Dieta Brandsma

Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial

BACKGROUND Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma. METHODS The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929). FINDINGS Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment. INTERPRETATION The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment. FUNDING Roche Nederland and KWF Kankerbestrijding.

Pseudoprogression and pseudoresponse in the treatment of gliomas.

Purpose of reviewTreatment response of brain tumours is typically evaluated with gadolinium-enhanced MRI using the Macdonald criteria. These criteria depend on changes in the area of enhancement. However, gadolinium enhancement of brain tumours primarily reflects impairment of the blood–brain barrier. Recent findingsCombined chemo-irradiation with temozolomide may induce in 20–30% of cases pseudoprogression, defined as an increase of contrast-enhancement and/or oedema on MRI without true tumour progression. Also, full-blown radiation necrosis may be more frequent after combined chemo-irradiation. After treatment with vascular endothelial growth factor receptor signalling pathway inhibitors pseudoresponse is frequent: a decrease in contrast-enhancement of brain tumours on MRI without a decrease of tumour activity. This to some extent explains the high response rate without a major increase in survival after treatment with these agents for recurrent glioblastoma. SummaryBoth pseudo-phenomenona confuse the assessment of outcome of brain tumours in clinical practice and in clinical trials. To overcome these issues, alternative endpoints and response criteria are being developed by an international working party [response assessment in neuro-oncology (RANO)]. It is as yet unclear to what extent alternative imaging tools (positron emission tomography and MRI techniques) provide more reliable indicators of outcome.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings

BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Leptomeningeal metastasis: A Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials

PURPOSE To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM). METHODS A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM. RESULTS A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis. CONCLUSION Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.

Neurological immune-related adverse events of ipilimumab

Ipilimumab enhances the T lymphocyte mediated immune response to both tumour cells and healthy tissue, improving survival in patients with metastatic melanoma but also leads to more immune-related adverse events (irAEs) than previously used treatments, such as dacarbazine. We present three patients with neurological irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain–Barré syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks, but can be life-threatening if unrecognised.

EANO guidelines for the diagnosis and treatment of meningiomas

Although meningiomas are the most common intracranial tumours, the level of evidence to provide recommendations for the diagnosis and treatment of meningiomas is low compared with other tumours such as high-grade gliomas. The meningioma task force of the European Association of Neuro-Oncology (EANO) assessed the scientific literature and composed a framework of the best possible evidence-based recommendations for health professionals. The provisional diagnosis of meningioma is mainly made by MRI. Definitive diagnosis, including histological classification, grading, and molecular profiling, requires a surgical procedure to obtain tumour tissue. Therefore, in many elderly patients, observation is the best therapeutic option. If therapy is deemed necessary, the standard treatment is gross total surgical resection including the involved dura. As an alternative, radiosurgery can be done for small tumours, or fractionated radiotherapy in large or previously treated tumours. Treatment concepts combining surgery and radiosurgery or fractionated radiotherapy, which enable treatment of the complete tumour volume with low morbidity, are being developed. Pharmacotherapy for meningiomas has remained largely experimental. However, antiangiogenic drugs, peptide receptor radionuclide therapy, and targeted agents are promising candidates for future pharmacological approaches to treat refractory meningiomas across all WHO grades.

Molecular targeted therapies and chemotherapy in malignant gliomas.

Purpose of review To review current developments in the field of chemotherapy and targeted treatment of high-grade glioma. Recent findings Two independent large phase III trials on adjuvant procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendroglial tumors have shown this improves progression-free survival, but not overall survival, regardless of 1p/19q status. If given sequentially, the timing of procarbazine, lomustine and vincristine chemotherapy has no clear effect on the survival of anaplastic oligodendroglioma. Virtually none of the many new targeted agents directed against pathways that are upregulated in high-grade gliomas has shown significant clinical activity as single agent in phase II studies. The exception are trials with the vascular endothelial growth factor signaling system inhibiting agents bevacizumab and AZD2171 (cediranib) that showed high response rates (which might be due to vessel normalization similar to the effects of steroid treatment) and promising 6-month progression-free survival rates in glioblastoma multiforme. Summary Further research to define the role of vascular endothelial growth factor inhibition in the management is indicated. For the many other targeted agents, a critical review of the pathological role of their targets in glioblastoma multiforme is required, especially if combination regimens are investigated. The role of combined chemo-irradiation for non-glioblastoma multiforme high-grade glioma remains to be identified.

Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab.

Until recently, dacarbazine (DTIC) was the only registered chemotherapeutic drug for systemic treatment of metastatic melanoma. Patients with progressive disease during DTIC treatment can now also be treated with ipilimumab, a human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor. Binding of ipilimumab to the CTLA-4 receptor enhances the immune response of T-lymphocytes, resulting in an offensive against the tumor and an increased median survival of patients with metastatic melanoma [1]. Few data are available on the effect of ipilimumab on central nervous system (CNS) metastases of melanoma [2, 3]. Here, we report a patient with stage IV melanoma, who showed a remarkable response of leptomeningeal metastases (LM) after whole brain radiotherapy (WBRT) and ipilimumab treatment. In January 2009, a 63-year-old woman was diagnosed with lung metastases of a melanoma. DTIC (800 mg/m, q3 weeks) was initiated. In May 2010, after 17 courses, treatment was discontinued due to progression of lung metastases. Concurrently, the patient complained of morning headache, nausea and vomiting. Neurological examination showed no abnormalities. MRI of the brain demonstrated a hyperintense signal in the cerebellar foliae on FLAIR images (Fig. 1a) and slight contrast enhancement of the leptomeninges on T1 images with gadolinium (Fig. 1b). No brain metastases were detected. According to the Dutch guidelines, LM was diagnosed [4–8]. The patient received WBRT (5 9 4 Gy) and low dose dexamethasone. However, her neurological symptoms did not diminish. In June 2010 ipilimumab (3 mg/kg, q3 weeks, four courses) was initiated. After the first course morning headache, nausea, and vomiting disappeared. After three courses the patient developed low grade dermatitis and diarrhea, which both recovered spontaneously. Repeated neurological examination after four courses of ipilimumab showed a slight dexamethasone-induced myopathy and some hearing loss due to the WBRT. The radiological signs of LM on MRI of the brain had disappeared and the CT-thorax showed regression of the lung metastases. On last followup, in October 2011, there were no signs of CNS recurrence on MRI (Fig. 1c, d) and lung metastases were stable. The patient had no complaints and she was near fully active in daily life (WHO 1). This is the first case report describing a metastatic melanoma patient with LM demonstrating a complete clinical and radiological response of LM after WBRT and four courses of ipilimumab. One should consider that, following the USA National Comprehensive Cancer Network (NCCN) CNS tumors section guidelines, CSF examination and MRI of the spine I. Bot (&) D. Brandsma Department of Neuro-oncology, Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands e-mail: i.bot@neuro.umcn.nl

Leptomeningeal metastases: A RANO proposal for response criteria

Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use.

Symptomatic brain metastases from small-cell carcinoma of the urinary bladder: The Netherlands Cancer Institute experience and literature review

BACKGROUND The incidence of symptomatic brain metastases in small-cell carcinoma of the urinary bladder (SCBC) is unknown. This precludes advice about prophylactic cranial irradiation (PCI). PATIENTS AND METHODS The medical records of all patients with SCBC seen at The Netherlands Cancer Institute from 1993 to 2009 (n = 51) were reviewed. Limited disease (LD) was defined as any pT, cN₀₋₁, and cM₁. Patients with LD were offered bladder-preserving treatment involving combined chemoradiotherapy. Patients with extensive disease (ED) were treated with palliative chemotherapy. PCI was not applied in any patient. RESULTS Among 39 patients with LD, median disease-specific survival was 35 months. Four developed symptomatic brain metastases after a median follow-up of 15 months (range 3-24) and were treated with whole-brain radiotherapy. No patient with ED developed symptomatic brain metastases during a median follow-up of 6 months. The reported incidence of brain metastases in SCBC in the literature ranges between 0% and 40%. On the basis of all reported series, the pooled estimate of the cumulative incidence of brain metastases is 10.5% (95% confidence interval 7.5% to 14.1%). CONCLUSIONS The incidence of symptomatic brain metastases from SCBC is significantly lower than that from small-cell lung cancer. Therefore, we do not routinely advise PCI in patients with SCBC.