1. Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesotheliomaKatja Goričar, Viljem Kovač, Vita Dolžan, 2014, izvirni znanstveni članek Povzetek: Introduction. A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM. Methods. MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival. Results. Patients with at least one polymorphic MTHFD 1 rs2236225 allele had a significantly lower response rate (p = 0.005: odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03-0.54) and shorter progression-free survival (p = 0.032: hazard ratio [HR) = 3.10: 95% CI = 1.10-8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028: OR = 0.23; 95% CI = 0.06-0.85). SLC01Bl rs4149056 (p = 0.028: OR = 0.23: 95% CI = 0.06-0.85) and rsll045879 (p = 0.014: OR = 0.18; 95% CI = 0.05-0.71) alleles compared to non-carriers, as well as in patients with SLC01Bl GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03-0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004: OR = 10.67; 95% CI = 2.15-52.85) and ABCC2 CAG haplotype (p = 0.006: OR = 5.67: 95% CI = 1.64-19.66). Conclusions. MTHFD 1 polymorphism affected treatment response and survival. while polymorphisms in ABCC2 and SLC01Bl transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.
Ključne besede: polymorphisms, folate pathway, mesothelioma
Objavljeno v DiRROS: 16.04.2024; Ogledov: 29; Prenosov: 5
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2. Intercalated chemotherapy and erlotinib for advanced NSCLC : high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutationsMatjaž Zwitter, Karmen Stanič, Mirjana Rajer, Izidor Kern, Martina Vrankar, Natalija Edelbaher, Viljem Kovač, 2014, izvirni znanstveni članek Povzetek: 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.
Ključne besede: non-small cell lung cancer, EGFR activating mutations, gemicitabine, erlotinib
Objavljeno v DiRROS: 11.04.2024; Ogledov: 82; Prenosov: 20
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3. Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer : a randomized phase II clinical trialMartina Vrankar, Matjaž Zwitter, Tanja Bavčar-Vodovnik, Ana Milič, Viljem Kovač, 2014, izvirni znanstveni članek Povzetek: The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. Patients and methods. Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m2 in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m2 in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m2 on day 2 was administered. All patients continued treatment with radiation therapy with 60-66 Gy concurrent with cisplatin 50 mg/m2 on days 1, 8, 29 and 36 and etoposid 50 mg/m2 on days 1-5 and 29-33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results. From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively. Conclusions. Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance
Ključne besede: induction chemotherapy, non-small cell lung cancer, radiation therapy, randomized clinical trial
Objavljeno v DiRROS: 11.04.2024; Ogledov: 81; Prenosov: 20
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4. Glioblastoma patients in Slovenia from 1997 to 2008Uroš Smrdel, Viljem Kovač, Mara Popović, Matjaž Zwitter, 2014, izvirni znanstveni članek Povzetek: Glioblastoma is the most common primary brain tumour. It has a poor prognosis despite some advances in treatment that have been achieved over the last ten years. In Slovenia, 50 to 60 glioblastoma patients are diagnosed each year. In order to establish whether the current treatment options have any influence on the survival of the Slovenian glioblastoma patients, their data in the period from the beginning of the year 1997 to the end of the year 2008 have been analysed. Patients and methods. All patients treated at the Institute of Oncology Ljubljana from 1997 to 2008 were included in the retrospective study. Demographics, treatment details, and survival time after the diagnosis were collected and statistically analysed for the group as a whole and for subgroups. Results. From 1997 to 2008, 527 adult patients were diagnosed with glioblastoma and referred to the Institute of Oncology for further treatment. Their median age was 59 years (from 20 to 85) and all but one had the diagnosis confirmed by a pathologist. Gross total resection was reported by surgeons in 261 (49.5%) patients; good functional status (WHO 0 or 1) after surgery was observed in 336 (63.7%) patients, radiotherapy was performed in 422 (80.1%) patients, in 317 (75.1%) of them with radical intent, and 198 (62.5 %) of those received some form of systemic treatment (usually temozolomide). The median survival of all patients amounted to 9.7 months. There was no difference in median survival of all patients or of all treated patients before or after the chemo-radiotherapy era. However, the overall survival of patients treated with radical intent was significantly better (11.4 months; p < 0.05). A better survival was also noticed in radically treated patients who received additional temozolomide therapy (11.4 vs. 13.1 months; p = 0.014). The longer survival was associated with a younger age and a good performance status as well as with a more extensive tumour resection. In patients treated with radical intent, having a good performance status, and receiving radiotherapy and additional temozolomide therapy, the survival was significantly longer, based on multivariate analysis.
Ključne besede: glioblastoma, treatment, survival, surgery, radiotherapy, termozolomide
Objavljeno v DiRROS: 11.04.2024; Ogledov: 73; Prenosov: 36
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6. Outcome of small cell lung cancer (SCLC) patients with brain metastases in a routine clinical settingMirko Lekić, Viljem Kovač, Nadja Triller, Lea Knez, Aleksander Sadikov, Tanja Čufer, 2012, izvirni znanstveni članek Povzetek: Background. Small cell lung cancer (SCLC) represents approximately 13 tomediansurvival of SCLC patients treated by specific therapy (chemotherapy andžor radiotherapy) with regard to the 18%months in patients treated with standard chemotherapy and radiotherapy. Inpresence or absence of brain metastases at the time of diagnosis. Patients and methods. All SCLC patients have been treated in a routine clinical practice and followed up at theUniversity Clinic Golnik in Slovenia. In the retrospective study the medical files from 2002 to 2007 were review. All patients with cytological or histological confirmed disease and eligible for specific oncological treatment were included in the study. They have been treated according to the guidelines valid at the time. Chemotherapy and regular followed-up were carried out at the University Clinic Golnik and radiotherapy at the Institute of Oncology Ljubljana. Results. We found 251 patients eligible for the study. The median age of them was 65 years, majoritywere male (67%), smokers or ex-smokers (98%), with performance status 0 to 1 (83%). At the time of diagnosis no metastases were found in 64 patients(25.5%) and metastases outside the brain were presented in 153 (61.0%). Brain metastases, confirmedby a CT scan, were present in 34 patients (13.5%), most of them had also metastases at other localisations. (Abstract truncated at 2000 characters)
Ključne besede: pljuča, rak (medicina), drobnocelični rak, metastaze, možgani
Objavljeno v DiRROS: 22.03.2024; Ogledov: 69; Prenosov: 29
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7. Improved survival after introduction of chemotherapy for malignant pleural mesothelioma in Slovenia : population-based survey of 444 patientsViljem Kovač, Matjaž Zwitter, Tina Žagar, 2012, izvirni znanstveni članek Povzetek: Background. Malignant pleural mesothelioma is a rare tumour with increasing frequency throughout the world. Due to long latency after exposure to asbestos, restrictions in the production and use of asbestos have not yet alleviated the burden of mesothelioma. During the last decade, several trials confirmed the benefit of systemic treatment with drugs such as doublets with cisplatina and gemcitabine or pemetrexed for carefully selected patients in good performance status. The purpose of this survey was to assess the impact of systemic treatment for the whole national population of patients with mesothelioma. Patients and methods. A retrospective study included all patients in Slovenia with histologically confirmed diagnosis of malignant pleural mesothelioma in the period from 1974 till 2008. Data from the Cancer Registry of Slovenia were supplemented by review of clinical records of the Institute of Oncology in Ljubljana where virtually all non-surgical treatment for mesothelioma was performed. We analysed the incidence, treatment, and survival of patients treated in the era of infrequent chemotherapy (1974-2003,the first period) and after it (2004-2008, the second period). Results. The survey included 444 patients, of whom 325 and 119 were diagnosed in the first and second period, respectively. Joinpoint regression analysis showed that after 1995 the trend in crude incidence rates increased more rapidly; the annual change was 0.03 per 100,000 per year before 1995 and 0.06 per 100,000 per year after. There was clear male predominance (70%) throughout the period covered by the survey. The proportion of patients above 65 years of age increased from 41.8% to 54.6% for the first and second period, respectively (p = 0.02). With a total of 52 (11.7%) operated patients, surgical treatment was rare and used only for selected patients with early disease and without comorbidity, leading to their relatively long median survival of 13.6 months. Chemotherapy was applied to 56 (17.2%) and to 96 (80.7%) patients during the first and second period, respectively. While a variety of older drugs were used in the first period, the most common regimen in the second period (applied to 91 patients) was doublet of low-dose gemcitabine in prolonged infusion and cisplatin. For the whole population of patients regardless the mode of treatment, median survival was 7.4 and 12.6 months (p-value = 0.037) for the first and second period, respectively. Conclusions. Increasing incidence, male predominance and increased proportion of older patients confirm that the burden of mesothelioma persists in spite o fa 15-years old ban in the production of asbestos. Modern chemotherapy, and in particular treatment with low-dose gemcitabine in prolonged infusion and cisplatin significantly prolonged median survival of patients with malignant pleural mesothelioma in Slovenia.
Objavljeno v DiRROS: 21.03.2024; Ogledov: 72; Prenosov: 28
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