- The Role of Molecular Diagnostics in the Management of Patients with Gliomas. [Journal Article, Review]
- Curr Treat Options Oncol 2016 Oct; 17(10):51.
The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diagnosis. Reclassification of gliomas by molecular similarity beyond histological boundaries improves outcome prediction and will increasingly guide treatment decisions. This change in paradigms implies more personalized and eventually more efficient therapeutic approaches, but the era of molecular targeted therapies for gliomas is yet at its onset. Promising results of molecularly targeted therapies in genetically less complex gliomas with circumscribed growth such as subependymal giant cell astrocytoma or pilocytic astrocytoma support further development of molecularly targeted therapies. In diffuse gliomas, several molecular markers that predict benefit from alkylating agent chemotherapy have been identified in recent years. For example, co-deletion of chromosome arms 1p and 19q predicts benefit from polychemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) in patients with anaplastic oligodendroglioma, and the presence of 1p/19q co-deletion was integrated as a defining feature of oligodendroglial tumors in the revised WHO classification. However, the tremendous increase in knowledge of molecular drivers of diffuse gliomas on genomic, epigenetic, and gene expression levels has not yet translated into effective molecular targeted therapies. Multiple reasons account for the failure of early clinical trials of molecularly targeted therapies in diffuse gliomas, including the lack of molecular entry controls as well as pharmacokinetic and pharmacodynamics issues, but the key challenge of specifically targeting the molecular backbone of diffuse gliomas is probably extensive clonal heterogeneity. A more profound understanding of clonal selection, alternative activation of oncogenic signaling pathways, and genomic instability is warranted to identify effective combination treatments and ultimately improve survival.
- Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. [JOURNAL ARTICLE]
- Oncotarget 2016 Jul 28.
Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.
- Targeting homologous recombination by pharmacological inhibitors enhances the killing response of glioblastoma cells treated with alkylating drugs. [JOURNAL ARTICLE]
- Mol Cancer Ther 2016 Jul 29.
Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First and second line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNUs) lomustine, nimustine, fotemustine and carmustine. These agents target the tumor DNA, forming O6-chloroethylguanine adducts and secondary DNA interstrand crosslinks (ICLs). These crosslinks are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacological inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggests that pharmacological inhibition of HR, e.g. by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs.
- Case of a miniature dachshund with a primitive neuroectodermal tumor confined to the forebrain region treated with a combination of surgery and chemotherapy. [JOURNAL ARTICLE]
- J Vet Med Sci 2016 Jul 18.
A miniature dachshund aged 9 years and 7 months with a history of polyuria/polydipsia and depression was referred. General physical and neurological examinations revealed no obvious abnormalities. MRI of the brain revealed a large space-occupying lesion in the left frontal lobe. This was surgically removed and pathologically diagnosed as a primitive neuroectodermal tumor (PNET). Although the clinical signs had been improved, follow-up MRI revealed recurrence of the tumor. Lomustine was administered, but 1 year after surgery, the dog exhibited cluster seizures and died. This is the first reported case of a dog with PNET confined to the forebrain region treated by surgical resection in combination with chemotherapy, as observed by repeated follow-up MRI.
- A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. [JOURNAL ARTICLE]
- J Neurooncol 2016 Jul 12.
Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.
- Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. [JOURNAL ARTICLE]
- Neuro Oncol 2016 Jul 1.
Optimal treatment and precise classification for anaplastic glioma are needed.The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2).Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMP(pos) with (CIMP(codel)) versus without 1p/19 co-deletion (CIMP(non-codel)) versus CIMP(neg). but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMP(codel) tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMP(neg). tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy.There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology.clinicaltrials.gov Identifier: NCT00717210.
- Chemotherapy for Adults with Malignant Glioma: A Systematic Review and Network Meta-analysis. [JOURNAL ARTICLE]
- Turk Neurosurg 2015 Aug 25.
Malignant glioma is the most common primary brain tumor in adults and the survival rate has remained very low. Thus, determining the optimal treatment for patients can be challenging. To compare the efficacy of common therapies, we performed network meta-analysis to estimate the efficacy and safety among procarbazine, lomustine, vincristine, temozolomide, bevacizumab plus temozolomide, and placebo for patients with malignant glioma.Relevant studies (as of March, 2014) were identified by searching PubMed, Embase, and Central databases. The primary endpoint of the analysis was the overall survival (OS) and progression-free survival (PFS) of glioma patients.Nine trials with a total of 3472 patients were included in our network meta-analyses. Compared with placebo, bevacizumab plus temozolomide was associated with the highest estimates of OS and PFS for 12 and 24 months (12 month OS odds ratio [OR]: 2.44; 95% credibility interval [CrIs]: 0.76-9.69; 24 month OS OR: 2.56; 95% CrIs: 1.12-5.24; 12 month PFS OR: 6.76; 95% CrIs: 2.80-17.34; 24 month PFS OR: 3.69; 95% CrIs: 0.62-28.63). However, bevacizumab plus temozolomide did not significantly improve OS or PFS compared to temozolomide alone.The results of this analysis suggest that bevacizumab plus temozolomide combination therapy is not significantly more effective than temozolomide alone in improving survival of glioma patients. Moreover, bevacizumab was associated with higher hematologic toxicities. Based on the results, we suggest that bevacizumab should be used with caution in glioma patients. Additional randomized controlled trials are required to confirm this finding.
- A retrospective evaluation of lomustine (CeeNU) in 32 treatment naïve cats with intermediate to large cell gastrointestinal lymphoma (2006-2013). [JOURNAL ARTICLE]
- Vet Comp Oncol 2016 Jun 9.
Multi-drug chemotherapy protocols for feline lymphoma have demonstrated variable efficacy and tolerability. In phase I trials, lomustine has demonstrated efficacy for cats with lymphoma though its use for treatment naïve feline intermediate/large cell gastrointestinal (GI) lymphoma remains unknown. This study evaluated the efficacy and tolerability of lomustine for the treatment of feline GI lymphoma. Thirty-two cats with histologically or cytologically confirmed intermediate/large cell GI lymphoma were evaluated retrospectively. Factors assessed included clinical signs, hematologic/biochemical parameters and use of l-asparaginase at induction. A response rate of 50% (16/32), with median duration of response of 302 days (range 64-1450 days), was found. Median progression-free interval was 132 days (range 31-1450 days), with overall median survival time of 108 days (range 4-1488 days). History of hyporexia, presence of anaemia and dose of lomustine were significantly associated with progression-free survival. Overall, lomustine is a well-tolerated and effective treatment for feline GI lymphoma.
- Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. [Journal Article]
- PLoS One 2016; 11(5):e0156369.
Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma.This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm.Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted.ClinicalTrials.gov NCT01310855.
- Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models. [JOURNAL ARTICLE]
- Neuro Oncol 2016 May 10.
Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, used in combination with 5-fluorocytosine (5-FC) kills tumor by local production of 5-fluorouracil (5-FU), inducing local and systemic immunotherapeutic response resulting in long-term survival after cessation of 5-FC. Toca 511 and Toca FC (oral extended-release 5-FC) are under investigation in patients with recurrent high-grade glioma. Lomustine is a treatment option for patients with high-grade glioma.We investigated the effects of lomustine combined with Toca 511 + 5-FC in syngeneic orthotopic glioma models. Safety and survival were evaluated in immune-competent rat F98 and mouse Tu-2449 models comparing Toca 511 + 5-FC to lomustine + 5-FC or the combination of Toca 511 + 5-FC + lomustine. After intracranial implantation of tumor, Toca 511 was delivered transcranially followed by cycles of intraperitoneal 5-FC with or without lomustine at the first or fourth cycle.Coadministration of 5-FC with lomustine was well tolerated. In F98, combination Toca 511 + 5-FC and lomustine increased median survival, but "cures" were not achieved. In Tu-2449, combination Toca 511 + 5-FC and lomustine increased median survival and resulted in high numbers of cure. Rejection of tumor rechallenge occurred after treatment with Toca 511 + 5-FC or combined with lomustine, but not with lomustine + 5-FC. Mixed lymphocyte-tumor cell reactions using splenocytes from cured animals showed robust killing of target cells in an effector:target ratio-dependent manner with Toca 511 + 5-FC and Toca 511 + 5-FC + lomustine day 10.The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murine glioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression.