M. Hanse

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.

Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment

Leptomeningeal involvement in patients with CLL is relatively rare and the prognosis is usually considered to be poor. The authors reviewed all CLL patients treated in a tertiary referral center to assess the incidence and outcome of leptomeningeal involvement (LI) in CLL. They found an incidence of 1–2% of LI. Most of the patients with LI had a longterm survival, despite failure to clear the cerebrospinal fluid from tumor cells.

The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: Results of the randomised controlled phase 2 BELOB trial

BACKGROUND The BELOB study, a randomised controlled phase 2 trial comparing lomustine, bevacizumab and combined lomustine and bevacizumab in patients with recurrent glioblastoma, showed that the 9-month overall survival rate was most promising in the combination arm. Here we report the health-related quality of life (HRQoL) results, a secondary trial end-point. METHODS HRQoL was measured at baseline and every 6weeks until progression using the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20). HRQoL was assessed over time for five preselected scales (global health (GH), physical (PF) and social functioning (SF), motor dysfunction (MD) and communication deficit (CD)). Moreover, mean changes in HRQoL from baseline until progression were determined. RESULTS 138/148 patients with at least a baseline HRQoL assessment were analysed. Over time, HRQoL remained relatively stable in all treatment arms for all five scales, at least during the first three treatment cycles. More than half (54-61%) of the patients showed stable (<10 point change) or improved (⩾10 point change) HRQoL during their progression-free time, except for SF (43%), irrespective of treatment arm. Deterioration of mean HRQoL was most profound at disease progression for all scales except SF, which deteriorated earlier in disease course. Compared to baseline, 40% of patients had clinically relevant (⩾10 points) worse GH, PF and SF, while 44% and 31% had increased MD and CD at disease progression, irrespective of treatment arm. CONCLUSIONS Bevacizumab, whether or not in combination with lomustine, did not negatively affect HRQoL in patients treated for recurrent glioblastoma in this randomised study.

Hemangioblastomatosis in a patient with von Hippel-Lindau disease

A woman developed a cerebellar hemangioblastoma in 1991 at the age of 17 and von Hippel-Lindau disease was diagnosed. She underwent five craniotomies for recurrent hemangioblastoma. In 2001 she had a laminectomy for an intramedullar hemangioblastoma at C2-C3 level. In 2004 a renal cell carcinoma was found and a partial nephrectomy was performed. A few weeks after her last craniotomy in July 2005 she developed progressive right hemisensory disturbances and sensory ataxia. Spinal MRI showed leptomeningeal contrast enhancement around the entire spinal cord (see Figure). The sensory ataxia progressed and she got tetraparesis, most severe proximally in her arms, especially myotome C4. Although hemangioblastoma are not very radiosensitive, radiotherapy was started because of the rapid clinical deterioration. High-dose total neuraxis radiotherapy was considered to toxic. It was judged that most of her clinical complaints could be attributed to the cervical spine. Also the MRI showed the most severe lesions at the cervical region. Therefore she was treated from C1 to Th1 (30 · 1.8 Gy) combined with dexamethasone (2 · 8 mg). During radiotherapy she developed also symptoms outside the radiotherapy field (thoracal radiculopathy). As the main problem in VHL is uncontrolled angiogenesis by overexpressing VEGF and VEGF receptors, Thalidomide (400 mg, later 600 mg) was added. Thalidomide inhibits angiogenesis induced by VEGF [1]. Despite the treatment she developed a total tetraplegia and died 3 months after diagnosis as a result of respiratory failure. This syndrome appears to result from delayed growth of subarachnoid tumor cells disseminated by surgery. Hemangioblastomatosis is also seen in hemangioblastoma patients without von Hippel-Lindau disease and it is thought that additional genes are likely to be the source of this malignant behaviour [2].

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial

Background:Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.Methods:In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.Results:The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18–0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05–0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.Conclusion:CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

NIMG-13. RADIOLOGICAL RESPONSE ASSESSMENT IN THE ERA OF BEVACIZUMAB: RANO OR VOLUMETRY? A REPORT FROM THE BELOB TRIAL

Purpose: Response assessment in brain tumors is currently done with the 2D Response Assessment in Neuro-Oncology (RANO) criteria. However, bevacizumab-treated patients may show pseudoresponse on contrast enhanced T1w- (T1w+C), and more infiltrative growth on T2w/FLAIR images at recurrence. We assessed whether in recurrent glioblastoma volumetric methods improve assessment of progressive disease (PD) over the RANO criteria, by correlating PD with overall survival (OS), the golden endpoint in oncology studies.

Two exceptional phenomena in an anaplastic oligo-astrocytoma

M.C.J. Hanse, J.H. Franssen, H.P. Sleeboom, C.F.E. Hoffmann and W. Taal Neuro-Oncology Unit, Daniel den Hoed Oncology Center Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Neurology Catharina Ziekenhuis, Eindhoven, The Netherlands; Department of Radiotherapy Haga Ziekenhuis, The Hague, The Netherlands; Department of Medical Oncology Haga Ziekenhuis, The Hague, The Netherlands; Department of Neurosurgery Haga Ziekenhuis, The Hague, The Netherlands