Abstract: OBJECTIVE: The clinical use of cisplatin chemotherapy is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m(2). The present study evaluates the neuroprotective effect of antioxidant supplementation (vitamin E) in patients treated with cisplatin chemotherapy. METHODS: A total of 108 patients treated with cisplatin chemotherapy were randomly assigned to receive vitamin E supplementation (alpha-tocopherol 400 mg/day) or placebo. Treatment was started orally before chemotherapy and continued for 3 months after the suspension of cisplatin. RESULTS: Of 108 randomized patients, 68 received at least one clinical and neurophysiologic examination after cisplatin CT; 41 patients received a cumulative dose of cisplatin higher than 300 mg/m(2) and were eligible for statistical analysis: 17 in the vitamin E group (group 1) and 24 in the placebo group (group 2). The incidence of neurotoxicity was significantly lower in group 1 (5.9%) than in group 2 (41.7%) (p < 0.01). The severity of neurotoxicity, measured with a validated neurotoxicity score (Total Neuropathy Score [TNS]), was significantly lower in patients receiving vitamin E than those receiving placebo (mean TNS 1.4 vs 4.1; p < 0.01). CONCLUSIONS: This phase III study confirms the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity. Vitamin E supplementation should be adopted in patients receiving cisplatin-based chemotherapy. Classification of evidence: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02-1.00, p < 0.05).
Abstract: PURPOSE: In order to evaluate the activity of gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM), a prospective single-center phase II study was conducted. METHODS: Eligible patients were required to have histologically proven GBM with evaluable and/or measurable disease after surgery. They were treated by standard cranial irradiation plus concomitant fixed dose rate gemcitabine given intravenously at 175 mg/m(2) weekly for 6 weeks. After chemo-radiotherapy, irrespective of tumor response, patients went on to receive oral temozolomide at 150-200 mg/m(2) for 5 days every 28 days. RESULTS: Twenty-three patients were enrolled. Median age was 57 years (range 43-72) and median Karnofsky performance status was 90 (range 70-100). Seventeen patients had received subtotal resection of the tumor, while six patients had biopsied-only tumors. Four patients responded to treatment (17.5%) with additional 14 (61%) experiencing stable disease for an overall disease control rate of 78.5%. Median progression-free and overall survival were 6.8 and 10.1 months, respectively. The concomitant radiotherapy-gemcitabine combination was well tolerated and severe adverse events were rare, consisting of grade 3 neutropenia and hypertransaminasemia in two cases each. Twenty patients were assessable for methylguanine methyltransferase (MGMT) promoter methylation, 11 of which were found methylated. In the methylated and unmethylated cohorts, disease control was obtained in 10/11 patients (91%) and 7/9 patients (77.5%), respectively. CONCLUSIONS: Concomitant radiotherapy-gemcitabine is active and well tolerated in newly diagnosed glioblastoma multiforme. Activity is observed both in tumors with methylated and unmethylated MGMT promoter.
Abstract: BACKGROUND: The 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). METHODS: The 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. RESULTS: Tumors 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 PatRsq and PS as equally reliable metrics for discriminating between malignant and normal tissues, with areas under curves (AUCs) of 0.82 and 0.81, respectively. CONCLUSION: CT 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.
Abstract: BACKGROUND: In recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m(2) 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. METHODS: 40 patients with recurrent pretreated MG were identified as being treated with fotemustine at doses ranging from 65 mg/m(2) to 100 mg/m(2). 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. RESULTS: Overall, 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. CONCLUSION: Low-dose fotemustine at 65-75 mg/m(2) (induction phase) followed by 75-85 mg/m(2) (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.
Abstract: 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.
Abstract: The aim of this pilot study was to investigate the effects of levetiracetam monotherapy on seizure control, quality of life and neurocognitive performance in patients with brain tumor-related epilepsy. We present here preliminary data from 18 patients with follow-up of 6 months. We evaluated seizure frequency at baseline. We used administered Mini Mental State Examination (MMSE), Karnofsky Performance Status (KPS), Barthel index (BI), QOLIE 31P (V2), EORTC QLQ-C30 and Adverse Events Profile. After 6 months, 16 patients were seizure free (88.9%), 2 (11.1%) had reduction in seizure frequency >50%. Compared to baseline, we observed a worsening of performance (KPS p = 0.011; BI = 0.008) and global lower cognitive performance (MMSE p = 0.011); distress related to seizure frequency (p = 0.003) and medication effects (p = 0.046) were significantly lower. Levetiracetam caused mild and reversible side effects. These preliminary data on LEV monotherapy in patients with brain tumor-related epilepsy show that this antiepileptic drug is efficacious and well tolerated.
Abstract: BACKGROUND: Seizure control doesn't represent the only challenging goal in patients with brain tumor-related epilepsy. Side effects have often taken precedence for patients' quality of life. METHODS: We performed an observational retrospective study on patients with brain tumor-related epilepsy: 35 who had assumed oxcarbazepine monotherapy and 35 patients who had undergone treatment with traditional antiepileptic drugs. Primary variable of efficacy was the mean seizure frequency per month and safety variables were the drop-out for side effects and total incidence of side effects. We applied the Propensity Score technique to minimize selection bias. RESULTS: Our results showed a similar efficacy of oxcarbazepine and traditional antiepileptic drugs over time, but the difference in safety and tolerability between the two groups was significant: traditional AEDs caused more side effects, both serious and non serious. CONCLUSION: This study highlights the importance of taking into consideration not only seizure control but also the appearance of side effects when choosing antiepileptic drugs in this patients population.
Abstract: In patients with newly diagnosed glioblastoma multiforme (GBM), concurrent chemo-radiotherapy with temozolomide is the new standard of care. In the present phase I study we investigated the association of gemcitabine, a cell-cycle antimetabolite with radiosensitizing properties, with radiotherapy (RT) in the first line treatment. Gemcitabine was delivered at a fixed dose-rate of 10 mg/m(2)/min weekly for 6 weeks starting 24-72 h prior to, and then concomitantly with RT (2.0 Gy per fraction, total dose 60 Gys). The primary end-point was the identification of dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Planned dose levels of gemcitabine started from 200 mg/m(2)/weekly (level 1), with sequential dose escalations of 25 mg/m(2). Ten patients were enrolled, all with evaluable disease after surgery. Six patients were male, median age was 55 years (44-75), and median baseline Karnofsky performance status was 85 (70-100). Four patients entered level 1, one patient being excluded from the study because of early disease progression. At this level, two of three patients developed progressive neurological deterioration, potentially related to the experimental treatment. On this basis gemcitabine dose was prudentially reduced to 175 mg/m(2)/weekly in the subsequent step (level -1). No DLT was encountered in the six patients enrolled at this level. Interestingly, at this dose only two grade three toxicities (one neutropenia and one raise in serum transaminases) were reported. Thus, fixed dose-rate gemcitabine at 175 mg/m(2)/weekly is the recommended regimen for further evaluation in a phase II study that is presently in progress.
Abstract: OBJECTIVE: Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC). METHODS: Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T(0)), at its end (T(7)) and after further 1-3 weeks (T(14)-T(28)). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection. RESULTS: Mean TPM concentrations were 5.4 +/- 2.4 microg/ml at T(0) vs. 5.5 +/- 2.4 microg/ml at T(7) (n = 14), and 5.4 +/- 2.4 microg/ml at T(0) vs. 5.6 +/- 2.8 microg/ml at T(14)-T(28) (n = 14). Mean MHD concentrations were 16.4 +/- 7.6 microg at T(0) vs. 18.5 +/- 9.0 microg/ml at T(7) (n = 5), and 16.8 +/- 7.0 microg/ml at T(0) vs. 18.0 +/- 8.7 microg/ml at T(14)-T(28) (n = 8) (all comparisons not statistically significant; Student's t-test for paired samples). CONCLUSION: Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.
Abstract: Epilepsy in brain tumor patients is often refractory to pharmacological treatments and can complicate the therapeutic management of these patients. We conducted a prospective, observational study. The aim of this study was to investigate the efficacy and tolerability of topiramate (TPM) in brain tumor associated epilepsy. We studied 47 patients with brain tumors and epilepsy. The entire group was administered AEDs. TPM was the first therapeutic choice in 14 patients, while in the remaining 33 patients previous AEDs were modified and TPM was introduced due to side effects or inefficacy of the first drug. Follow-up ranged from 3 to 48 months (mean 16.5 months). Considering the final follow-up of each patient who assumed TPM for at least 3 months, we observed 45 patients: 25 were seizure free (55.6%), 9 had a reduction of seizure frequency (SF) higher than 50% (20%) and 11 were stable (24.4%). TPM responder rate was 75.6%. Three patients (6.4%) discontinued TPM for severe side effects (1 after 4 months and 2 after 1 month) and 4 (8.5%) had mild and reversible side effects. In the group of patients who had been in therapy with other AEDs prior to entering the study (n = 33), 19 patients had side effects (57.6%). During follow-up, the haematological parameters were in the normative ranges. Tumor-related seizures are difficult to control with AEDs; the precise reasons for this difficulty are not yet clear. Using TPM, we obtained good seizure control with a low incidence of side effects.
Abstract: BACKGROUND: Recent reports on large number of patients with brain metastases report that Whole Brain Radiotherapy (WBRT) and Radiosurgery (RS) should be the treatments of choice, particularly in multiple lesions cases. Among the prognostic factors, the cerebellar location was never considered, although this results in hydrocephalus, brain stem compression, ataxia, intracranial hypertension. MATERIALS AND METHODS: We evaluated 44 patients with cerebellar metastases operated over 6 years. Primary lesions were: Lung (15), Breast (12), Gastrointestinal (9), Gut (3), Ovary (2), Melanoma (1), Salivary gland carcinoma (1), Unknown (1). Lesions were <3 cm in 11 cases, > or =3 cm in 33. Average KPS scoring at admission was 69.9. Twenty nine scored > or =70, 15 < 70. RESULTS: Two patients died for surgical complications, 2 died within 1 months for other causes, 2 were lost to follow up. Eight had postoperative hematoma requiring reoperation, 1 had an occipital infarction. Average KPS scoring at discharge was 76.4, P < 0.002. Those patients that had complications scored less, the difference is significant (P < 0.008). Median survival was 8 months, 1 year survival rate 29.9%. Survival was correlated with either admission or discharge KPS (> or =70 vs. <70): P = 0.05 and P = 0.0001 respectively. None of the other parameters considered reached statistical significance. CONCLUSIONS: Open microneurosurgery is probably still the most effective therapy in improving survival and KPS in patients with large cerebellar metastases, given that the proper surgical technique is used and that complications do not occur. Specific data on cerebellar metastases as an independent subgroup are needed from radiosurgical series.
Abstract: PURPOSE: The rationale for intensification strategies is that more frequent exposure to chemotherapeutics could enhance antitumor activity. Several trials investigated weekly paclitaxel administration, but there are no clear data concerning peripheral neurotoxicity. The aim of this study was to assess the incidence of peripheral neurotoxicity in patients affected by advanced breast cancer treated with weekly paclitaxel. PATIENTS AND METHODS: Neurotoxicity was assessed with neurologic and neurophysiologic evaluation before treatment and after 12 weeks and 24 weeks. A total neurotoxicity score was assigned to each patient on the basis of neurophysiologic and neuropathic signs and symptom changes. Seventeen patients entered the study. RESULTS: After 12 weeks of treatment, 71% showed moderate clinical and/or neurophysiologic signs of neurotoxicity; after 24 weeks, the incidence of neurotoxicity increased to 96%. Sural amplitude at the 24-weeks examination significantly decreased from basal mean value (13.5 microv, standard deviation [SD] 6 microv vs. 7 microv, SD 5.9 microv, respectively; P = 0.01), whereas median sensory amplitude decreased after 24 weeks from 10.3 microv, SD 6.2 microv to 4.9 microv, SD 3.8 microv (P = 0.001). In a subset of 11 patients, we obtained a follow-up examination after 6 months from the end of treatment. In all patients, examined signs and symptoms of neurotoxicity improved with recovery of subjective neuropathic symptoms and neurophysiologic findings. CONCLUSION: Our results demonstrate, in a little population of patients evaluated with a comprehensive neurologic assessment, that weekly paclitaxel is related to a very high incidence of peripheral neurotoxicity. Follow-up data obtained in a subset of patients indicate that peripheral neurotoxicity is reversible.
Abstract: Methotrexate (MTX)-based chemotherapy extends survival in patients with primary brain lymphomas, but it is not clear whether multiagent chemotherapy is superior to MTX alone. Treatment options for patients with recurrent primary brain lymphoma are limited; there is no standard second-line chemotherapy. New chemotherapeutic agents with clear activity in brain lymphoma are needed for treatment of recurrent disease. We report the results of a phase II trial assessing activity of the alkylating agent temozolomide in immunocompetent patients with recurrent primary brain lymphomas, previously treated with high-dose MTX-containing chemotherapy and/or radiotherapy. A median of two courses (range 1-12) of temozolomide 150 mg m-2 day-1, for 5 days every 4 weeks was administered to 36 patients yielding nine complete and two partial responses (response rate: 31%; 95% confidence interval 16-46%). One-year survival was 31% (95% confidence interval 16-46%). Toxicity was negligible. We conclude that temozolomide is active in recurrent primary brain lymphomas and should further be evaluated in this disease, perhaps in combination with MTX as initial treatment.
Abstract: We conducted a phase II study to determine the activity and tolerability of weekly epirubicin-paclitaxel and granulocyte colony-stimulating factor in breast cancer patients untreated for metastatic disease. The phase II study was designed following the Simon optimal-two stage method. Patients received epirubicin 25 mg/m and paclitaxel 80 mg/m every week, and granulocyte colony-stimulating factor on days 2 and 4 for 24 consecutive weeks in the absence of progression. From 1999 to 2004, 53 patients entered the study; 1093 weekly courses were delivered, with a median number of cycles of 22. Patients received a median relative dose intensity of 94%. No hematological grade 3-4 toxicities were observed. One patient had one episode of grade 3 mucositis and two patients (3.8%) suffered grade 2 asthenia. Eight patients (15.1%) experienced grade 2 neutropenia, grade 2 anemia was registered in seven patients (13.2%). No cardiotoxicity was observed. Ten out of 53 patients (18.9, 95% confidence interval 8.3, 29.4%) showed a complete response, whereas 28 (52.8, 95% confidence interval 39.4, 66.3%) had a partial response, with an overall response rate of 71.7% (95% confidence interval 59.6, 83.8%). In addition, 14 patients (26.4%) had stable disease. Median time to progression was 12 months (95% confidence interval 7, 17). Median response duration was 14 months (range 3-60). The 1-, 3- and 5-year survival rates were 90.1, 68.0 and 56.6%, respectively. In untreated metastatic breast cancer patients, the weekly administration of epirubicin and paclitaxel with granulocyte colony-stimulating factor support seems to be extremely tolerable and active, and deserves further investigation into a phase III trial.
Abstract: To determine whether a program of post-discharge rehabilitation at home for patients operated for brain tumor was associated with functional gain and improvement in Quality of Life (QoL). One hundred and twenty-one patients affected by malignant brain tumor were enrolled in a program of post-discharge home care including neurorehabilitation. Functional outcome was evaluated with Barthel Index (BI) and Karnofsky Performance Status (KPS) measured before and after rehabilitation. The impact of rehabilitation on quality of life was evaluated with a quality of life questionnaire (EORTC QLQ-C30-BM 20). Results: Barthel Index improved in 47 (39%) patients, was stable in 20 (16%) and worsened in 54 (44%). Only 54 patients completed the QoL questionnaire before and after treatment. After three months of rehabilitation, 72% of patients were found to have an improvement in at least one domain score compared with their baseline QoL scores. Rehabilitation at home in brain tumor patients was associated with significant functional gain measured both with BI and KPS. The benefit of rehabilitation may influence patient's perception of quality of life.
Abstract: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.
Abstract: Epilepsy is a common clinical problem in patients with brain tumours, strongly affecting patients' quality of life. Tumour-related seizures are often difficult to control, and the clinical picture is complicated by frequent interactions between antiepileptic drugs (AEDs) and antineoplastic agents. We studied the safety and efficacy of levetiracetam (LEV), a new AED with a different pharmacological profile from traditional anticonvulsants, in 19 patients (6 females; age range 28-70 years, mean 48 years) with supratentorial gliomas and epilepsy. Seizure types were simple partial in four patients, complex partial in 4, complex partial with secondary generalization in 7, and generalized tonic-clonic in 4. LEV was added to the existing AED treatment on account of persisting seizures, and titrated at dosages of 1,000-3,000 mg/day. Patients were seen at the Outpatient's Centre every 1-3 months, and followed-up for 7-50 months (mean 25 months, median 20 months). At the end of the observation period, nine patients were seizure free (seizure free period ranging from 7 to 33 months, mean 16, median 12) and five patients reported an improvement in seizure-frequency from daily to weekly (n=1) or from weekly to monthly (n=3). Seizure frequency was unmodified in four patients and increased (from monthly to weekly) in one. No LEV-related adverse effects were observed. LEV plasma concentrations monitored in 12 subjects ranged from 11.9 to 82.1 microg/ml. Our preliminary open data indicate that add-on treatment with LEV in patients with brain tumours is safe and appears to be effective in reducing seizure frequency. Controlled studies on larger populations are warranted to confirm these open observations.
Abstract: The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.
Abstract: Neoplastic meningitis (NM) is the result of the diffuse or multifocal localization of cancer cells in the cerebral spinal fluid (CSF). NM is more often a late complication of solid tumor or lymphoproliferative malignancies. At present, the goal of therapeutic strategies is palliative and the evaluation of high or low risk is important in identifying which patients could benefit from aggressive treatments such as radiation therapy and chemotherapy. Given that NM is a cancer complication that can spread throughout the entire subarachnoid space, chemotherapy, whether intrathecal or systemic, is currently considered the best treatment option, but optimal treatment is still controversial. This review summarizes intrathecal and systemic chemotherapeutic options in the treatment of NM and the related toxicities.
Abstract: Forty-seven patients with Glioblastoma (42) and Anaplastic Astrocytoma (5) were studied with MR 24 hrs after surgery. In order to evaluate the role of early MR in defining the extent of surgical resection and its relation with the prognosis of malignant glioma patients, three categories of surgical resection were considered: gross total, sub-total and partial resection. The results were correlated with progression-free survival (PFS) and overall survival (ST). As demonstrated by early-MR, gross total resection was performed in 17 patients, sub-total and partial resection in 19 and 11 patients, respectively. The PFS was 6 months in gross total resection, 6 and 3 months in sub-total and in partial resection, respectively. The median survival time was 16 months in total resection patients, 13 months and 7 months in sub-total resection and partial resection patients, respectively. The study confirms that early-MR has to be considered an accurate technique for monitoring the extension of malignant glioma surgical resection and shows a good correlation between early-MR findings, PFS and ST.
Abstract: Choroid plexus carcinoma is a rare primary brain neoplasm arising from epithelial differentiated tissue, originating from the choroids plexus of the ventricles and, in 90% of the cases, in the lateral and fourth ventricles. This neoplasm is seen mainly in children and reported infrequently in adults. The treatment of choroid plexus carcinoma is based on scarce evidence in literature. We report a rare case of an adult woman affected by a choroid plexus tumour and a discussion on the therapeutic management of this uncommon adult malignancy.
Abstract: Temozolomide is a well-tolerated alkylating agent, that is able to permeate the blood-brain barrier (BBB), and has additive cytotoxicity when given with radiotherapy (RT). A phase II trial assessing temozolomide 150 mg/m(2)/day, for 5 days every 28 days in primary central nervous system (CNS) lymphoma (PCNSL) patients with negative human immunodeficiency virus (HIV) serology, Eastern Cooperative Oncology Group (ECOG) performance status (PS)<4, previously treated with high-dose methotrexate-containing (HD-MTX) chemotherapy and/or RT was started. Twenty-three patients were enrolled. Median age was 60 years. Five complete remissions (median duration 6+ months; range 2-36 months), one partial response, four stable disease (median duration 7.2 months, range 2-16.5 months), and 13 progressions were observed. No major toxicities were observed, apart grade 3 vomiting in a single cycle. Main grade 1-2 toxicities were: 15% nausea, 6% vomiting, 9% fatigue and 9% neurological symptoms. This is the first prospective trial assessing single-agent activity in PCNSL at failure. Although some patients had a poor PS and had been heavily pre-treated, temozolomide yielded 26% objective responses and was well tolerated without any major toxicity.
Abstract: The extraneural diffusion of malignant gliomas is not frequent and some authors have reported single or multiple bone metastases from glioblastoma contemporary to the time of primary cerebral tumor or accompanying relapse on the brain. We report the case of a man affected by a glioblastoma who had a lumbar spine metastases without any brain relapse after excision of cerebral glioblastoma multiforme and brain radiotherapy.
Abstract: Our aim was 2-fold: to investigate the role of alpha-tocopherol supplementation on the antitumor activity of DDP and to evaluate the effect of alpha-tocopherol on the survival and neurotoxicity of DDP-treated mice. Experiments performed on the M14 human melanoma line demonstrated that alpha-tocopherol supplementation did not influence the efficacy of DDP; the inhibition of cell survival and of the in vivo tumor growth after treatment with alpha-tocopherol and DDP combination was similar to that observed after DDP alone. Conversely, alpha-tocopherol was also able to increase survival of mice treated with a high dose of DDP. While DDP alone produced death in about 70% of mice, the combination reduced deaths to about 30%. Analysis of oxidative stress markers and peroxidative damage in organs indicated that the protective effect of alpha-tocopherol was mainly related to its antioxidant activity. A significant increase in the concentration of TBARS and decreased PUFAs and catalase activity were observed after DDP treatment, while with alpha-tocopherol the levels of these markers were comparable to those observed in untreated mice. Histologic analysis performed on peripheral nerve revealed that alpha-tocopherol also protected mice from severe neurologic damage induced by DDP treatment. In conclusion, our results demonstrate that alpha-tocopherol protects against the systemic toxicity and neurotoxicity induced by DDP without interfering with its antitumor activity and suggest that this combination is a promising strategy to improve the therapeutic index of DDP-based chemotherapy.
Abstract: PURPOSE: The aim of this study is to evaluate the neuroprotective effect of antioxidant supplementation with vitamin E in patients treated with cisplatin chemotherapy. METHODS: Between April 1999 and October 2000, forty-seven patients were randomly assigned to either group one, which received vitamin E supplementation during cisplatin chemotherapy, or to group two, which received cisplatin chemotherapy alone. Alpha-tocopherol (vitamin E; 300 mg/d) was administered orally before cisplatin chemotherapy and continued for 3 months after the suspension of treatment. For preclinical studies, nude mice carrying the human melanoma tumor were treated with cisplatin alone or in combination with vitamin E. RESULTS: Twenty-seven patients completed six cycles of cisplatin chemotherapy: 13 patients in group one and 14 patients in group two. The incidence of neurotoxicity was significantly lower in group one (30.7%) than it was in group two (85.7%; P <.01). The severity of neurotoxicity, measured with a comprehensive neurotoxicity score based on clinical and neurophysiological parameters, was significantly lower in patients who were supplemented with vitamin E than in patients who were not supplemented with vitamin E (2 v 4.7, P <.01). The results of the preclinical studies showed that when cisplatin was combined with vitamin E, no differences were observed in tumor weight inhibition, tumor growth delay, or life span as compared with treatment with cisplatin alone. CONCLUSION: Supplementation of patients receiving cisplatin chemotherapy with vitamin E decreases the incidence and severity of peripheral neurotoxicity.
Abstract: We describe herein the case of a 57 year old man who, over the last five years, has presented ataxic and spastic gait on the right side, a reduction in fine motor movement of the fingers mainly on the right side, superficial right side brachiocrural hypoesthesia and a marked dysarthria associated with internuclear ophthalmoplegia. The neurological picture, after an initial progressive worsening which lasted some months, remained relatively stable over the years. Repeated magnetic resonance imaging (MRI) of the brain and spinal cord documented the presence of demyelinating plaques spread in the white matter of the periventricular region and the semioval centres, and a right side paramedian plaque at the C4-C5 level, none of which were in the active phase. Oligoclonal bands were revealed in the cerebrospinal fluid (CSF). Monoclonal IgM/lambda gammopathy with anti-myelin and anti-nucleo reactivity, found with serum immunofixation, were confirmed several times in successive annual controls, not associated to myeloproliferative pathology. The lack of progression in the clinical picture would seem to contradict the diagnosis of late Multiple Sclerosis. The presence of antibody activity against the myelin might support the hypothesis of a pathogenetic role of the immunoglobulins at the onset of the demyelinating disease in this patient. However, in the end, there is the possibility of casual association with a poorly functioning immune system connected to age.
Abstract: BACKGROUND: The optimal treatment for low-grade glioma (LGG) is still controversial. Recent data indicate a potential influence of chemotherapy on the natural evolution of these tumors, allowing for the deferral of more aggressive therapies. PATIENTS AND METHODS: Forty-three patients affected with LGG (29 astrocytoma, four oligodendroglioma and 10 mixed oligo-astrocytoma) were treated with temozolomide (TMZ) at the time of documented clinical and radiological progression. McDonald's response criteria were utilized to evaluate TMZ activity. Thirty patients (69.7%) had previously received radiotherapy; 16 (37.2%) had received prior chemotherapy. Clinical benefit was evaluated measuring seizure control, reduction in steroid dose and modification of Karnofsky performance status and Barthel index. Quality of life was assessed with the QLQ-C30 questionnaire. RESULTS: We observed a complete response in four patients, 16 partial responses, 17 stable disease (with four minor response) and six progressive disease. Median duration of response was 10 months [95% confidence interval (CI) 8-12], with a 76% rate of progression free survival (PFS) at 6 months, and a 39% rate of PFS at 12 months. A relevant clinical benefit was observed particularly in patients presenting epilepsy. CONCLUSIONS: The high response rate of 47% (95% CI 31% to 61%) confirms that TMZ chemotherapy is a valid option in the treatment of progressive LGG. The present preliminary results seem interesting and warrant further evaluation of TMZ clinical activity in a larger series of progressive LGG.
Abstract: OBJECT: After radical surgery for childhood cerebellar astrocytomas, patients are considered to be cured. Long-term follow up demonstrates that these patients survive, with most of them leading a normal life. The study reported here was aimed at assessing the quality of life (QOL) of these adults, which is defined as a person's sense of well-being, as derived from his or her current experience of life as a whole. METHODS: Twenty patients who had undergone surgery between 1970 and 1985 were enrolled in the study. In four patients ventriculoperitoneal shunts were in place; two of these patients had required more than six shunt revisions. At present, all patients have clear neuroimaging studies and their Karnofsky Performance Scale (KPS) scores are as follows: 70 in three, 80 in seven, 90 in six, and 100 in four. A QOL questionnaire was administered to the patients and to a control group consisting of 20 healthy volunteers of matching age and sex. The chi-square test was applied to compare patients and controls. Traditional questions on the level of education, work, whether the patients have their own families, and whether they possessed a driver's license were asked at the end of the questionnaire. In all the dimensions assessed except one (sex life), the difference between patients and control volunteers was significant, socializing and adolescence being the most striking ones. This was also true when the three patients with the lowest KPS scores and the worst QOL results were excluded. CONCLUSIONS: By traditional standards, these patients appear to fare quite well. Nevertheless, their self-reported life experience is unsatisfying when compared with the control group. The authors conclude that psychosocial factors are critical to complete recovery and the QOL of children who undergo successful operations for benign cerebellar astrocytoma.
Abstract: The authors present a retrospective study on major plantar foot reconstruction to evaluate the role of the free fasciocutaneous flap and the importance of sensory nerve reconstruction in improving long-term results. Between 1995 and 1999, 20 patients with major defects of the sole of the foot underwent free forearm flap reconstruction performed by the senior author (F.S.). Sensory nerve reconstruction was added to this technique in 1997. The age and sex of the patients and the cause, location, and dimensions of their defects were recorded. The patients were clinically and neurophysiologically evaluated at 3, 6, and 12 months after the procedure for the following parameters: flap contour, flap stability, load capacity, walking ability, touch sensation, pain sensation, static two-point discrimination, and thermal sensibility. Dermatomic somatosensory-evoked potentials were also tested at 12 months. Follow-up ranged from 1 to 5 years. Patients were divided into two groups according to sensory nerve reconstruction. Group A consisted of 11 patients with nerve repair, and group B consisted of nine patients without nerve repair. One patient from group A who had an idiopathic neuropathy was excluded from the study because of interference with the reinnervation process. Five more patients (three from group A and two from group B) were lost at follow-up and excluded from the study. The final sample size in each group was seven. Data from both groups were compared and statistically analyzed with the Mann-Whitney test and the Fisher exact test. Long-term results confirmed in all reconstructions long-lasting stability. During the first postoperative year, patients with sensory nerve reconstruction showed better sensibility. The statistical analyses confirmed significant differences between the two groups to be dependent upon surgical technique at 3 and 6 months. Two-point discrimination and dermatomic somatosensory-evoked potentials were recorded. After 12 months, flaps without surgical nerve repair showed progressive improvement of sensitive thresholds, achieving a good protective sensibility, similar to that of the other group, but these flaps never regained two-point discrimination or dermatomic somatosensory-evoked potentials.
Abstract: Peripheral sensory neuropathy is the main non-hematological side-effect related to cisplatin chemotherapy. The strong similarity between clinical and neuropathological aspects in peripheral neuropathy induced by cisplatin and neurologic syndromes due to vitamin E deficiency, prompted us to investigate the relationship between cisplatin neuropathy and plasmatic level of vitamin E (alpha-tocopherol). We measured vitamin E in the plasma of 5 patients (Group 1) which developed severe neurotoxicity after cisplatin treatment and in another group of 5 patients (Group 2) we analyzed the plasmatic level of vitamin E before and after 2 or 4 cycles of cisplatin treatment. The results showed that the patients of group 1 presented low plasmatic levels of vitamin E and that the patients of group 2 presented significantly lower levels of vitamin E after 2 or 4 cycles of cisplatin than before treatment. Our preliminary data suggest that an inadequate amount of the antioxidant vitamin E due to cisplatin treatment could be responsible of the peripheral nerve damage induced by free-radicals. Given the lack of toxicity of vitamin E, we need to systematically assess the possible neuroprotective role of vitamin E supplementation in patients treated with cisplatin chemotherapy.
Abstract: The aim of our study was to explore whether nerve growth factor (NGF) plays any role in the development of peripheral neuropathy induced by anticancer treatment. We measured the circulating NGF levels in 23 cancer patients before and after chemotherapy. We evaluated whether the development of peripheral neurotoxicity was associated with changes in basal NGF concentrations in patients studied with a comprehensive neurological and neurophysiological examination. The results of these studies showed that the circulating levels of NGF, which are about 20 pg/ml in plasma of controls, decrease during chemotherapy and in some cases completely disappeared after prolonged treatment with antitumor agents. The decrease in NGF levels seems to be correlated with the severity of neurotoxicity. These results clearly suggest that NGF might become a useful agent to prevent neuropathies induced by antineoplastic drugs and restore peripheral nerve dysfunction induced by these pharmacological compounds.
Abstract: PURPOSE: In this phase II study, we explored tolerability and activity of vinorelbine administered according to a dose-dense weekly schedule with hematopoietic growth factor support in pretreated, advanced breast cancer patients. PATIENTS AND METHODS: From January 1994 to March 1996, 40 patients with metastatic breast cancer, pretreated with at least one prior anthracycline-containing regimen, were entered into the study. Patient characteristics: median age 53 years (range 32-70); ECOG performance status 0-1: 34 patients, 2: 6 patients; dominant visceral metastatic disease: 15 patients, dominant non-visceral: 25; anthracycline-refractory/resistant: 2 patients, sensitive: 38 patients. Six patients were treated as first-line therapy for metastatic disease and 34 in second- or subsequent lines. All patients received vinorelbine at the dose of 25 mg/m2/week as a short intravenous infusion, together with routine antiemetic medication. Granulocyte-colony stimulating factor (Lenograstim) at the dose of 150 microg/m2 subcutaneously on day 3 was included in the treatment schedule. RESULTS: The median number of treatment weeks was 23 (range: 4-24), with a delivered dose-intensity (DDI) of 23.8 mg/m2/week (range: 18.7-25, 95.2% of projected dose-intensity). Toxicity was mild, with non-complicated neutropenia being the main toxicity observed (grade 3-4 in 25% of the patients but only 2% of treatment weeks). Overall response rate was 52.5%, with complete responses in 12.5% of patients. Median duration of the response and median time to progression were 10 and 9 months, respectively. Median overall survival was 19 months. CONCLUSION: Dose-dense weekly vinorelbine is safe and effective with minimal toxicity in pretreated advanced breast cancer patients.
Abstract: Sexual dysfunction after colorectal cancer surgery may be severe and occurs in 25% to 100% of cases. Thirty-eight patients underwent colorectal resection; eight (21%) who were totally impotent and two (5%) who had ejaculatory failure were therefore studied to better understand the neurophysiological alterations related to this type of surgery. The patients were evaluated after surgery with electrophysiological testing, including examination of the sacral reflex (SR), pudendal somatosensory evoked potential (PEP), and motor evoked potential (MEP) responses. Sudomotor skin response (SSR) was also studied in a group of patients. Of the 38 patients studied, 29 showed abnormalities: six of SR, three of PEP, six of MEP, and fourteen of SSR. Only a combination of all these tests permits correct evaluation of the sexual dysfunction.
Abstract: One hundred and nineteen consecutive patients affected by supratentorial gliomas were studied in order to determine the incidence of seizure at diagnosis, the occurrence of subsequent seizures and the efficacy of anticonvulsant treatment. The overall incidence of seizures as presentation symptom was 52% (62 patients). Preoperative seizures were present in 83% of patients affected by low-grade astrocytoma, in 46% of patients affected by anaplastic astrocytoma and in 36% of patients affected by glioblastoma. Postoperative epilepsy refractory to anticonvulsant treatment significantly related to low-grade histology and presence of preoperative seizures occurred in 48% of patients. Adverse effects associated with anticonvulsants were observed in 33.8% of patients treated with phenobarbital, 14.3% in the group treated with carbamazepine and 12% of patients treated with vigabatrin. We conclude that anticonvulsant treatment in patients affected by gliomas is often ineffective and prophylactic treatment should be discontinued after 6 months in patients preoperative seizures free. In patients with high risk of seizures antiepileptic drugs with good efficacy and lower incidence of adverse effects than phenobarbital are indicated.
Abstract: The presence of anaemia and serum protein alteration frequently makes the treatment of pressure ulcers more difficult. Several haemato-chemical parameters were observed in 40 patients with sacral pressure ulcers in order to determine the pathogenesis of these complications. All of the patients showed mild-moderate anaemia with low serum iron and normal or increased ferritin and hypoproteinemia with hypoalbuminemia. Our results suggest that both anaemia and serum protein alteration depend on the chronic inflammatory state due to the presence of pressure ulcers. Both anaemia and hypoproteinemia disappeared after pressure ulcer healing. A correct diagnosis is important for the treatment. Iron therapy is useless and potentially dangerous (iatrogenic haemochromatosis) since anaemia is the result of the inability to use iron stores and not iron deficiency. The treatment of serum protein alterations should be based on a dietary therapy rich in protein and calories; the administration of albumin should be reduced, since albumin is low in essential amino-acids and too expensive; albumin administration should be limited to cases with severe hypoproteinemia and oedema.
Abstract: Paclitaxel is the prototype of a new class of chemotherapeutic agents with an antimitotic effect that is related to its ability to interfere with the microtubule system. It causes peripheral neurological toxicity by means of its activity on the axonal microtubules. To define the clinical and neurophysiological characteristics of paclitaxel neuropathy 23 patients undergoing paclitaxel therapy at a dose of 175 mg/m2 were studied. The patients were divided into two groups, with only one group receiving pretreatment with potentially neurotoxic drugs such as cisplatin and carboplatin. The results showed a high incidence of mild neurotoxicity in both groups. Treatment was discontinued due to severe neurotoxicity in only one patient pretreated with platinum-compounds. The clinical and neurophysiological data make it possible to define paclitaxel neurotoxicity as a distal axonal neuropathy with a summatory effect in patients pretreated with cisplatin; the possible reversibility of paclitaxel neurotoxicity requires further confirmation.
Abstract: Vinorelbine (5'-noranhydrovinblastine) is a new semisynthetic antineoplastic vinca alkaloid which interfers with axonal transport, inducing spiralisation of axonal microtubules and resulting in peripheral neurotoxicity. A prospective detailed neurological and electrophysiological evaluation was performed in 23 patients treated with 25 mg vinorelbine a week. All patients developed a sensory-motor distal symmetric axonal neuropathy. The neurotoxicity increased with cumulative vinorelbine doses and peripheral neuropathy was mild or moderate in most patients. After discontinuation of vinorelbine treatment, neuropathic signs and symptoms were partially reversible.
Abstract: Twenty-eight patients affected by lung cancer were studied with neurophysiological and clinical examinations to show the prevalence of alteration of neuromuscular transmission. During repetitive stimulation at 20 Hz we found in 6 cases (22%) an increment (> 20%) and in 4 cases a decrement ( > 10%) of the size of muscle action potentials. In 15 patients (57%) we found low sensory action potential amplitude (< 11 uv). In 3 (11%) of the 6 cases with incremental response the overall examination suggested a disorder of neuromuscular junction such as Eaton-Lambert syndrome. Our results suggest that the peripheral nervous system involvement in patients affected by lung cancer is higher than usually estimated.
Abstract: BACKGROUND AND PURPOSE: This study was conducted to evaluate local cerebral blood flow changes in patients with depression after a subcortical stroke. METHODS: Clinical and neuropsychological assessments were performed in 15 patients with a single subcortical lesion. Depression was assessed by DSM-III-R. In addition, the Hamilton Rating Scale for depression, the Zung Self-Rating Depression Scale, and the Beck scale were administered to each patient. Single-photon emission-computed tomography study was performed with 99mTc hexamethylpropyleneamine oxime. RESULTS: In all patients cortical regions ipsilateral to subcortical lesions were significantly less perfused than the contralateral cortex. Cerebral blood flow values were significantly lower in depressed patients (n = 8) than in nondepressed patients (n = 7) only in the mesial temporal cortex of the affected hemisphere. Cerebral blood flow values in the mesial temporal cortex of the affected hemisphere significantly correlated with the severity of depression. CONCLUSIONS: Temporal lobe hypoperfusion may reflect a dysfunction of the limbic system, suggesting that this location may be critical for the occurrence of depressive symptoms in patients with subcortical stroke.
Abstract: Antitumoral interleukin-2 (IL-2) therapy is frequently associated with a neurotoxicity that manifests itself in neuropsychiatric disturbances and, more rarely, with neurological focal signs. With the aim of documenting the involvement of cognitive functions after IL-2 treatment, we studied 20 patients using evoked cognitive potentials (P300) and computer analysis of the EEG signal. A comparison of the tests performed before and after the subcutaneous infusion of IL-2 showed a significant lengthening in mean P300 latencies and a percentage increase in the EEG frequencies contained with the delta and theta bands, especially in the frontal regions.
Abstract: A group of 42 adult patients with supratentorial brain tumors were studied with computed tomography (CT or/and NMR) and brain-stem evoked potentials (BAEPs). 12 patients had meningiomas and 30 had malignant tumors (gliomas and metastases). The latencies of wave V and of the interpeak latency I-III, III-V and I-V were evaluated both on the lesion side and the opposite side. In meningiomas mean latencies did not show significant differences from normal, while mean latencies in malignant tumors were significantly prolonged, except for the I-III interpeak latency. The results of this study demonstrate that BAEPs may be altered by supratentorial brain tumors. This examination appears to be useful in the monitoring of these lesions after treatment.
Abstract: Nine patients with lung cancer without brain metastasis were studied pre and post brain prophylactic radiotherapy (30 Gy) to verify the effect of radiation on the cognitive processes. The P3 component of event-related potentials was used in this study. The latencies pre and post-radiation were compared and a significant delay (p less than 0.01) was detected in patients after treatment. These results suggest that brain radiotherapy may produce a cognitive impairment, as reported by many Authors.
Abstract: Clinical data of 233 patients (202 definite and 31 probable MS) have been examined in relation to the following prognostic indicators: sex, age at onset, poussè frequency, interval between the first two relapses, initial symptomatology. Regression analysis technique and covariate analysis have been used versus the latest Expanded Disability Status Scale of each patients. Onset at younger age and a longer interval between the first two episodes have resulted statistically significant for a more favourable prognosis. The shift from a remitting toward a progressive course appears to happen within the first five years in 60% of the cases.
