikrookolje smo preučevali z imunohistokemično analizo na karcinomskem in melanomskem tumorskem modelu. Rezultati: S spremljanjem odgovora na zdravljenje smo dokazali, da je elektrokemoterapija varno in učinkovito zdravljenje raka glave in vratu. Pokazali smo, da je z optimizacijo tehnoloških postopkov elektrokemoterapije možno učinkovito in varno zdraviti tudi v globini ležeče tumorje glave in vratu. Pri starejših bolnikih je terapevtsko okno za aplikacijo električnih pulzov po intravenoznem injiciranju bleomicina daljše kot pri mlajših. Hkrati je pri njih nižji odmerek bleomicina enako učinkovit kot standardni odmerek. Odgovor na zdravljenje z elekokemoterapijo je odvisen od ožiljenosti tumorja, ki vpliva na razporeditev bleomicina v tumorju. Zaključki: Elektrokemoterapija se je izkazala za učinkovit in varen način zdravljenje raka v različnih predelih glave in vratu. Rezultati raziskave pomembno prispevajo k širjenju terapevtskih možnosti pri tem raku in k prilagoditvi elektrokemoterapevtskih protokolov posameznemu bolniku. Značilnosti tumorskega mikrookolja so pomemben dejavnik za napoved uspešnosti elektrokemoterapije.

• Language: Slovenian
• Keywords: elektrokemoterapija, rak glave in vratu, bleomicin, elektroporacija
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2019
• PID: 20.500.12556/RUL-108010
• COBISS.SI-ID: 4015380
• Publication date in RUL: 11.06.2019

Secondary language

• Language: English
• Title: Efficiency of electrochemotherapy in treatment of head and neck cancer

Abstract

Scientific background: Electrochemotherapy is an inventive approach to cancer treatment. Howevwer, only a few studies so far have focused on its role in the treatment of skin and mucosal head and neck cancers. Properly designed and well-conducted prospective clinical trials are required to determine the efficiency and safety of electrochemotherapy in this group of patients. Technological improvements implement electrochemotherapy as a feasible treatment also for deep-seated head and neck tumors. Nevertheless, intravenously administrated bleomycin is currently the most utilized drug for electrochemotherapy, but it might have some specific side effects, predominantly lung fibrosis and possible ulceration in the treated areas. The main parameters of bleomycin pharmacokinetics need to be determined in order to provide optimal effectiveness and safety of electrochemotherapy. Furthermore, the role of tumor microenvironment in bleomycin distribution and its consequential impact on tumor response to electrochemotherapy has to be explained. Aim: The aim of the study was to evaluate the effectiveness and safety of bleomycin-based electrochemotherapy in the treatment of head and neck cancer. Specific objectives were: (i) to determine an optimal time frame between bleomycin injection and electroporation and optimal bleomycin concentration required for effective electrochemotherapy, (ii) the improvement of technological procedure in the treatment of deep-seated head and neck tumors and (iii) determination of predictive factors for effective electrochemotherapy. Hypothesis: Electrochemotherapy is an effective and safe treatment modality for the treatment of head and neck cancer. Methods: In the scope of the study, the local anti-cancer effectiveness and safety were followed on the skin and mucosal head and neck cancers treated with electrochemotherapy. The efficiency of electrochemotherapy as a treatment option of deep-seated head and neck tumors was evaluated by coupling treatment planning and navigation system. The parameters of bleomycin pharmacokinetics were determined in patients and in vivo in mice by liquid chromatography coupled with high-resolution mass spectrometry. Tumor microenvironment on carcinoma and melanoma tumor models was additionaly investigated with immunohistochemical analysis. Results: The evaluation of treatment outcome in patients with head and neck cancer treated with electrochemotherapy confirms the efficacy and safety of electrochemotherapy in this group of patients. The optimized technological approach enables the treatment of deep-seated tumors in the head and neck region. In the group of elderly patients, therapeutic window is prolonged compared to younger patients and a reduced dose of bleomycin is equally effective as a standard dose. The tumor response to electrochemotherapy is influenced by tumor vascularization, which affects bleomycin distribution in the tumor. Conclusion: Electrochemotherapy proved to be an efficient and safe treatment of cancers in different head and neck regions. The results of the study broaden therapeutic options in the treatment of head and neck cancer and contribute to the adaptation of the electrochemotherapeutic protocols to each individual patient. Characteristics of tumor microenvironment are an important predictive factor to the tumor response to electrochemotherapy.

• Keywords: electrochemotherapy, head and neck cancer, bleomycin, electroporation