Obinutuzumab in the treatment of patients with chronic lymphocytic leukemia and follicular lymphoma

03/2017 MUDr. Jana Zuchnická, MUDr. Jana Fečková Mihályová, MUDr. Juraj Ďuraš, prof. MUDr. Roman Hájek, CSc.
Monoclonal antibodies are used in the treatment of chronic lymphocytic leukemia and follicular lymphoma especially in combination with chemotherapy. The introduction of rituximab into clinical practice meant a real turning point, it changed medical procedures and the results of the treatment of both diseases. As of recently new monoclonal antibodies are being introduced into clinical practice which are being developed to enhance the antitumor effect. One of them is a humanized monoclonal antibody obinutuzumab. Obinutuzumab combined with chlorambucil is in the Czech Republic approved for the treatment of chronic lymphocytic leukemia in previously untreated patients with multiple comorbidities, who can't undergo fludarabin based treatment. In follicular lymphoma the indication of using obinutuzumab in combination with bendamustine is used for treating patients with rituximab refractory follicular lymphoma, we refer to the current summary of product characteristics. The use of obinutuzumab for patients with follicular lymphoma in the Czech Republic is still bound to being approved by the payer according to §16 of Act No. 48/1997 Coll.

Crizotinib in the treatment of generalized non‑small‑cell lung cancer – a case report

03/2017 MUDr. Leona Koubková
Targeted therapy on the basis of predictive biomarkers that predict the efficacy, at least some patients allows to individualize the treatment and in recent years led to improved treatment outcomes in patients with unfavorable diagnosis of NSCLC (non-small-cell lung cancer). One of these predictive biomarkers is a gene rearrangement EML-4-ALK and ROS1, where is indicated treatment with ALK and ROS1 inhibitors.

Hormonal treatment of metastatic castration‑resistant prostate cancer

03/2017 MUDr. Otakar Čapoun, FEBU
Castration-resistant prostate cancer is a heterogeneous disease, which maintains a dependence of tumor cells to hormonal stimulation. In the case of a failure of the first-line testosterone-lowering therapy one of the next options are new hormonal agents (abiraterone, enzalutamide). Enzalutamide proved to be more effective in the second-line treatment than commonly used bicalutamide. Subanalysis of an abiraterone trial shows that the greatest benefit from the second-line hormonal therapy have patients with low levels of prostate-specific antigen, minimal pain and more differentiated tumors. However, higher Gleason score should not affect the choice of the second-line treatment. Extended follow-up in the trial with enzalutamide before chemotherapy confirmed the efficacy of this drug. The duration of a prior castration therapy has only a minimal impact on the efficacy of abiraterone in the second-line hormonal therapy. Patients receiving corticosteroids concurrently with enzalutamide in the post-docetaxel trial had generally poorer survival outcomes, however enzalutamide always demonstrated superior efficacy in comparison with placebo. Questions about sequence of treatment in the third and additional lines have not yet been resolved. The future of new hormonal agents lies in their using within the first-line hormonal therapy or adjuvantly to a radical treatment.

Enzalutamide in treatment in patients with metastatic castration‑resistant prostate cancer after previous chemotherapy

03/2017 MUDr. Igor Richter, Ph.D., doc. MUDr. Josef Dvořák, Ph.D., MUDr. Věra Hejzlarová, MUDr. Jiří Bartoš, MBA
Introduction: The aim of this retrospective study is demonstrated efficacy and tolerance of enzalutamide therapy in real clinical practice in 33 patients with metastatic castration-resistant prostate cancer (mCRPC) who had previous chemotherapy.
Patients and methods: Between November 2014 and June 2016 we treated with enzalutamide a total of 33 patients with metastatic castrate resistant prostate cancer. The all patients were previous treated by one or two lines of chemotherapy. The enzalutamide was administered by standard dose 160 mg daily.
Results: One patient had cerebral hemorrhage grade IV. In other patients the non-hematological toxicity evaluation did not achieve the grade III or IV. Anemia grade III-IV was described in 6 patients and thrombocytopenia grade III-IV in 2 patients. The median of progression free survival was 7.0 (95% CI 6.1-7.9) months. The median of overal survival was 8.4 (95 % CI 5.1-11.7) months.
Conclusion: The study demonstrated our first experience with enzalutamid in postchemo-indication in patients with mCRPC with good toleration and efficacy.

Is there any difference in treatment strategy between squamous and non‑squamous lung cancer?

03/2017 MUDr. Libor Havel
Lung cancer is one of the most common cancer worldwide. There is approximately 1.8 million of new lung cancer cases, and 1,6 million deaths by lung cancer. There are changes is in frequency of histologic subtypes during past two decades. Predominant histology became non-squamous non-small cell lung cancer, and majority of new therapies are related to this histologic subtype. Is there any fundamental difference in treatment strategy between squamous and non-squamous lung cancer?

Pembrolizumab in the treatment of non‑small‑cell lung carcinoma

03/2017 Prof. MUDr. Jana Skřičková, CSc.
Bronchogenic carcinoma is one of the most common carcinomas of the world. Roughly 85% of all bronchogenic carcinoma is a non-small-cell lung carcinoma (NSCLC). A new approach to its treatment is immunotherapy. This treatment is not directed to the tumor itself, but on the immune system of the patient. Pembrolizumab is a human monoclonal antibody that binds to a PD-1 receptor of programmed cell death and thus blocks its interaction with ligands of PD-L1 and PD-L2. Blocking PD-1 receptor by pembrolizumab prevents binding of the respective ligands and, thus, enhances the T-cell immune response, which may thus be used in the fight against the tumor itself. The article presents the results of studies that demonstrate the effectiveness pembrolizumab in the first and other lines of treatment. It is necessary to know the state of PD-L1 expression in all NSCLC, regardless of histological type, before pembrolizumab can is indicated for any line of treatment.

How to choose the first‑line treatment of the advanced and metastatic melanoma

03/2017 MUDr. Eugen Kubala
The treatment of a metastatic melanoma has progressed so much that before we choose it, we have to ask some questions. What first-line treatment strategy should we choose for patients with the BRAF mutation? Which first-line patients are suitable for immunotherapy? Is the presence of BRAF mutation definite predictor for biological treatment? Pharmacological inhibition of mitogen-activated protein kinase signaling pathways (MAPK) has brought significant advances in the treatment of patients with BRAF-mutated metastatic melanoma. Among these successful pharmaceutics belong BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), and MEK inhibitors (trametinib, selumetinib, cobinetinib, binimetinib). Their advantage is a fast induction of the overall response to 70 %, but the major disadvantage is the development of resistance in the majority of patients (100 %). Its overcoming is investigated in the use of other kinase inhibitors of the MAPK signaling pathway including RAS/RAF/MEK/ERK kinase. A certain disadvantage is the ability to induce resistance to immunotherapy anti-PD1 by inducing mesenchymal transformation. Innately resistant tumors exhibit transcriptional signature (IPRES or innate resistance to PD-1), which exhibits an increased expression of genes involved in the regulation of mesenchymal transformation, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. The same genetic signature that induces IPRES, was observed in melanoma tissues after treatment BRAF inhibitors, and thus induces cross-resistance to anti-PD-1 treatment. Immunotherapy is another treatment option for metastatic melanoma. Its use does not require the presence of BRAF mutation, however, it also lacks a clear predictor of treatment effectiveness. The number of responses to treatment is only about 30-40 %, but the resistance occurs in only about 25 %. We can influence the immune system by blocking anti-CTLA4 antibody ipilimumab, or by blockade of a local immune response in the tumor itself using anti PD1 antibodies nivolumab. Both drugs belong to a group checkpoint inhibitors, which block the blinding of the immune system and the tumor escape from immune surveillance. At present, we can use both compounds in the first-line treatment in the monotherapy or in combination. More effective treatment is by nivolumab. If we achieve the treatment response it lasts even long after discontinuation of therapy. Evidence showed the advantages of biological treatment over immunotherapy in the first-line treatment of metastatic melanoma. This could help in the correct orientation in choosing the right method of treatment for an individual patient.

Interdisciplinary approach to the treatment of renal clear cell carcinoma

03/2017 MUDr. Darja Šustrová
Czech Republic has the highest incidence of kidney cancer in the world. Although the incidence of renal cell carcinoma has been increasing, the survival rate has improved substantially. Renal cancer consists of an heterogeneous group of tumors with distinct genetic and metabolic characteristics and histopathologic and clinical features. It has become more evident that a multidisciplinary team approach is necessary to provide optimal care to patients. This team includes medical oncologists, radiologists, urologist pathologists, radiation oncologists and surgeons. In the era of tyrosinkinase inhibitors therapy the role of cytoreductive nephrectomy should be discussed. There is a role of surgeon in the management of oligometastatic disease. Resection of oligometastatic disease can in selected patients prolong survival and delay the need to commence systemic treatment. When determining the prognosis of RCC, MSKCC criteria based on Motzer criteria are still used, although The MSKCC model was developed during the cytokine era, and was subsequently validated in the TKI population era by Heng, who confirmed four of the five MSKCC criteria (excluding elevated LDH) as independent predictors of poor prognosis, and added neutrophilia and thrombocytosis as additional risk factors, with a median survival rate of 43.2, 22.5 and 7.8 months in the favourable, intermediate and poor prognostic groups. Renal cell carcinoma can sometimes follow an indolent course, therefore a period of observation should be considered before starting treatment.