Juraj Ďuraš, Michal Kaščák, Milan Navrátil, Roman Hájek
Petra Richterová, Zdeněk Kořistek,Lukáš Stejskal, Roman Hájek
Zuzana Donátová, Drahomíra Kordíková, Jitka Abrahámová
Alexandr Poprach, Radek Lakomý
Aneta Kyllarová, Ondřej Kubeček, Jindřich Kopecký
Pixantrone is a novel aza-anthracenedione developed with aim of reducing cardiac toxicity whilst preserving the efficacy of anthracyclines. Pixantrone acts as an intercalating and an alkylating agent and weak topoisomerase II inhibitor. Unlike anthracycline pixantrone has reduced potential for the production of oxygen free radicals, which are probably the main factor of anthracycline’s cardiotoxicity. The maximum tolerated dose identified in the phase I study in relapsed and refractory aggressive non-Hodgkin’s lymphoma was 56 mg/m2 i.v. day 1, 8 and 15 in a 28day cycle. In Phase II and III was observed overall response in 27–40 %, complete remission in approximately 15 % of patients. In a randomized phase III study PIX 301 chieved overall response rate (40 %), complete or unconfirmed complete remission (24 %) and median time to progression (5,3 months) in the pixantrone arm was significantly higher than in the arm with single agent investigator choice. The main side effect of drug is haematotoxicity, primarily neutropenia. The risk of cardiotoxicity is not completely eliminated, but unlike in anthracyclines involves mainly subclinical decrease in left ventricular ejection fraction, symptomatic congestive hear failure has been observed only rarely. Based on the study PIX 301 pixantrone was approved in monotherapy in the treatment of multiple relapsed or refractory aggressive B-non-Hodgkin lymphomas. Efficacy of pixantrone combined with rituximab vs. gemcitabine + rituximab in rituximab pretreated patients is investigated in the ongoing PIX 306 study.
Non-small cell lung cancer (NSCLC) is a disease with a poor prognosis. Today we know that it involves a genetically distinct group of tumors. And of such genetic diversity leads to the tendency of individualized treatments based on the predictive factors that predict the efficacy of treatment. One of the predictive factors in NSCLC are mutations of the epidermal growth factor receptor (EGFR), in which case is indicated treatment EGFR tyrosine kinase inhibitors (TKI). Even if this treatment, we have to calculate with the formation of resistance. The mechanisms of its formation are different, most (up 60%), it is the T790M mutation at exon 20. In 11/2015 FDA and 2/2016 EMA approved EGFR TKI 3rd generation osimertinib to treat patients with locally advanced or metastatic NSCLC T790M mutation of EGFR.
Myelodysplastic syndrome is a clonal disorder of the bone marrow caused by damage to the genetic information myeloid stem cell. It represents a heterogeneous group of disorders characterized by ineffective hematopoiesis with dysplasia of one or more myeloid lineage leading to cytopenia (or cytopenias) and the high incidence of progression to acute myeloid leukemia (about 1/3 cases). The blood count is most prevalently represented by anemia alone, in combination with thrombocytopenia or leucopenia, neutropenia. Clinical symptoms are consistent with the type and depth of the cytopenia – anemic syndrome, bleeding manifestation from thrombocytopenia or infectious complications in neutropenic patients. Myelodysplastic syndrome is a disease occurring almost solely in patients of older age (most frequent occurrence between 65–70 years), with an incidence of 3–5 new cases per 100,000 population per year. The incidence of myelodysplastic syndrome increases with age rapidly and in a group of people over 70 years amounts to 20 to 40 new cases per 100,000 inhabitants. Myelodysplastic syndrome is diagnosed as in the case of primary – unknown etiology, or secondary – often after chemotherapy or radiotherapy for an other cancer or after exposure to a known toxic agent.
Palbociclib in the treatment of advanced and/or metastatic hormone‑sensitive HER2‑negative breast cancer
Recently, we have the possibility to use in clinical practice a new targeted drug – palbociclib in the treatment of endocrine receptor positive, HER2 negative breast cancer. In the first line setting of treatment advanced/metastatic disease it is combined with letrozole and in the second line with fulvestrant. Cyclin dependent kinases 4 and 6 (CDK4/6) blockade inhibit the cell cycle progression in G1 phase and is associated with tumor cells proliferation prevention. The drug obtained a very high degree of recommendation and is a part of international guidelines.
Breast cancer in metastatic stage is considered as incurable disease. About 20% of all patients have distant metastases. The offer of new cytotoxic and biological agents caused prolongation of the overall survival in patients with metastatic disease. Eribulin is considered as the new effective cytotoxic agent for pre-treated patients with locally recurrent and metastatic breast cancer. Continuous research of its use was followed with extension of the indication in treatment of liposarcoma.
Ovarian cancer is among gynecological tumors the most common cause of death and the fifth in deaths among oncological diseases. In the last decade there have been significant advances in genomic mapping of tumor cells and in the knowledge of molecular mechanisms in the pathogenesis of ovarian cancer. Targeted molecular therapy starts to apply in addition to cytotoxic chemotherapy. Widely researched and promising possibility of targeted treatment of ovarian cancer are PARP inhibitors olaparib, veliparib, niraparib, rucaparib and talazoparib that are examined in monotherapy and in combination with other molecules as potential amplifiers or cytotoxic damage during chemotherapy or radiation treatment. Poly(ADP-ribose)-polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including gene BRCA1, BRCA2 mutated tumours, by exploiting synthetic lethality. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA1/2 mutated advanced ovarian cancer as a single agent in the treatment and maintenance setting, particularly in platinum sensitive disease. Current research is extending the use of PARP inhibitors beyond BRCA1/2 mutations to other sensitising molecular defects that result in HR-deficient cancer.
Adenocarcinoma of distal oesophagus and gastric adenocarcinoma still have a poor clinical outcome. In locally advanced adenocarcinoma multimodal treatment has reached maximum of median overall survival. New molecular predictors defined recently by The Cancer Genome Atlas offer an opportunity of patient stratification to optimal treatment approach. PET/CT is a valuable method providing earlier identification of non-responders and enabling a well-timed change of ineffective treatment. Metastatic gastric cancer is very heterogeneous disease. Trastuzumab is the only clinically valid targeted therapy with a known molecular predictor. Antiangiogenic treatment is a standard of care in the second line treatment. Despite promising phase I/II clinical trials results, several phase III studies assessing receptor tyrosine kinase-related signaling pathways such as epidermal growth factor receptor, hepatocyte growth factor receptor (MET/HGF) or mammalian target of rapamycine receptor (mTOR) failed. Novel treatment targets include activation of immune response by PD-1/PD-L1 checkpoint inhibitors, inhibition of cancer stemness-related signaling pathways like STAT3, targeting DNA damage repair, stroma modification by matrix metalloproteinase-9 inhibition and Claudin-18.2, a tight junction protein antibody.
Metastatic and/or locally advanced inoperable melanoma is still an incurable disease. On the other hand the progress in the new treatment's options causes significant prolongation of time to progression and overall survival. Treatment of metastatic melanoma could be divided into three goups. Checkpoint inhibitors - anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed death 1) or PD-L1 inhibitors - are in the first group, BRAF and MEK inhibitors belong to the second group. Cytostatics are in the last group. We will point out drugs from the first group in this review and the results of the actual studies will be mentioned.
Immunotherapy has gradually become a part of standard treatment of selected solid tumours since 2011. The spectrum of malignancies suitable for this treatment modality has been increasing since then. Consequently, the amount of patients treated with immunotherapy has been rising. Despite undeniable efficacy of this modality, we are facing a new spectrum of adverse effect distinct from conventional therapies (radiotherapy, chemotherapy). The aim of this article is to provide a brief review on the most common adverse effects of immunotherapy and their management. We aim to provide physicians, who do not routinely deal with these drugs, with some basic information, so that they are able to manage some minor toxicities or refer the patients to appropriate cancer centre.