Moritz Stuplich

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

PURPOSE In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Nimustine (ACNU) Plus Teniposide (VM26) in Recurrent Glioblastoma

Background: In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated glioblastoma (GBM). After establishing temozolomide as standard first-line therapy in GBM patients, the nimustine (ACNU)/teniposide (VM-26) combination has been employed as salvage chemotherapy for recurrent GBM. However, data on the toxicity and efficacy of this regimen in recurrent GBM are lacking. Patients and Methods: In two neurooncological centers, all patients with recurrent GBM treated with nimustine (90 mg/m2, day 1/42) and teniposide (45–70 mg/m2, days 1–3/42) were analyzed retrospectively for progression-free survival (PFS), overall survival (OS) and toxicity. Results: Thirty-five patients (median age 51 years, range 25–71 years) were identified. Six months after chemotherapy initiation, PFS was 29% and the median OS 6 months; 23% of patients were alive ≥1 year after initiation of nimustine-teniposide chemotherapy. Grade 4 hematotoxicity was observed in 12 of 35 patients (34%) and in 14 of 83 evaluable chemotherapy courses (17%). Conclusions: The benefit of the nimustine-teniposide combination is moderate in patients with recurrent GBM. The data support the efficacy of the nimustine-teniposide chemotherapy, but the rate of high-grade hematotoxicity is increased.

Ifosfamide, Carboplatin and Etoposide in Recurrent Malignant Glioma

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Non-enhancing primary CNS lymphoma

Primary central system lymphomas (PCNSL) are highly proliferative tumors that require aggressive treatment, e.g. using high-dose methotrexate-based chemotherapy. Early histological diagnosis is crucial for proper management of PCNSL. Histological diagnosis is obtained through stereotactic biopsy which is usually performed upon demonstration of the typical hallmarks of PCNSL on MRI. This includes large, preferentially periventricular, homogenously contrast-enhancing lesions [1]. Although the MRI presentation of PCNSL is relatively uniform regarding the appearance as homogenously contrast-enhancing lesion(s), the MRI presentation of PCNSL may very rarely be atypical [2, 3] and may lead to significant delay in diagnosis and therapy initiation in such patients. We here present a patient with the rare case of a PCNSL without contrastenhancement. An 81-year-old patient presented with a 5-week history of rapidly progressive dementia. On examination, he was disoriented and showed psychomotor slowing and gait difficulty. The Mini Mental state examination (MMSE) revealed 16/30 points. He was HIV negative and all serological and biochemical tests were normal. The CSF examination showed just a slight increase in protein content (556 mg/l), no pleocytosis and no atypical cells. The MRI of the brain taken without prior steroid treatment revealed diffuse white matter changes involving both hemispheres. No pathological contrast-enhancement could be detected (Fig. 1). A diagnosis of gliomatosis cerebri was initially suspected. A biopsy was taken from the right frontal lobe. Histological examination revealed a diffuse large cell lymphoma (non-Hodgkin’s lymphoma of germinal B cell origin; Fig. 2). The present case highlights the fact that, in very rare cases, PCNSL may present as a non-enhancing lesion. Non-enhancing presentation was found in 1% of patients in a large series of immunocompetent patients [1] and is just one form of atypical MRI presentation of PCNSL. Another atypical form is the presentation with a central nonenhancing necrosis; this is found in 6–17% of immunocompetent PCNSL patients [1]. PCNSL without contrast uptake are usually caused by angiotropic large cell lymphoma or intravascular lymphomatosis [4]. In contrast, the present case did not show a particular angiotropic pattern but had the typical pattern of a diffuse large cell lymphoma with some perivascular accentuation (Fig. 2c). Unusual non-enhancing presentation may lead to substantial prolongation of definitive diagnosis and start of therapy. This underlines that PCNSL without contrast-enhancement has to be kept in the differential diagnosis of diffuse white matter disorders. Also, it further supports the importance of histologic verification before the onset of therapy. Since histological diagnosis of PCNSL may be greatly hampered by the use of lympholytic steroids prior to biopsy, it M. L. Lachenmayer and E. Blasius contributed equally.

Liposomal cytarabine given concomitantly with radiotherapy in a patient with leptomeningeal metastasis from breast cancer

JO N 3 01 4 therapy (WBRT) and MTX lead to severe neurotoxic side effects [5]. Liposomal cytarabin (DepoCyte) may be an alternative to MTX with a longer application interval of 14 days. Patients treated with DepoCyte showed a longer time to neurological progression as compared to patients treated with MTX [6]. However, the combination of DepoCyte given concomitantly with WBRT has never been reported so far. Thus, it appears to be interesting to evaluate toxicity and efficacy of this combined treatment modality.

Carmustine (BCNU) plus Teniposide (VM26) in Recurrent Malignant Glioma

Background: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking. Methods: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m2, day 1/42) and VM26 (45-60 mg/m2, days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity. Results: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed. Conclusion: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.

Intravascular CNS lymphoma: Successful therapy using high-dose methotrexate-based polychemotherapy.

Intravascular diffuse large B-cell lymphoma limited to the CNS (cIVL) is a very rare malignant disorder characterized by a selective accumulation of neoplastic lymphocytes (usually B cells) within the lumen of CNS blood vessels but not in the brain parenchyma. In the past, treatment of cIVL with anthracycline-based regimens was unsatisfactory with very short survival times. In the case of cIVL presented here, high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab therapy was successful and led to a complete clinical and MRI remission which is ongoing 29 months after diagnosis.

Richter syndrome and brain involvement: low-grade lymphoma relapsing as cerebral high-grade lymphoma.

Richter syndrome (RS) describes the development of high-grade non-Hodgkin’s lymphoma (NHL) from low-grade NHL. RS isolated to the brain is very rare and has a poor prognosis. We describe the cases of high-grade large B-cell diffuse NHL in a 56-year-old male with chronic lymphocytic leukemia and in a 71-year-old female with previously unknown low-grade NHL, both with initial appearance of neurological symptoms. This report extends the literature of central nervous system RS and particularly highlights the importance of a thorough diagnostic evaluation of patients with low-grade NHL presenting with neurological symptoms.

Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial

BackgroundWe evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial.MethodsIn 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher’s exact test.ResultsAt baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42).ConclusionsThe tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity

Erratum to: Acta Neuropathol DOI 10.1007/s00401‑015‑1495‑z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly.