Imunoterapie, cílená léčba a chemoterapie jsou dnes základní pilíře léčby nemocných s pokročilým, neresekovatelným či generalizovaným nemalobuněčným plicním karcinomem (non-small cell lung cancer, NSCLC). Zatímco v cytostatické léčbě bylo nejspíše dosaženo stropu, co se týká nových látek, u imunoterapie a cílené léčby je tomu naopak. I díky testování a vyhledávání vzácnějších mutací se daří zacílit správnou molekulou na tento „terč", a posouvá se tak příznivě přežití nemocných. Naše kazuistika byla vybrána záměrně k tomu, abychom doložili dobrý a léta trvající léčebný účinek u nemocné ve vyšší linii léčby NSCLC, která neměla prokázány mutace, tedy wild-type (wt) receptoru pro epidermální růstový faktor (epidermal growth factor receptor, EGFR), a přesto erlotinib, cílená léčba EGFR, ji zajistil dlouhá léta remise.
mmunotherapy, targeted therapy and chemotherapy are now the mainstays of treatment for patients with advanced, unresectable or generalized non-small cell Lung cancer (NSCLC). While a ceiling has probably been reached in cytostatic therapy in terms of new agents, the opposite is true for immunotherapy and targeted therapy. Even by testing and searching for rarer mutations, it is possible to target the right molecule to this "target" and thus shift the survival of patients favorably. Our case report was deliberately chosen to demonstrate a good and long-lasting therapeutic effect in a patient in a higher line of NSCLC treatment who had no proven mutations, i.e. wild-type (wt) epidermal growth factor receptor (EGFR), and yet erlotinib, a targeted EGFR therapy, provided her with long years of remission.
BACKGROUND/AIM: Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC. PATIENTS AND METHODS: Retrospective data from 9 Czech and 1 Polish comprehensive oncology Centers were used. All patients with stage IV NSCLC and PD-L1 expression ≥50% treated with pembrolizumab in daily practice were included. The groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89% and 90-100%. The log-rank test and the Cox regression model were used to compare survival between study groups. RESULTS: A total of 617 patients were included in the study. We did not observe a statistically significant difference in OS between groups of patients with different levels of PD-L1 expression in the pooled comparison (p=0.445). Furthermore, we did not observe a statistically significant difference even when comparing OS in patients with PD-L1expression of 50-59% (reference) with the group of other patients according to the level of expression of PD-L1 in the Cox regression model including the effect covariates. CONCLUSION: PD-L1 expression showed no significant effect on OS in patients with NSCLC with PD-L1≥50% treated with pembrolizumab.
- MeSH
- antigeny CD274 * metabolismus genetika MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- nádory plic * farmakoterapie mortalita metabolismus patologie genetika MeSH
- nemalobuněčný karcinom plic * farmakoterapie mortalita metabolismus patologie genetika MeSH
- prognóza MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- atezolizumab, durvalumab,
- MeSH
- analýza přežití MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- imunoterapie metody MeSH
- lidé MeSH
- malobuněčný karcinom plic * terapie MeSH
- monoklonální protilátky farmakologie terapeutické užití MeSH
- protinádorové látky imunologicky aktivní farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- směrnice pro lékařskou praxi MeSH
BACKGROUND: Stage III non-small cell lung cancer (NSCLC) is a highly heterogeneous stage due to its subgroups (IIIA-IIIC) comprising both resectable and unresectable tumors. Accurate determination of the extent of the disease is essential for excluding stage IV and choosing the optimal treatment regimen. Whole body positron emission tomography and computed tomography scan (PET/CT) is recommended as an initial staging imaging in locally advanced NSCLC. Despite international guidelines for NSCLC diagnosis and treatment, they are not always adhered to due to various reasons. Even in such a groundbreaking study, the phase 3 trial PACIFIC investigating the efficacy of durvalumab as consolidation therapy in patients with stage III NSCLC PET/CT was not mandatory. With the premise that whole body PET/CT of the trunk is essential for diagnosing stage III NSCLC, we performed a retrospective study evaluating the relationship of the use of PET/CT versus conventional staging with CT of the chest and abdomen, in terms of survival. METHODS: This retrospective study of stage III NSCLC patients used the Czech lung cancer registry LUCAS, which was established in June 2018. As of the data export (up to February 9, 2022), a total of 703 patients were eligible for the analysis. Overall survival (OS) was compared using Kaplan-Meier analysis and a Cox regression model. Continuous variables were tested using the Mann-Whitney test, and categorical variables using the Pearson's Chi-square or Fisher's exact test. RESULTS: A total of 703 patients were included in the cohort with an average age of 69 years. PET/CT was performed on 354 patients, and conventional staging using chest and abdominal CT on 349 patients. The median OS among patients with PET/CT was 20.9 months [95% confidence interval (CI): 18.1-23.7], and it was statistically significantly higher (P<0.001) than among patients without PET/CT, where the median OS was 9.0 months (95% CI: 7.3-10.6). The observed effect of PET/CT was also statistically significant when comparing individual stages (IIIA, IIIB, IIIC). The multivariate Cox model confirmed the use of PET/CT as an independent prognostic factor. The most common reason for omission of PET/CT was the local or time unavailability of the examination. CONCLUSIONS: Omission of PET/CT can mean a significant decrement in survival for the patients in stage III NSCLC, likely due to poor staging and suboptimal treatment. Routine use of PET/CT is strictly recommended for the optimal management of stage III NSCLC patients even outside the high-income countries.
- Publikační typ
- časopisecké články MeSH
Standardem léčby inoperabiiního nemaiobuněčného karcinomu III. klinického stadia je u pacientů únosných k radikálnímu přístupu konkomitantní chemoradioterapie následovaná konsolidační imunoterapií v déice až 12 měsíců. Tento postup vede ke zlepšení léčebných výsledků (včetně celkového přežití). U pacientů, kteří nejsou schopni absolvovat konkomitantní chemoradioterapii, se nabízí sekvenční chemoradioterapie s využitím akcelerované hypofrakcionace.
The standard of care for inoperable clinical stage III non-small cell lung carcinoma is concurrent chemoradiotherapy followed by consolidation immunotherapy for up to 12 months in patients amenable to radical approach. This approach leads to improved treatment outcomes (including overall survival). For patients who are unable to undergo concomitant chemoradiotherapy, sequential chemoradiotherapy using accelerated hypofractionation is offered.
Osimertinib je tyrosinkinázovým inhibitorem třetí generace, vysoce účinný i v oblasti centrálního nervového systému, kde často nádory plic generalizují. Léčba je vyhrazena pro nemocné s nemalobuněčným plicním karcinomem s mutací receptoru epidermálního růstového faktoru (epidermal growth factor receptor, EGFR). V současné době je hrazena u pacientů s pokročilým či generalizovaným onemocněním, ale i v adjuvanci po dobu tří let, kdy významně snižuje riziko vzniku relapsu nemoci.
Osimertinib is a third-generation tyrosine kinase inhibitor, highly effective in the central nervous system, where lung tumors often metastasize. Treatment is specifically reserved for patients with an epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer. It is currently reimbursed for patients with advanced or metastatic disease, and also as adjuvant therapy for up to three years, significantly reducing the risk of disease recurrence.
Standardem adjuvantní léčby pacientů s resekabilním NSCLC s přestavbou genu ALK byla dosud kombinovaná chemoterapie založená na platině, navzdory jejímu použití však zůstávalo riziko recidivy vysoké. Povzbudivé výsledky osimertinibu v adjuvantní léčbě pacientů s resekovaným EGFR-pozitivním NSCLC vedly k testování tyrosinkinázového inhibitoru ALK alektinibu v adjuvantní léčbě ALK-pozitivního NSCLC. Ve studii ALINA, která porovnávala alektinib oproti standardní chemoterapii u pacientů s resekovaným ALK-pozitivním NSCLC, byla adjuvantní léčba alektinibem spojena se 76% snížením rizika recidivy nebo úmrtí a se 78% snížením rizika recidivy v CNS nebo úmrtí. Alektinib byl obecně dobře snášen a nebyly zaznamenány žádné neznámé či neočekávané nežádoucí účinky. Tyto výsledky vedly k registraci alektinibu v EU v adjuvantní terapii pacientů s kompletně resekovaným ALK-pozitivním NSCLC s vysokým rizikem rekurence.
The standard of adjuvant treatment for patients with resectable NSCLC with ALK rearrangement has been platinum-based combination chemotherapy, but despite its use, the risk of recurrence remained high. The encouraging results of osimertinib in the adjuvant treatment of patients with resected EGFR-positive NSCLC led to the testing of the ALK tyrosine kinase inhibitor alectinib in the adjuvant treatment of ALK-positive NSCLC. In the ALINA trial, which compared alectinib to standard chemotherapy in patients with resected ALK-positive NSCLC, adjuvant treatment with alectinib was associated with a 76% reduction in the risk of recurrence or death and a 78% reduction in the risk of CNS recurrence or death. Alectinib was generally well tolerated and no unknown or unexpected adverse effects were reported. These results led to the EU registration of alectinib in adjuvant treatment for patients with completely resected ALK-positive NSCLC at high risk of recurrence.
FTO and ALKBH5 proteins are essential erasers of N6-adenosine methylation in RNA. We studied how levels of FTO and ALKBH5 proteins changed during mouse embryonic development, aging, cardiomyogenesis, and neuroectodermal differentiation. We observed that aging in male and female mice was associated with FTO up-regulation in mouse hearts, brains, lungs, and kidneys, while the ALKBH5 level remained stable. FTO and ALKBH5 proteins were up-regulated during experimentally induced cardiomyogenesis, but the level of ALKBH5 protein was not changed when neuroectodermal differentiation was induced. HDAC1 depletion in mouse ES cells caused FTO down-regulation. In these cells, mRNA, carrying information from genes that regulate histone signature, RNA processing, and cell differentiation, was characterized by a reduced level of N6-adenosine methylation in specific gene loci, primarily regulating cell differentiation into neuroectoderm. Together, when we compared both RNA demethylating proteins, the FTO protein level undergoes the most significant changes during cell differentiation and aging. Thus, we conclude that during aging and neuronal differentiation, m6A RNA demethylation is likely regulated by the FTO protein but not via the function of ALKBH5.
- MeSH
- adenosin metabolismus MeSH
- alfa-ketoglutarát-dependentní dioxygenasa, AlkB homolog 5 * genetika metabolismus MeSH
- buněčná diferenciace MeSH
- embryonální vývoj MeSH
- gen pro FTO * genetika metabolismus MeSH
- myši MeSH
- RNA metabolismus MeSH
- stárnutí genetika MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
S příchodem imunoterapie v léčbě nemalobuněčného karcinomu plic došlo k prodloužení života velké části nemocných. Pokud organismus nemocného reaguje na léčebné impulsy a podaří se probudit protinádorovou imunitu, je to úspěch. V praxi jsme ale svědkem situací, kdy se to přes veškerou snahu nedaří podle našich plánů a nemocný neprofituje z této léčby. Stále existuje mnoho otázek, proč tomu tak je. Jednou z teorií, proč určitá skupina pacientů má z léčby prospěch, a jiná nikoli, je složení střevního mikrobiomu. Naše kazuistika dokládá krásnou léčebnou odpověď u nemocné s adenokarcinomem, která podstoupila fekální transplantaci. A po roce od diagnózy začínáme být optimisty.
The advent of immunotherapy in the treatment of non-small cell lung cancer has prolonged the lives of a large proportion of patients. If the patient’s body responds to treatment and manages to activate anti-tumor immunity, it is considered a success. However, in practice, we often encounter situations where, despite our best efforts, things do not go as planned and the patient does not benefit from the treatment. Many questions remain as to why this is the case. One theory suggests that the composition of the gut microbiome may determine why certain groups of patients benefit while others do not. Our case report shows a significant treatment response in a patient with adenocarcinoma who underwent fecal transplantation. A year after diagnosis, we are becoming optimistic.
- Klíčová slova
- pembrolizumab,
- MeSH
- fekální transplantace metody MeSH
- imunoterapie klasifikace metody MeSH
- inhibitory kontrolních bodů * farmakologie klasifikace terapeutické užití MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- senioři MeSH
- střevní mikroflóra účinky léků MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
