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INTRODUCTION Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation. METHODS We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy. RESULTS 54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%). CONCLUSION the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.

BACKGROUND: Brain Tumours (BTs) have been widely evaluated using the 3,4-dihydroxy-6-18 fluoro-L-phenylalanine (F-18-FDOPA) PET. The aim of the study was to evaluate the role of PET FDOPA in low grade glioma (LGG). METHODS: We enrolled all patient affected by LGG. All patients underwent FDOPA PET and MRI examination. METHODS: Both FLAIR and contrast-enhanced T1-weighted sequences were considered for the response assessment to treatment in according to RANO criteria. The PET images were interpreted as positive when the lesion definitely increased F-FDOPA accumulation taking into consideration the background and the controlateral site. The slices with a maximal F-FDOPA uptake in the ROI were chosen for quantitative measurement of metabolic activity of the tracer [standardized uptake value (SUV)]. In order to evaluate the concordance between diagnostic test 1 (MRI) and diagnostic test 2 (FDOPA) we calculated the unweighted kappa statistic and its relative 95% Confidence interval (95%CI). This value was interpreted in a qualitative manner on the basis of the Landis and Koch classification criteria. RESULTS: We enrolled 56 (35 males and 21 females) patients affected by LGG. The mean age at diagnosis was 44.5 years. Out of the 56 patients recruited for this study, 23% were a newly diagnosed, 45% in chemotherapy treatment, and 32% were untreated but had a regular follow-up. The Kappa statistic for the whole sample was equal to 0.301 (95%CIs from 0.21 to 0.40) showing a fair concordance between the two tests in terms of diagnostic capability. We found a good correlations between residual volume and SUV max (r = 0.435, p = 0.002 by Spearman Rank Correlation Coefficient), indicating that the greater the residual volume, the higher the SUV max was. Also the multivariate analysis showed that a SUV max greater than 1.65 was the only independent predictor of disease progression (HR = 4.59, 95% CIs from 0.99 to 21.31, p = 0.054). This implies that a patient with a SUV max higher than 1.65 had an almost 5-fold increased risk of disease progression, regardless of its clinical and MRI characteristics. CONCLUSION: Our results confirm that PET 18F-FDOPA may be a role diagnostic and prognostic in patients with LGG.

AIM: The treatment of recurrent glioblastoma remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. METHODS: A multicenter, open-label, randomized (2:1), non-comparative phase II study (EudraCT:2011-001363-46; AVAREG-ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks, was conducted. Primary endpoint was overall survival at 6 months (OS6). RESULTS: 91 pts with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 years (range:28-78), PS was 0/1/2 in 42/35/14 pts. All pts were treated with RT/TMZ accordingly with EORTC 26981-22981/NCIC-CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At time of recurrence, 21 pts (23.1%) received re-resection before the study inclusion (13/8 pts in BEV/FTM arms). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI:48.4-74.5) and 73.3% (95%CI:54.1-87.7), OS9 was 37.9% (95%CI:25.5-51.6) and 46.7% (95%CI:28.3-65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI:5.8-9.2) in the BEV arm and 8.7 months (95%CI:6.3-15.4) in the FTM arm. PFS6 was 26.3% and 10.7%, respectively. In the BEV arm, OS6 and OS9 were 77.8% (95%CI:57.7-91.4) and 59.3% (95%CI:38.8-77.6) in pts =55 yrs, and were 48.4% (95%CI:30.1-66.9) and 19.3% (95%CI:7.4-37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts =55 yrs was 2.0 (95%CI:1.0-4.1, p = 0.05). G3-4 toxicity: thrombocytopenia 0% vs 21.9%, neutropenia 1.7% vs 12.5%, intestinal perforation and cerebral ischaemia/hemorrhage 3.4% vs 0%, pulmonary thromboembolism 1.7% vs 0%, and acute myocardial infarction 1.7% vs 0%, in the Bev and FTM arms respectively. CONCLUSIONS: BEV in recurrent GBM showed survival rates superimposable with FTM.

Brain tumors have been widely evaluated using the 3,4-dihydroxy-6-18fluoro-L-phenylalanine (18F-FDOPA) PET imaging. The aim of the study is to evaluate the role of 18F-FDOPA PET in low-grade glioma (LGG). We enrolled 60 patients (37 males and 23 females) affected with LGG; 23% were newly diagnosed, 45% were studied during treatment; and 32% were observed out of treatment during a periodic follow-up. All patients underwent 18F-FDOPA PET and MRI examination; both FLAIR and contrast-enhanced T1-weighted sequences were considered for the response assessment in according to RANO criteria. The PET images were interpreted as positive when the lesion presented definite tracer accumulation considering background and controlateral site. The slices with a maximal 18F-FDOPA uptake in the ROI were chosen for quantitative measurement of metabolic activity of the tracer [standardized uptake value (SUV)]. The concordance between MRI and 18F-FDOPA PET was evaluated measuring the unweighted kappa statistic and its relative 95% Confidence interval (95%CI). The Kappa statistic for the whole sample was equal to 0.301 (95%CIs from 0.21 to 0.40) showing a fair concordance between the two tests in terms of diagnostic ability. We found a good correlations between residual volume and SUV max (r = 0.435, p = 0.002 by Spearman Rank Correlation Coefficient), indicating that the greater the residual volume, higher the SUV max is. Also multivariate analysis documented that a SUV max greater than 1.75 represents the only independent predictor of disease progression (HR = 4.59, 95% CIs from 0.99 to 21.31, p = .054). This implies that a patient with a SUV max higher than 1.75 yielded an almost 5-fold increased risk of disease progression, regardless of its clinical and MRI characteristics. Present results confirm that 18F-FDOPA PET imaging may assume a relevant role mainly in the prognostic assessment of patients affected with primary and recurrent LGG.

BACKGROUND: Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), a monoclonal antibody against VEGF, has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the possible predictive value of circulating VEGF, von Willebrand factor (vWF) and procoagulant factors in patients with recurrent GBM. METHODS: We conducted a prospective analysis of recurrent malignant gliomas (MG) patients treated with BV alone or in combination with chemotherapy performing serial evaluations of plasma VEGF levels, vWF antigen and procoagulant factors such as thrombin-antithrombin complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), Factor VIII and D-Dimer. Baseline, and post-treatment samples were collected at each administration of BV. RESULTS: Forty-nine recurrent MGs (glioblastoma = 26, astrocytoma = 17, oligodendroglioma = 6) who received BV at 10 mg/kg intravenously every 3 weeks, of whom 26 in association with chemotherapy were included in the study. Median age was 45 years (22-73), median Karnofsky performance status was 80 (60-100). Out of the 48 evaluable, 17 partial responses (35%), 7 stable disease (15%) and 24 disease progressions (50%) were observed. At baseline all patients presented with laboratory signs of coagulation activation (i.e. high TAT and FVIII levels). Circulating plasma levels of VEGF and vWF antigen significantly increased in all patients post-treatment of BV (p = 0.0001 and 0.009 respectively). No responder patients showed significantly higher vWF antigen levels than responders (p = 0.01) after second administration of BV. CONCLUSIONS: These preliminary data suggest that low vWF antigen levels might help predict response in recurrent MG patients treated with BV. This marker should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment.

BACKGROUND: Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with High Grade Gliomas (HGG) but few options exist for the management of recurrent or resistant disease. Long survivors are often treated with more lines of chemotherapy (CT) after failure of second line treatment but no data are available about the real impact of third line of CT. METHODS: We retrospectively analyzed the clinical records of HGG patients treated with third line CT at the Regina Elena Cancer Institute in the last 10 years (2003-2013) with the aim to evaluate the benefit in term of time to treatment failure (TTF) and overall survival (OS). RESULTS: 62 HGG (31 GBM, 31 Anaplastic gliomas) were included in this analysis. Mean age was 43 y; 47 male, 15 female; all patients received in their previous history surgery (2 biopsy) radiotherapy and at least 2 line of chemotherapy (temozolomide and nitrosurea based CT). Third line treatment included bevacizumab (alone or in combination with citotoxic drugs) in 47% of cases and citotoxic drugs alone in 53% of cases. Median TTS was 3 months in both group of patients. TTF was significantly longer in patients with previous history higher than 3 years (5 months p 0.015) respect to patients with previous history shorter than 3 y (TTF 2 months). MGMT methilation status was obtained ony in 17 patients and was not significantly correlated to TTF or OS. OS after third line treatment resulted significantly longer in patients with histology different than GBM and in patients with less than 50 y at diagnosis. Clinical benefit with stable or improved Karnoky performance status after third line treatment was observed in 37% of patients. CONCLUSION: The role of third line chemotherapy in HGG progressing after second line treatment failure requires to be better defined in order to avoid futile treatment in HGG patients with short life expectancy.

Correspondence: Gianluigi Ferretti M.D., Ph.D., Division of Medical Oncology A, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. Telephone: 00390652665354; Fax: 00390652665637; e-mail: gia.fer@flashnet.it Received April 13, 2006; accepted for publication May 26, 2006. ©AlphaMed Press 1083-7159/2006/$20.00/0 Colozza et al. [1] recently presented an overview of four adjuvant trials with trastuzumab in patients with HER-2overexpressing and/or amplified breast cancers (the North Central Cancer Treatment Group Trial N9831, the National Surgical Adjuvant Breast and Bowel Project Trial B31, the Breast Cancer International Research Group Trial 006, and the HERceptin® Adjuvant study). A very recent study showed that a short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER-2/ neu gene [2]. In vitro studies indicated that the combination of trastuzumab and vinorelbine exerts synergistic activity [3]. In fact, the results of recent clinical studies of this combination in untreated or heavily pretreated patients with HER-2-positive metastatic breast cancer [4, 5] have shown high objective response rates. In vitro, the combination of trastuzumab with docetaxel exerts synergistic activity, as well [2]. This combination in untreated patients with HER-2-positive metastatic breast tumors showed remarkable efficacy [6]. Concerning the adjuvant setting, Joensuu et al. [2] randomly assigned 1,010 women with axillary node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER-2/ neu gene were assigned to receive or not to receive nine weekly trastuzumab infusions. Within the subgroup of patients with HER-2/neu-positive breast cancer, those who received trastuzumab had better 3-year recurrencefree survival than those who did not (hazard ratio [HR], 0.42; p = .01). Interestingly, the hazard ratio remained similar (0.41) when adjustment was made according to the type of chemotherapy given (trastuzumab combined with docetaxel or vinorelbine). Thus, even though, globally, recurrence-free survival at 3 years was better with docetaxel than with vinorelbine (HR, 0.58; p = .005), the concurrent administration of trastuzumab with one of these drugs was able to overcome this difference. Moreover, in the adjuvant setting, delayed administration of trastuzumab may be less effective than concurrent administration with paclitaxel [7]. Thus synergy for trastuzumab plus cytotoxic drug combinations is specific for HER-2-overexpressing tumor cells [3] and is not observed in HER-2-negative cells, which show different sensitivity to docetaxel or vinorelbine.

Correspondence: Gianluigi Ferretti, M.D., Ph.D., Department of Medical Oncology, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. Telephone: 011390652665354; Fax: 011390652665637; e-mail: gia.fer@flashnet.it Received February 1, 2006; accepted for publication March 16, 2006. ©AlphaMed Press 1083-7159/2006/$20.00/0 Concerning the controversies in the use of trastuzumab for early-stage breast cancer, Cianfrocca and Gradishar [1] have recently reported that an unplanned interim analysis of the North Central Cancer Treatment Group N9831 trial revealed a 36% relative reduction in the risk for recurrence for concurrent compared with sequential trastuzumab (p = .0114) [2], even though further follow-up is needed to ascertain whether this trend continues. Romond et al. [3] have recently presented the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. The authors conclude that trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. In trial B-31, 805 patients received doxorubicin and cyclophosphamide every 21 days for four cycles followed by paclitaxel every 3 weeks for four cycles plus weekly trastuzumab for 52 weeks; in only 59 patients, paclitaxel was given weekly for 12 weeks. In trial N9831, 808 patients were administered doxorubicin and cyclophosphamide as in trial B-31 but followed by 12 weekly doses of paclitaxel plus weekly trastuzumab for 52 weeks. It might be highlighted that exposure to lower and more frequent doses of paclitaxel could potentially exploit antiangiogenic and proapoptotic effects [4]. In metastatic breast cancer, weekly administration of paclitaxel has been reported to be superior to once-every-3-weeks administration [5]. As primary systemic chemotherapy, weekly paclitaxel, compared with once-every-3-weeks administration, improved the likelihood of pathologic complete remission [6]. By contrast, Romond et al. [3] assert that there was no evidence that the benefit of trastuzumab differed significantly between the B-31 and N9831 trials. The finding that the same effect of trastuzumab was observed in both the studies deserves further investigation, given the difference in the paclitaxel schedule.