Patrizia Farina

Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature.

Treatment with angiogenesis inhibitors is becoming a cornerstone of modern anticancer therapy. Hypertension (HTN) is a common adverse event during antiangiogenic treatment and might represent a cancer biomarker in patients with recurrent glioblastoma treated with angiogenesis inhibitors. In a retrospective study, we analyzed 53 patients with recurrent glioblastoma treated with antiangiogenic drugs. Thirty patients were treated with sorafenib and 23 patients were treated with bevacizumab. All patients underwent brain gadolinium-enhanced MRI assessments according to the Radiologic Assessment in Neuro-Oncology criteria every 2 months or when clinically indicated. Blood pressure was measured before and during the treatment. We investigated whether treatment-related HTN may be associated with outcome in patients treated with antiangiogenic drugs. After 2 months of treatment, 24 patients (45%) achieved disease control: stable disease (17 patients) or a partial response (seven patients). The median overall survival from the start of antiangiogenic treatment was 7.3 months [95% confidence interval (CI) 6.02–8.5]; the median progression-free survival (PFS) was 2.7 months (95% CI 1.5–3.5); and the 6-month PFS was 32%. Twenty patients (38%) developed grades 2–3 HTN within 2 months of treatment. A significant association was found between HTN and disease control rate, and HTN and 6-month PFS; no significant association was found between HTN and the median PFS. According to univariate and multivariate analyses, HTN was related to a longer survival from antiangiogenic drug administration: 9.8 versus 4.8 months (P=0.001; hazard ratio=3.5, 95% CI 1.6–7.6). Our data indicate that HTN may be an effective biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs; in particular, it may be associated with a favorable effect on disease control, 6-month PFS, and the median overall survival.

Neoplastic Meningitis from Solid Tumors: New Diagnostic and Therapeutic Approaches

Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%-15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography-computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.

Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: an overview of the literature.

The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results. This review focuses on systemic cytotoxic drugs and, in particular, on new targeted therapies and their clinically relevant activities in brain metastases from solid tumors in adults.

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study.

Background:Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. Patients and Methods:From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O6-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. Results:We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of ⩽3,00,000/mm3, methylated O6-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. Conclusions:Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

Cisplatin and temozolomide combination in the treatment of leptomeningeal carcinomatosis from ethmoid sinus intestinal-type adenocarcinoma

Intestinal-type adenocarcinoma of the nasal cavities and paranasal sinuses is a relatively rare tumor. Standard therapeutic modalities include surgery followed by radiotherapy, sometimes with chemotherapy treatment. Despite these treatments, the outcome is poor due to frequent local recurrences constituting the main cause of death among patients; leptomeningeal carcinomatosis is not a frequent event, and its presence indicates short expected survival. The therapy of neoplastic meningitis includes cranial irradiation, intrathecal chemotherapy and high-dose systemic chemotherapy. However, these approaches report important side effects with only modest efficacy. Thus, it is important to discover better treatment for this cancer complication. We present, for the first time, a case of leptomeningeal carcinomatosis from invasive intestinal-type adenocarcinoma treated with temozolomide and cisplatin chemotherapy obtaining a prolonged reduction and stabilization of the lesion improving the clinical condition of the patient.

Treatment of Malignant Gliomas in Elderly Patients: A Concise Overview of the Literature

Gliomas are the most frequent primary brain tumors and the incidence data has increased in the elderly population. Unfortunately, prospective studies on this population are few and so the right treatment is unknown. In the elderly patients no standard treatment has been established and therefore the optimal treatment should be individualized. We performed a review analyzing the prognostic and predictive factors, the clinical studies, and the correct management of this population.

Angiopoietin-2 May Be Involved in the Resistance to Bevacizumab in Recurrent Glioblastoma

ABSTRACT Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ.

Bevacizumab-Based Therapy for Patients with Brain Metastases from Non-Small-Cell Lung Cancer: Preliminary Results.

Background: Bevacizumab is a recombinant humanized monoclonal antibody that obstructs the vascular endothelial growth factor (VEGF) pathway. Despite its extensive employment in the treatment of primary tumors of the brain, experience of brain metastatic disease, a frequent complication in patients with lung cancer, is very limited. On the basis of the strong antiedemigenous effect and no risk of intracranial bleeding, we administered a bevacizumab-based chemotherapy to patients with non-small-cell lung cancer (NSCLC) and symptomatic metastatic brain lesions who were not suitable candidates for a specific local therapy. Methods: The patients received bevacizumab 7.5 mg/kg and cisplatin 75 mg/m2 on day 1, and gemcitabine 1,250 mg/m2 on days 1 and 8, every 21 days. Results: We studied 13 patients with clinical and radiological progressive brain metastases; the majority had a treatment-naïve disease. Bevacizumab-based chemotherapy was found to be well tolerated and effective: progression-free survival (PFS) was 9.1 months (range: 0.9-39.2+) and overall survival (OS) was 9.6 months (range 3-41.5+). Conclusions: Bevacizumab-based therapy proved to be feasible and safe. The PFS and the OS data are very encouraging as well as the symptomatic benefit due to bevacizumabs high capacity to provide a long-lasting decrease of perilesional edema.

Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life.

Patients with high-grade gliomas (HGG) and their caregivers have to confront a very aggressive disease that produces major lifestyle disruptions. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). We examine, in a sample of patient-caregiver dyads in the specific context of newly diagnosed cases of HGG, whether the QoL of patients and caregivers is influenced by the coping processes they and their relatives use from a specific actor–partner interdependence model (APIM). This cross-sectional study involved 42 dyads with patients having recent diagnoses of HGG and assessed in the time-frame between diagnosis and treatment initiation. The self-reported data included QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology QoL), emotional status, and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. Coping strategies, such as social support, avoidance, and problem solving, exhibited evidence of either an actor effect (degree to which the individual’s coping strategies are associated with their own QoL) or partner effect (degree to which the individual’s coping strategies are associated with the QoL of the other member of the dyad) for patients or caregivers. For positive-thinking coping strategies, actor and partner effect were not observed. This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies.

Treating patients with metastatic renal carcinoma: an escape from Phase III

The wide availability of drugs for the treatment of advanced renal cell carcinoma has recently provided many alternatives for patients historically treated with immunotherapy alone. The six drugs currently available for the treatment of metastatic renal cell carcinoma became available to physicians after the approval processes performed by regulatory agencies, based mainly on the results of Phase III studies. Owing to the stringent entry criteria of the studies, patients are not representative of the entire population. Results of Phase III studies are extrapolated to all renal cell carcinoma populations without taking into account patients with different comorbidities. The purpose of this review is to analyze and weigh the safety data available for the drugs approved for metastatic renal cell carcinoma and to suggest the best therapy in terms of both efficacy and safety based on the multiplicity of features of each patient in relation to the main characteristics of each agent.