Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer.

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.

Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group.

BACKGROUND: Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer. METHODS: Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m-2 followed by four cycles of docetaxel 75 mg m-2 (sequential regimen) or six cycles of epirubicin 75 mg m-2 plus docetaxel 75 mg m-2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990-2.556; P=0.055). Toxicity included grade 2-4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths. CONCLUSIONS: Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.

Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study.

BACKGROUND: In this superiority study, pemetrexed was compared with erlotinib in pre-treated patients with metastatic non-small cell lung cancer (NSCLC). METHODS: Patients with stage IIIB/IV NSCLC who progressed after first-line or second-line treatment were randomized to receive either pemetrexed or erlotinib. In total, 21.7% of patients in the pemetrexed arm and 23.5% of patients in the erlotinib arm had squamous cell histology, and treatment was third line in 39.2% and 46.4% of patients, respectively. The primary study endpoint was time to tumor progression (TTP). Epidermal growth factor receptor/v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (EGFR/KRAS) mutation status also was investigated. RESULTS: There was no difference in terms of the TTP (P = .195), the objective response rate (P = .469), or overall survival (P = .986) between the 2 treatment arms. In patients who had squamous cell histology, erlotinib resulted in a superior TTP compared with pemetrexed (4.1 months vs 2.5 months, respectively; P = .006). The incidence of grade 3 and 4 neutropenia, thrombocytopenia, and asthenia was significantly higher in the pemetrexed arm, whereas the incidence of grade 3 and 4 skin rash was higher in the erlotinib arm. CONCLUSIONS: Both pemetrexed and erlotinib had comparable efficacy in pre-treated patients with metastatic NSCLC, and the current results indicated that genotyping of tumor cells may have an important effect on treatment efficacy.

Overcoming phenotypic switching: targeting protein-protein interactions in cancer.

Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.

Sentinel Lymph Node Staging in Early-Stage Cervical Cancer: A Comprehensive Review.

Cervical cancer (CC) continues to be a significant global public health concern, even with preventive measures in place. In women with early-stage CC, the status of lymph nodes is of paramount importance, not only for the final prognosis but also for determining the best therapeutic strategy. According to main international guidelines, pelvic full lymphadenectomy (PLND) is recommended for lymph node staging. However, in these early stages of CC, sentinel lymph node biopsy (SLNB) has emerged as a precise technique for evaluating lymph node involvement, improving its morbidity profile. We performed a literature review through PubMed articles about progress on the application of SLNB in women with early-stage CC focusing on the comparison with PET/CT and PLND in terms of oncological outcomes and diagnostic accuracy. While the superiority of SLNB is clear compared to radiologic modalities, it demonstrates no clear oncologic inferiority over PLND, given the higher detection rate of positive lymph nodes and predominance of no lymph node recurrences. However, due to a lack of prospective evidence, particularly concerning long-term oncological safety, SLNB is not the current gold standard. With careful patient selection and adherence to straightforward protocols, a low false-negative rate can be ensured. The aim of the ongoing prospective trials is to address these issues.

Real-world Data and Economic Evaluation of Nivolumab in Previously Treated Non-small Cell Lung Cancer Greek Patients.

BACKGROUND/AIM: Nivolumab is an FDA-approved immune checkpoint inhibitor (ICI) for patients with advanced, pre-treated non-small cell lung cancer (NSCLC). However, treatment profiles and patient outcomes often differ in routine clinical practice while the financial impact of approved therapies is largely unknown. In this study, we investigated the efficacy, tolerability, and economic impact of nivolumab in real-world settings (RWS) in Greece. PATIENTS AND METHODS: Patients diagnosed with advanced pre-treated NSCLC, receiving nivolumab were recruited from October 2015 until November 2019 across 18 different clinical centers in Greece. Endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Cost analysis was conducted using a third-party public-payer perspective (National Organization for Healthcare Services Provision; EOPYY). RESULTS: A total of 346 patients, median age 66.5 years, were included. With 43.4 months median follow-up, median PFS was 7.8 months and median OS 15.8 months. The 1-year OS rate was 56.5%, 2-year OS 38.8%, and 3-year OS 27.3%. The ORR was 29.5% and DCR 58.7%, with a median response duration of 26.8 months. Patients with objective response were more likely to experience long-term survival (HR=0.14, p<0.001). Only 8.4% of patients experienced grade 3-4 adverse events. The presence of immune-related adverse events was associated with improved OS (HR=0.77, p=0.043). Nivolumab-associated economic burden accounted for €2,214.10 per cycle for each patient, mainly attributed to drug-acquisition costs. CONCLUSION: This is the first report of real-world efficacy, safety, and economic burden of nivolumab in pre-treated patients with NSCLC in Greece. Indirectly compared to clinical trials, nivolumab was associated with improved efficacy in RWS, further supporting its use in clinical practice and providing insights on clinical prognosticators. The main cost component affecting the nivolumab economic burden was drug-acquisition costs, while toxicity-associated cost was negligible.

Anticoagulation for atrial fibrillation in active cancer.

Atrial fibrillation (AF) may often pre-exist in patients with newly diagnosed cancer or occur with increased frequency shortly after cancer diagnosis. Patients with active cancer and AF have a particularly high risk of thromboembolic complications, as both conditions carry a risk of thrombosis. Thromboembolic risk is determined by several factors, including advanced age, sex (females), cancer histology (adenocarcinomas), location (e.g., pancreas, stomach), advanced stage, anticancer regimens (e.g., platinum compounds, anti-angiogenic therapies, immune modulators), comorbidities (e.g., obesity, kidney disease) and concurrent therapies (e.g., surgery, central catheters). Physicians are often reluctant to prescribe anticoagulants to patients with active cancer and AF, mainly due to fear of bleeding complications, which is partly related to the paucity of evidence in the field. Decision making regarding anticoagulation for the prevention of ischemic stroke and systemic embolism in patients with active cancer and AF may be challenging and should not simply rely on the risk prediction scores used in the general AF population. By contrast, the administration and choice of anticoagulants should be based on the comprehensive, individualized and periodic evaluation of thromboembolic and bleeding risk, drug-drug interactions, patient preferences and access to therapies.

A Multicenter, Prospective, Observational Study to Assess the Clinical Activity and Impact on Symptom Burden and Patients' Quality of Life in Patients with Advanced Soft Tissue Sarcomas Treated with Trabectedin in a Real-World Setting in Greece.

This non-interventional, multicenter, prospective study aimed to evaluate the real-world activity of trabectedin, and its impact on symptom burden and quality of life in patients with advanced soft tissue sarcoma (aSTS) treated in routine clinical settings in Greece. Patients with histologically confirmed aSTS newly initiated on trabectedin were enrolled. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS rate at 3 months, median PFS, objective response rate (ORR), disease control rate (DCR), overall survival (OS), and an assessment of the impact of treatment on health-related quality of life (HRQoL), cancer-related symptom burden and symptom interference with function, as well as all-cause treatment discontinuation rate. A total of 64 eligible patients from 13 Greek centers were evaluated. Patients received a median of three trabectedin cycles per patient (interquartile range [IQR]: 2.0-6.0). Median PFS was 6.6 months with 67.9% and 51.2% of patients free from progression at 3 and 6 months, respectively. ORR was 7.8% and DCR 21.9%. Median OS was 13.1 months. No significant changes from enrolment were noted in HRQoL scores. In total, 30 patients (46.9%) had at least one trabectedin-related adverse drug reaction (ADR) and 9 (14.1%) at least one serious ADR. The treatment discontinuation rate due to toxicity was 9.4%. These results suggest that trabectedin is an active treatment with clinically meaningful benefits in patients with aSTS with no new safety signals.

Cost-effectiveness of trifluridine/tipiracil as a third-line treatment of metastatic gastric cancer, including adenocarcinoma of the gastrohesophageal junction, among patients previously treated in Greece.

OBJECTIVE: To evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) compared with best supportive care (BSC) for the treatment of patients with metastatic gastric cancer(mGC), including gastroesophageal junction adenocarcinoma(GEJ), who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, in Greece. METHODS: A partitioned survival model was locally adapted from a public payer perspective over a 10-year time horizon. Clinical, safety and utility data were extracted from literature. Resource consumption data obtained from a panel of local experts using a questionnaire developed for the study was combined with unit costs obtained from official sources. All costs reflect the year 2020 (€). Outcomes of the model were patients' life years (LYs) and quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratio (ICER) per QALY and LY gained. RESULTS: The total cost per patient was estimated to be €6,965 for FTD/TPI and €1,906 for BSC, while FTD/TPI was associated with 0.180 and 0.107 increments in LYs and QALYs, respectively, compared with BSC, resulting in an ICER of €47,144 per QALY gained and €28,112 per LY gained. CONCLUSION: FTD/TPI was estimated to be a cost-effective treatment option for eligible third line mGC patients, including GEJ in Greece.

Prophylaxis of cancer-associated venous thromboembolism with low-molecular-weight heparin-tinzaparin: Real world evidence.

Thromboprophylaxis, as a preventive measure for cancer-associated thrombosis (CAT), may be beneficial for patients with active cancer and high-risk for thrombosis. The present post hoc analysis include a total of 407 patients enrolled in the Greek Management of Thrombosis study, who received thromboprophylaxis with tinzaparin. The objectives of the present analysis were: i) To obtain sufficient evidence for the administration of prophylaxis in patients with active cancer, irrespective of Khorana risk assessment model score; ii) to identify the selection criteria for both dose and duration of tinzaparin; and iii) to evaluate the efficacy and safety of tinzaparin administered for CAT prophylaxis. The main tumor types for the patients included in the present study were as follows: Lung (25.1%), pancreatic (14.3%), breast (9.1%), stomach (8.4%), colorectal (7.9%) and ovarian (7.6%). Furthermore, metastatic disease was observed in 69.5% of the patients. High thrombotic burden agents (HTBAs) were administered to 66.3% of the patients, and 17.4% received erythropoietin. A total of 43.7% of the patients exhibited a Khorana score <2. The results of the present study demonstrated that both the presence of metastatic disease and the use of HTBAs seemed to influence oncologists' decisions for the use of thromboprophylaxis in patients with active cancer, regardless of Khorana score. Tinzaparin, in dose expressed in the standard notation for heparins, i.e., anti-Xa factor international units (Anti-Xa IU), was administered at an intermediate dose (InterD; 8,000-12,000 Anti-Xa IU; once daily) to 52.4% of patients, while the remaining patients received a prophylactic dose (ProD; ≤4,500 Anti-Xa IU; once daily). The average duration of thromoprophylaxis was 5 months. Furthermore, a total of 14 (3.4%) thrombotic events and 6 (1.5%) minor bleeding events were recorded. A total of four thrombotic events were observed following an InterD treatment of tinzaparin, while 10 thrombotic events were observed following ProD treatment. The present study also demonstrated that an InterD of tinzaparin was administered more frequently to patients with a body mass index >30 kg/m2, a history of smoking and a history of metastatic disease, along with administration of erythropoietin. InterD tinzaparin treatment was found to be potentially more efficacious and without safety concerns. The present study is a registered clinical trial (ClinicalTrials.gov code, NCT03292107; registration date, September 25, 2017).

The Impact of Thromboprophylaxis on the Survival of Patients with Advanced Pancreatic Cancer. The Pancreatic Cancer and Tinzaparin (PaCT) Study.

Pancreatic cancer (PaC) induces a prothrombotic and hypercoagulable state. The aim of this study was to investigate the effect of tinzaparin in combination with chemotherapy. The PaCT (pancreatic cancer and tinzaparin) study was a retrospective observational study that collected data regarding progression free survival (PFS) in advanced or metastatic PaC patients who received thromboprophylaxis with tinzaparin during chemotherapy with nab-paclitaxel (N) and gemcitabine (G). The primary end point was to compare, from already published data, the PFS of patients receiving thromboprophylaxis with tinzaparin with the PFS of patients receiving chemotherapy with N-G but no thromboprophylaxis. Secondary end points were efficacy and safety of anticoagulation. In total, 110 PaC patients, 93% with advanced or metastatic disease, treated with N-G and tinzaparin (10,291 ± 1176 Anti-Xa IU, OD, median duration 8.7, IQR: 5.6-11.9 months) were enrolled. Of these, 52% were males and; the median age was 68 (40-86 years). The tumor was located to in the pancreatic head at in 45% of the patients. The median PFS was 7.9 months (IQR: 5.0-11.8 months). Out of 14 similar studies (involving 2994 patients) identified via systematic search, it was determined that the weighted PFS of patients receiving N-G but no anticoagulation was 5.6 months. Therefore, patients receiving tinzaparin had 39.54% higher PFS than patients without thromboprophylaxis (p < 0.05). During the follow-up period of 18.3 ± 11.7 months, three (2.7%) thrombotic events were recorded while two clinically relevant non-major bleeding events occurred (1.9%). In conclusion, PFS in advanced PaC patients undergoing chemotherapy is positively impacted by anticoagulation. Thromboprophylaxis with tinzaparin in treatment dose is efficient and safe.

An Observational Study to Assess the Molecular Epidemiology and Direct Medical Costs of Epidermal Growth Factor Receptor (EGFR) Mutations in Patients with Advanced EGFR Mutation-Positive Non-Small Cell Lung Cancer Treated with Afatinib in Real-World Clinical Settings in Greece.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking. MATERIALS AND METHODS: This was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered. RESULTS: A total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37-91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9-51.4), the median PFS was 14.3 months (95% CI 12.2-16.4), and the median OS was 29 months (95% CI 25.6-33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5-18.5) and 28.1 months (95% CI 21.1-32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs. CONCLUSION: Long-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04640870.

FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG).

A randomized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer. Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were randomized to receive either 4 cycles of docetaxel (100 mg/m(2)) followed by 4 cycles of epirubicin (75 mg/m(2)) plus cyclophosphamide (700 mg/m(2)) (experimental arm) or 6 cycles of FEC (epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2), and 5-fluorouracil 700 mg/m(2); control arm). All regimes were administered every 3 weeks. The primary end point was five-year disease-free survival (DFS). After a median follow-up period of 5 years, 233 (30.8%) relapses had occurred (108 and 125 in the experimental and control arms, respectively; P = 0.181). The five-year DFS was 72.6% (95% CI 63.8-81.3%) and 67.2% (95% CI 58.0-76.4%) for women randomized in the experimental and control arms, respectively (P = 0.041; log rank test). There was no difference in the overall survival between the two arms (83.8 and 81.4% in the experimental and control arms, respectively; P = 0.533). The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5% of the patients as compared with 74.1% in the control arm (P = 0.0001). The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen resulted in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity.

Non-platinum-based first-line followed by platinum-based second-line chemotherapy or the reverse sequence in patients with advanced non-small cell lung cancer: a retrospective analysis by the lung cancer group of the Hellenic Oncology Research Group.

BACKGROUND: Non-platinum-containing regimens have been proposed as alternatives to platinum-based doublets in the first-line treatment of patients with non-small cell lung cancer (NSCLC). However, conflicting results about their equivalence have been reported. METHODS: We reviewed the records of patients enrolled in randomized controlled first-line trials conducted by the Hellenic Oncology Research Group from February 1997 to September 2006. The outcome of patients treated with first-line non-platinum-based chemotherapy who received platinum-based chemotherapy upon progression (cohort A) or platinum-based first-line chemotherapy followed by non-platinum-containing second-line chemotherapy (cohort B) was retrospectively analyzed. RESULTS: Two-hundred and sixty-seven patients were identified in cohort A, and 123 in cohort B. Median follow-up time was 12.5 and 15.7 months for cohorts A and B. A significantly higher response rate and time to tumor progression (TTP) was recorded for patients treated with platinum-based compared to those receiving non-platinum-based first-line chemotherapy (45.5 vs. 21.3%, p < 0.0001 and 5.8 vs. 3.1 months, p= 0.002, respectively). Platinum-based regimens administered as second-line treatment resulted in a 13.1% response rate. TTP for second-line chemotherapy did not differ significantly between the two cohorts. Median overall survival was 13.3 and 15.7 months for cohorts A and B (p = 0.538). CONCLUSION: Both sequences resulted in similar efficacy in terms of overall survival. Encouraging median survival was achieved for selected patients with NSCLC who received both first- and second-line chemotherapy.

Myelotoxicity of oral topotecan in relation to treatment duration and dosage: a phase I study.

Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m(2) for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m(2) and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m(2) daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m(2) for 3 days, 2.0 and 2.3 mg/m(2) for 4 days, and 2.3 mg/m(2) for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46-77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m(2) for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m(2) 3-day treatment developed grade 3-4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m(2) developed grade 3-4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3-4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m(2) for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m(2) for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m(2).

Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas.

Immune checkpoint inhibitors have revolutionized cancer treatment in the last decade. Despite the progress in immunotherapy, most pancreatic cancer patients still do not derive benefit when receiving immune-based therapies. Recently, resistance mechanisms to immune therapies have been mainly focused on tumor microenvironment properties. Pancreatic cancer is considered one of the most lethal and difficult to treat tumors due to its highly immunosuppressive and desmoplastic microenvironment. Low molecular weight heparins (LMWHs) have been used for the treatment and prevention of thromboembolic disease in these patients. However, many nonanticoagulant properties attributed to LMWHs have been described. Exploiting LMWH properties in a combined treatment modality with immune checkpoint inhibition and chemotherapy could provide a new approach in the management of pancreatic adenocarcinoma patients. The ability of LMWH to interfere with various aspects of the tumor microenvironment could result in both the alleviation of immunosuppression and improvement in drug delivery within the tumor, leading to higher cancer cell destruction rates and more potent immune system activity that would, ultimately, lead to better patient outcomes.

Real-World Data on Thromboprophylaxis in Active Cancer Patients: Where Are We? Are We Getting There?

Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m2) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding events were recorded. Notably, patients on higher doses of LMWHs compared to patients who received standard prophylactic doses had 70% lower odds to develop thrombotic events (OR: 0.3, 95% CI: 0.10-1.0, p = 0.04). Conclusion: CAT is an important issue in oncology. Along with the Khorana score, factors as metastasis and use of HTRCAs should also be taken into consideration. Thromboprophylaxis for active cancer patients with LMWHs, even on higher doses is safe and efficient.

Management of Cancer-associated Thrombosis (CAT): Symptomatic or Incidental.

BACKGROUND: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. PATIENTS AND METHODS: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. RESULTS: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m2), trauma history, renal insufficiency and bevacizumab use. CONCLUSION: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.

Clinical feasibility of NGS liquid biopsy analysis in NSCLC patients.

BACKGROUND: Analysis of circulating tumor nucleic acids in plasma of Non-Small Cell Lung Cancer (NSCLC) patients is the most widespread and documented form of "liquid biopsy" and provides real-time information on the molecular profile of the tumor without an invasive tissue biopsy. METHODS: Liquid biopsy analysis was requested by the referral physician in 121 NSCLC patients at diagnosis and was performed using a sensitive Next Generation Sequencing assay. Additionally, a comparative analysis of NSCLC patients at relapse following EGFR Tyrosine Kinase Inhibitor (TKIs) treatment was performed in 50 patients by both the cobas and NGS platforms. RESULTS: At least one mutation was identified in almost 49% of the cases by the NGS approach in NSCLC patients analyzed at diagnosis. In 36 cases with paired tissue available a high concordance of 86.11% was observed for clinically relevant mutations, with a Positive Predictive Value (PPV) of 88.89%. Furthermore, a concordance rate of 82% between cobas and the NGS approach for the EGFR sensitizing mutations (in exons 18, 19, 21) was observed in patients with acquired resistance to EGFR TKIs, while this concordance was 94% for the p.T790M mutation, with NGS being able to detect this mutation in three 3 additional patients. CONCLUSIONS: This study indicates the feasibility of circulating tumor nucleic acids (ctNA) analysis as a tumor biopsy surrogate in clinical practice for NSCLC personalized treatment decision making. The use of new sensitive NGS techniques can reliably detect tumor-derived mutations in liquid biopsy and provide clinically relevant information both before and after targeted treatment in patients with NSCLC. Thus, it could aid physicians in treatment decision making in clinical practice.

Gemcitabine plus oxaliplatin (GEMOX) in pretreated patients with advanced ovarian cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

The aim of this study was to evaluate the safety and activity of a gemcitabine-oxaliplatin combination (GEMOX) regimen in pretreated patients with advanced ovarian cancer. Twenty-seven platinum-refractory/resistant and 14 platinum-sensitive patients received gemcitabine 1500 mg/m2 intravenously in days 1+8 and oxaliplatin 130 mg/m2 in day 8 every 21 days. Ten responses (one complete, nine partial) were observed; five in platinum-sensitive and five in platinum-resistant tumors. Grade 3-4 neutropenia and thrombocytopenia were observed in 17 and 10 patients, respectively. There were two treatment-related deaths due to thrombocytopenia and non-neutropenic sepsis. The GEMOX regimen has moderate activity in both platinum-sensitive and resistant ovarian cancer and a toxicity profile that can be significant and therefore requires careful monitoring.