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1.
Značilnosti poteka bolezni pri žleznem raku pljuč glede na aktivirajoče mutacije gena za epidermalni rastni faktor
Karmen Stanič, 2015, doctoral dissertation

Abstract: Uvod Zdravljenje žleznega raka pljuč je zaradi novih odkritij na področju molekularne biologije in novih tarčnih zdravil vse bolj prilagojeno posameznemu bolniku. Najbolj raziskan je receptor za epidermalni rastni dejavnik (EGFR), pri katerem aktivirajoče mutacije omogočajo zdravljenje z novimi tarčnimi zdravili. Pri kliničnem delu smo opažali precejšnje razlike med bolniki z žleznim rakom pljuč glede na EGFR-status, zato smo želeli ugotovili, ali se pri teh bolnikih mesta zasevkov ob diagnozi in njihovo pojavljanje med boleznijo, način zdravljenja, čas do napredovanja bolezni in preživetje, razlikujejo. Naša hipoteza je bila, da imajo bolniki z aktivirajočimi EGFR-mutacijami že ob diagnozi drugačen vzorec razsoja. Po kliničnih izkušnjah in do tedaj skromnih objavljenih podatkih smo domnevali, da imajo ti bolniki več zasevkov v centralni živčni sistem (CŽS) in kosti. Metode Raziskava je bila populacijsko observacijska, delno retrospektivna in delno prospektivna. Med bolniki z nedrobnoceličnim rakom pljuč, pri katerih je bilo opravljeno testiranje na aktivirajoče mutacije EGFR v letih 2010 in 2011, smo izbrali bolnike z žleznim rakom pljuč ter pregledali njihovo medicinsko dokumentacijo in njihovo zdravljenje spremljali do oktobra 2013. Rezultati Med 629 bolniki z žleznim rakom pljuč je imelo 137 (21,8 %) bolnikov prisotne aktivirajoče EGFR-mutacije. Značilno več bolnikov z EGFR-mutacijami je bilo med ženskami in nekadilci, mejno značilno več pa je bilo bolnikov z razsejanim stadijem bolezni. Bolniki z EGFR-mutiranimi tumorji, ki so kadarkoli med boleznijo razvili oddaljene zasevke, so imeli v primerjavi z bolniki brez mutacij značilno več zasevkov v CŽS (34 % proti 25 %), kosti (49 % proti 31 %), plevro (38 % proti 24 %) in pljuča (64 % proti 46 %). Razliko smo zaznali že ob diagnozi, saj so imeli EGFR-mutirani bolniki več zasevkov v kosti (35 % proti 22 %) in pljuča (37 % proti 22 %). Za CŽS je bila razlika ob diagnozi mejno značilna (19 % za mutirane in 13 % za nemutirane), vendar klinično pomembna. Pri tistih bolnikih, pri katerih je prišlo do razsoja bolezni, se je čas do razvoja zasevkov v posamezne organe razlikoval glede na EGFR-status. Zasevki so se značilno kasneje razvili pri EGFR-mutiranih bolnikih kot pri nemutiranih v CŽS (25,8 proti 11,8 meseca), pljuča (25,9 proti 9,9 meseca) in plevro (20,6 proti 9,9 meseca). Celokupno srednje preživetje vseh bolnikov je bilo 16,0 mesecev, značilno daljše za EGFR-pozitivne (32,7 meseca) kot za EGFR-negativne bolnike (13,7 meseca). Zaključki Bolniki z EGFR-mutacijami so imeli že ob diagnozi značilno več zasevkov v kosteh in pljučih, za CŽS pa je bila vrednost mejno značilna. Med potekom bolezni se je pojavilo pri bolnikih z EGFR-mutacijami več novih zasevkov v plevro, pri razsoju v druge organe pa ni bilo razlike med mutiranimi ter nemutiranimi tumorji. Bolniki z EGFR-mutiranimi tumorji so kasneje razvili zasevke v CŽS, pljuča in plevro kot nemutirani bolniki, pri napredovanju v ostale organe pa nismo beležili razlik glede na EGFR-status. Celokupno srednje preživetje bolnikov z EGFR-mutacijami je bilo značilno daljše kot za bolnike brez mutacij, ne glede na stadij bolezni in mesto ter število zasevkov. Pri polovici bolnikov z EGFR-mutacijami, lahko pričakujemo zasevke v kosti. Za bolnike, ki nimajo opravljene PET/CT preiskave v sklopu diagnostičnih preiskav za zamejitev bolezni, je zato kljub znanemu razsejanemu stadiju bolezni smiselno narediti scintigrafijo skeleta že ob diagnozi. Čas do razsoja bolezni v CŽS in preživetje sta za bolnike z odkritimi zasevki ob diagnozi za EGFR-mutirane bolnike ob ustreznem zdravljenju bistveno daljša kot za nemutirane bolnike, zato je tudi pri teh bolnikih pomembna skrbna diagnostika za prognozo ter zdravljenje bolezni.
Keywords: EGFR-mutacije, žlezni rak pljuč, zasevki, vzorec razsoja, preživetje
Published: 16.04.2015; Views: 1500; Downloads: 220
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2.
Intercalated chemotherapy and erlotinib for advanced NSCLC
Matjaž Zwitter, Karmen Stanič, Mirjana Rajer, Izidor Kern, Martina Vrankar, Natalija Edelbaher, Viljem Kovač, 2014, original scientific article

Abstract: Background: Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC). Patients and methods: Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance. Results: Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2%3 (11 patients - 21%) and brain metastases (15 patients - 28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months. Conclusions: While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.
Keywords: non-small cell lung cancer, EGFR activating mutations, gemicitabine, erlotinib
Published: 21.12.2015; Views: 784; Downloads: 46
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3.
Brain metastases in lung adenocarcinoma
Karmen Stanič, Matjaž Zwitter, Nina Turnšek Hitij, Izidor Kern, Aleksander Sadikov, Tanja Čufer, 2014, original scientific article

Abstract: The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice. Patients and methods. We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival. Results. Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later. Conclusions. Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.
Keywords: brain metastases, lung adenocarcinoma, EGFR mutations
Published: 05.04.2017; Views: 343; Downloads: 47
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4.
Selection of non-small cell lung cancer patients for intercalated chemotherapy and tyrosine kinase inhibitors
Matjaž Zwitter, Antonio Rossi, Massimo Di Maio, Maja Pohar Perme, Gilberto Lopes, 2017, original scientific article

Abstract: Background: When treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment. Methods: Published documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson's correlation coefficient and the coefficient of determination, separately for first-line and second-line setting. Results: The series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with nonsquamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months. Conclusions: Most suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.
Keywords: lung cancer, NSCLC, intercalated treatment, EGFR, tyrosine -kinase inhibitors
Published: 30.10.2017; Views: 458; Downloads: 167
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