Anastasia Laudisi

Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study

Although surgical resection is considered the adequate treatment in early stages of nonsmall cell lung cancer, long‐term survival is not satisfactory and recurrence rate is high. We previously showed that postoperative chemotherapy at stage IB reduces recurrences and prolongs overall survival. We extended size and observation period of the study sample and performed a separate analysis for minimally resected patients. The trial was designed as a randomized, 2‐armed study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure (defined as anatomical or minimal). Chemotherapy consisted of cisplatin (100 mg/m2 day 1) and etoposide (120 mg/m2 days 1–3) for 6 cycles. The primary endpoint was overall survival; secondary endpoint was disease‐free survival (DFS). One hundred and forty patients entered the study: 70 were assigned to the adjuvant chemotherapy group and 70 to the control group. Groups were homogeneous for conventional risk factors. There was no clinically significant morbidity associated to chemotherapy. Patients were followed for a mean period of 40.31 ± 30.86 months. A significant difference in overall (p = 0.02) and disease‐free (p = 0.0001) survival was observed between patients undergoing adjuvant chemotherapy vs. control group. Adjuvant chemotherapy significantly improved both overall (p = 0.02) and DFS (p = 0.003) of anatomically resected patients, but only the DFS (p = 0.02) of minimally resected patients. Our results confirm that adjuvant chemotherapy may have a real impact on long‐term survival in patients with stage IB nonsmall cell lung cancer being this effect especially evident for those anatomically resected.

Impact of chemotherapy on activated protein C-dependent thrombin generation—Association with VTE occurrence

Chemotherapy has been associated with an increased risk of venous thromboembolism (VTE). However, the prevalence of coagulation abnormalities or VTE occurrence as a consequence of different anti‐cancer agents or treatment schemes is largely uncharacterized. Thus, this study was aimed at analyzing the impact of different anticancer drugs on the prothrombotic status of cancer out‐patients scheduled for chemotherapy. To this purpose, a mono‐institutional study was prospectively conducted to monitor serial changes of activated protein C (APC) function in 505 consecutive cancer out‐patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. The results obtained showed that age >65 years (p = 0.01), ECOG performance status (p = 0.01), platinum‐based (p = 0.035) and fluoropyrimidine‐based regimens (p = 0.008) were independent predictors of an acquired APC resistance during the first chemotherapy cycle. Multivariate model of Cox proportional hazards survival analysis demonstrated that a decline in APC functionality (HR = 2.4; p = 0.013) and platinum‐based regimens (HR = 2.2; p = 0.042) were both capable of predicting the occurrence of a first VTE episode during chemotherapy. Indeed, 14% of patients with platinum‐associated APC impairment had VTE over a 1‐year follow‐up, compared to 3% of patients treated with other regimens and in whom APC functionality remained stable (HR = 1.5; p = 0.003). We may, thus, conclude that use of platinum‐based regimens is responsible for induction of an acquired thrombophilic condition and represents a predictor for VTE even after adjustment for other risk factors.

Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer

INTRODUCTION Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients. PATIENTS AND METHODS PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status. RESULTS No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p=0.002), particularly in patients with large tumors (p<0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p<0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p=0.02). CONCLUSIONS We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.

An activated protein C-dependent thrombin generation assay predicts chemotherapy-associated venous thromboembolism in cancer patients.

An activated protein C-dependent thrombin generation assay predicts chemotherapy-associated venous thromboembolism in cancer patients -

TNF-α gene promoter polymorphisms and risk of venous thromboembolism in gastrointestinal cancer patients undergoing chemotherapy

BACKGROUND TNF-α has been proposed as a predictive factor for venous thromboembolism (VTE). Genetic polymorphisms could regulate TNF-α production. However, the relationship between TNFA gene variants and VTE is not clarified. This study aims to investigate the predictive role of five different TNFA gene promoter SNPs, or their haplotype combination(s), for a first VTE episode in gastrointestinal cancer out-patients treated with chemotherapy. PATIENTS AND METHODS Serum TNF-α levels and TNFA -863C/A, -857C/T, -376G/A, -308G/A and -238G/A gene promoter polymorphisms were retrospectively evaluated in 314 subjects, including 157 controls and 157 Caucasian patients with histologically diagnosed GI cancers beginning chemotherapy delivery (5-fluorouracil either as monotherapy or in combination with platinum compounds or irinotecan). RESULTS Haplotype analysis showed that a five-loci haplotype (CTGGG haplotype) has higher frequency in GI cancer patients who developed VTE (n = 15) during chemotherapy [odds ratio = 2.7, 95% confidence interval (CI) 1.04-7.11, P = 0.04]. GI patients who remained VTE-free did not differ in CTGGG haplotype frequency from controls. No association was observed between serum TNF-α levels and TNFA haplotype, but both were independent predictors of VTE. Approximately 20% of GI cancer patients carrying the CTGGG haplotype developed VTE compared with 4% of the remaining 101 patients (hazard ratio = 5.6, 95% CI 1.8-17.6, P = 0.003). CONCLUSION These results suggest that TNFA might represent a candidate gene contributing to VTE pathogenesis in GI cancer patients and suggest that VTE risk during chemotherapy might be genetically identified. Validation studies are needed for translation into clinical practice.

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients—a pilot study

PurposeIdentifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification.MethodsA retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen.ResultsRetrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10–0.19; p < 0.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12–0.52, p < 0.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group.ConclusionsWe may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.

Estimated Glomerular Filtration Rate Is an Easy Predictor of Venous Thromboembolism in Cancer Patients Undergoing Platinum-Based Chemotherapy

Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy. Methods. Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population. Results. Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values. Conclusion. The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.

Prognostic Significance of Neutrophil–to–lymphocyte Ratio in the Framework of the 8th TNM Edition for Breast Cancer

Background/Aim: To investigate whether neutrophil–to–lymphocyte ratio (NLR) might represent an additional biological criterion able to identify patients with worse prognosis within the 8th edition TNM prognostic staging system for breast cancer (BC). Patients and Methods. Pre-treatment NLR was retrospectively analyzed in 475 BC women prospectively followed for a mean time of 3.8 years. The optimal NLR cutoff, identified by ROC analysis, was set at 2. Results: Elevated pre-treatment NLR was associated with worse disease-free survival (DFS) (HR=2.28) and overall survival (OS) (HR=3.39). The prognostic value of NLR was mostly evident in stage I BC (HR for DFS=2.89; HR for OS=1.30), in whom NLR significantly stratified patients who developed distant metastasis (HR= 4.62), but not local recurrence. Conclusion: NLR might provide important information in risk stratification, especially in stage I BC patients in whom the presence of a high NLR might raise the question as to whether they should be more aggressively managed.

BMI and health-related quality of life (HR-QoL) in patients with metastatic colorectal cancer (mCRC).

249Background: Relationship between BMI and HR-QoL has been extensively studied in CRC survivors. Increasing BMI has been recently associated with improved survival in mCRC pts, however data on the relationship between BMI and common HR-QoL measures in mCRC are scarce Methods: The EORTC QLC C30 and the NCCN distress thermometer (DT) and problem list (PL) questionnaires were administered to consecutive mCRC pts candidate for firstline chemotherapy. The effect of BMI on HR-QoL were analyzed using the Kruskal-Wallis and Mann-Whitney tests. The interaction between BMI and other variables of interest (such as inflammatory indexes) for the effect on HR-QoL was also analysed using a logistic regression analysis Results: Of 135 screened pts, 119 completed the questionnaires. A direct association was observed between BMI and GH score, with the score gradually improving from BMI 14 to 21, then plateauing between 21 and 41. A significantly lower GH was observed for BMI 21 (GH 50 vs 67, p 0.014). DT and BMI...