Relapse patterns in pediatric embryonal central nervous system tumors

To evaluate in a single center retrospectively the efficacy and tolerability of a weekly regimen, which alternates temozolomide (TMZ) in patients with recurrent or progressive high-grade glioma (HGG). From January 2005 until June 2011, 54 patients with recurrent or progressive HGG were treated with TMZ 150 mg/m²/day on days 1–7 and 15–21 of a 28-day cycle (“one week on–one week off” scheme; TMZ 7/14) with individual dose adjustment depending on toxicity. The majority of patients (n = 48, 89 %) was treated at first tumor recurrence or progression. All patients had received prior radiotherapy with or without concomitantly administered TMZ and, optionally, adjuvant chemotherapy. After initiation of TMZ 7/14, MRI was obtained every 8–12 weeks. Tumor response or progression was assessed according to Macdonald criteria. Blood examinations were performed weekly. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). A total of 434 treatment weeks with TMZ 7/14 were delivered. The median number of treatment weeks was 7 (range, 1–41 weeks). No grade 4 hematological toxicity and no opportunistic infections occurred. Patients with neutropenia were not observed. Two patients developed grade 3 and 4 patients grade 2 leukocytopenia. Thrombocytopenia grade 3 and grade 2 occurred in 4 patients and 6 patients, respectively. The progression-free survival (PFS) rate at 6 months was 43 %. Median PFS from treatment initiation was 18 weeks (95 % CI, 14–22 weeks) and median overall survival (OS) was 37 weeks (95 % CI, 31–42 weeks). The rates for PFS and OS at 1 year were 24 and 28 %, respectively. Our data suggest that treatment with TMZ 7/14 is safe and effective in patients with recurrent or progressive HGG.     

Retrospective study of nivolumab for patients with recurrent high grade gliomas

Introduction

Patients with recurrent high-grade gliomas (HGG) have limited treatment options. HGG utilize the PD-1 pathway to evade immune responses. Checkpoint inhibitors have demonstrated safety and clinical activity in patients with recurrent glioblastoma. We explored the efficacy of nivolumab in recurrent HGG with a primary objective of progression free survival (PFS) and overall survival (OS).

Methods

We retrospectively analyzed HGG patients treated with nivolumab in our institution. We included patients with advanced HGG who received nivolumab at their oncologist’s decision. Patients received nivolumab 3 mg/kg every 2 weeks until confirmed progression, intolerable toxicity, death, or physician decision. Radiographic assessments were performed every 8 weeks.

Results

Between April 2015 and October 2017, 50 HGG patients received nivolumab. 43 patients received nivolumab with bevacizumab. 44 patients were bevacizumab refractory and 7 patients received nivolumab monotherapy. All had received prior radiation and chemotherapy. 39 adverse events (AEs) were noted [most commonly fatigue (16%) and constipation (10%)]. 4 (8%) patients experienced grade 3–4 AEs. 36 (72%) patients experienced stable disease (SD) at the 2-month assessment. Median duration of SD was 4.3 months (5.1 months in the bevacizumab naïve, 3.8 months in the bevacizumab refractory). Median PFS was 4.3 months (95% CI 3.5–5.3); median OS was 6.5 months (95% CI 6.0–8.8).

Conclusion

Treatment with nivolumab therapy was associated with a manageable safety profile. In a subset of patients, there was disease stabilization in heavily pre-treated recurrent HGG.

     

Phase II study of sunitinib malate in patients with recurrent high-grade glioma

Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-??, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ??3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8?C2.5) and 3.8 (95% CI 2.2?C5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-??, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.     

Bevacizumab in recurrent high-grade pediatric gliomas

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m². Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald''s criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference.     

Treatment of children with recurrent high grade gliomas with a bevacizumab containing regimen

Children with recurrent high grade gliomas (HGG) have a dismal outcome with a median progression free survival (PFS) of 12 weeks. Adults with recurrent HGG treated with irinotecan and bevacizumab reportedly have a 63% response rate and a median PFS of 23 weeks. There is a paucity of corresponding published pediatric data. We retrospectively reviewed the records of patients less than 21 years of age with recurrent or progressive WHO grade 3–4 gliomas who were treated with bevacizumab containing regimens at our institution between January 2006 and September 2008. We identified eight patients. Six out of eight patients received irinotecan, temozolomide and bevacizumab, one patient received irinotecan and bevacizumab, and one patient received CCNU and bevacizumab. Three patients had stable disease for 30–93 weeks. The remaining five patients developed progressive disease within 17 weeks. The median PFS was 15 weeks and the 6-month PFS was 38%. Contrast enhancing disease responded or remained stable in five out of seven patients whereas non-enhancing disease progressed in three out of four patients. New distant non-enhancing lesions developed in three patients. The most common side effects included diarrhea, vomiting, thrombocytopenia and neutropenia. Bevacizumab was well tolerated when used in combination with conventional chemotherapy (irinotecan in most cases). PFS in our cohort was much shorter and the response rate was inferior in this small cohort of patients when compared with published adult data. However, bevacizumab containing regimens might be effective in a subset of pediatric patients, especially those with predominantly contrast-enhancing disease.     

Carboplatin chemotherapy in patients with recurrent high-grade glioma

Aims

To investigate the efficacy of carboplatin chemotherapy in patients with recurrent high-grade glioma (HGG) who had received at least two previous lines of chemotherapy.

Materials and methods

Case notes of patients who had received chemotherapy with carboplatin for recurrent HGG between June 2005 and July 2008 were reviewed. Baseline characteristics and outcomes after treatment were recorded.

Results

Twenty-six patients received carboplatin as third- or fourth-line chemotherapy for recurrent HGG (grade III glioma n = 8; grade IV glioma n = 18). The median number of cycles completed was 2.5. The most common reasons for discontinuing treatment were progressive disease and death (n = 19; 73%). Three patients (12%) had a partial response, five (19%) had stable disease and 18 (69%) had progressive disease. Six month progression-free survival was 23% (25% in patients with grade III glioma and 22% in patients with grade IV glioma). The median time to disease progression from the first treatment with carboplatin was 9.0 weeks. The median survival was 19.4 weeks (27.9 weeks for patients with grade III glioma and 8.1 weeks for patients with grade IV glioma). Among patients with either stable disease or a partial response, the median survival was 42.4 weeks compared with 11.7 weeks in patients with progressive disease (hazard ratio for death with progressive disease on treatment: 5.02; 95% confidence interval 1.64-15.4; P = 0.005). Carboplatin was well tolerated overall.

Conclusions

Single-agent carboplatin has modest activity in patients with recurrent HGG who have received at least two lines of chemotherapy. The overall time to progression is short and over two-thirds of patients had to discontinue treatment due to progressive disease. Among the small proportion of patients achieving stable disease or a partial response to treatment, the median survival is improved. More effective but well tolerated regimens are required for this patient population.     

Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma

A retrospective study of bevacizumab only in adults with recurrent temozolomide (TMZ)-refractory anaplastic astrocytoma (AA) with a primary objective of determining progression free survival (PFS). There is no standard therapy for alkylator-resistant AA and hence a need exists for new therapies. Twenty-five patients (15 men; 10 women) ages 26–63 (median 50), with radiographically recurrent AA were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and alkylator-based chemotherapy. Fourteen patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab (10 mg/kg), once every 2 weeks (defined as a single cycle). Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial two cycles of bevacizumab and subsequently after every four cycles of bevacizumab. All patients were evaluable for toxicity and response. A total of 360 cycles of bevacizumab (median 14 cycles; range 2–40) was administered. Bevacizumab-related toxicity included fatigue (14 patients; 2 grade 3), leukopenia (7; 1 grade 3), deep vein thrombosis (5; 2 grade 3), hypertension (5; 1 grade 3), anemia (4; 0 grade 3) and wound dehiscence (1; 1 grade 3). Sixteen patients (64%) demonstrated a partial radiographic response, 2 (8.0%) stable disease and 7 (28%) progressive disease following two cycles of bevacizumab. Time to tumor progression ranged from 1 to 20 months (median: 7). Survival ranged from 2 to 23 months (median: 9.0). 6-month and 12-month PFS were 60 and 20%, respectively. Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator refractory AA.     

A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study

BACKGROUND: An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG). METHODS: Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata. RESULTS: Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >or=4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/-standard deviation) was 14%+/-6% for HGG, 6%+/-6% for MB/PNET and 3%+/-3% for BSG. CONCLUSIONS: Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies.     

Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology)

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6 % (95 % CI 29.3–55.2) and a median PFS of 5.2 months (95 % CI 3.8–6.6). The median OS was 9.1 months (95 % CI 7.3–10.3). Twenty-eight patients (52 %) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60 %). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76 %), while the diffuse non-enhancing progression accounted for 9.5 %. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22 %) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4 %) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.     

Salvage therapy with single agent bevacizumab for recurrent glioblastoma

A retrospective evaluation of single agent bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no standard therapy for recurrent GBM after failure of alkylator-based chemotherapy. A total of 50 adults, ages 36–70 years (median 64), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, post-radiotherapy temozolomide and in 34 patients, one salvage regimen (PCV: 21, cyclophosphamide: 13). A total of 13 patients underwent repeat surgery. Patients were treated at first or second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab. A total of 468 cycles of bevacizumab (median 2 cycles; range 1–30) was administered. Bevacizumab-related toxicity included fatigue (16 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (7; 1 grade 3), deep vein thrombosis (4; 1 grade 3) and wound dehiscence (2; 1 grade 3). 21 patients (42%) demonstrated a partial radiographic response and 29 (58%) progressive disease following 1–2 cycles of bevacizumab. Time to tumor progression ranged from 0.5 to 15 months (median: 1.0 months). Survival ranged from 2 to 17 months (median: 8.5 months). 6-month and 12-month PFS were 42% and 22% respectively. Single agent bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator-refractory GBM.     

Salvage therapy with bendamustine for methotrexate refractory recurrent primary CNS lymphoma: a retrospective case series

There is comparatively limited therapy for recurrent primary central nervous system lymphoma (PCNSL). Salvage therapies include re-challenge with high-dose methotrexate (HD-MTX), whole brain radiotherapy, temozolomide, topotecan and premetrexed. Bendamustine is a novel bifunctional alkylator with established activity in B cell systemic lymphomas but never previously evaluated in PCNSL. The objective of the current study was to assess response and toxicity of bendamustine in recurrent PCNSL following prior salvage therapy in a retrospective case series. Twelve adults [six males; six females: median age 59 years (range 43–74)] with HD-MTX refractory recurrent PCNSL were treated with bendamustine. All patients were treated at second recurrence following failure of prior salvage therapy. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m²/day) administered once every 4 weeks (maximum number of cycles 6). Toxicities seen were Grade 2 (24 episodes in 10 patients) and 3 (10 episodes in 5 patients) only and included lymphopenia (8 patients), hyperglycemia (7 patients), fatigue (7 patients) and nausea (4 patients). The median number of cycles of therapy was 3.5 (range 1–6). Radiographic response was progressive disease in 5 (42 %), stable disease in 1 (8 %), partial response in 3 (25 %) and complete response in 3 (25 %). Median progression free survival (PFS) was 3.5 months (range 1–14 months) and 6-month PFS was 33 %. In this small retrospective series of select patients with recurrent PCNSL refractory to HD-MTX, bendamustine appears to have modest single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.     

A phase II trial of bevacizumab and everolimus as treatment for patients with refractory,progressive intracranial meningioma

Meningiomas that progress after standard therapies are challenging with limited effective chemotherapy options. This phase II trial evaluated the efficacy of everolimus plus bevacizumab in patients with recurrent, progressive meningioma after treatment with surgical resection and local radiotherapy when appropriate. Patients with recurrent meningioma (WHO grade I, II, or III) following standard treatments with surgical resection and radiotherapy received bevacizumab (10 mg/kg IV days 1 and 15) and everolimus (10 mg PO daily) each 28 day cycle. Evaluation of response occurred every 2 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, overall survival and safety. Seventeen patients with a median age of 59 years (29–84) received study treatment. WHO grades at study entry included: I, 5 (29?%); II, 7 (41?%); III, 4 (24?%); unknown, 1 (6?%). Patients received a median of 8 cycles (1–37); all patients are off study treatment. A best response of SD was observed in 15 patients (88?%), and 6 patients had SD for >12 months. Overall median PFS was 22 months (95?% CI 4.5–26.8) and was greater for patients with WHO grade II and III compared to grade I tumors (22.0 months vs 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1). However, other grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The combination of everolimus and bevacizumab was well-tolerated, and produced stable disease in 88?% of patients; the median duration of disease stabilization of 10 months (2–29). The median PFS from this prospective trial was similar to previous retrospective reports of bevacizumab in the treatment of recurrent meningioma.     

Metastatic melanoma: prognostic factors and survival in patients with brain metastases

There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy, re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration never previously evaluated in AG. Assess response and toxicity of bendamustine in recurrent AG in a phase II trial. Adults with radiation and temozolomide refractory recurrent AG were treated with bendamustine. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m²/day) administered once every 4 weeks. Success of treatment was defined as progression free survival (PFS) at 6 months of 40?% or better. Twenty-six adults [16 males; 10 females: median age 40 years (range 30–65)] were treated, 12 at first recurrence and 17 at second recurrence. Prior salvage therapy included re-resection (14), chemotherapy (11) and re-radiation (2). Grade 3 treatment-related toxicities included lymphopenia (11 patients; Grade 4 in 3), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in one patient each. One patient discontinued therapy due to toxicity. There were five instances of bendamustine dose delays all due to lymphopenia. There were no dose reductions due to toxicity. The median number of cycles of therapy was 3 (range 1–8). Best radiographic response was progressive disease in 12 (46?%), stable disease in 13 (50?%) and partial response in 1 (4?%). Median, 6- and 12-month PFS was 2.7 months (range 1–52), 27 and 8?% respectively. In patients with recurrent AG refractory to Z, bendamustine has manageable toxicity and modest single agent activity though not meeting pre-specified study criteria.     

Recurrent high-grade glioma treated with bevacizumab: prognostic value of MGMT methylation, EGFR status and pretreatment MRI in determining response and survival

Although bevacizumab represented an important advance in treatment of recurrent high-grade gliomas (HGG), responses occur in fewer than half of patients. There are no validated biomarkers for anti-angiogenic therapy that are available for routine clinical use. We assessed the prognostic values of imaging and molecular markers in this patient population. MRI scans from 191 patients with recurrent HGG obtained prior to initiating bevacizumab were reviewed for areas of enhancement, necrosis, T2/FLAIR abnormality, and ADC values. Serial MRI scans following the initiation of bevacizumab were evaluated for response and progression. Non-radiographic markers including EGFR and MGMT status were also assessed with respect to response and patient survival. 65 of 191 patients (34 %) showed complete or partial response at the time of their best response MRI and demonstrated longer progression free survival (PFS) and overall survival (OS) compared to the group without response (PFS: 6.9 vs 3.5 months, OS: 10.9 vs 6.1 months). Minimum ADC values within enhancing and non-enhancing regions were lower in responders compared to those of non-responders (1,099 vs 984 × 10^?6 mm²/s, p = 0.006). Smaller enhancing area was associated with longer OS (HR = 1.99, p = 0.017). The ratio of T2/FLAIR to enhancing area was prognostic of OS for only the Grade III HGG subgroup (HR = 0.14, p = 0.004). Area of enhancing tumor at baseline can stratify survival in patients with recurrent HGG treated with bevacizumab. The extent of edema relative to enhancing area may have a prognostic role specific to Grade III HGG.     

Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma

The prognosis for patients with recurrent glioblastomas (GBMs) is dismal, with a median survival of 3–6 months. We performed a phase II trial of low-dose continuous (metronomic) treatment using temozolomide (TMZ) for recurrent GBMs. TMZ-refractory patients with GBM who experienced disease recurrence or progression during or after the cyclic treatment schedule of TMZ after surgery and standard radiotherapy were eligible. This phase II trial included 2 cohorts of patients. The initial cohort, comprising 10 patients, received TMZ at 40 mg/m² everyday. After this regimen seemed safe and effective, the metronomic schedule was changed to 50 mg/m² everyday. The second cohort, comprising 28 patients, received TMZ at 50 mg/m² everyday. The 6-month progression-free survival in all 38 patients was 32.5% (95% CI: 29.3%–35.8%) and the 6-month overall survival was 56.0% (95% CI: 36.2%–75.8%). One patient developed a grade III neutropenia, grade II thrombocytopenia in 3 patients, and grade II increase of liver enzyme (GOT/GPT) in 3 patients. Of all patients included in this study, 4 patients were withdrawn from this study because of side effects including sustained hematological disorders, cryptococcal infection, and cellulitis. In a response group, quality of life measured with short form-36 was well preserved, when compared with the pretreatment status. Metronomic treatment of TMZ is an effective treatment for recurrent GBM that is even refractory to conventional treatment of TMZ and has acceptable toxicity.     

Correlation between arterial spin-labeling perfusion and histopathological vascular density of pediatric intracranial tumors

A single institution retrospective evaluation of nivolumab following disease progression on bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no accepted therapy for recurrent GBM after failure of bevacizumab. 16 adults, ages 52–72 years (median 62), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, and post-radiotherapy temozolomide. Bevacizumab (with or without lomustine) was administered to all patients at first recurrence. Patients were treated with nivolumab only (3 mg/kg) once every 2 weeks at second recurrence. One cycle of nivolumab was defined as 2 treatments. Neurological evaluation was performed bi-weekly and neuroradiographic assessment every 4 weeks. A total of 37 treatment cycles (median 2) were administered of nivolumab in which there were 14 Grade 2 adverse events (AEs) and Grade 3 AEs in two patients. No Grade 4 or 5 AEs were seen. Following 1 month of nivolumab, seven patients demonstrated progressive disease and discontinued therapy. No patient demonstrated a response though nine patients demonstrated neuroradiographic stable response. Survival in the entire cohort ranged from 2 to 6 months with a median of 3.5 months (CI 2.8, 4.2). Median and 6-month PFS at 6 months was 2.0 months (range 1–5 months; CI 1.3, 2.7) and 0% respectively. Nivolumab salvage therapy demonstrated no survival advantage in patients with recurrent bevacizumab refractory GBM emphasizing a continued unmet need in neuro-oncology.     

Second-line chemotherapy with low-dose CPT-11 and cisplatin for colorectal cancer resistant to 5-FU-based chemotherapy

Purpose With the aim of reducing the toxicities of irinotecan (CPT-11) while maintaining its antitumor effect, we treated colorectal cancer patients resistant to chemotherapy based on 5-fluorouracil (5-FU) with low-dose CPT-11 and cisplatin (CDDP).Methods CPT-11 (27 mg/m²) and CDDP (6 mg/m²) were administered on days 1, 8 and 15 every 4 weeks to 20 patients with recurrent or metastatic colorectal cancer. When toxicities were noted, administrations were delayed or the dose was reduced.Results No severe toxicity (i.e. grade 3 or more) was observed in this study. Nausea was observed in 50% of patients (10/20) and fatigue in 30% (6/20). Only four patients developed leukopenia (three grade 1 and one grade 2). Although the overall response rate was 15% (three partial response, seven no change, and ten progressive disease), the median time to progression was 7.0 months and the median survival time was 18.0 months. The treatment was well tolerated as outpatient therapy.Conclusion Low-dose CPT-11 and CDDP treatment should be considered as second-line chemotherapy for patients with recurrent or metastatic colorectal cancer resistant to 5-FU-based chemotherapy.     

Bevacizumab and re-irradiation for recurrent high grade gliomas: does sequence matter?

Purpose/objectives

We report the outcomes of the largest cohort to date of patients receiving both bevacizumab (BEV) and fractionated stereotactic radiotherapy (FSRT) for progressive or recurrent high grade glioma (HGG). Furthermore, the sequence of these two treatment regimens was analyzed to determine an optimal treatment paradigm for recurrent HGG.

Materials/methods

After Institutional Review Board approval, patients with pathologically confirmed WHO grade III anaplastic astrocytoma (AA) or IV glioblastoma multiforme (GBM) glioma who subsequently underwent re-irradiation at recurrence with FSRT were retrospectively reviewed. Patients from this group who had received BEV were also identified. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were analyzed as study endpoints. Date of recurrence was defined as the date of radiographic evidence of progressive/recurrent disease. Kaplan–Meier curves were generated utilizing a log-rank test with a p-value?≤?0.05 considered significant to compare treatment sequences in terms of survival outcomes.

Results

A total of 118 patients with recurrent/progressive HGG (GBM?=?87, AA?=?31) had received both BEV and FSRT. Patient characteristics were as follows: median KPS at recurrence was 80 (range 50–100); median age at recurrence was 57 years; median time to radiographic recurrence/progression was 10.8 months (mo) and 33.1% of patients had surgery for recurrence. The median time from the start of BEV to FSRT was 6.4 months and from FSRT to the start of BEV was 5.1 months. For the entire cohort, median overall survival (OS) was 26.7 months and median survival time (MST) from recurrence was 13.8 months (24.4 months and 11.9 months for GBM only). In patients that received BEV prior to FSRT (n?=?50), median OS and MST from recurrence were 25.2 and 13.3 months respectively. In patients receiving FSRT first (n?=?56), median OS and MST from recurrence were 28.8 months and 13.9 months, respectively. Sequencing of BEV and FSRT at recurrence was not significantly associated with OS (p?=?0.08) or median survival from recurrence (p?=?0.75).

Conclusions

The combination of FSRT and BEV for recurrent/progressive HGG provides promising results in terms of overall survival and survival from recurrence. Combining these treatment modalities appears to improve upon the historic outcomes of either treatment alone. The outcomes data from this study support the ongoing RTOG trial exploring the combination of BEV and FSRT for recurrent HGG.

     

Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma

BACKGROUND: The primary objective of this prospective phase 2 study of CPT-11 in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) was to evaluate 6-month progression-free survival (PFS). METHODS: Forty patients (27 men and 13 women) ages 17 to 58 years (median age, 38 years) with radiographically recurrent AA were treated. All patients had been treated previously with surgery, involved-field radiotherapy, and adjuvant chemotherapy. Fifteen patients were treated at first recurrence with an alternative chemotherapy. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks, which was defined operationally as a single cycle. Neurologic and neuroradiographic evaluations were performed every 9 weeks. RESULTS: All patients were evaluable for toxicity, and 39 patients were evaluable for response. In total, 302 cycles of CPT-11 (median, 6 cycles; range, 1-22 cycles) were administered. CPT-11-related toxicity included diarrhea (19 cycles), leukopenia (16 cycles), fatigue (11 cycles), anemia (6 cycles), delayed nausea/vomiting (5 cycles), neutropenia (5 cycles), and renal failure (1 patient, 1 toxic death). Two patients (5%) patients required erythrocyte transfusions. Nine patients (23%) demonstrated a radiographic complete response (1 patient) or partial response (8 patients), 16 patients (41%) demonstrated stable disease, and 14 patients (36%) had progressive disease after 3 cycles of CPT-11. The median time to tumor progression was 4.1 month. The median survival was 6.9 months, and the 6-month and 12-month PFS rates were 40% and 5%, respectively. CONCLUSIONS: CPT-11 demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent AA, all of whom had failed on prior temozolomide chemotherapy.     

尼莫司汀联合贝伐珠单抗治疗复发性高级别胶质瘤:附7例经验

背景与目的:多项荟萃分析(Meta-analysis)及研究显示,复发性高级别胶质瘤即便后续综合治疗,其客观反应率(objective response rate,ORR)、6个月无进展生存率(progression-free survival,PFS)仍然较低。因此,探索复发性高级别胶质瘤新的治疗策略十分必要。本文总结我们应用尼莫司汀(nimustine,ACNU)联合贝伐珠单抗(bevacizumab,Bev)治疗7例复发性高级别胶质瘤的临床经验,探讨其安全性与近期疗效。方法:7例复发性高级别胶质瘤均行ACNU联合Bev治疗。化疗方案的选择基于肿瘤组织DNA甲基转移酶(O6-methylguanine-DNAmethyltransferase,MGMT)的免疫组织化学检测结果以及甲基化特异PCR(MSP-PCR)检测MGMT启动子甲基化程度。MGMT阴性表达或MGMT启动子甲基化程度高者,给予ACNU,80~100mg/(m2.d),d1,静脉输注,四周方案;Bev用法:5mg/kg,静脉输注,每两周一次。结果 :7例患者共接受ACNU联合Bev治疗28次,中位3次(3~6次)。患者均可评价客观疗效,完全缓解(complete remission,CR)2例(28.6%),部分缓解(partial remission,PR)3例(42.9%),微效(minimal remission,MR)1例(14.3%),进展(progressive disease,PD)1例(14.3%)。疾病控制率(CR+PR+MR)为85.7%。中位PFS为4.2月(95%CI:3~7月),6个月的PFS为41.6%。最严重不良反应是Ⅳ度粒细胞减少症与白细胞减少症,各1例次(3.6%),Ⅲ度粒细胞减少症与白细胞减少症各2例次(7.1%)。最常见的轻至中度不良反应包括Ⅱ度脱发10例次(35.7%)、Ⅱ度粒细胞减少症与白细胞减少症各4例次(14.3%)、腹泻3例次(10.7%)、Ⅱ度疲乏2例次(7.1%)、高血压2例次(7.1%)。结论:ACNU联合Bev治疗复发性高级别胶质瘤患者是安全的,疗效也令人较满意。