Aneta Rozsypalová, Josef Dvořák, Igor Richter, David Buka, Jana Grimová, Michaela Matoušková
Ivo Kocák, Zdenek Řehák
Adam Guňka, Markéta Pospíšková, Milan Kohoutek
František Antoš, Pavel Vítek, Jiří Kopic, Josef Marx, Petr Bartoška
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.
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.
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.
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.
Erlotinib in the treatment of patients with non‐small cell lung cancer – current possibilities of its use, experience in the Czech Republic
Target therapy is a subcellular approach to the treatment of cancer. It is targeted on the intracellular mechanisms of signal transduction inhibiting. This treatment targets the natural regulatory mechanisms controlling metabolism, proliferation and migration of cancer cells. The most data are available on the epidermal growth factor receptor as a target for antitumor strategies. Inhibition of epidermal growth factor receptor has become an important target in the treatment of advanced non-small cell lung cancer. Erlotinib is small molecular agents that target the tyrosine kinase domain of the epidermal growth factor receptor. It is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer as a first, second- or third-line regimen alone or combined with bevacizumab as first-line therapy for advanced epidermal growth factor receptor mutation-positive non-small cell lung cancer.
Prostate cancer is mostly hormonal dependent disease from the beginning but during sometime develops in castration-resistant prostate cancer - it is time when the progression of the disease is occurring despite androgen deprivation therapy and patients have a testosterone level drawn. Many trials are interested in finding new opportunities of treatment of this stage. Thanks these trials we have new drugs: in category of cytotoxic chemotherapy cabazitaxel, new generation of androgen deprivation therapy ARTA (abirateron acetate, enzalutamide). For patients with bone-only metastatic disease, without visceral metastasis, there is an opportunity to use radium 223. And we can't forget immunotherapy agents as sipuleucel-T and check point inhibitors. So we have many opportunities which significantly prolong median of overall survival with good quality of life.
The sequence of docetaxel‐cabazitaxel‐enzalutamid in men with metastatic castration‐resistant prostate cancer
In the present case, we present a possible sequential treatment for metastatic castration-resistant prostate cancer into the skeleton (mCRPC). Because of symptomatic disease, chemotherapy therapy has been launched that has been able to effectively reduce the symptoms of the disease. The tolerance of the docetaxel-cabazitaxel sequence was very good. Once the chemotherapy options have been exhausted, ARTA treatment with enzalutamide has been chosen, which further effectively stabilizes the disease, maintains overall good status. Sequential treatment of mCRPC has lasted nearly 4 years.
Long‐term treatment of prostate cancer with a well‐chosen treatment algorithm while maintaining a good quality of life
Prostate cancer is after lung cancer the most common type of malignant tumor in the male population worldwide. We can gradually decrease the number of lung patients by educating the population and using anti-smoking campaigns and hopefully the incidence and prevalence of the illness can be changed in the future. The probability of prostate cancer rises with age. Despite frequent occurrence this disease is not one of the diagnoses with poor prognosis depending on incidence. 80% of the patients are diagnosed with the disease which is not locally advanced and there is approximately 95% survival rate that the patients would live up to five years. This is not only thanks to early diagnosis but also thanks to new medications available in clinical practice. In Hormone-Dependent Prostate Cancer, the development of hormone-resistant disease can be delayed by an average of three years by the luteinizing hormone-releasing hormone analog. Subsequently, the inclusion of androgen receptor targeted agents in the therapeutic algorithm of cast rationally-resistant prostate cancer has brought great advances in the treatment. Also, we cannot forget about the chemotherapy systematic treatment for generalized carcinoma where, for example, the Tax 327 study in 2004 showed a significantly longer survival of docetaxel-treated patients in combination with prednisone against mitoxantrone with prednisone.
Targeted therapy of renal cell carcinoma has evolved enormously during past ten years. Inhibitors of angiogenesis have dominated exclusively in the treatment algorithm until recently, when immunotherapy has become a potential rival. Immunotherapy has been going through a revival due to a different and attractive mechanism of fight against cancer. New molecules have emerged to show efficacy with a regard of response rate, improving survival outcome, however, the key question remains unanswered - what is the optimal sequence of therapy including immunotherapy in the treatment of renal cell carcinoma?
In the European Union, Lartruvo® (olaratumab) has been conditionally registered and approved under the Phase 2 study in the European Union on 9 November 2016 with the status of Orphan Drug - rare disease medication for the treatment of patients with advanced soft-tissue sarcoma. Olaratumab is a human monoclonal antibody binding to the PDGFR (platelet derived growth factor receptor) alpha and blocking ligand binding and activation of the receptor signal pathway. It represents the first biological treatment that clinically significantly prolonged overall survival when combined with doxorubicin, compared to the standard of doxorubicin monotherapy and achieved a median survival of 80%, i.e. 11.8 months from 14.7 to 26.5 months, and reducing the risk of death by 54% (hazard ratio 0.463; p = 0.0003).
Colorectal cancer represents second most frequent cancer in the population. In the last years there is a growing evidence about predictive and prognostic role of the tumor location in the gut in the case of metastatic cancer. There are several possible explanations based on the embryogenesis of the gut, bacterial colonization or genetic predisposition. Retrospective evaluation of clinical trials with targeted therapy (panitumumab, cetuximab) has clearly proven the advantage of anti-EGFR treatment in the case of left-sided colorectal cancer however not in right-sided cancer. Right-sided colorectal cancer has worse prognosis regardless of treatment. This difference is also apparent in subsequent treatment lines. In summary, side location represents predictive factor for anti-EGFR therapy and probably only predictive factor for bevacizumab treatment.
Cytoreductive surgery and hyperthermic peroperative chemotherapy in the treatment of peritoneal surfaces malignancy
In our countries the cytoreductive surgery + hyperthemic peroperative chemotherapy (HIPEC) is a relatively new method in the treatment of peritoneal surfaces malignancy. The 15 years experience of only one center in the Czech Republic dealing with this conditions since 1999, where more than 300 operations were performed, shows a significant benefit for patients suffering from pseudomyxoma peritonei, malignant peritoneal mesothelioma, colorectal carcinoma, ovarial epithelial cancer and primary peritoneal carcinoma. On the other hand the results in gastric cancer diagnosis were not improved. In our group of patients the lethality 7.3 % and the morbidity 6.6 % has been detected. The gradual establishment of new centers dealing with this condition is desirable.
The patients with cancer are prone to developing venous thromboembolism. The thromboprophylaxis and treatment of thrombosis in these patients are thus somewhat different from prophylaxis and treatment of thrombosis in patients without cancer.
Low molecular weight heparins (LMWH) are the best choice for pharmacological thromboprophylaxis. The pharmacological postoperative thromboprophylaxis should be extended to 4 weeks in patients undergoing large surgery (including laparoscopic surgery) for malignancy. The intermittent pneumatic compression or foot pumps are reasonable alternatives to LMWH in patients with very high risk of severe bleeding. The pharmacological thromboprophylaxis is recommended for patients with cancer, which are hospitalized for an acute illness or confined to bed. The pharmacological thromboprophylaxis is not generally recommended for ambulatory patients undergoing chemotherapy; it should be considered in patients with history of venous thromboembolism or multiple additional risk factors for thrombosis. The pharmacological thromboprophylaxis with LMWH is useful for patients undergoing chemotherapy for pancreatic cancer or lung cancer. LMWH is the best choice for most multiple myeloma patients undergoing therapy with the exception of patients which are not treated with imids or with anthracyclines combined with high dose of dexamethasone. Aspirin is an acceptable alternative to LMWH in patients with relapsed multiple myeloma, which are treated with imids monotherapy or using combination of imids with low dose of corticosteroids. Venous thromboembolism in patients with cancer should be treated with therapeutic dose of LMWH for 1 month; the dose can be reduced to 2/3-3/4 thereafter. Edoxaban is an alternative to LMWH with comparable efficacy and safety. The therapy should be re-evaluated after 6 months; subsequent therapy using LMWH or warfarin is recommended indefinitely, unless the cancer is resolved or any major contraindication of this therapy arises.