Selected articles

Crizotinib in the treatment of non‐small cell lung cancer

02/2018 MUDr. Ondřej Venclíček
Crizotinib is an ALK, ROS1 and MET tyrosine kinase inhibitor approved for the treatment of ALK and ROS1 positive, advanced, non-small cell lung cancer, both in the first line of treatment and in previously treated patients. The following text presents the results of studies that showed the role of crizotinib in the treatment of non-small cell lung cancer, its different molecular targets (ALK, ROS1 and MET), mechanism of action and side effects.
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Monoclonal antibodies in relapsed or refractory multiple myeloma treatment

02/2018 MUDr. Martin Štork
Nowadays the multiple myeloma treatment with monoclonal antibodies goes through a dynamic development. Within the clinical trials there are available new three monoclonal antibodies - daratumumab, elotuzumab and isatuxiamb. The efficacy of anti-CD38 monoclonal antibody daratumumab is already known from monotherapy in heavily pretreated patients. Daratumumab monotherapy in heavily-pretreated patients shows 30% overall response rate and response persisted for more than half a year. Combination of daratumumab and imunomodulatory drugs shows more than 90% response rate and significant extension of progression-free survival versus standard care in relapsed patients. Elotuzumab in combination with lenalidomide and dexamethasone, achieved in 79% of patient's partial remission and better treatment response and median PFS was 19.4 months. Isatuximab is a new anti-CD38 monoclonal antibody. In phase Ib or II clinical trials Isatuximab achieved very promising results in heavily pre-treated patients. Monoclonal antibodies are highly effective and minimally toxic in the multiple myeloma treatment. They are an ideal complement to the standard treatment protocols. This review summarizes present clinical data about monoclonal antibodies treatment in relapsed multiple myeloma patients.
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Bosutinib in the treatment of chronic myelogenous leukemia

02/2018 MUDr. Petra Bělohlávková, Ph.D.
In recent years, significant progress has been made in the treatment of chronic myelogenous leukemia, which has led to the discovery of tyrosine kinase inhibitors. The younger representatives of this drug group include bosutinib, which is used in cases of development of resistance or severe toxicity to previous tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib). Therefore bosutinib is most commonly used as a 3rd or higher treatment line for chronic myelogenous leukemia. Bosutinib has very different side effects, with the most common side effect being diarrhea. Other side effects include elevations of liver tests, rash or myelosuppression. Conversely, with electrolyte abnormalities or cardiovascular events, we rarely see bosutinib treatment.
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Venetoclax – new drones to deploy against chronic lymphocytic leukemia

02/2018 Prof. MUDr. Tomáš Kozák, Ph.D., MBA
Venetoclax is orally available bcl-2 inhibitor effective in tumors with high antiapoptotic activity as chronic lymphocytic leukemia and some other haematological malignancies. Venetoclax also bypasses TP53 and is active in diseases with lack or mutation of TP53. All clinical studies so far have shown high activity of venetoclax in monotherapy and in combination therapy in both relapsing/refractory chronic lymphocytic leukemia and in the 1st line. Venetoclax can induce response in 70-100% with high complete remission rate. Venetoclax is able to achieve minimal residual disease negativity in up to 60% in relapsing/refractory setting and up to 70% in 1st line. Venetoclax is well tolerated with major toxicity being hematological. After the introduction of rump-up stepwise strategy to the initial phase of treatment the clinical tumor lysis syndrome, originally associated with venetoclax, became very rare. After final results of current clinical studies are reported we can expect significant change in the treatment strategy especially in high risk chronic lymphocytic leukemia.
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Biosimilar preparations in oncology – also manufacturers of original drug associations in AIFP are developing biosimilars

01/2018 Mgr. Jakub Dvořáček, MHA
Biosimilar medicinal products are not new, but monoclonal antibodies have raised the interest of the general public. At present, about 30 biosimilar products are available or are expected to be marketed prior to the very careful regulatory procedure. Oncology is one of the most economically demanding disciplines, and new biological drugs represent an extreme increase in health care costs. Increased availability of care is expected from biosimilar drugs such as rituximab, trastuzumab, bevacizumab and others.
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Gastric cancer surgery – current status

01/2018 Doc. MUDr. David Hoskovec, Ph.D.
Treatment results of the gastric cancer are still unsatisfactory. Late diagnosis in European region is one of reason for these results. The disease is often diagnosed in late stage with generalisation. Adequate surgical resection is the only chance for long term survival. Type and timing of the treatment depend on decision of the multidisciplinary team. There is a summary of the diagnosis and treatment of gastric cancer in this article
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Cyberknife – relentless assistant in a local treatment of the malignant tumors

01/2018 MUDr. Jakub Cvek, Ph.D., Ing. Lukáš Knybel
The progress in radiation oncology allows stereotactic radiosurgery and radiotherapy to be used more and more frequently. Moreover, beside to dedicated stereotactic devices such as GamaKnife or CyberKnife, modern linear accelerators with a stereotactic superstructure can also be used in some indications. However, in case of spinal and lung stereotactic irradiation, the role of the CyberKnife is irreplaceable very often.
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Efficacy of erlotinib in subsequent lines of non‑small cell lung cancer therapy

01/2018 MUDr. Jana Krejčí, MUDr. Daniel Krejčí, doc. MUDr. Norbert Pauk, Ph.D.
Targeted therapy is becoming more and more important part of bronchial carcinoma treatment. One of the approaches includes administering erlotinib in later lines of therapy of non-small cell carcinoma. Our two case studies document a very good therapeutical effect as well as minimal toxicity of such an approach when treating adenocarcinoma (EGFR wild-type) and/or squamous carcinoma.
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Erlotinib in the first line treatment of the metastatic non‑small cell lung cancer

01/2018 MUDr. Daniel Krejčí, MUDr. Jana Krejčí, doc. MUDr. Norbert Pauk, Ph.D.
In the following text, we are discussing the case of a patient with non-small cell lung cancer, whom the presence of the activating mutation of the epidermal grow factor has been proved. We begun treatment with erlotinib in the first line until progression which appeared on computed tomography after 15 months. In the second line treatment she received three cycles of the chemotherapy with pemetrexed. The second line treatment was terminated due to progression and high hematotoxicity. Following the patient's wishes, further steps regarding treatment are now in the competence of the regional oncologist.
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Afatinib in clinical practice – patient case study with eighteen months of progression‑free survival and high quality of life

01/2018 MUDr. Jaromír Roubec, Ph.D., MUDr. Radoslava Černeková
The author presents the case report of the patient treated with afatinib. This is a man, the year 1961, in which, on June 3, 2014, a perthoraxal puncture of the left lung bearing under CT control was diagnosed with primary pulmonary adenocarcinoma of the acinaric micropapillary type according to TNM classification T4N3M1b grade IV, with bilateral metastatic lung disease, carcinomatous lymphangiitis, exudate, and metastases to the liver and thyroid. The metastasis of the thyroid gland has been verified punctually and compared to a sample of tissue taken from the lung. Performance status of ECOG 1. Molecular genetic examination on 20 June 2014 detected EGFR activation mutation in L858R exon 21, EGFR gene amplification was detected, ALK and ROS1 gene reconstruction was not found. The patient was only an occasional smoker, the patient visited his physician for weight loss of seven kilograms in three months, and dyspnoea with dry cough. Early treatment with afatinib was initiated on June 27, 2014, less than one month after tissue collection. The patient was on regular monitoring with long-term severe partial regression of lung, liver and thyroid involvement in ECOG 0 performance improvement until disease progression after 18 months of CNS treatment with a total survival of 28 months.
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Cellular mechanisms and signal pathways transduction in pancreatic cancer

01/2018 As. RNDr. Ing. Libor Staněk, PCTM; prof. MUDr. Robert Gurlich, DrSc.; doc. MUDr. Petra Tesařová, CSc.; Mgr. Zdeněk Musil; prof. MUDr. Luboš Petruželka, CSc.
Pancreatic cancer is one of the most severe types of human tumors. It is the second most common cause of cancer deaths in the world. Worldwide, more than 300,000 new diseases are diagnosed annually and approximately the same number of patients die of this disease. In 2015, the incidence of 20/100,000 inhabitants in the Czech Republic was the second highest in the world. Despite all the advances in modern oncology treatment, the long-term survival of people with this type of malignant growth is rather exceptional. Therefore, attention is focused on the genetic causes of this cancer. Essentially, this is a genetic disease where the exact sequence of somatic DNA mutations with a multistage process is known, with the cumulative effect of mutations obtained in both coding and regulatory genes, changes in ploidy, gene amplification, structural rearrangement, deletion or loss of heterozygosity. The most frequent mutations occur in the protooncogenes of K-ras and tumor suppressor genes p16, p53, BRCA2 and DPC4/SMAD4, leading to malignant change of the epithelium of leads.
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Advances in the treatment of metastatic melanoma

01/2018 MUDr. Ondřej Kodet, Ph.D., MUDr. Ivana Krajsová
Advances in the treatment of metastatic melanoma significantly affected the prognosis of patients with metastatic disease. Currently therapy is based on two basic therapeutic principles, namely immunotherapy with monoclonal antibodies anti-CTLA-4 and anti-PD-1 and targeted oncology therapy with BRAF inhibitors alone or in combination with MEK inhibitors. The knowledge of these therapeutic modalities leads to combination treatment, which is subject of a number of clinical trials. The work provides an overview of key contemporary knowledge and outline new options in the treatment of metastatic melanoma.
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New possibilities of systemic treatment of thyroid cancer

01/2018 MUDr. Kateřina Kopečková
Differentiated carcinomas represent 90% of all thyroid malignancies. Median survival in radioiodine-refractory carcinomas (10-20% of all tumors) is 2.5-3.5 years. New knowledge in the field of molecular genetics has been the basis for the development of new systemic drug therapies. Sorafenib, a multikinase inhibitor, is approved for the treatment of radioiodine-refractory differentiated carcinoma on the basis of a randomized placebo-controlled clinical trial in which a longer progression of the disease was achieved in patients treated with sorafenib for 5 months. The second new drug to be registered is lenvatinib with the same indication and time to disease progression of 18.3 months. Medullar carcinoma is a rare thyroid gland tumor. The first registered drug for this diagnosis is the multikinase inhibitor of vandetanib followed by cabozantinib. In the vandetanib registration study, median time to progression was not reached and estimated age based on statistical modeling was 30.5 months. The time to progression of the disease in the clinical trial with cabozantinib was 11.2 months compared to 4.0 months for placebo.
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Third‑generation inhibitors targeting EGFR T790M mutation in non‑small cell lung cancer

01/2018 MUDr. Libor Havel
EGFR tyrosinkinase inhibitors became a cornerstone of therapy patients with advanced non-small cell lung cancer harbouring mutations in the EGFR kinase domain. EGFR TKI therapy is characterized by high response rate and prolonged progression free survival when compared with standard platinum-based chemotherapy dublets. Despite this, vast majority of patients develope during first 12 months of therapy resistence to TKI and tumor progression. The most common mechanism of this resistence is a secondary T790M mutation. EGFR TKI of third generation are deginged to overcome this type of resistence. Osimertinib became only one of these 3rd generation tyrosinkinase inhibitors adopted for clinical use. This paper will summarize data about 3rd generation EGFR TKI in the treatment of patients with non-small cell lung cancer.
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Advances in oncological treatment of head and neck carcinomas

01/2018 MUDr. Petra Holečková, Ph.D., MBA; as. RNDr. Ing. Libor Staněk, PCTM
Carcinoma of the head and neck is a one of cause of cancer-associated illness and death. Most patients present with locoregionally advanced disease, and more than 50% have recurrence within 3 years. Standard of curative care are surgery and radiotherapy. Patients with head and neck carcinoma who progressed or have metastatic disease are treated with platinum-based chemotherapy in combination event. with cetuximab. New treatments agents are checkpoint inhibitors pembrolizumab and nivolumab. Important role in diagnostics and therapy can play molecular biology and genetics.
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The family of CDK4/6 inhibitors is growing

01/2018 MUDr. Věra Benešová
The breast carcinoma belongs among the most frequently occurred malignant female illnesses in our country. Implementation of the screening programme enables to detect carcinoma at the I. or at the II. clinical stage in spite of the fact that the diagnosis of patients at the metastatic stage takes place, metastasis occurs by already cured patients too. Approximately 70 % of patients affected by the breast carcinoma is hormonally positive. Application of hormonal treatment has currently been prioritized for its efficiency and favourable effect with low profile of toxicity. Exception are just the patients with visceral crisis. The issue of the hormonal treatment efficiency is the creation of resistance against it. One of the ways how to postpone creation of resistance against hormonal treatment and to improve its efficiency is to combine it with the inhibitors CDK4/6.
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Treatment of patients with ovarian carcinoma with a BRCA1/2 mutation present

01/2018 MUDr. Mária Zvaríková
Poly(ADP-ribose)polymerase inhibitors (PARP) are considered to be one of the most exciting new options for patients with ovarian carcinoma. In monotherapy, PARP inhibitors have shown the greatest activity in tumor cells carrying mutations in BRCA genes. Recent Phase III studies have shown that PARP inhibitor activity is also present in nonmutated patients, especially if they have certain clinical characteristics such as platinum sensitivity and histologically verified high-grade serous carcinoma. PARP inhibitors were also combined with chemotherapy, but overlapping myelosuppression was observed with both PARP inhibitors and chemotherapy, inhibiting the development of these combinations. In contrast, combinations of PARP inhibitors and biological agents, particularly antiangiogenic agents, appear to be well tolerated and show promising activity in both BRCA mutants and wild type BRCA. There are currently numerous clinical trials investigating the anti-tumor activity of combination therapy of PARP inhibitors.
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Management of diarrhea as an undesirable effect of treatment with afatinib – case report

06/2017 MUDr. Gabriela Krákorová, Ph.D., MUDr. Hynek Mírka, Ph.D., prof. MUDr. Miloš Pešek, CSc.
Afatinib is an oral preparation, a tyrosine kinase inhibitor of the second-generation EGFR. It is used in the treatment of unresectable locally advanced or metastatic non-small cell lung carcinoma in patients with positive mutations in the gene encoding the epidermal growth factor receptor (EGFR). Afatinib as the first tyrosine kinase inhibitor EGFR demonstrated overall survival compared to chemotherapy in patients with positive EGFR mutation on exon 19 (prolongation of median survival by 12.2 months using afatinib). The most common side effects are rash, diarrhea, stomatitis and paronychia. To cope with side effects, patients need to be cooperative and well informed. At the clinic of pneumology and phthisiology, we have witnessed a brief written lesson that is part of a medical report. In the case of diarrhea, adequate hydration, dietary precautions, and the use of loperamide, which should be provided to patients immediately upon initiation of treatment with afatinib. The case study demonstrates good controlled side effects in collaborating patients with high adherence to treatment. In line with the literature, a good therapeutic effect remains unaffected even when reducing the daily dose of afatinib by half.
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The inclusion of Lonsurf (trifluralin/tipiracil, TAS‑102) in the treatment of metastatic colorectal cancer

06/2017 MUDr. Eugen Kubala
Fluoropyrimidines have represented the cornerstone of treatment of colorectal cancer for a long time. Lonsurf is an orally administered combination of a thymidine-based nucleic acid analogue - trifluridine and a thymidine phosphorylase inhibitor - tipiracil hydrochloride with trifluridine being the active cytotoxic component of this combination. Its triphosphate form is incorporated into DNA appearing to result in antitumor effects. Tipiracil hydrochloride is a strong inhibitor of the thymidine phosphorylase and, when combined with trifluridine prevents the rapid degradation of the trifluridine, allowing longer maintenance of adequate plasma concentration of the active drug. The results of the placebo-controlled, double-blind, phase 3 clinical trial RECOURSE confirmed the results of previous assessments of oral Lonsurf in patients with metastatic colorectal cancer, who had already undergone extensive treatment. Lonsurf was associated with a clinically relevant prolongation of overall survival in essentially all treatment subgroups. Combination of trifluridine and tipiracil is able to replace 5-fluorouracil in patients who have developed resistance to this treatment. It turns out that the combination with a biologic therapy or oxaliplatin and irinotecan has a great future in the treatment of not only metastatic colorectal cancer.
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Crizotinib – still „gold standard“ for patients with pulmonary adenocarcinoma with ALK translocation?

06/2017 MUDr. Martin Svatoň, prof. MUDr. Miloš Pešek, CSc.
Crizotinib is a tyrosine kinase inhibitor targeting ALK translocation. Based on Profile 1007 and Profile 1014 trial, it has become the basis of treatment for patients with ALK translocation in the first as well as the second line of treatment. Its toxic profile is acceptable and usually well manageable. In the Czech Republic, due to the form of payment, it has been used exclusively in the second line, where we document the experience from our workplace with this drug. Currently, other drugs (ceritinib, alectinib) have proven to be effective in patients with ALK translocations, when it is a question of choosing a treatment plan, which is discussed in more detail in the discussion.
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