Asi u 25 % pacientů s renálním karcinomem (RCC) dochází k recidivě po radikálním odstranění nádoru. Po několika desetiletích neúspěšných klinických studií jsme se dočkali významného pokroku a nového standardu adjuvantní léčby pacientů s RCC a vyšším rizikem recidivy. Randomizovaná, dvojitě zaslepená studie KEYNOTE-564 prokázala, že pembrolizumab podávaný po dobu 1 roku významně zlepšuje přežití bez rekurence i celkové přežití. Léčba je plně hrazená a je novým standardem v terapii RCC.

Approximately 25% of patients with renal cell carcinoma (RCC) relapse after radical removal of the tumour. After several decades of unsuccessful clinical trials, significant progress has been achieved recently and a new standard of adjuvant treatment for patients with RCC and a higher risk of recurrence has been established. The randomized, double-blind KEYNOTE-564 trial demonstrated that pembrolizumab administered for 1 year after surgery significantly improved both recurrence-free and overall survival. The treatment is fully reimbursed and is the new standard in RCC therapy.

• Klíčová slova
• pembrolizumab,
• MeSH
• adjuvantní chemoterapie * metody   MeSH
• analýza přežití MeSH
• everolimus aplikace a dávkování   MeSH
• imunoterapie metody   MeSH
• inhibitory tyrosinkinasy terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   terapie   MeSH
• randomizované kontrolované studie jako téma MeSH
• riziko MeSH
• sekundární prevence metody   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH

Adjuvantní imunoterapie představuje významný pokrok v léčbě renálního karcinomu. Aktualizace výsledků studie KEYNOTE-564 potvrdila, že pembrolizumab nejen prodlužuje přežití bez onemocnění (disease free survival, DFS), ale také významně zlepšuje celkové přežití. Po 48 měsících přežívalo 91,2 % pacientů s pembrolizumabem oproti 86,0 % pacientů v placebové skupině (poměr rizik [hazard ratio, HR] 0,62; p = 0,005). Přínos v DFS zůstal zachován (HR 0,72). Nevyřešenou otázkou je vliv adjuvantní imunoterapie na následnou léčbu recidivujícího onemocnění. Zatím je nejasné, zda předchozí imunoterapie neovlivní účinnost dalších léčebných možností. Výsledky KEYNOTE-564 poprvé prokázaly benefit adjuvantní imunoterapie v celkovém přežití u renálního karcinomu.

Adjuvant immunotherapy represents a major advancement in renal cancer treatment. The latest analysis of KEYNOTE-564 trial confirmed that pembrolizumab not only improves disease free survival (DFS) but also significantly enhances overall survival. After 48 months, 91.2% of pembrolizumab-treated patients were alive compared to 86.0% in the placebo group (hazard ratio [HR] 0.62; P = 0.005). The DFS benefit remained consistent (HR 0.72). A major challenge is the impact of adjuvant immunotherapy on subsequent treatment strategies. It is currently uncertain whether prior immunotherapy could affect the efficacy of future treatments. For the first time, KEYNOTE-564 demonstrated an overall survival benefit with adjuvant immunotherapy in renal cancer.

BACKGROUND: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. FINDINGS: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab. INTERPRETATION: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy. FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky MeSH
• hypertenze * MeSH
• karcinom z renálních buněk * farmakoterapie   chirurgie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   etiologie   chirurgie   MeSH
• následné studie MeSH
• nefrektomie škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

• MeSH
• adjuvantní chemoterapie metody   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory endometria * patologie   farmakoterapie   terapie   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. METHODS: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

• MeSH
• adenokarcinom farmakoterapie   mortalita   radioterapie   MeSH
• adenoskvamózní karcinom farmakoterapie   mortalita   radioterapie   MeSH
• chemoradioterapie * metody   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory děložního čípku * farmakoterapie   mortalita   radioterapie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• spinocelulární karcinom farmakoterapie   mortalita   radioterapie   MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Více než polovina všech případů nádorových onemocnění plic postihuje pacienty ve věku ≥ 65 let, přičemž platí, že starší pacienti mají ve srovnání s mladšími pacienty vyšší mortalitu. Vyšší výskyt nádorů plic u starších osob odráží celosvětový trend stárnutí populace, roli také hraje zvýšená incidence nádorových onemocnění, asociovaná s věkem. Navzdory vysoké incidenci nádorových onemocnění plic u starších osob nebývají tito pacienti dostatečně zastoupeni v klinických studiích. Do studií bývají nejméně často zařazováni pacienti ve věku ≥ 75 let. Zatímco věk sám o sobě nebývá vylučovacím kritériem, vstup starších pacientů do klinických studií je limitován (pacienti nemusejí být schopni léčbu absolvovat, bývají v horším výkonnostním stavu, mívají komorbidity nebo u nich probíhá jiná léčba). Navíc se předpokládá, že s narůstajícím věkem dochází k poklesu funkcí imunitního systému a jeho remodelaci (imunosenescence), což může ovlivňovat účinnost imunoterapie u starších pa cientů. Limitovaná účast starších pacientů ve studiích a nedostatek dat o účinnosti a bezpečnosti protinádorové léčby v této konkrétní populaci pacientů tak u starších pacientů omezuje rozvoj léčebných doporučení založených na důkazech.

• Klíčová slova
• pembrolizumab, KEYNOTE, poolovaná analýza dat,
• MeSH
• analýza přežití MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   MeSH
• lidé MeSH
• nemalobuněčný karcinom plic * farmakoterapie   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• randomizované kontrolované studie jako téma MeSH
• senioři MeSH
• statistika jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH

• Klíčová slova
• pembrolizumab, studie KEYNOTE-355,
• MeSH
• analýza přežití MeSH
• doba přežití bez progrese choroby MeSH
• humanizované monoklonální protilátky farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory prsu farmakoterapie   MeSH
• protinádorové látky imunologicky aktivní farmakologie   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• randomizované kontrolované studie jako téma MeSH
• triple-negativní karcinom prsu * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

• MeSH
• antigeny CD274 metabolismus   MeSH
• humanizované monoklonální protilátky MeSH
• hypertenze * farmakoterapie   MeSH
• lidé MeSH
• myokarditida * MeSH
• nádory plic * farmakoterapie   metabolismus   chirurgie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   chirurgie   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

• MeSH
• adjuvancia imunologická aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• analýza přežití MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• karcinom z renálních buněk * farmakoterapie   mortalita   chirurgie   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   mortalita   chirurgie   MeSH
• přežití bez známek nemoci MeSH
• protinádorové látky imunologicky aktivní * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH