Carmine Maria Carapella

End of life issues in brain tumor patients

Despite aggressive antitumor treatment, the prognosis of brain tumor (BT) patients remains poor. In the last stage of disease, BT patients present severe symptoms due to the growing tumor or to treatment side-effects, which require adequate palliative management and supportive therapy. However, studies specifically addressing palliative care and end-of-life (EoL) issues in BT patients are lacking. This study explores symptoms experienced by BT patients in the last weeks of disease and EoL issues observed in a population of brain tumor patients followed at home until death by a neuro-oncological home care palliative unit set up in our Institution in 2000. From October 2000 to December 2005, 324 patients affected by brain tumor and discharged from our Institution were enrolled in a comprehensive program of neuro-oncological home care supported by the Regional Health System. Out of 324 patients enrolled in the home care program, 260 patients died of which 169 (65%) were assisted at home until the end of life and have been included in this study. Clinical symptoms, palliative treatments and EoL treatment decisions were collected from home clinical records. Among the 169 patients assisted at home until death, the most frequent symptoms observed in the last four weeks of life were: epilepsy 30%, headache 36%, drowsiness 85%, dysphagia 85%, death rattle 12%, agitation and delirium 15%. Palliative management of brain tumor patients requires a multidisciplinary approach performed by a well trained neuro-oncology team. Development of home care models of assistance may represent an alternative to in-hospital care for the management of patients dying of brain tumor and may improve the quality of end-of-life care.

Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center

BackgroundTo evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center.MethodsFour Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre.ResultsClinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had ≤ 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with ≤ 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients.ConclusionsIn clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance.

Perioperative thromboprophylaxis in patients with craniotomy for brain tumours: a systematic review

Venous thromboembolism (VTE) events are frequent in neurooncological patients in perioperative period thus increasing mortality and morbidity. The role of prophylaxis has not yet been established with certainty, and in various neurosurgery and intensive care units the practice is inconsistent. A better definition of the risk/cost/benefit ratio of the various methods, both mechanical (intermittent pneumatic compression-IPC, graduated compression stockings-GCS) and pharmacological (unfractionated heparin-UFH or low molecular weight heparin-LMWH), is warranted. We aim to define the optimal prophylactic treatment in the perioperative period in neurooncological patients. A systematic review of the literature was performed in Medline, Embase and Cochrane Library. Thirteen randomized controlled trials (RCTs) were identified, in which physical methods (IPC or GCS) and/or drugs (UFH or LMWHs) were evaluated in perioperative prophylaxis of neurological patients, mostly with brain cancer not treated with anticoagulants for other diseases. The analysis was conducted on a total of 1,932 randomized patients of whom 1,558 had brain tumours. Overall data show a trend of reduction of VTE in patients treated with mechanical methods (IPC or GCS) that should be initiated preoperatively and continued until discharge or longer in case of persistence of risk factors. The addition of enoxaparin starting the day after surgery, significantly reduces clinically manifest VTE, despite an increase in major bleeding events. Further studies are needed to delineate the types of patients with an increase of VTE risk and risk/benefits ratio of physical and pharmacological treatments in the perioperative period.

Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BackgroundIn recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m2 weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting.Methods40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m2 to 100 mg/m2. Patients were classified into 3 groups according to the dose of fotemustine received, from the lowest dosage received in group A, to the highest in group C. Analysis of MGMT promoter methylation in tumor tissue was successfully performed in 19 patients.ResultsOverall, 20% of patients responded to treatment, for a disease control rate (DCR, responses plus stabilizations) of 47.5%. Groups A and B experienced a response rate of 40% and 26.5% respectively, while the corresponding value for group C was 10%. Out of 19 patients, MGMT promoter was found methylated in 12 cases among which a DCR of 66.5% was observed. All 7 patients with unmethylated MGMT promoter were progressive to fotemustine.ConclusionLow-dose fotemustine at 65–75 mg/m2 (induction phase) followed by 75–85 mg/m2 (maintenance phase) has an activity comparable to that of the conventional schedule. By determination of the MGMT promoter methylation status patients might be identified who are more likely to benefit from fotemustine chemotherapy.

Early perfusion changes in patients with recurrent high-grade brain tumor treated with Bevacizumab: preliminary results by a quantitative evaluation

BackgroundTo determine whether early monitoring of the effects of bevacizumab in patients with recurrent high-grade gliomas, by a Perfusion Computed Tomography (PCT), may be a predictor of the response to treatment assessed through conventional MRI follow-up.MethodsSixteen patients were enrolled in the present study. For each patient, two PCT examinations, before and after the first dose of bevacizumab, were acquired. Areas of abnormal Cerebral Blood Volume (CBV) were manually defined on the CBV maps, using co-registered T1- weighted images, acquired before treatment, as a guide to the tumor location. Different perfusion metrics were derived from the histogram analysis of the normalized CBV (nCBV) maps; both hyper and hypo-perfused sub-volumes were quantified in the lesion, including tumor necrosis. A two-tailed Wilcoxon test was used to establish the significance of changes in the different perfusion metrics, observed at baseline and during treatment. The relationships between changes in perfusion and morphological MRI modifications at first follow-up were investigated.ResultsSignificant reductions in mean and median nCBV were detected throughout the entire patient population, after only a single dose of bevacizumab. The nCBV histogram modifications indicated the normalization effect of bevacizumab on the tumor abnormal vasculature. An improvement in hypoxia after a single dose of bevacizumab was predictive of a greater reduction in T1-weighted contrast-enhanced volumes at first follow-up.ConclusionsThese preliminary results show that a quantification of changes in necrotic intra-tumoral regions could be proposed as a potential imaging biomarker of tumor response to anti-VEGF therapies.

Surgery of malignant gliomas: advances and perspectives

Purpose of review One of the most controversial issues in the combined treatment of malignant gliomas is the role of surgical resection, even though the relevance of surgery in obtaining tissue diagnosis and alleviating clinical symptoms is well defined; more debated is the importance of radical surgery in improving the patient final outcome. This review aims to present an overview of the recommendations for surgical treatment of malignant gliomas, and to describe the potential role of locoregional treatments. Recent findings An increasing series of data are being collected in favour of radical surgical removal, with the support of intraoperative imaging and fluorescence guide. More controversial, but theoretically relevant, are the experiences of locoregional treatments, mainly in the contest of present combined modality treatments; different interesting approaches are being studied, without any significant therapeutical advantage in phase III studies, and only biodegradable carmustine wafers entered in the clinical practice. Summary The gold standard of surgical treatment of malignant gliomas has to include well tolerated and radical tumour removal, taking advantage of the introduction of new technological tools. The future role of neurosurgical treatment of malignant glioma is linked to intratumoural administration of antiblastic agents and the development of more efficient delivery systems; localized therapies have to be considered in a well defined multistep therapeutic strategy.

Quantitative analysis of CT-perfusion parameters in the evaluation of brain gliomas and metastases

BackgroundThe paper reports a quantitative analysis of the perfusion maps of 22 patients, affected by gliomas or by metastasis, with the aim of characterizing the malignant tissue with respect to the normal tissue. The gold standard was obtained by histological exam or nuclear medicine techniques. The perfusion scan provided 11 parametric maps, including Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF), Average Perfusion (Pmean) and Permeability-surface area product (PS).MethodsThe perfusion scans were performed after the injection of 40 ml of non-ionic contrast agent, at an injection rate of 8 ml/s, and a 40 s cine scan with 1 s interval was acquired. An expert radiologist outlined the region of interest (ROI) on the unenhanced CT scan, by using a home-made routine. The mean values with their standard deviations inside the outlined ROIs and the contralateral ROIs were calculated on each map. Statistical analyses were used to investigate significant differences between diseased and normal regions. Receiving Operating Characteristic (ROC) curves were also generated.ResultsTumors are characterized by higher values of all the perfusion parameters, but after the statistical analysis, only the PS, PatRsq(Patlak Rsquare) and Tpeak(Time to Peak) resulted significant. ROC curves, confirmed both PatRsqand PS as equally reliable metrics for discriminating between malignant and normal tissues, with areas under curves (AUCs) of 0.82 and 0.81, respectively.ConclusionCT perfusion is a useful and non invasive technique for evaluating brain neoplasms. Malignant and normal tissues can be accurately differentiated using perfusion map, with the aim of performing tumor diagnosis and grading, and follow-up analysis.

Establishment, characterization and chemosensitivity of two human glioma derived cell lines

SummaryTwo continuous human glioma derived cell lines, LI and DF, were established in our laboratory. Both cell lines showed cytological features andin vitro behavior similar to those of the respective original neoplasms. These two lines were characterized for their main biological properties includingin vitro andin vivo growth rate, clonogenic ability and tumorigenicity in nude mice. The plating efficiencies were generally high both during exponential and stationary growth phases and a high tumorigenicity was observed. All injected nude mice developed tumors. The two lines were tested for chemosensitivity to 1,3-bis(2-chloroethyl)-1-1nitrosourea (BCNU) and cis-Diamminedichloroplatinum II (DDP).Heterogeneity in biological features and in drug sensitivity was observed. Exposure of the two lines to BCNU and DDP showed that the glioblastoma (LI) was less sensitive than the anaplastic astrocytoma (DF). For both lines BCNU was more effective on cells in plateau than in exponential phase, while the killing effect of DDP was not phase-dependent.

Effect of pregabalin add-on treatment on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy: a pilot study

ObjectiveAn open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE).Materials and methodsWe recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given.ResultsDuring follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant (p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale “seizureworry” (p=0.004) and a significant decrease in distress scores related to AEDs and social life (p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAMA score (p=0.002) was documented.ConclusionsThese data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

The potential role of lonidamine (LND) in the treatment of malignant glioma. Phase II study.

SummaryUp-to-date unsatisfactory results obtained in multimodality treatments of malignant glioma have prompted the research of new therapeutic modalities with ‘unconventional’ modes of action. Lonidamine (LND) is a drug which reduces aerobic glycolytic activity in both human and experimental tumors. This effect mainly depends on the inhibition of mitochondrially-bound hexokinase (HK) which is present in large amounts in malignant cells. A Phase II study was conducted on patients with recurrent glioma; 12 patients were admitted to the study. Clinical side effects were moderate, necessitating a reduction of the dosage in only 1 case. The objective results were evaluated according to the indications of Levin. 2 responders and 3 cases of stable disease were observed out of 10 evaluable patients. The potential value of this new drug is discussed.