Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma.

Lung cancer is one of the most common malignant neoplasms. As a result of the disease's progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies-neurosurgery and radiation therapy-do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases.

Current views on molecularly targeted therapy for lung cancer - a review of literature from the last five years.

Lung cancer is the main cause of cancer-related deaths in Poland. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a new group of agents for non-small-cell lung cancer (NSCLC) patients. Determining the predictive value of activating mutations in the EGFR and ROS-1 genes and ALK rearrangement in non-small-cell lung cancer has enabled the identification of patients likely to achieve true clinical benefits. EGFR-TKIs may produce objective response in more than 60% of patients and prolong progression-free survival to 10 months in mutation-positive patients. No improvement of overall survival was shown in randomized trials. The era of immunotherapy implementing PD-1 and PD-L1 inhibitors has changed the face of lung cancer therapy. We aimed to review the literature on the use of EGFR-TKIs and immunotherapeutic agents for NSCLC patients.

The comparison of acute toxicity in 2 treatment courses: Three-weekly and weekly cisplatin treatment administered with radiotherapy in patients with head and neck squamous cell carcinoma.

The most appropriate cisplatin treatment schedule delivered with radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) is unknown. The aim of this study was to compare the acute toxicity and its impact on the course of the treatment, administered cisplatin and radiation doses, the length of hospitalization and supportive drugs administration in patients with HNSCC receiving 2 different cisplatin treatment schedules administered with radiotherapy.In this retrospective analysis, 104 patients with HNSCC were enrolled. Patients received radiation concurrently with 100 mg/m cisplatin administered 3-weekly (n = 50; group A) or 35 to 40 mg/m cisplatin administered weekly (n = 54; group B). Chemoradiotherapy was performed in locally and/or regionally advanced disease (stage III-IV), in a definitive radical upfront setting (71.1%) or after surgical resection in patients with high-risk factors (28.8%).Both study groups were equally distributed in terms of age, gender, stage of the disease, Eastern Cooperative Oncology Group performance score, chronic diseases and primary tumor site. The schedule of cisplatin dosing did not influence the duration of hospitalization, the number of additional supportive drugs (antibiotics, opioids) administered or total doses of received radiotherapy. However, postponement of radiotherapy due to adverse events was significantly more frequent in patients treated with 35/40 mg/m (55.56% vs 32%; P = .015). Furthermore, patients treated with weekly treatment schedule received lower total cisplatin dose (160 mg/m) in comparison to those treated with the 3-weekly schedule (200 mg/m). Grade 3 and 4 mucositis occurred more frequently in patients treated in group A (70% vs 50%; P = .037). Leukopenia was also observed more frequently in group A (88% vs 72.2%; P = .04), however there was no difference in grade 3/4 leukopenia between both study arms. There was no statistically significant difference in any other adverse effects.These results do not demonstrate the advantage of modified weekly schedule over standard 3-weekly cisplatin treatment plan. However, severe mucositis occurred more frequently in patients receiving 3-weekly cisplatin, both chemotherapy schedules seemed to present similar toxicity. Due to conflicting efficacy and toxicity, the results and compliance of weekly and 3-weekly cisplatin schedules should be evaluated in further randomized, controlled trials and retrospective studies.