Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases.

Central nervous system (CNS) metastases can be seen at a rate of 30% in advanced stages for patients with non-small cell lung cancer (NSCLC). Growing evidence indicates the predictive roles of driver gene mutations in the development of brain metastases (BM) in recent years, meaning that oncogene-driven NSCLC have a high incidence of BM at diagnosis. Today, 3rd generation targeted drugs with high intracranial efficacy, which can cross the blood-brain barrier, have made a positive contribution to survival for these patients with an increased propensity to BM. It is important to update the clinical and pathological factors reflected in the survival with real-life data. A multi-center, retrospective database of 306 patients diagnosed with driver mutant NSCLC and initially presented with BM between between November 2008 and September 2022 were analyzed. The median progression-free survival (mPFS) was 12.25 months (95% CI, 10-14.5). While 254 of the patients received tyrosine kinase inhibitor (TKI), 51 patients received chemotherapy as first line treatment. The median intracranial PFS (iPFS) was 18.5 months (95% CI, 14.8-22.2). The median overall survival (OS) was 29 months (95% CI, 25.2-33.0). It was found that having 3 or less BM and absence of extracranial metastases were significantly associated with better mOS and iPFS. The relationship between the size of BM and survival was found to be non-significant. Among patients with advanced NSCLC with de novo BM carrying a driver mutation, long-term progression-free and overall survival can be achieved with the advent of targeted agents with high CNS efficacy with more conservative and localized radiotherapy modalities.

Efficacy and safety of folfiri plus aflibercept in second-line treatment of metastatic colorectal cancer: Real-life data from Turkish oncology group.

Aims: The addition of aflibercept to the fluorouracil and irinotecan (FOLFIRI) regimen significantly improved clinical outcomes in patients with metastatic colorectal cancer (CRC) previously treated with oxaliplatin. We aimed to investigate the efficacy and safety of second-line FOLFIRI and aflibercept combination in patients with metastatic CRC in real-life experience. Materials and Methods: Four hundred and thirty-three patients who treated with FOLFIRI and aflibercept in the second-line were included in the study. The clinical and pathological features of the patients were recorded retrospectively. Survival (overall and progression-free survival [PFS]), response rates, and safety data were analyzed. Results: The median age was 61. Majority of patients (87.5%) received first-line bevacizumab and 10.1% of patients received anti-epidermal growth factor receptor agents. About 80% of patients had KRAS, 18.6% of patients had NRAS, and 6.4% of patients had BRAF mutations. The median OS was 11.6 months (95% confidence interval [CI], 10.6-12.6) and the median PFS was 6 months (95% CI, 5.5-6.5). About 4.6% of patients had complete response and 30.6% of patients had partial response as best tumor response. Grade 1-2 toxicities were seen in 33.4% of patients, while grade 3-4 toxicities were recorded in 27% of patients. Eight patients (2%) died due to treatment toxicity. Conclusions: Overall and PFS were similar in routine clinical practice compared to phase III pivotal VELOUR trial. However, response rates were found to be higher. It was observed that there were fewer adverse events compared to the VELOUR trial.

Prognostic factors of perioperative FLOT regimen in operable gastric and gastroesophageal junction tumors: real-life data (Turkish Oncology Group).

BACKGROUND: Perioperative FLOT regimen is a standard of care in locally advanced operable gastric and GEJ adenocarcinoma. We aimed to determine the efficacy, prognostic factors of perioperative FLOT chemotherapy in real-life gastric and GEJ tumors. METHODS: The data of patients who were treated with perioperative FLOT chemotherapy were retrospectively analyzed from 34 different oncology centers in Turkey. Baseline clinical and demographic characteristics, pretreatment laboratory values, histological and molecular characteristics were recorded. RESULTS: A total of 441 patients were included in the study. The median of age our study population was 60 years. The majority of patients with radiological staging were cT3-4N(+) (89.9%, n = 338). After median 13.5 months (IQR: 8.5-20.5) follow-up, the median overall survival was NR (95% CI, NR to NR), and median disease free survival was 22.9 (95% CI, 18.6 to 27.3) months. The estimated overall survival at 24 months was 62%. Complete pathological response (pCR) and near pCR was achieved in 23.8% of all patients. Patients with lower NLR or PLR have significantly longer median OS (p = 0.007 and p = 0.033, respectively), and patients with lower NLR have significantly longer median DFS (p = 0.039), but PLR level did not affect DFS (p = 0.062). The OS and DFS of patients with better ECOG performance scores and those who could receive FLOT as adjuvant chemotherapy instead of other regimens were found to be better. NLR was found to be independent prognostic factor for OS in the multivariant analysis. At least one adverse event reported in 57.6% of the patients and grade 3-4 toxicity was seen in 23.6% patients. DISCUSSION: Real-life perioperative FLOT regimen in operable gastric and GEJ tumors showed similar oncologic outcomes compared to clinical trials. Better performance status, receiving adjuvant chemotherapy as same regimen, low grade and low NLR and PLR improved outcomes in real-life. However, in multivariate analysis, only NLR affected OS.

The relationship between adjuvant chemotherapy and thiol-disulfide compounds.

Aim: Thiols are the organic compounds of the antioxidant system. There is limited data in the literature concerning chemotherapy (CT) in cancer and thiol balance. In this study, we aimed to evaluate the possible changes of thiol/disulfide levels with the recurrent CT cycles and type of cancer. Materials and Methods: The 40 healthy individuals and 40 patients who had been newly diagnosed with early-stage breast, ovary and endometrium cancer receiving adjuvant CT. Blood samples were taken from all patients three times as basal and after the first and second CT sessions. Results: We compared preadjuvant treatment levels of thiol and disulfide parameters in the patients group with the control group. The median of native thiol and total thiol was found to be higher in the control group than in the study group (P < 0.001). In addition, disulfide/native thiol and disulfide/total thiol rates were found to be higher in the patient group (P = 0.001). When we look at the comparison before and after CT in the patient group, disulfide/native thiol and disulfide/total thiol rates, which represent increased oxidative stress (OS) levels were found to be higher after CT than before CT measurement (P < 0.016). Discussion: This is the first study, which has researched the relationship between cancer type and thiol compounds and changes of thiol compounds during CT therapy, by using the method designed by Erel and Neselioglu. In this study, we found that pre-CT thiol disulfide balance in cancer patients shifted toward disulfide direction and OS levels may increase after repetitive CT sessions.

Can the host immune response against SARS-CoV2 also cause an anticancer effect?

During the COVID-19 pandemic, it is important to assure the safety and management of cancer patients. Despite preliminary studies revealed that patients with cancer are more susceptible to infection and have poorer prognosis than other infected patients without cancer, mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. So, we have some comments about the pathogenesis attributed to the COVID-19 disease and cancer relationship and determination of subgroups in this and oncoming studies. Variable effects of anticancer treatments on the patient's immune system are yet to be elucidated. On the other hand, the effect of SARS-CoV-2 virus on tumor microenvironment or immune responses in cancer is not yet fully proven. Very recently, Challenor and her colleague reported a case with classical Hodgkin lymphoma with stage IIIs disease, which went into remission without corticosteroid or immunochemotherapy. They assumed that the putative mechanisms of action include cross-reactivity of pathogen-specific T cells with tumor antigens and natural killer cell activation by inflammatory cytokines produced in response to infection. During the course of COVID-19 disease, immune checkpoint blockade effect might be induced naturally.

The effect of EML4-ALK break-apart ratio on crizotinib outcomes in non-small cell lung cancer harboring EML4-ALK rearrangement.

PURPOSE: Anaplastic lymphoma kinase (ALK) gene rearrangement exists in approximately 3-7% of non-small cell lung cancer (NSCLC) and more than 15% split or isolated red signals among 50 tumor nuclei scored in the FISH analysis defines as ALK-positive. The previous studies showed that the high EGFR mutational load related to better outcomes in EGFR mutant NSCLC. Therefore, we aimed to investigate the effect of the ALK break-apart ratio on treatment outcome in metastatic ALK-positive NSCLC. METHODS: The patients (pts) who ALK-positive and treated with crizotinib were retrospectively enrolled. The 30%, 40%, 50%, 60%, and 70% break-apart ratios were determined as a threshold value, and each of these was evaluated separately. Based on the results of these analyses, we detected the optimal threshold value and also performed further investigations. RESULTS: A total of 70 patients were enrolled in the study. The most significant decrease in the risk of the progression or death was detected at the 50% threshold value and it was accepted as the optimal threshold. The median PFS was 17.9 vs. 7.06 months (mo) in the pts with high ALK rearrangement than low (HR: 0.43, 95% CI 0.24-0.76, p 0.004). The median OS was also significant longer in high ALK rearrange group (44.6 mo vs. 16.8 mo; HR: 0.37, 95% Cl 0.1883-0.7315; p 0.004). The intracranial progression during crizotinib treatment was significantly frequent in the pts with high ALK rearrangement (62.5-32.5%, P 0.039) DISCUSSION: In this study, we found that the high break-apart ratio can predict the extent of benefit from targeted therapy in ALK-positive NSCLC patients. Based on the results of this study, the percentage of the ALK rearrangement can be used to predict treatment outcome and to choose the optimal targeted agent in the treatment of metastatic ALK-positive NSCLC.

Real-life comparison of the afatinib and first-generation tyrosine kinase inhibitors in nonsmall cell lung cancer harboring EGFR exon 19 deletion: a Turk Oncology Group (TOG) study.

BACKGROUND: The new second-generation tyrosine kinase inhibitors (TKIs) have superior survival outcome and worse toxicity profile when compared with first-generation TKIs according to the results of clinical trials. However, there are limited studies that investigate the efficacy and safety of the new generation TKIs in real-world patients. Thus, we aimed to compare the efficacy and safety of the afatinib, an irreversible inhibitor of ErbB family receptor, and first-generation TKIs in real-world patients. MATERIALS AND METHODS: We included advanced nonsmall cell lung cancer (NSCLC) patients who had EGFR exon 19del mutation and treated with afatinib or first-generation TKIs as upfront treatment between 2016 and 2020. All patient's information was collected retrospectively. The study cohort was divided as afatinib arm and erlotinib/gefitinib arm. RESULTS: A total of 283 patients at the 24 oncology centers were included. The 89 and 193 of whom were treated with afatinib and erlotinib/gefitinib, respectively. After 12.9 months (mo) of follow-up, the median PFS was statistically longer in the afatinib arm than erlotinib/gefitinib arm (19.3 mo vs. 11.9 mo, p: 0.046) and the survival advantage was more profound in younger patients (< 65 years). The 24-mo overall survival rate was 76.1% and 49.5% in the afatinib arm and erlotinib/gefitinib arm, respectively. Although all-grade adverse event (AE) rates were similar between the two arms, grade 3-4 AE rates were higher in the afatinib arm (30.7% vs. 15.2%; p: 0.004). DISCUSSION: In our real-world study, afatinib has superior survival outcomes despite worse toxicity profile as inconsistent with clinical study results and it is the good upfront treatment option for younger patients and elderly patients who have good performance status.

The association of clinicopathologic features and peripheral blood parameters with high PD-L1 expression in non-small cell lung cancer.

INTRODUCTION: Programmed death ligand 1 (PD-L1) is a marker that widely used for prediction of response to immunotherapy. Dynamic alteration of PD-L1 expression are the major problems for reflection of the actual status of the PD-L1. So, we aimed to investigate the factors that may be associated with PD-L1 expression in lung cancer. MATERIALS AND METHODS: The patients diagnosed with non-small cell lung cancer were enrolled, retrospectively. The patients were stratified according to PD-L1 expression level as ≥ 50% and < 50%. RESULT: Totally, 217 patients were enrolled. The clinicopathologic features were similar between two groups, except the amount of cigarette consumption. Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and systemic immune-inflammmotry index were found significantly lower in PD-L1 ≥ 50% (p< 0.001, p= 0.006 and p= 0.003, respectively) and also negatively correlated with PD-L1 level (rho= -0.255, p< 0.001; rho= -0.17, p= 0.013; rho= - 0.185, p= 0.006, respectively). CONCLUSIONS: According to the results of our study, peripheral blood parameters can be used to the prediction of the high PD-L1 expression and can be used for reflection of current PD-L1 expression.

A historical turning point for the treatment of advanced renal cell carcinoma: inhibition of immune checkpoint.

Background: Renal cell carcinoma (RCC) is the most common type of renal malignancy with 87% frequency. As a global health problem, kidney cancer is responsible for 2.2% of new cancer cases. One of the highly effective mechanisms that renal cancer cells avoid in the immune system is PD-1 and PD-L1 interaction.Scope: Literature search is made from PubMed, Medline, and ASCO and ESMO Annual Meeting abstracts using the following search keywords: "nivolumab," "pembrolizumab," "atezolizumab," "avelumab," "durvalumab," and "renal cell cancer." The last search was on November 1, 2019.Findings: The combination of nivolumab and ipilimumab have better survival results than sunitinib for intermediate and poor risk patients but not for favorable risk groups. In 2019, two combination regimens with pembrolizumab plus axitinib and avelumab plus axitinib demonstrated efficacy over sunitinib for every risk group. The overall survival data of these trials are still immature.Conclusions: Advanced RCC has high morbidity and mortality with an increasing prevalence. Following tyrosine kinase inhibitors, checkpoint inhibitors have a great influence on treatment of advanced RCC, especially the combination of these two strategies. In 2019 these combined strategies demonstrated 5% complete remission with up to 60% objective response rate. While not immediately, but perhaps in the near future, advanced RCC will become a manageable chronic disease, even if a cure is not possible.

Prognostic effect of red cell distribution width-to-platelet ratio in colorectal cancer according to tumor stage and localization.

INTRODUCTION: Colorectal cancer (CRC) is one of the most common cancers worldwide and survival is still approximately 24 months. Recently, importance of the molecular features, tumor localization, and also inflammatory status is increased, and most of these entities can be used as a predictive marker for colon tumor. However, since most of these tests are expensive and unachievable, there is a need for new prognostic and predictive markers that can be used easily and are inexpensive. AIM: We aimed to investigate the prognostic effect of red cell distribution width (RDW)-to-platelet ratio (RPR) which reflects inflammatory status and can be calculated basically by using center blood count (CBC) parameters on CRC according to tumor stage and localization. METHODS: Newly diagnosed 312 CRC patients between 2010 and 2016 were retrospectively analyzed. Patients' demographics, including survival data and tumor characteristics, were obtained from medical charts. RPR was calculated using CBC parameters at the time of diagnosis. Cutoff value for RPR was set at 0.05 and the patient population was divided into two arms (arm A: RPR ≥0.05 and arm B: RPR <0.05). The patients were stratified according to the tumor stage (early and advanced disease) and tumor localization (right sided and left sided). RESULTS: Totally, 312 patients were enrolled to the study. Nearly 81.9% of the patients were at early stage and 18.1% were at advanced stage at the time of diagnosis. In patients with early-stage disease, no significant disease-free survival and overall survival (OS) was found in both arms (P = 0.88 and P = 0.085, respectively). In arm A, OS was nonsignificantly better in the entire and left-sided advanced tumor compared to arm B. In patients with right-sided advanced cancer, OS was statistically significantly better for arm A compared to arm B (median OS; RPR ≥0.05: 24.8 months vs. <0.05: 13.9 months; P = 0.035). DISCUSSION: RPR can be a useful prognostic marker in CRC, especially in right-sided advanced tumors. CONCLUSION: RPR can be used as a prognostic marker in CRC but should be validated with further investigation.

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer.

BACKGROUND: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. SCOPE: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017. FINDINGS: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment. CONCLUSION: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.

Thrombotic thrombocytopenic purpura following salvage chemotherapy with paclitaxel, ifosfamide and cisplatin in a patient with a refractory germ cell tumor: A case report and review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy that is characterized by microvascular thrombosis, thrombocytopenia, hemolysis and end organ damage. An extensive variety of drugs, including certain chemotherapeutic agents, have been associated with TTP. However, paclitaxel, cisplatin and ifosfamide regimen (TIP)-induced TTP has not previously been described. The present study reports the case of a 43-year-old patient with a refractory testicular germ cell tumor who developed acute TTP during TIP chemotherapy. Following the third cycle of TIP chemotherapy, the patient developed fever, anemia, thrombocytopenia and confusion. A diagnosis of TTP was established. Plasmapheresis was initiated as daily treatment in the first week, then continued every other day for 4 weeks. TIP chemotherapy was discontinued. The patient's clinical and neurological symptoms improved markedly after a week. Renal function and hemolysis improved, and the patient was discharged in a stable condition. The patient did not develop any complications and has been in remission for 5 months. The Naranjo adverse drug reaction probability scale indicated a likely association between TTP and the TIP chemotherapy regimen in this patient. This case is also investigated with regard to the associated literature to increase the awareness of TTP following chemotherapy.

Clinical Significance of HER2 Overexpression in Gastric and Gastroesophageal Junction Cancers.

BACKGROUND: In this study, we investigated the rate of human epidermal growth factor receptor 2 (HER2) overexpression in gastric (GC) and gastroesophageal junction cancers (GEJCs) and the relationship with HER2 expression and clinical, pathological parameters and prognosis. METHODS: Surgery or biopsy specimen of 598 (436 males, 162 females) patients with GC or GEJC was evaluated for the presence of HER2 overexpression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. RESULTS: HER2 IHC scores were as follows: 418 (69.9%) IHC 0, 58 (9.7%) IHC 1+, 50 (8.4%) IHC 2+, 72 (12%) IHC 3+. Among 50 patients with IHC 2+, 18 (38.2%) were FISH positive, and 29 (61.7%) were FISH negative for HER2 amplification. Patients were regarded as HER2 positive in case of IHC 3+ disease or IHC 2+ disease with a positive FISH test result for HER2 amplification. In the primary analysis population, 90 (15%) were considered HER2 positive. HER2 positivity was higher in intestinal GC compared to diffuse GC (16.9 vs 6.6%, p = 0.014). HER2 positivity was significantly higher in well and moderately differentiated tumors than poorly differentiated tumors (p < 0.0001). HER2 positivity had no significant effect on median OS (23.2 vs 19.1 months, p = 0.44). But in the early stages (stages I and II), median OS of HER2-positive patients was shorter than HER2-negative patients (51.4 months vs not reach, p = 0.047). However, median OS was similar in patients with advanced stages (stages III and IV) HER2-positive and HER2-negative disease (16.2 vs 13.7 months, p = 0.72). CONCLUSIONS: Rate of HER2 positivity is similar in Turkish patients with GC and GEJCs. HER2 positivity is associated with poor prognosis in patients with early-stage disease.