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- 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. [JOURNAL ARTICLE]
- Lancet Oncol 2014 Jul 14.
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.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).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.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.Roche Nederland and KWF Kankerbestrijding.
- Cutaneous T-cell lymphoma in two captive Tasmanian devils (Sarcophilus harrisii). [Journal Article]
- J Zoo Wildl Med 2014 Jun; 45(2):367-71.
Two captive adult female Tasmanian devils (Sarcophilus harrisii) were investigated for pruritis and dermatitis. In both cases skin lesions consisted of multifocal, superficial patches of crusting, hyperkeratosis, and ulceration. Lesions started on the ventral surfaces of the animal but then appeared on the dorsum as the disease progressed. In both animals, a diagnosis of cutaneous T-cell lymphoma was made based on histologic appearance of skin biopsies using immunohistochemistry. Attempt at treatment with lomustine 20 mg p.o. once every 3 wk in one individual did not slow progression of the condition. As a result of their propensity for developing neoplastic conditions, the use of chemotherapeutic agents in Tasmanian devils warrants further investigation.
- Treatment of Children With Central Nervous System Primitive Neuroectodermal Tumors/Pinealoblastomas in the Prospective Multicentric Trial HIT 2000 Using Hyperfractionated Radiation Therapy Followed by Maintenance Chemotherapy. [Journal Article]
- Int J Radiat Oncol Biol Phys 2014 Jul 15; 89(4):863-71.
The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4.After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine).Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (±standard error [SE]) were each 58% (±10%) for the entire cohort: CNS-PNET was 53% (±13); pinealoblastoma was 64% (±15%; P=.524 and P=.627, respectively).Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.
- Multiple cutaneous histiocytomas treated with lomustine in a dog. [JOURNAL ARTICLE]
- Vet Dermatol 2014 Jun 25.
Histiocytoma is a common benign neoplasm of young dogs. Multiple histiocytomas are rare. Surgical or medical treatment of solitary tumours is not required in the majority of cases because the tumour usually undergoes spontaneous regression. Therapy is required when lesions are persistent, recurrent, ulcerated or in uncomfortable locations.To describe a case of canine multiple cutaneous histiocytomas treated with lomustine.A 5-year-old miniature Pinscher dog was presented with multiple, disseminated, alopecic cutaneous nodules, with no associated systemic signs on initial presentation.Histopathological examination of skin biopsies and immunocytochemistry of biopsy imprints were performed. Inguinal lymph node, liver, spleen and bone marrow cytological examination and abdominal ultrasound examination were also performed.The clinical, histopathological and immunocytochemical findings supported a diagnosis of canine multiple cutaneous histiocytomas. Owing to the increasing number and size of the nodules, medical treatment was initiated. Prednisone and ciclosporin resulted in worsening of lesions. Lomustine orally once monthly led to complete resolution followed by relapse. Metabolic disorders such as increased serum alanine transaminase and alkaline phosphatase activities were recorded, and therapy was stopped. Increase in size of the tumours, severe dullness and anorexia led the owner to elect euthanasia.To the best of the authors' knowledge, this is the first case report of canine multiple cutaneous histiocytomas treated with lomustine. Lomustine is effective in histiocytic diseases, but adverse effects must be considered because they can be severe and life threatening.
- Retrospective study of using carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. [JOURNAL ARTICLE]
- Neuro Oncol 2014 Jun 23.
Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen.In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment.Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen.The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.
- Can bevacizumab prolong survival for glioblastoma patients through multiple lines of therapy? [Journal Article]
- Future Oncol 2014 May; 10(7):1137-45.
Glioblastoma has a poor prognosis accompanied by debilitating neurological symptoms and impaired quality of life. Effective treatment strategies are needed, beyond the current standard of care (SOC), to improve outcomes. Glioblastomas are highly vascularized with elevated levels of VEGF, representing an appropriate target for selective therapies. The role of the anti-VEGF agent bevacizumab in newly diagnosed and recurrent glioblastoma is not fully clear at this time. Although bevacizumab has demonstrated improvements in progression-free survival in newly diagnosed and recurrent glioblastoma, there remain challenges in assessing disease progression after antiangiogenic treatment. The bevacizumab mechanism of action suggests a rationale for continuing bevacizumab treatment through multiple lines of therapy, strengthened by longer progression-free and overall survival observed with bevacizumab continuation beyond progression in a Phase III study in metastatic colorectal cancer and in pooled analyses of Phase II trials in glioblastoma. A novel study (randomized, double-blind, Phase IIIb; TAMIGA [MO28347]) aims to evaluate whether continuing bevacizumab plus lomustine (as second-line therapy) and SOC (third line and beyond) improves survival compared with placebo plus lomustine and then placebo plus SOC in patients with glioblastoma who progressed after first-line bevacizumab plus SOC.
- Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia(R)) in canine mast cell tumor. [JOURNAL ARTICLE]
- BMC Vet Res 2014 May 6; 10(1):105.
Mast cell tumors (MCTs) are the most common skin tumors in dogs and exhibit variable biologic behavior. Mutations in the c-kit proto-oncogene are associated with the tumorigenesis of MCTs, resulting in growth factor-independent and constitutive phosphorylation of the KIT receptor tyrosine kinase (RTK). Toceranib (TOC) phosphate (Palladia(R)) is a KIT RTK inhibitor that has biological activity against MCTs. Despite these benefits, patients ultimately develop resistance to TOC. Therefore, there is a need to identify distinguishing clinical and molecular features of resistance in this population.The canine C2 mastocytoma cell line contains an activating mutation in c-kit. Three TOC-resistant C2 sublines (TR1, TR2, TR3) were established over seven months by growing cells in increasing concentrations of TOC. TOC inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-naive, parental C2 line (IC50 < 10 nM). In contrast, the three sublines were resistant to growth inhibition by TOC (IC50 > 1,000 nM) and phosphorylation of the KIT receptor was less inhibited compared to the TOC-sensitive C2 cells. Interestingly, sensitivity to three structurally distinct KIT RTK inhibitors was variable among the sublines, and all 3 sublines retained sensitivity to the cytotoxic agents vinblastine and lomustine. Sequencing of c-kit revealed secondary mutations in the juxtamembrane and tyrosine kinase domains of the resistant sublines. These included point mutations in TR1 (Q574R, M835T), TR2 (K724R), and TR3 (K580R, R584G, A620S). Additionally, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines compared to the parental line. C2, TR1, TR2, and TR3 cells demonstrated minimal P-glycoprotein (P-gp) activity and no functional P-gp.This study demonstrates the development of an in vitro model of acquired resistance to targeted therapy in canine MCTs harboring a c-kit-activating mutation. This model may be used to investigate the molecular basis of and strategies to overcome TOC resistance.
- Addition of lomustine for bevacizumab-refractory recurrent glioblastoma. [JOURNAL ARTICLE]
- Acta Oncol 2014 May 26.:1-4.
- Update on treatment strategies for anaplastic glioma: a review of literature. [JOURNAL ARTICLE]
- Neurol Sci 2014 May 25.
Anaplastic gliomas (AG) include 6-10% of all newly diagnoses of primary brain tumors. They have an unfavourable prognosis and, to date, there is not an established treatment universally recognized. Four recent randomized clinical trials were identified for a total of 1,170 patients (anaplastic-astrocytomas, anaplasticoligoastrocytoma, anaplastic-oligodendroglioma), in order to define the better sequence and timing of chemo-radiotherapy, Three studies compared radiotherapy (RT) treatment vs. radio-chemotherapy with procarbazine-lomustine-vincristine (PCV) or temozolomide (TMZ) or dibromodulcitol and bichloroethylnitrosurea (DBD/BCNU) and only one compared RT vs chemotherapy (CT) with PCV or TMZ. Results show no significant differences in terms of PFS/OS between RT/CT alone or combined treatment although a trend toward an improvement of OS was observed after RT + CT treatment (m-OS in RT + adjuvant PCV was 42.3 vs. 30.6 months in RT alone p=0.0003). Grade 3-4 mielotoxicity has been observed in almost all cases of patients treated with PCV + RT. None of four studies reviewed conducted a head to head comparison between PCV vs. TMZ. Only a study randomized patients to PCV/TMZ without however providing data in terms of PSF and OS between the two treatments. It found no significant differences in PFS from initial RT and adjuvant CT (PCV-TMZ) at progression compared to initial CT followed by RT at progression. The optimal treatment of AG should reasonably consider not only the histology as well as the molecular markers of the tumor, but also clinical conditions, age of patients, life expectancy, Karnofsky-performance-status and tumor resection to achieve in future the personalization of care.