Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged ≥18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15·4 months (IQR 13·8-18·1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7·4 months (95% CI 5·8-12·0) in the regorafenib group and 5·6 months (4·7-7·3) in the lomustine group (hazard ratio 0·50, 95% CI 0·33-0·75; log-rank p=0·0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. FUNDING: Veneto Institute of Oncology and Bayer Italy.

Temozolomide cytoreductive treatment in a giant cabergoline-resistant prolactin-secreting pituitary neuroendocrine tumor.

Dopamine agonists (DAs, especially cabergoline) are recommended as first-line treatment in patients with prolactin-secreting pituitary adenomas, to reduce hormone secretion and tumor size. Pituitary surgery, suggested in nonresponsive patients, cannot achieve a gross total resection or is not feasible in some cases. Temozolomide (TMZ) has been proposed in patients with aggressive pituitary neuroendocrine tumors (PitNETs) who do not respond to conventional treatments. We present a 47-year-old man with a giant (70×51×64 mm) prolactin-secreting PitNET. Cabergoline treatment (at first 1.5 mg/week, and then increased to 3.5 mg/week after 3 months) achieved prolactin suppression; however, magnetic resonance revealed a stable mass. After explanation of surgical complications, the patient rejected the procedure. Therefore, a primary neoadjuvant cytoreductive TMZ treatment was discussed during a meeting of the Pituitary Multidisciplinary Team, and added to cabergoline. After 13 cycles of TMZ (1 year of treatment), we observed dramatic reduction of the PitNET (from 18 cm of adenoma to 6 cm of necrotic tissue). MRI performed 4, 12, and 18 months after TMZ discontinuation revealed a stable residual PitNET, and 1.5 mg/week of cabergoline has been continued until today. Recently, the criteria for developing Pituitary Tumors Centers of Excellence have been proposed, indicating that a multidisciplinary team is the best care for patients. Surgery, rejected by the patient, could only achieve a partial resection; therefore, we decided to combine TMZ and cabergoline. An early initiation of TMZ could be considered in selected cases, especially when surgery could be only partially effective.

Good tolerability of maintenance temozolomide in glioblastoma patients after severe hematological toxicity during concomitant radiotherapy and temozolomide treatment: report of two cases.

Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.

Clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent glioblastoma: a mono-institutional retrospective study.

The optimal treatment of recurrent glioblastoma (GBM) in elderly patients is unclear. Fotemustine (FTM) is a third-generation nitrosourea showing efficacy in gliomas and it has been used with different schedules in adult patients. We performed, for the first time anywhere, a mono-institutional retrospective study to analyze the clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent GBM. Retrospectively, we analyzed all GBM patients 65 years or older previously treated with the combination of radiation therapy and temozolomide (TMZ), receiving an alternative FTM schedule as second-line treatment at our Oncological Center from October 2011 to October 2014 with an ECOG PS ≤ 2. FTM was administrated at 80 mg/m(2) every 2 weeks for five consecutive administrations (induction phase), and then every 4 weeks at 80 mg/m(2) as maintenance. We enrolled 44 patients, 33 males and 11 females; average age was 70 years. ECOG PS was 0-1 in 80 % of the patients. 38 patients relapsed during temozolomide (TMZ) therapy. MGMT methylation status was analyzed in 34 patients and MGMT was methylated in 53 % of the patients. The median progression free survival (PFS) and overall survival (OS) from FTM treatment was 4.1 months (95 % CI 3.1-5.2) and 7 months (95 % CI 5.2-8.4), respectively. Patients with MGMT methylated status and patients who relapsed after completing TMZ therapy had a longer PFS and OS from the beginning of FTM. Thrombocytopenia was the most frequent grade 3-4 haematological toxicity (9 %). The alternative schedule of FTM may be an active and safe treatment for elderly patients with recurrent glioblastoma, especially patients with methylated MGMT and who relapsed after completing temozolomide therapy.

Diagnostic value of plasma and urinary 2-hydroxyglutarate to identify patients with isocitrate dehydrogenase-mutated glioma.

BACKGROUND: Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert α-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma. MATERIALS AND METHODS: All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry. RESULTS: A total of 84 patients were enrolled: 38 with R132H-IDH1 mutated and 46 with wild type. Among the 38 patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high- and low-grade glioma, respectively. In all patients, we analyzed the mean 2HG concentration in the plasma, urine, and plasma/urine ratio (Ratio_2HG). We found a significant difference in the Ratio_2HG between patients with and without an IDH1 mutation (22.2 ± 8.7 vs. 15.6 ± 6.8; p < .0001). The optimal cutoff value for Ratio_2HG to identify IDH1 mutation was 19 (sensitivity, 63%; specificity, 76%; accuracy, 70%). In the patients with high-grade glioma only, the optimal cutoff value was 20 (sensitivity, 76%; specificity, 89%; accuracy, 84%; positive predictive value, 80%; negative predictive value, 86%). In 7 of 7 patients with high-grade glioma, we found a correlation between the Ratio_2HG value and the response to treatment. CONCLUSION: Ratio_2HG might be a predictor of the presence of IDH1 mutation. The measurement of 2HG could be useful for disease monitoring and also to assess the treatment effects in these patients.

Predictors of survival and effect of short (40 Gy) or standard-course (60 Gy) irradiation plus concomitant temozolomide in elderly patients with glioblastoma: a multicenter retrospective study of AINO (Italian Association of Neuro-Oncology).

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

What do cancer patients experience of the simultaneous care clinic? Results of a cross-sectional study on patient care satisfaction.

BACKGROUND: Veneto Institute of Oncology has activated a simultaneous care outpatient clinic (SCOC) in which cancer patients with advanced-stage cancer are evaluated by oncologist and palliative care specialists. This cross-sectional study investigated patients' perceptions of the quality of this service. MATERIALS AND METHODS: An ad-hoc self-administered questionnaire, developed by SCOC team, was used to assess the satisfaction of patients admitted at SCOC consultation. The questionnaire, in addition to the socio-demographic questions, contains eight questions with the Likert scale: time dedicated, feel listened to, feel understood, feel free to speak openly and to express doubts and concerns, feeling about information and indication received, level of empathy of health care and quality of the relationship, level of professional/quality of performance and utility of consultation, and one open-ended question. The questionnaire has been proposed to all 174 consecutively admitted patients at SCOC. RESULTS: One hundred and sixty-two patients filled in the questionnaire: 66.7% were male, median age was 71 years, 88.3% had metastatic disease. The time dedicated to SCOC consultation was judged more than adequate (55%) or adequate (35%) by 90% of subjects. Patients completely satisfied about being listened to were 92.5%, with 80.9% being completely satisfied with understanding of their issues and 92% with the freedom to speak and express doubts. Usefulness of the SCOC was rated as excellent by 40% and good by 54.4% of patients. No statistically significant differences were observed in the responses to the questions by gender, age (< or ≥70 years old) and type of tumor. CONCLUSION: Our study shows high levels of satisfactions after SCOC consultation in advanced cancer subjects. Patients' feedback confirmed that SCOC model was effective in helping them during their treatment journey and decision at the end of life. This study encouraged us to enhance our practice of SCOC consultation. IMPLICATIONS FOR PRACTICE: A joint evaluation of patients living with cancer by oncologist and palliative care team (SCOC-embedded model), has shown to enhance patients' experience/satisfaction with care-such as listening, understanding, receiving information, symptom control, and decision about future, independently of age, gender, and kind of tumor.

Cisplatin and temozolomide combination in the treatment of supratentorial anaplastic ependymoma.

Anaplastic ependymomas are rare tumors in adult patients. Maximal safe resection and use of radiation therapy are standard treatment approaches in patients with anaplastic ependymoma. Recurrent anaplastic ependymomas are treated by reoperation when the tumors are surgically accessible, by radiotherapy if not previously administered and by salvage chemotherapy. However, the role of chemotherapy is still unclear. A few retrospective studies showed interesting results with platinum-based regimens, while the administration of temozolomide alone demonstrated conflicting results. We present, for the first time, the case of a patient with anaplastic ependymoma refractory to platinum-based chemotherapy and temozolomide only, but showing a prolonged reduction of the lesion after receiving combination chemotherapy with cisplatin and temozolomide. A brief review of the literature on the treatment of anaplastic ependymoma follows.

Case report: The lesson from opioid withdrawal symptoms mimicking paraganglioma recurrence during opioid deprescribing in cancer pain.

Pain is one of the predominant and troublesome symptoms that burden cancer patients during their whole disease trajectory: adequate pain management is a fundamental component of cancer care. Opioid are the cornerstone of cancer pain relief therapy and their skillful management must be owned by physicians approaching cancer pain patients. In light of the increased survival of cancer patients due to advances in therapy, deprescription should be considered as a part of the opioid prescribing regime, from therapy initiation, dose titration, and changing or adding drugs, to switching or ceasing. In clinical practice, opioid tapering after pain remission could be challenging due to withdrawal symptoms' onset. Animal models and observations in patients with opioid addiction suggested that somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related process (mainly cortisol and catecholamines mediated). In this narrative review, we highlight how the lack of validated guidelines and tools for cancer patients can lead to a lower diagnostic awareness of opioid-related disorders, increasing the risk of developing withdrawal symptoms. We also described an experience-based approach to opioid withdrawal, starting from a case-report of a symptomatic patient with a history of metastatic pheochromocytoma-paraganglioma.

Advanced Adrenocortical Carcinoma: From Symptoms Control to Palliative Care.

The prognosis of patients with advanced adrenocortical carcinoma (ACC) is often poor: in the case of metastatic disease, five-year survival is reduced. Advanced disease is not a non-curable disease and, in referral centers, the multidisciplinary approach is the standard of care: if a shared decision regarding several treatments is available, including the correct timing for the performance of each one, overall survival is increased. However, many patients with advanced ACC experience severe psychological and physical symptoms secondary to the disease and the cancer treatments. These symptoms, combined with existential issues, debase the quality of the remaining life. Recent strong evidence from cancer research supports the early integration of palliative care principles and skills into the advanced cancer patient's trajectory, even when asymptomatic. A patient with ACC risks quickly suffering from symptoms/effects alongside the disease; therefore, early palliative care, in some cases concurrent with oncological treatment (simultaneous care), is suggested. The aims of this paper are to review current, advanced ACC approaches, highlight appropriate forms of ACC symptom management and suggest when and how palliative care can be incorporated into the ACC standard of care.

Simultaneous Care in Oncology: A 7-Year Experience at ESMO Designated Centre at Veneto Institute of Oncology, Italy.

Benefits of early palliative care referral in oncology are well-validated. At the Veneto Institute of Oncology-IRCCS, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients with advanced cancer are evaluated by an oncologist together with a palliative care team. We prospectively assessed SCOC patients' characteristics and SCOC outcomes through internal procedure indicators. Data were retrieved from the SCOC prospectively maintained database. There were 753 eligible patients. The median age was 68 years; primary tumor sites were gastrointestinal (75.2%), genitourinary (15.0%) and other sites (9.8%). Predominant symptoms were psychological issues (69.4%), appetite loss (67.5%) and pain (65.9%). Dyspnea was reported in 53 patients (7%) in the referral form, while it was detected in 226 patients (34.2%) during SCOC visits (p < 0.0001). Median survival of patients after the SCOC visit was 7.3 months. Survival estimates by the referring oncologist were significantly different from the actual survival. Psychological intervention was deemed necessary and undertaken in 34.6% of patients, and nutritional support was undertaken in 37.9% of patients. Activation of palliative care services was prompted for 77.7% of patients. Out of 357 patients whose place of death is known, 69.2% died at home, in hospice or residential care. With regard to indicators' assessment, the threshold was reached for 9 out of 11 parameters (81.8%) requested by the procedure. This study confirmed the importance of close collaboration between oncologists and palliative care teams in responding properly to cancer patients' needs. The introduction of a procedure with indicators allowed punctual assessment of a team's performance.

Simultaneous care in oncology: Assessment of benefit in relation to symptoms, sex, and age in 753 patients.

Background: Early activation of palliative care for patients with advanced cancer is central in the treatment trajectory. At the Veneto Institute of Oncology, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients are evaluated by an oncologist together with a palliative care team. Recently, we reported on consecutive patients admitted at SCOC from 2018 to 2021 in terms of appropriateness, process, and outcome indicators. Here, we report further analysis in the same group of 753 patients, evaluating other parameters and the correlation between symptom intensity, gender, age, and survival. Methods: SCOC data were retrieved from a prospectively maintained database. Results: Among the patients, 42.2% were women, and the median age was 68 years, with 46.7% of patients aged ≥70 years. The most prevalent disease type was gastrointestinal cancer (75.2%), and 90.9% of the patients had metastatic disease. The median score for the distress thermometer was 4; the vast majority of the patients (98.6%) reported physical problems, and 69.4% presented emotional issues. Younger women demonstrated a significantly greater median distress than other patients (p=0.0018). Almost all symptoms had a higher prevalence on the 0-3 Edmonton Symptom Assessment Scale (ESAS) score, except for fatigue. About 43.8% of the patients received systemic anticancer treatment (SAT) in the last 60 days of life, 15.0% of whom received SAT in the last month and 3.1% in the last 2 weeks. For some symptoms, women frequently had more ESAS >3. Pain and nausea were significantly less reported by older patients compared with younger adults. Men had a lower risk of having MUST score ≥ 2 (p=0.0311). Men and older patients showed a lower prognosis awareness (p=0.0011 and p=0.0049, respectively). Older patients received less SAT within the last 30 days of life (p=0.0006) and had death risk decreased by 20.0%. Conclusion: Our study identified two subgroups of patients with advanced cancer who require special attention and support due to important symptoms' burden detected by Patient Reported Outcome Measures tests: women and younger adults. These categories of patients require special attention and should be provided early access at SCOC. The role of an oncologist remains crucial to intercept all patients in need of early palliative care and balancing trade-offs of anticancer treatment in advanced metastatic disease.

Genetic, Epigenetic, and Immunologic Profiling of MMR-Deficient Relapsed Glioblastoma.

PURPOSE: In-depth characterization of recurrent glioblastoma (rGBM) might contribute to a better understanding of the mechanisms behind tumor progression and enable rGBM treatment with targeted drugs.Experimental Design: In this study, GBM samples were collected at diagnosis and recurrence from adult patients treated with Stupp protocol. Expression of mismatch repair (MMR) proteins was evaluated by IHC, followed by whole exome sequencing (WES) of tumor samples showing loss of MSH6 reactivity. Established genetic, epigenetic, and immunologic markers were assessed by standard methods and correlated with loss of MMR proteins and patient survival. RESULTS: Expression of MMR proteins was partially or completely lost in 25.9% rGBM samples. Specifically, 12 samples showed partial or total MSH6 expression reduction. Conversely, 96.4% of GBM samples at diagnosis expressed MMR markers. WES disclosed lack of variants in MMR genes in primary samples, whereas two MSH6-negative rGBM samples shared a c.3438+1G>A* splicing MSH6 variant with a potential loss of function effect. MSH6-negative rGBM specimens had high tumor mutational burden (TMB), but no microsatellite instability. In contrast, GBM samples with partial loss of MMR proteins disclosed low TMB. MMR-deficient rGBM showed significant telomere shortening and MGMT methylation and are characterized by highly heterogeneous MHC class I expression. CONCLUSIONS: Multilevel profiling of MMR-deficient rGBM uncovered hypermutated genotype uncoupled from enriched expression of immune-related markers. Assessment of MHC class I expression and TMB should be included in protocols aiming to identify rGBM patients potentially eligible for treatment with drugs targeting immune-checkpoint inhibitors.

Quality of Life Perception, Cognitive Function, and Psychological Status in a Real-world Population of Glioblastoma Patients Treated With Radiotherapy and Temozolomide: A Single-center Prospective Study.

BACKGROUND: Health-related quality of life (HRQoL), cognitive function, and psychological status represent an important focus during the treatment of glioblastoma patients. Nevertheless, few randomized, prospective clinical trials have analyzed these factors, and very little is known in the real-clinical world. We evaluated these characteristics in glioblastoma patients treated with standard first-line therapy outside clinical trials. PATIENTS AND METHODS: In total, 111 newly, histologically diagnosed glioblastoma patients treated at our oncology center with radiotherapy and temozolomide were prospectively enrolled. No patient was enrolled in an experimental clinical trial. We assessed HRQoL, cognitive function, and psychological status before starting treatment, at the end of radiotherapy, and every 3 months until 9 months after the end of radiotherapy using EORTC QLQ-C30, BN20, MMSE, and HADS questionnaires. RESULTS: Global health status, physical, cognitive, and social functioning remained unchanged throughout the study period. A statistically significant change was found in emotional functioning as well as a clinically meaningful amelioration in role functioning between the baseline assessment and 9 months after radiotherapy. Patients older than 65 years reported greater impairment on the bladder control scale than younger patients. When considering tumor location, global health status, communication deficit, and drowsiness, scores were significantly different between the right and left hemispheres. Female patients had a clinically relevant lower score for physical functioning at baseline and 3 months after radiation therapy. Female patients also had a clinically relevant lower depression score at 9 months after radiation therapy. CONCLUSIONS: In routine neurooncology practice, HRQoL, cognitive function, and psychological status did not worsen during first-line treatment in glioblastoma patients receiving standard radiotherapy and temozolomide treatment. However, some patient subgroups, such as elderly and female patients, may have different experiences with treatment, and further investigation is required.

Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). CONCLUSIONS: antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.

An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab.

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience.

BACKGROUND: To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. METHODS: Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. RESULTS: Twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. CONCLUSION: This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions.