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Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: Results of a multiinstitutional study (SJHG-98)
Abstract
The role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.
Patients ages 3-21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5-day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), were analyzed during Cycles 1 and 3.
Thirty-three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n=5) or toxicity (n=1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty-nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one-third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1-year survival rate was 48% (standard error, 8%).
The administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children.
... In particular, temozolomide (TMZ) is limited to salvage therapy with moderate effectiveness since DILGGs are low-grade tumors. Bevacizumab showed a discrete clinical and radiological improvement in recurrent disease after TMZ and RT failure [19][20][21]. ...
... EMGs are usually resistant to RT since a radiological and clinical response is appreciable in only 13% of patients. The combination of TMZ and bevacizumab has shown a discrete efficacy in RT failures [19][20][21]. As already described in the treatment of DILGGs, radiation necrosis and pseudoprogression may be distinguished from tumor progression via advanced MRI sequences [5,9]. ...
The 2021 WHO (World Health Organization) classification of brain tumors incorporated the rapid advances in the molecular, genetic, and pathogenesis understanding of brain tumor pathogenesis, behavior, and treatment response. It revolutionized brain tumor classification by placing great emphasis on molecular types and completely splitting adult-type and pediatric-type diffuse gliomas. Brainstem gliomas (BSGs) are the leading primary tumors of the brainstem, although they are quite uncommon in adults compared with the pediatric population, representing less than 2% of adult gliomas. Surgery is not always the treatment of choice since resection is rarely feasible and does not improve overall survival, and biopsies are not generally performed since the location is treacherous. Therefore, MRI (Magnetic Resonance Imaging) without and with gadolinium administration represents the optimal noninvasive radiological technique to suggest brainstem gliomas diagnosis, plan a multidisciplinary treatment and for follow-up evaluations. The MRI protocol encompasses morphological sequences as well as functional and advanced sequences, such as DWI/ADC (Diffusion-Weighted Imaging/Apparent Diffusion Coefficient), DTI (Diffusion Tensor Imaging), PWI (Perfusion-Weighted Imaging), and MRS (Magnetic Resonance Spectroscopy), which improve the accuracy of the diagnosis of BSGs by adding substantial information regarding the cellularity, the infiltrative behavior toward the v fiber tracts, the vascularity, and the molecular changes. Brainstem gliomas have been divided into four categories on the basis of their MRI radiological appearance, including diffuse intrinsic low-grade gliomas, enhancing malignant gliomas, localized tectal gliomas, and other forms. The aim of our review is to provide insight into the role of advanced MRI sequences in the diagnosis and follow-up of adult brainstem gliomas.
... Treatment of brainstem gliomas includes steroids, surgery, RT, and chemotherapy [11][12][13][14] . Chemotherapy has limited effect in brainstem gliomas [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] . Temozolomide and RT combination has been standard approach in treatment of brainstem gliomas [11][12][13][14][15][16][18][19][20][21]27,28 . ...
... Chemotherapy has limited effect in brainstem gliomas [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] . Temozolomide and RT combination has been standard approach in treatment of brainstem gliomas [11][12][13][14][15][16][18][19][20][21]27,28 . ...
Brainstem tumors are rare pathologies, brainstem glioblastoma is even rarer. We report three pediatric patients who underwent subtotal tumor resection for brainstem tumors diagnosed as brainstem glioblastoma. The clinical courses and treatment procedures were discussed alongside a comprehensive literature review. Treatment of brainstem high-grade gliomas includes steroids, surgery, radiotherapy, and chemotherapy. However, none of these treatment modalities effectively prolongs survival time. According to literature, the median overall survival of these patients are approximately between 9 to 12 months. Glioblastoma has a poor prognosis in pediatric patients with high-grade brainstem gliomas. Radiotherapy is associated with a decreased risk of mortality at 9 months but not long-term. Öz Beyin sapı tümörleri nadir görülen patolojilerdir, beyin sapı glioblastomu daha da nadirdir. Beyin sapı tümörleri için subtotal tümör rezeksiyonu uygulanan ve beyin sapı glioblastomu tanısı alan üç pediatrik hastayı sunmaktayız. Bu hastaların klinik gidişatlarını ve tedavi prosedürlerini, kapsamlı bir literatür taraması eşliğinde tartışmaktayız. Beyin sapında yerleşimli yüksek dereceli gliomaların tedavisinde steroidler, cerrahi rezeksiyon, radyoterapi ve kemoterapi bulunmaktadır. Bununla birlikte, bu tedavi yöntemlerinden hiçbiri hayatta kalma süresini etkili bir şekilde uzatmamaktadır. Literatüre göre, bu hastaların medyan genel sağ kalımı yaklaşık 9 ila 12 ay arasındadır. Glioblastom histopatolojisi, yüksek dereceli beyin sapı gliomaları olan pediatrik hastalarda kötü prognoz göstergesidir. Radyoterapi, uzun vadede değil ancak ilk 9 aylık süreçte mortalite riskinde azalma ile ilişkili olarak tespit edilmiştir.
... Radiation therapy is the standard treatment of these tumors, which at best provides temporary neurological and radiographic improvement [8,9]. Various strategies for delivering radiation therapy (i.e.: hypo-or hyper-fractionated irradiation +/-sensitizers) have failed to improve OS for these children, at times with unacceptable toxicities [10][11][12][13][14][15][16][17][18]. ...
... Other pre-irradiation chemotherapy strategies have failed to show improved EFS and OS [22,26,27]. In addition to the pre-irradiation chemotherapy strategies detailed above, numerous efforts over the years have attempted to use chemotherapy during irradiation, but this also failed to provide any additional survival benefit [11][12][13][14][15][16][17][18]. ...
Background
The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG.
Methods
Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on “Head-Start” I and II protocols (HSI and HSII). Treatment included Induction with 4–5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation.
Results
We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9–55%) and 38% (95% CI 14–63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression.
Conclusions
Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.
... Despite the initial positive responses observed among children with high-grade gliomas treated in phase I trials, 12,13 Broniscer et al. 16 reported a disappointing response to TMZ in children with DIPG. Accordingly, Cohen et al. found no improvement in the outcome of these children receiving concurrent TMZ and RT, followed by adjuvant TMZ for a total of 10 cycles. ...
... Therefore, the survival and response rate of children treated with RT and TMZ did not differ from the historical data, showing PFS and OS ranging from 5 to 8.8 months and 7 to 16 months, respectively. 21 According to these studies, [16][17][18][19][20] our results are not encouraging. Although a majority of our cases showed some neurological recovery after the conclusion of the initial concurrent RT-TMZ phase, allowing a reduction of steroid dose, the time to progression ranged from 3.4 to 15.3 months (median: 7.15 months). ...
Background:
The purpose of this study was to assess the efficacy and toxicity of radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG).
Methods:
Patients younger than 18 years with newly diagnosed DIPG were enrolled. Children were treated with focal RT along with concurrent daily TMZ. Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ was given every 28 days up to 12 cycles or progression disease.
Results:
Fifteen children with a median age of 9 years were enrolled. Fourteenth out of the 15 patients completed the chemoradiotherapy. The toxicity associated with TMZ was primarily haematopoietic. At a median follow-up of 15 months 13 children had died and 2 children were alive with progressive disease. No patient experienced complete response (CR). The median time to progression was 7.15 months.
Conclusion:
Chemoradiotherapy with TMZ followed by adjuvant TMZ did not improve the poor prognosis associated with DIPG in children.
... Other causes of lesions in the brainstem other than tumors include: vascular malformations 63 , encephalitis 64 , injuries 65 , demyelinating disorders 66 , and hamartomas 47 . In particular, brainstem gliomas can be associated with neurofibromatosis type 1, a clinical entity that tends to have a far more indolent course than DIPG 67 . ...
... In fact, radiosensitizers have already been employed in numerous clinical trials [57][58][59] , but none of these therapeutic agents has thus far resulted in a survival benefit. Notably, the e↵ects of temozolomide in conjunction with RT has been extensively studied in these patients, but no significant increase in survival was detected [60][61][62][63][64][65] , in contrast to adult GBM 66 . Nonetheless, given the lack of DIPG tissue and of in vitro and in vivo models available for preclinical research, the clinical use of agents to radiosensitize DIPG was not and could not be based on translational studies. ...
... Adjuvant chemotherapy was started 2 weeks after the end of radiotherapy. Temozolomide 180 mg/m 2 /day was administered as monotherapy in 10 patients on day 1-5 every 4 weeks for up to 12 cycles or until progression [12]. Other four patients received temozolomide 150 mg/m 2 /day on days 1-5, irinotecan 125 mg/m 2 /day on days 1 and 15, and bevacizumab 10 mg/kg/day on days 1 and 15 (TMZIRIBEV) [13]. ...
Purpose
Pediatric diffuse intrinsic pontine glioma (DIPG) is a fatal disease associated with a median survival of < 1 year despite aggressive treatments. This retrospective study analyzed the treatment outcomes of patients aged < 18 years who were diagnosed with DIPG between 2012 and 2022 and who received different chemotherapy regimens.
Methods
After radiotherapy, patients with DIPG received nimotuzumab-vinorelbine combination or temozolomide-containing therapy. When nimotuzumab was unavailable, it was replaced by vincristine, etoposide, and carboplatin/cyclophosphamide (VECC). Temozolomide was administered as a single agent or a part of the combination chemotherapy comprising temozolomide, irinotecan, and bevacizumab. Furthermore, 1- and 3-year overall survival (OS), progression-free survival (PFS), and median OS and PFS were analyzed.
Results
The median age of 40 patients with DIPG was 97 ± 46.93 (23–213) months; the median follow-up time was 12 months. One and 3-year OS were 35.0% and 7.5%, respectively. Median OS was 12 months in all patients (n = 40), and it was 16, 10, and 11 months in those who received first-line nimotuzumab-vinorelbine combination (n = 13), temozolomide-based (n = 14), and VECC (n = 6) chemotherapy regimens, respectively (p = 0.360). One patient who received gefitinib survived for 16 months. Conversely, patients who never received radiotherapy and any antineoplastic medicamentous therapy (n = 6) had a median OS of 4 months.
Conclusion
Nimotuzumab-vinorelbine combination therapy prolonged OS by 6 months compared with temozolomide-containing chemotherapy, although the difference was not statistically significant.
... Since Temodal approval, many PK clinical investigations of TMZ have been conducted, currently offering a bigger set of patients. Thirty-one (31) PK studies of TMZ in adult patients [3,6, and 12 PK studies conducted in children [58,[63][64][65][66][67][68][69][70][71][72][73], where the AUC and Cmax mean value are reported with or without CV, were selected for the determination of PK parameters in these two populations. Despite the limitations of pooling the data (e.g., quality not necessarily the same across all studies), the mean value of the AUC and Cmax calculated from the pooled data of these studies were reported in the Figures 6 and 7, as a function of the administrated dose in mg/m 2 . ...
Background:
Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO®) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules.
Methods:
In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m2 Ped-TMZ suspension and TMZ capsules (Temodal®) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (Cmax) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety.
Results:
Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and Cmax were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation.
Conclusions:
This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).
... [15] Other chemotherapeutic drugs such as interferon, bradykinin, RMP-7, cyclosporine, and tamoxifen with or without radiotherapy also did not show any survival advantage. [16,17] Despite the initial positive responses observed among children with high-grade gliomas treated with temozolomide in phase I trials, Broniscer et al. [18] reported that administration of temozolomide after radiotherapy, as an adjuvant therapy, does not change the poor outcome of children. He showed results of a multi-institutional study examining the role of neoadjuvant irinotecan followed by radiotherapy and then temozolomide. ...
Background: Brainstem gliomas account for approximately 25% of all posterior fossa tumors. In pediatric age group, it constitutes about 10% of all brain tumors. Brainstem glioma is an aggressive and lethal type of malignancy with poor outcome despite all treatments. Aim: We studied the incidence and treatment outcome in pediatric patients with brainstem glioma depending on their tumor volume presenting in our institution in last 5 years. Brain tumors comprised 2.95% of all cancers and brainstem gliomas were 8% of all brain tumors. Materials and Methods: Nine pediatric patients were included in this analysis, who were treated with localized external radiotherapy 54-59.4 Gy along with temozolomide 75 mg/m 2 during the whole course of radiotherapy. Results: The median survival in all these patients was 20 months and the overall 2 years survival is 44.4% (4/9). The median survival of patients with primary disease volume <40cc is 26 months whereas when the volume is more than 40cc the median survival is 13.5 months as calculated by Chi-square test. Conclusion: As this study includes a small number of patients with unknown histology and treated on the basis of magnetic resonance imaging findings, no definite opinion can be given as some patients may have a low-grade tumor. More studies are required to establish the relation of size of the tumor with survival.
... Several studies have been conducted on neoadjuvant, concurrent, and adjuvant chemotherapy in addition to radiotherapy to improve the prognosis of DIPG patients [24][25][26]. A phase II study evaluating the e cacy of chemoradiotherapy with TMZ followed by adjuvant TMZ conducted by the Children's Oncology Group showed a disappointing result [9]. ...
Purpose
This multicenter retrospective study aimed to investigate prognostic factors for survival, encompassing clinical and radiologic features and treatments, in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients treated with radiotherapy.
Methods
Patients <30 years of age who underwent radiotherapy as an initial treatment for DIPG between 2000 and 2018 were included; patients who did not undergo an MRI at diagnosis and those with pathologically diagnosed grade I glioma were excluded. We examined medical records of 162 patients collected from 10 participating centers in Korea. The patients’ clinical and radiological variables, molecular and histopathologic data, and treatment response were evaluated to identify the prognosticators for DIPG and estimate survival outcomes.
Results
The median follow-up period was 10.8 months (interquartile range, 7.5–18.1). The 1- and 2-year overall survival (OS) rates were 53.5% and 19.0%, respectively, with a median OS of 13.1 months. Long term survival rate (≥2 years) was 16.7%, and median OS was 43.6 months. Age (<10 years), poor performance status, treatment before 2010, and post-radiotherapy necrosis were independent prognostic factors related to poor OS in the multivariate analysis. In patients with increased post-radiotherapy necrosis, the median OS was 13.3 months for bevacizumab group and 11.4 months for no-bevacizumab group (P = 0.138).
Conclusion
Therapeutic strategy for DIPG has remained unchanged over time, and its prognosis remains poor. Our findings suggest that appropriate efforts are needed to reduce the occurrence of post-radiotherapy necrosis. Further well-designed clinical trials are recommended to improve the poor prognosis observed in DIPG patients.
... If there is an expression of MGMT recovery enzyme, it may take away the methyl or alkyl group and put the normal guanine in place and thus cause resistance to TMZ [25]. Despite the initial positive responses observed among children with high-grade gliomas treated in phase I trials, Broniscer et al. [4] reported a disappointing response to TMZ in children. Accordingly, Sirachainan et al. [26], Jalali et al. [15], Kim et al. [17], Chassot et al. [5], and Cohen et al. [7] established no improvement in the outcome of DIPG patients with RT-TMZ (Table 3). ...
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Background: The prognosis of children with diffuse intrinsic pontine gliomas (DIPG) is dismal. Despite various studies undertaken to improve outcome, radiotherapy (RT) remains the standard treatment, which is mostly palliative. This study aims to evaluate characteristics and treatment outcome of children with DIPG in a single center. Methods: We retrospectively reviewed the demographic, clinical characteristics and treatment outcome of children with DIPG treated at Istanbul University, Oncology Institute from 1999 to 2011. We also evaluated the group that prospectively recieved RT with concurrent and adjuvant temozolamide after 2004. Results: 47 children (24 female, 23 male) with the median age of 7 years (6 months-16 years) were analyzed. The median duration of symptoms was 30 days (2-630 days). The frequent clinical findings were ataxia, strabismus and motor weakness. All patients received RT, 54-60 Gy to the tumor site. 12 recieved only RT. 35 had concomitant and/or adjuvant chemotherapy with RT. 8 recieved cisplatinum, 7 vincristine. Since 2004, 20 patients recieved the institutional protocol consisting of temozolomide (TMZ) (75 mg/m2/day) for 6 weeks concurrent with RT, followed by TMZ (200 mg/m2/day) for 5 days every 28 days for 12 cycles or until progression. There was no major side effect due to TMZ, thrombocytopenia being the most frequent, but managable side effect. The median overall survival after diagnosis was 13 months (3-132 mo.) for the whole group. The median overall survival in 20 patients that received RT and TMZ [ 17 months (3-132 months)], was significantly superior than that in 12 patients that recieved only RT [ 12 months (3-20 months)] ( (p=0.03). Nimotuzumab was given to 4 patients that progressed after RT and TMZ. There was no major side effect due to nimotuzumab. One was stable for 1 year with significant clinical improvement, the others were stable for 5, 2 and 2 months after nimotuzumab. Conclusions: In our series, the median survival was significantly superior in patients who received RT with concurrent and adjuvant temozolamide in comparison to patients that recieved RT alone. Nimotuzumab may be promising in some progressive patients, its role as upfront treatment needs further investigation.
... Furthermore, only 50% (8/16) of Wakabayashi et al. (20) were diagnosed as DIPG; the remaining 50% were pure focal or exophytic brainstem gliomas. Local relapse has been extensively documented in many series as the primary mode of failure in DIPG (21)(22)(23), that is why we did not undergo in our study routine neuraxis imaging after initial therapy and spinal imaging were reserved for symptomatic patients. However; study done by Sethi et al. (24) recommended that all DIPG patients undergo spine and brain MRI scans at the time of initial presentation and at regular intervals during follow up as high incidence of leptomeningeal disease was observed at diagnosis and recurrence. ...
Background: Pediatric diffuse intrinsic pontine glioma (DIPG) remains dismal regardless the new therapeutic and technical advances. Objective: To investigate the value of magnetic resonance imaging (MRI) in predicting DIPG prognosis. Patients and methods: Twenty-five DIPG patients with 95 (initial and post radiotherapy) MR examinations were studied. Hydrocephalus was detected in 6 cases (24%), basilar artery encasement in 20 (80%), ill defined border in 16 (64%), perilesional edema in 2 cases (8%) and none showed leptomeningeal spread. Conformal 3-dimensional radiotherapy (39 Gy/13 fractions or 54 Gy/30 fractions) was applied. Results: The median overall survival (MOS) was 9.3 months (95% CI: 7.9-10.8) and the one year overall survival was 18 ± 8.9%. Post radiation MRI performed 3-6 months after treatment showed regression in 8 cases (32%), stationary course in 5 (20%) and progression in 12 cases (48%). The MOS was higher in children whose MRI showed regression (10.0, CI: 6.3-13.7) than those with Open access under CC BY-NC-ND license. radiological progression (8.0, CI: 5.9-10.1 months) or stationary course (7.0, CI: 4.9-9.1). However; these differences did not rank to the level of significance. There was no statistical association of tumor size (p = 0.907), presence of hemorrhage (p = 0.314), or surrounding edema (p = 0.263); entrapment of the basilar artery (p = 0.782); pattern of enhancement (p = 0.851); and hydroceph-alus (p = 0.354) with the length of the overall survival. Conclusions: Though MRI is the mainstay for the diagnosis of DIPG, yet its prognostic value is limited. New MR techniques as MR spectroscopy and diffusion tensor imaging should be evaluated as additional tools for prognostic evaluation of DIPG.
... Data on 2-year PFS were limited and only reported in 3 studies. [37][38][39] 40 When stratified by age (<20 vs 20 years at diagnosis), the median OS was 11.8 versus 59.9 months (P Z .03), suggesting that older age (20 years) may confer a survival benefit. ...
Purpose:
Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG.
Methods and materials:
A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT.
Results:
We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months.
Conclusions:
As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.
... There has been scant data on pHGGs regarding the role of MGMT promoter methylation either as an independent predictive and/or prognostic marker. Few studies, including phase 1 and 2 trials, evaluating the activity of TMZ in childhood CNS tumors have shown some promising results (Nicholson et al. 2007;Broniscer et al. 2005Broniscer et al. , 2006Verschuur et al. 2004;Barone et al. 2006;Jakacki et al. 2008;Lashford et al. 2002;Estlin et al. 1998;Loh et al. 2005). Donson et al. (2007) reported the average survival time of 13.7 months for TMZ-treated children with methylated MGMT compared to 2.5 months for patients with an unmethylated MGMT. ...
Pediatric high grade gliomas (pHGGs) constitute about 20% of childhood gliomas and show poor survival. The underlying molecular pathogenesis of pHGGs is significantly distinct from histologically similar adult GBMs. Frequent driver mutations within chromatin remodeling genes histone H3.1-H3.3 (K27M-G34R/V)-ATRX-DAXX, in addition to alterations in ACVR1, SETD2, FGFR1, BRAF, PDGFRA, NTRK, MYCN, MYC and TP53 genes play a central role in the pHGG pathogenesis. Genome-wide methylation data of pediatric GBM (pGBM) has shown four biologically distinct subgroups, associated with enrichment for mutations (K27 and G34), PDGFRA-amplification, and/or mesenchymal gene expression signatures. pGBMs show rare IDH1-mutation/G-CIMP (Glioma-CpG-Island Methylator Phenotype) and are associated with reactive oxygen species production. Genome-wide miRNA profile of pHGGs has shown a set of uniquely expressed miRNAs distinct from adult GBMs which target PDGFR-b pathway. Functional consequences of histone H3.3 mutation in pHGGs show reprogramming of H3K27 methylation in conjunction with EZH2 over a set of biologically significant genes leading to tumorigenesis. A major loss of expression of global histone trimethylation (H3K-27/−9/−4) code has also been shown in pGBMs. Patients with H3F3A-G34R/V shown better overall survival compared with H3F3A-wild type and -K27M. However H3F3A-K27M show poorest prognosis in pHGGs. Clinical trial designs should now focus on distinct molecular subgrouping in pHGGs and stratify patients applying markers associated with specific subgroup. Targeting chromatin modifiers, central to pHGG pathogenesis offers a rational way to develop highly selective treatment strategies.
... [38]. Добавление к ЛТ различных видов ХТ, в том числе ТЗМ, как видно из доступных публикаций [39][40][41][42], не привело к улучшению показателей выживаемости и БРТ, а в некоторых случаях сопровождалось миелотоксическими осложнениями. Лучевая терапия сегодня остается единственным методом, позволяющим стабилизировать рост опухоли. ...
Widespread introduction in the protocols of treatment of patients with tumors of a CNS of a chemotherapy allowed to improve the prognosis for many patients. At the same time, for a part of patients use of an chemotherapy does not give desirable effect, significantly increases treatment cost, and followed by toxic complications. On the example of use of a temozolomide in treatment of gliomas it is shown that its application allows to improve results of treatment only at a part of patients with the concrete positive clinico-biological and molecular characteristics. For the others patients medicine does not give positive results and significantly increases treatment cost. Experience of application of a temozolomid demonstrates that it is possible to personalize programs of treatment on the basis of already established prognostic factors. Their use will allow to refuse reference application of drugs according to only morphologic or only clinicoradiological diagnostics and to be guided by the individualized indications based on the clinico-biological parameters and molecular characteristics of this tumor. It will allow to reduce treatment cost at preservation of its effectiveness and decrease of toxic complications.
... After the successes obtained in adults, multiple temozolomide trials were initiated in children and young adults with glioma, both with conventional and protracted dose schedules (Baruchel 2006;Broniscer 2006;Cohen 2011b;Jakacki 2008;Lashford 2002;Nicholson 2007;Ruggiero 2006;Verschuur 2004). This also applies to DIPG, where multiple studies were published from 2005 with temozolomide alone or in combination with other drugs (Broniscer 2005;Chassot 2012;Cohen 2011a;Jalali 2009;Kim 2010;Sharp 2010;Sirachainan 2008). Furthermore, temozolomide became a drug that was frequently prescribed off protocol to patients with DIPG. ...
... Although no studies have been reported regarding the combination of TMZ and RT for the treatment of BSG in adults, several clinical trials exploring BSG treatments in children have been reported (Table 3). 10,[25][26][27][28][29][30] Most of the previous studies described in Table 4 reported that TMZ and RT did not alter the poor prognosis of BSG in children. As shown in Table 3, children with BSG in the present study were treated with RT and various chemotherapeutic agents, and their survival outcomes were not different from those observed in other studies. ...
Aim:
To evaluate the treatment results of radiotherapy (RT) in children and adults with brainstem gliomas (BSGs) and review the previous literature.
Methods:
Thirty patients (14 children, 16 adults) with BSG treated using RT were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 2-16 years) and 49 years (range: 19-75 years), respectively. A histological diagnosis was obtained in 11 patients. The median total radiation dose was 56 Gy (range: 50-70 Gy) with a single fraction size of 1.8-2.0 Gy. Temozolomide was administered concurrently with RT in 14 patients.
Results:
Tumor progression after RT occurred in 26 patients (14 children and 12 adults). Four adults survived without tumor progression. The median survival times for children and adults were 8.5 and 39 months, respectively. The 1-, 2- and 3-year overall survival rates for children/adults were 29%/75%, 14%/68% and 0%/53%, respectively (P = 0.001), and the 1-, 2- and 3-year progression-free survival rates for children/adults were 14%/69%, 0%/49% and 0%/35%, respectively (P < 0.001). Grade 3 or higher acute and late toxicities did not occur.
Conclusion:
In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts should be made to improve the survival outcomes of patients with BSGs, especially children.
... It has been demonstrated to be active against high-grade gliomas in adults [15][16][17][18], including patients with recurrent disease following prior chemotherapy [19][20][21][22]. However, published studies to date have failed to show a clear role for temozolomide as a single agent in pediatric high-grade gliomas [23][24][25], although this is the subject of ongoing study. ...
... [15] Other chemotherapeutic drugs such as interferon, bradykinin, RMP-7, cyclosporine, and tamoxifen with or without radiotherapy also did not show any survival advantage. [16,17] Despite the initial positive responses observed among children with high-grade gliomas treated with temozolomide in phase I trials, Broniscer et al. [18] reported that administration of temozolomide after radiotherapy, as an adjuvant therapy, does not change the poor outcome of children. He showed results of a multi-institutional study examining the role of neoadjuvant irinotecan followed by radiotherapy and then temozolomide. ...
Background: Brainstem gliomas account for approximately 25% of all posterior fossa tumors. In pediatric age group, it constitutes about 10% of all brain tumors. Brainstem glioma is an aggressive and lethal type of malignancy with poor outcome despite all treatments.
Aim: We studied the incidence and treatment outcome in pediatric patients with brainstem glioma depending on their tumor volume presenting in our institution in last 5 years. Brain tumors comprised 2.95% of all cancers and brainstem gliomas were 8% of all brain tumors.
Materials and Methods: Nine pediatric patients were included in this analysis, who were treated with localized external radiotherapy 54–59.4 Gy along with temozolomide 75 mg/m2 during the whole course of radiotherapy.
Results: The median survival in all these patients was 20 months and the overall 2 years survival is 44.4% (4/9). The median survival of patients with primary disease volume
... [4,14,15] This is thought partly to be as a consequence of poor access of the drugs to the tumor site due to the presence of a highly selective blood-brain barrier, poor intratumoral drug distribution, and the intrinsic resistance of the tumor cells. [1,33,39] Similarly, SEER does not contain data about the type or dose of radiation therapy used. Nevertheless, it is important to note that, to date, no variation in type, dose of radiotherapy or combination with chemotherapy has been associated with increased survival in any clinical trials. ...
Background:
The purpose of this study was to use the National Cancer Institutes' Surveillance, Epidemiology, and End Results (SEER) database to perform a large-scale analysis of brainstem anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Use of the SEER database gave us a larger sample size of this rare tumor type, allowing for the analysis of the relationship between prognostic factors and survival.
Materials and methods:
We selected pediatric patients (<18 years old) from the SEER database with histologically confirmed diagnoses of primary high-grade gliomas (World Health Organization Grade III/IV) of the brainstem. In univariate and multivariate analysis, we analyzed the relationship between demographic (age, gender, race, diagnosis date), histologic (AA, GBM), and treatment (surgery, radiation) factors on survival.
Results:
In our cohort of 124 patients, those with AA had a median survival of 13 months and those with GBM 9 months. Higher-grade tumors were associated with statistically significantly increased mortality (hazard ratio [HR]: 1.74, confidence intervals [CIs]: 1.17-2.60). Surgical intervention was associated with a significantly lower mortality, either alone (HR: 0.14, CI: 0.04-0.5) or in combination with radiation (HR: 0.35, CI: 0.15-0.82). Radiation therapy alone was significantly associated with decreased mortality within the first 9 months after diagnosis but not with overall mortality. No demographic characteristics were significantly associated with mortality.
Conclusions:
Outcome remains poor in the pediatric high-grade brainstem glioma population. Survival is correlated with lower-grade tumor histology, radiation therapy only in the first 9 months after diagnosis, and surgical resection.
... No alternative radiation therapy technique has improved the survival outcome of children with diffuse intrinsic tumours [35][36][37][38][39][40][41]. So far, the application of chemotherapeutics either before, during or after radiation therapy has not resulted in a survival advantage in children with diffuse intrinsic brainstem gliomas [11,[42][43][44][45][46][47][48][49]. Most studies reveal a median overall survival time of shorter than one year, and nearly all children eventually die [6,28,50]. ...
... Many clinical trials of chemotherapy, both for primary disease (concurrent with radiation and/or adjuvant) and at recurrence, have shown no significant clinical benefit to patients over radiation alone. Temozolomide (TMZ) has been studied in many of these trials, given its proven benefit in adult GBM, but the substantial variety of dosing strategies and schedules studied have failed to identify any increased activity over radiation therapy alone and thus only add toxicity [96][97][98][99][100][101][102]. We therefore strongly recommend against its routine use in DIPG. ...
Pediatric brainstem gliomas include low-grade focal brainstem gliomas (FBSG) and high-grade diffuse intrinsic pontine gliomas (DIPG). These tumors share a crucial and eloquent area of the brain as their location, which carries common challenges for treatment. Otherwise, though, these two diseases are very different in terms of presentation, biology, treatment, and prognosis. FBSG usually present with greater than 3 months of symptoms, while DIPG are usually diagnosed within 3 months of symptom onset. Surgery remains the preferred initial treatment for FBSG, with chemotherapy used for persistent, recurrent, or inoperable disease; conversely, radiation is the only known effective treatment for DIPG. Recent developments in biological understanding of both tumors have led to new treatment possibilities. In FBSG, two genetic changes related to BRAF characterize the majority of tumors, and key differences in their biological effects are informing strategies for targeted chemotherapy use. In DIPG, widespread histone H3 and ACVR1 mutations have led to new hope for effective targeted treatments. FBSG has an excellent prognosis, while the long-term survival rate of DIPG tragically remains near zero. In this review, we cover the epidemiology, biology, presentation, imaging characteristics, multimodality treatment, and prognosis of FBSG and DIPG, with a focus on recent biological discoveries.
... Of note, age at diagnosis may also be prognostic. Children <3 years old at diagnosis can have a prolonged survival, living years after their diagnosis, often with temporary disease stabilization (Broniscer et al., 2008; Jackson et al., 2013; Thompson & Kosnik, 2005). While primary dissemination of DIPGs is rare (Benesch, Wagner, Berthold, & Wolff, 2005), dissemination of DIPGs at recurrence is common (Gururangan et al., 2006; Sethi et al., 2011). ...
Diffuse intrinsic pontine gliomas (DIPGs) are a fairly common pediatric brain tumor, and children with these tumors have a dismal prognosis. They generally are diagnosed within the first decade of life, and due to their location within the pons, these tumors are not surgically resectable. The median survival for children with DIPGs is less than 1 year, in spite of decades of clinical trial development of unique approaches to radiation therapy and chemotherapy. Novel therapies are under investigation for these deadly tumors. As clinicians and researchers make a concerted effort to obtain tumor tissue, the molecular signals of these tumors are being investigated in an attempt to uncover targetable therapies for DIPGs. In addition, direct application of chemotherapies into the tumor (convection-enhanced delivery) is being investigated as a novel delivery system for treatment of DIPGs. Overall, DIPGs require creative thinking and a disciplined approach for development of a therapy that can improve the prognosis for these unfortunate children.
... The clinical diagnosis for each patient was made in a consensus-based manner by an interdisciplinary team comprising specialists in neuroradiology, radiation oncology, neurooncology, neuropathology, neurology, and neurosurgery. Eighty-seven patients were enrolled in 1 of 6 chemotherapy-based protocols (SJBG07, PBTC-06, PBTC-07, PBTC-14, ACNS0126, and SJHG-98) as adjunctive treatment for DIPG along with RT [3,5,8,15,25,26]. All protocols are currently closed and have not demonstrated a clinically translatable benefit of chemotherapy in DIPG. ...
Children with diffuse intrinsic pontine glioma (DIPG) continue to have poor outcomes, and radiotherapy (RT) is the only temporarily effective treatment. In this retrospective analysis, we studied the effect of time from diagnosis to start of RT on event-free survival (EFS) and overall survival (OS) in children with DIPG.
Records of children (n = 95) with DIPG treated with RT at a single institution between April 1999 and September 2009 were analyzed. RT was delivered at doses of 54.0-55.8 Gy at 1.8 Gy per fraction, and children were followed prospectively. The effect of gender, race, interruption during treatment course, age at diagnosis, duration of symptoms prior to diagnosis, use of protocol-based chemotherapy, and time from diagnosis to initiation of RT on EFS and OS was assessed by the Cox proportional hazards model.
Time as a continuous variable from diagnosis to start of RT did not affect outcome. Time dichotomized to ≤14 days significantly affected OS (hazard ratio [HR] = 1.70, P = 0.014) and race other than white or black affected EFS (HR = 2.32, P = 0.017). The 95 patients had a 6-month EFS and OS of 60 ± 5% and 94.7 ± 2.3%, respectively, and a 12-month EFS and OS of 11.6 ± 3.1% and 49.5 ± 5%, respectively.
Time as a continuous variable did not affect OS or EFS in our cohort; however, children treated within 2 weeks of diagnosis had poor outcomes. Although rapid initiation of RT is desirable, our findings do not support intensive efforts aimed at shortening delays from diagnosis to start of RT. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
... Although we confirmed that a minority of children with DIPG survived for long periods of time, it was disappointing to observe that these patients remain at high risk for tumor progression even many years after their diagnosis. All surviving patients received therapies that were otherwise considered ineffective for the majority of children with DIPG [8,10,25,28,29]. Four of the surviving patients had characteristics at diagnosis associated with improved outcome consisting of young age (patients 1 and 2), long interval between the onset of symptoms and diagnosis (patient 1, 2, and 3), lack of pontine cranial nerve palsies (patient 5), and atypical radiologic imaging (patients 2 and 3) [1,[23][24]. ...
Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6 %) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range 5.3-13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome.
... If there is expression of the MGMT recovery enzyme the methyl or alkyl group may be removed and the normal guanine put back in place, thus causing resistance to temozolomide [22]. Despite the initial positive responses observed among children with HGGs treated in phase I trials, in a multi-institutional trial Broniscer et al. [23] showed that administration of temozolomide after radiotherapy, as an adjuvant therapy, did not change the poor outcome of children with newly diagnosed DIPG. Their results corroborate the findings of a recent phase II multi-institutional trial from the United Kingdom Children's Cancer Study Group (UKCCSG) and SFOP Intergroup Study, which reported a disappointing response to temozolomide in children with recurrent gliomas including 21 DIPG patients [24]. ...
The prognosis for children with diffuse intrinsic pontine gliomas (DIPGs) is dismal. Although DIPGs constitute only 10-15 % of all pediatric brain tumors, they are the main cause of death in this group with a median survival of less than 12 months. Standard therapy involves radiotherapy, which produces transient neurologic improvement. Despite several clinical trials having been conducted, including trials on targeted agents to assess their efficacy, there is no clear improvement in prognosis. However, knowledge of DIPG biology is increasing, mainly as a result of research using biopsy and autopsy samples. In this review, we discuss recent studies in which systemic therapy was administered prior to, concomitantly with, or after radiotherapy. The discussion also includes novel therapeutic options in DIPG. Continuing multimodal and multitargeted therapies might lead to an improvement in the dismal prognosis of the disease.
Among tumors of the pediatric central nervous system, masses arising within the brainstem pose a unique set of diagnostic and therapeutic challenges. Current population-based data from the United States estimate brainstem tumors to represent 10.9 % of new central nervous system neoplasms in pediatric patients aged 0–19 years, with over 500 cases expected in the year 2019 (Ostrom et al. 2018). A new diagnosis of brainstem tumor is most common between the ages of 5 and 9 years, and brainstem tumors represent 15.6% of new central nervous system (CNS) tumor diagnoses within this age range (Ostrom et al. 2015). In comparison, these tumors are far less common in adults: 1.5% of CNS tumors overall (Ostrom et al. 2018; Albright 1996). Masses in the brainstem display a substantial degree of histologic heterogeneity (Warren et al. 2012), and while diffuse tumors here are the most lethal pediatric high-grade tumors by location (Ostrom et al. 2015; Hargrave et al. 2006), other brainstem tumors are known to have a comparatively favorable prognosis (Frazier et al. 2009; Fried et al. 2012).
Les DIPG (Diffuse Intrinsic Pontine Glioma) sont des tumeurs cérébrales pédiatriques au pronostic des plus sombres, et ce notamment du fait de la résistance des cellules aux différents traitements de chimio et de radiothérapie. Une des caractéristiques majeures des cellules de DIPG est qu’elles sont quasi systématiquement porteuses d’une mutation mono-allélique de l’histone H3 au niveau de sa lysine 27, et ce majoritairement sur le variant d’histone H3.3. Cette mutation, H3.3K27M, inhibe la triméthylation en K27 de l’histone H3 (H3K27me3) par un effet dominant négatif, ayant pour conséquence une réorganisation de la chromatine et ainsi une modification profonde de l’expression des gènes. Actuellement, et bien que les mutations H3K27M soient décrites comme étant un élément « driver » dans la genèse des DIPG, leur implication dans la résistance aux traitements n’a toutefois pas été pleinement établie. Afin de décrypter finement les implications de la mutation H3.3K27M, l’établissement de modèles cellulaires complémentaires d’induction mais aussi de réversion de la mutation apparaissait nécessaire.Dans ce contexte, j’ai, par transfection plasmidique, induit la mutation H3.3K27M dans trois lignées cellulaires de gliome pédiatrique sustentoriel initialement non mutées. De façon complémentaire, j’ai créé un modèle de réversion de la mutation dans des cellules de DIPG mutées H3.3K27M par la mise en place d’une stratégie utilisant le système CRISPR/Cas9, générant une cassure double brin au niveau du site de la mutation, combinée à une approche de « gene trapping » visant à restaurer la forme sauvage du gène H3F3A. Ces deux stratégies d’induction et de réversion de la mutation nous ont permis de constituer un ensemble de modèles cellulaires disponible avec et sans la mutation H3.3K27M. Fort de ceux-ci, j’ai pu entreprendre d’évaluer le rôle exact de la mutation H3.3K27M sur la résistance aux traitements de chimio et radiothérapie, la croissance cellulaire ou encore les propriétés clonogéniques.Concernant le modèle d’induction, les effets épigénétiques liés à la mutation étaient confirmés au sein des trois lignées cellulaires établies. La présence de la mutation avait alors un effet sur la croissance cellulaire dans deux des trois lignées cellulaires, et ce concomitamment avec un pouvoir clonogénique accru par l’introduction de la mutation. Ces mêmes lignées cellulaires présentaient une résistance supérieure à la radiothérapie et un screening de chimiothérapies permettait de mettre en évidence plusieurs composés pour lesquels la mutation H3.3K27M conférait une résistance. D’un point de vue plus global, il semblerait que la mutation confère un caractère agressif et résistant principalement dans un contexte de gliome de bas grade. En parallèle, j’ai pu valider la création d’un modèle de réversion de la mutation dans une lignée cellulaire de DIPG originellement mutée. Dans celui-ci, les cellules ne diffèrent que par l’absence de la mutation et présentent un retour de la marque H3K27me3. Une évaluation préliminaire des effets de la réversion de la mutation tendait à confirmer ceux obtenus avec le modèle d’induction.Le décryptage des mécanismes sous-jacents aux effets biologiques observés, nous permettra d’évaluer et de comprendre pleinement le rôle de la mutation H3.3K27M dans l’agressivité et la résistance aux traitements des DIPG et d’identifier de possibles nouvelles stratégies de traitement des gliomes malins pédiatriques du tronc cérébral.
Purpose:
This multicenter retrospective study aimed to investigate clinical, radiologic, and treatment-related factors affecting survival in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) treated with radiotherapy.
Materials and methods:
Patients aged <30 years who underwent radiotherapy as an initial treatment for DIPG between 2000 and 2018 were included; patients who did not undergo magnetic resonance imaging at diagnosis and those with pathologically diagnosed grade I glioma were excluded. We examined medical records of 162 patients collected from 10 participating centers in Korea. The patients' clinical, radiological, molecular, and histopathologic characteristics, and treatment responses were evaluated to identify the prognosticators for DIPG and estimate survival outcomes.
Results:
The median follow-up period was 10.8 (interquartile range, 7.5-18.1) months. The 1- and 2-year overall survival (OS) rates were 53.5 % and 19.0%, respectively, with a median OS of 13.1 months. Long term survival rate (≥2 years) was 16.7%, and median OS was 43.6 months. Age (<10 years), poor performance status, treatment before 2010, and post-radiotherapy necrosis were independently associated with poor OS in multivariate analysis. In patients with increased post-radiotherapy necrosis, the median OS estimates were 13.3 months and 11.4 months with and without bevacizumab, respectively (p=0.138).
Conclusion:
Therapeutic strategy for DIPG has remained unchanged over time, and the associated prognosis remains poor. Our findings suggest that appropriate efforts are needed to reduce the occurrence of post-radiotherapy necrosis. Further well-designed clinical trials are recommended to improve the poor prognosis observed in DIPG patients.
As an intractable central nervous system (CNS) tumor, brainstem gliomas (BGs) are one of the leading causes of pediatric death by brain tumors. Owing to the risk of surgical resection and the little improvement in survival time after radiotherapy and chemotherapy, there is an urgent need to find reliable model systems to better understand the regional pathogenesis of the brainstem and improve treatment strategies. In this review, we outline the evolution of BG murine models, and discuss both their advantages and limitations in drug discovery.
Background:
A phase 1/2 trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase (HDAC) inhibitor, was conducted in children with newly-diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase 2 dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with an historical model from past COG trials.
Methods:
Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m 2 daily for a maximum of twelve 28-day cycles.
Results:
Twelve patients enrolled on the phase 1 study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m 2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled onto the phase 2 study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (p = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89 - 13.1%) and 1-year OS was 39.2% (27.8 - 50.5%).
Conclusions:
Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly-diagnosed DIPG but failed to improve outcome.
Objective
Diffuse intrinsic pontine glioma (DIPG) is a rare and devastating brainstem glioma that occurs predominately in children. To date, the prognostic impact of radiotherapy (RT) in conjunction with temozolomide (TMZ) in DIPG has not been thoroughly analyzed. The aim of this meta-analysis was to quantitatively and precisely analyze the effectiveness of RT in conjunction with TMZ in improving the prognosis of DIPG.
Methods
A systematic search of eight electronic databases was conducted. Articles mainly discussing the prognostic impact of RT in conjunction with TMZ in DIPG were selected. The pooled 1-year and 2-year overall survival (OS) and progression-free survival (PFS) were calculated.
Results
A total of 14 studies fulfilled our inclusion criteria, involving 283 cases of DIPG patients who were treated with RT in conjunction with TMZ. The pooled 1-year and 2-year OS of this treatment was 43% and 11%, respectively. The pooled 1-year and 2-year PFS of was 20% and 2%, respectively. Subgroup analysis revealed that the heterogeneity almost remained the same in all stratum. Egger’s test demonstrated the possibility of publication bias was low.
Conclusions
For DIPG patients who were treated with RT in conjunction with TMZ, the combined 1-year OS and 2-year OS were 43% and 11%. The pooled 1-year PFS and 2-year PFS were 20% and 2%. Requirements of up-to-date evidence on evaluating the prognostic impact of this therapy are urgent.
This report summarizes the current multimodality treatment approaches for children with low- and high-grade gliomas, germinoma, and nongerminomatous germ cell tumors, and craniopharyngiomas used in the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP). Treatment recommendations are provided in the context of historical approaches regarding the roles of surgery, radiation, and chemotherapy. Future research strategies for these tumors in both COG and SIOP are also discussed.
Gliomas originating in the brainstem are a heterogeneous group of tumors that can differ significantly in biology and prognosis. Despite recent insights into the biology of the most common brainstem glioma, diffuse intrinsic pontine glioma (DIPG), the standard treatment for brainstem gliomas has not changed significantly in nearly five decades. Radiation therapy is the mainstay of treatment for DIPG and other malignant brainstem gliomas, and is the only modality that improves outcomes for these tumors. While chemotherapy may have some utility for non-DIPG brainstem tumors, no chemotherapeutic agent has demonstrated significant efficacy within a clinical trial for children with DIPG. Diffuse brainstem gliomas in adults appears to have different biology, and adjuvant chemotherapy may have modest efficacy against adult malignant brainstem glioma. However, the prognosis for all patients with diffuse malignant brainstem gliomas remains dismal. Nevertheless, the recent distinction of DIPG as a unique clinical entity, development of tools such as cell lines and animal models to perform disease-specific pre-clinical studies, insight into its biologic underpinnings such as epigenetic dysregulation, and research to overcome defined obstacles to drug delivery have laid the groundwork for the development of novel, directed, disease-specific approaches that hold promise.
Purpose
Ribociclib, an orally bioavailable small-molecule CDK4/6 inhibitor is currently undergoing evaluation to treat pediatric central nervous system (CNS) tumors. However, it is crucial that it penetrates the brain and tumor. Thus, the objectives of the present study were to derive a clinically relevant mouse dosage for cerebral microdialysis studies, and to characterize ribociclib CNS penetration in non-tumor bearing mice and in mice bearing DIPGx7 (glioma) cortical allograft tumors.
Methods
A plasma pharmacokinetic study of ribociclib (100 mg/kg, orally) was performed in CD1 nude mice bearing glioma cortical allografts to obtain initial plasma pharmacokinetic parameters and to derive D-optimal plasma sampling time-points for microdialysis studies. Using a cerebral microdialysis technique, the extracellular fluid (ECF) disposition of ribociclib was evaluated after a single oral ribociclib dose (100 mg/kg) in non-tumor bearing mice and in mice bearing glioma cortical allografts. A one-compartment plasma model with absorption and ECF compartments were fit to plasma and ECF concentration–time data using a nonlinear mixed effects modeling approach (NONMEM 7.2).
Results
The mean unbound ribociclib plasma exposure (6812 ng/ml*h) was similar to that observed clinically at recommended dosages in adults. The median ribociclib ECF to plasma partition coefficient (Kp,uu) in non-tumor bearing and glioma mice was 0.10 and 0.07, respectively, and was not statistically different (t test, p = 0.19).
Conclusions
The CNS penetration observed was encouraging enough to move ribociclib forward with preclinical efficacy studies in models of pediatric brain tumors.
Background:
We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG).
Patients and methods:
Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m(2) /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m(2) /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10.
Results:
Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites.
Conclusion:
Capecitabine did not improve the outcome for children with newly diagnosed DIPG.
Pediatric cancer patients differ from adults both in the spectra of their malignancies and in their response to drugs. Our knowledge of the developmental pharmacology of anticancer drugs has increased, and yet we often do not have sufficient understanding to optimally treat pediatric cancer patients, particularly infants and young children. Well-designed clinical pharmacology studies in this group of patients are necessary for the development of novel dosing strategies tailored to children of different ages. The first section of this chapter reviews the basic principles of drug absorption, distribution, metabolism, and elimination in infants, children, and adolescents. Subsequent sections address the appropriate methods to select drug dosages in children, practical issues associated with clinical pharmacokinetic studies in children with cancer, and the pharmacokinetics of specific anticancer drugs in children. We then review the pharmacokinetics of selected anticancer drugs used in children with cancer.
Background:
The median survival of patients with diffuse intrinsic pontine glioma (DIPG) remains less than 1 year. The BSG 98 pre-irradiation chemotherapy protocol showed a significant increase in overall survival. In contrast to current treatment strategies, patients did not have to undergo surgical stereotactic biopsy, which can sometimes lead to complications, to be included in this protocol.
Materials and methods:
We retrospectively reviewed all the cases of DIPG that were treated in our department from September 15, 2004 to September 15, 2014. We compared the group of patients who followed our BSG 98 protocol to those who were treated with new targeted therapy protocols where systematic biopsy was required.
Results:
Patients in the BSG 98 protocol were treated with BCNU, cisplatin, and methotrexate, followed by radiation at disease progression. Targeted therapy protocols included radiation therapy along with treatment by erlotinib, cilengitide, or an association of nimotuzumab and vinblastine. Sixteen patients were treated with the BSG 98 protocol, and 9 patients were treated with new targeted therapy protocols. Median overall survival was significantly higher in the BSG 98 group compared to the targeted therapy group (16.1 months (95 % CI, 10.4-19.0) vs 8.8 months (95 % CI 1.4-12.3); p = 0.0003). An increase in the median progression-free survival was observed (respectively, 8.6 vs 3.0 months; p = 0.113).
Conclusion:
The present study confirms that the BSG 98 protocol is one of the most effective current treatment strategies for DIPG. It may be used as the control arm in randomized trials investigating the use of innovative treatments and may be proposed to families who are averse to biopsy.
This chapter will discuss malignant glioma, low-grade glioma, brainstem glioma, optic glioma, CNS lymphoma, ependymoma, choroid plexus tumor, meningioma, acoustic neuroma, craniopharyngioma, pituitary tumor, pineal tumor, medulloblastoma, primary spinal cord tumor, arteriovenous malformation, and trigeminal neuralgia. Brain metastases will be discussed in the palliative care chapter.
The brainstem is the connecting structure that joins the long tract from the cerebral hemispheres and midline diencephalic nuclei with the cerebellar tracts, forming the spinal cord as the tracts exit through the foramen magnum. Within the brainstem are the nuclei of the cranial nerves, the reticular activating system, and vital function centers (e.g., respiratory). The brainstem includes three anatomic segments: the midbrain, the pons, and the medulla.
Brainstem gliomas account for 20 % of all central nervous system tumors in children. They can be focal, dorsal exophytic tumors or diffuse infiltrating types. The management depends on the location and imaging characteristics. Treatment of diffuse tumors include radiotherapy with or without chemotherapy. Even with the high technological advances in the planning and delivery of radiation the outcomes of this tumors are still poor.
Brainstem tumors represent 10-15% of pediatric central nervous system tumors and diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor of childhood. DIPG is almost uniformly fatal and is the leading cause of brain tumor-related death in children. To date, radiation therapy (RT) is the only form of treatment that offers a transient benefit in DIPG. Chemotherapeutic strategies including multi-agent neoadjuvant chemotherapy, concurrent chemotherapy with RT, and adjuvant chemotherapy have not provided any survival advantage. To overcome the restrictive ability of the intact blood-brain barrier (BBB) in DIPG, several alternative drug delivery strategies have been proposed but have met with minimal success. Targeted therapies either alone or in combination with RT have also not improved survival. Five decades of unsuccessful therapies coupled with recent advances in the genetics and biology of DIPG have taught us several important lessons (1). DIPG is a heterogeneous group of tumors that are biologically distinct from other pediatric and adult high grade gliomas (HGG). Adapting chemotherapy and targeted therapies that are used in pediatric or adult HGG for the treatment of DIPG should be abandoned (2). Biopsy of DIPG is relatively safe and informative and should be considered in the context of multicenter clinical trials (3). DIPG probably represents a whole brain disease so regular neuraxis imaging is important at diagnosis and during therapy (4). BBB permeability is of major concern in DIPG and overcoming this barrier may ensure that drugs reach the tumor (5). Recent development of DIPG tumor models should help us accurately identify and validate therapeutic targets and small molecule inhibitors in the treatment of this deadly tumor.
Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all intracranial neoplasms. They are often phenotypically low-grade as compared to their more common paediatric counterparts. Since brainstem biopsies are rarely performed, these tumours are commonly classified according to their MR imaging characteristics into 4 subgroups (a) diffuse intrinsic low-grade gliomas, (b) enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic gliomas/other subtypes. The prognosis and treatment is variable for the different types and is almost similar to adult supratentorial gliomas. Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to the exophytic subtypes. Review of previous literature shows that the detailed imaging of adult BSGs has not received significant attention. This review illustrates in detail the imaging features of adult BSGs using conventional and advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as well as 18 F-fluoro-ethyl-tyrosine positron emission tomography (18F-FET/PET). We have discussed the pertinent differences between childhood and adult BSGs, imaging mimics, prognostic factors and briefly reviewed the treatment options of these tumours.
We present a case of inadvertent high-dose therapy with temozolomide in a child with recurrent diffuse intrinsic pontine glioma followed by a rapid clinical response. The patient was a 7-year-old boy who initially presented with a history of left facial palsy, double vision, headache, and ataxia. His symptoms were completely resolved following radiotherapy but recurred 3 months after. Following recurrence, he received temozolomide in a dose >3 times higher than prescribed inadvertently but tolerated well with a rapid clinical response. He eventually deteriorated after he was substituted with a lower dose of temozolomide and died.
Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG.
Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated.
The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9).
PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
Patients with diffuse intrinsic pontine glioma (DIPG) have a very poor prognosis. Only radiotherapy (XRT) has proven to be effective in delaying the disease progression. Several chemotherapy schedules have been applied so far, but none demonstrated significant improvements in progression and survival.
We retrospectively analyzed the clinical data of children diagnosed with DIPG at our center (Pediatric Hospital "Regina Margherita," Turin, Italy) between 1999 and 2013. Progression-free survival (PFS) and overall survival (OS) were used to describe the outcomes.
Twenty-four children were included in our report. Patients diagnosed before March 2003 (n = 12) were treated with XRT and vincristine (VCR); the remaining 12 patients received XRT and temozolomide (TMZ). Progression-free survival was 18.8 % at 1 year (SE = 7.6 %), while overall survival was 44.1 % at 1 year (SE = 9.9 %). Median PFS was 8.1 months, whereas median OS was 11.2 months. No statistically significant difference in PFS or OS was evidenced between the two treatment groups.
Radiotherapy followed by VCR or TMZ allows obtaining results that are in line with previous reports, with no advantages over other similar treatment schedules. DIPGs are challenging tumors with a dismal outcome. Further research and newer therapies are urgently needed in order to achieve improvements in survival.
Background
Pediatric diffuse intrinsic pontine glioma (DIPG) remains dismal regardless the new therapeutic and technical advances.
Objective
To investigate the value of magnetic resonance imaging (MRI) in predicting DIPG prognosis.
Patients and methods
Twenty-five DIPG patients with 95 (initial and post radiotherapy) MR examinations were studied. Hydrocephalus was detected in 6 cases (24%), basilar artery encasement in 20 (80%), ill defined border in 16 (64%), perilesional edema in 2 cases (8%) and none showed leptomeningeal spread. Conformal 3-dimensional radiotherapy (39 Gy/13 fractions or 54 Gy/30 fractions) was applied.
Results
The median overall survival (MOS) was 9.3 months (95% CI: 7.9–10.8) and the one year overall survival was 18 ± 8.9%. Post radiation MRI performed 3–6 months after treatment showed regression in 8 cases (32%), stationary course in 5 (20%) and progression in 12 cases (48%). The MOS was higher in children whose MRI showed regression (10.0, CI: 6.3–13.7) than those with radiological progression (8.0, CI: 5.9–10.1 months) or stationary course (7.0, CI: 4.9–9.1). However; these differences did not rank to the level of significance. There was no statistical association of tumor size (p = 0.907), presence of hemorrhage (p = 0.314), or surrounding edema (p = 0.263); entrapment of the basilar artery (p = 0.782); pattern of enhancement (p = 0.851); and hydrocephalus (p = 0.354) with the length of the overall survival.
Conclusions
Though MRI is the mainstay for the diagnosis of DIPG, yet its prognostic value is limited. New MR techniques as MR spectroscopy and diffusion tensor imaging should be evaluated as additional tools for prognostic evaluation of DIPG.
En dépit de la réalisation de nombreux essais thérapeutiques, le pronostic actuel des gliomes diffus infiltrants du tronc cérébral chez l’enfant reste particulièrement sombre. L’objet de cette revue est de faire le point sur les différentes stratégies thérapeutiques évaluées jusqu’à présent dans les gliomes malins du tronc cérébral. Seront abordés les résultats obtenus avec les différents essais cliniques de radiothérapie, de radiochimiothérapie concomitante et de chimiothérapie cytotoxique classique. Une discussion sera également faite sur des perspectives ouvertes par le développement récent des nouvelles molécules ciblées et antiangiogéniques comme les inhibiteurs des intégrines.
Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications.
Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0–5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time.
The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results.
Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.
Background
We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas.Methods
Children 3-21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m(2), given twice daily, with subsequent cohorts enrolled at 650 mg/m(2) and 850 mg/m(2) using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m(2) twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles.ResultsTwenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data.Conclusions
Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m(2), administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030).
A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.
The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers, reporting the results in the medical literature. One unreported result which deserves such publication is the development of the expertise to design and analyse such trials. This report was prepared by a group of British and American statisticians, but it is intended for people without any statistical expertise. Part I, which appears in this issue, discusses the design of such trials; Part II, which will appear separately in the January 1977 issue of the Journal, gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test, including a worked example, and discusses the interpretation of trial results, including brief reports of 2 particular trials. Both parts of this report are relevant to all clinical trials which study time to death, and wound be equally relevant to clinical trials which study time to other particular classes of untoward event: first stroke, perhaps, or first relapse, metastasis, disease recurrence, thrombosis, transplant rejection, or death from a particular cause. Part I, in this issue, collects together ideas that have mostly already appeared in the medical literature, but Part II, next month, is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration. Such trials include the majority of all clinical trials of cancer therapy; in cancer trials,however, it may be preferable to use these statistical methods to study time to local recurrence of tumour, or to study time to detectable metastatic spread, in addition to studying total survival. Solid tumours can be staged at diagnosis; if this, or any other available information in some other disease is an important determinant of outcome, it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive, and more intuitively satisfactory, for it will then only be necessary to compare like with like, and not, by chance, Stage I with Stage III.
The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI).
Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily.
Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up.
The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.
A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.
Images
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Figure 6
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We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT).
Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining.
Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs.
These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.
A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.
A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.
Temozolomide is a novel second-generation oral alkylating agent with demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). A multicenter phase II trial was conducted to determine the efficacy and safety of temozolomide before radiotherapy in patients with newly diagnosed GBM and AA. Fifty-seven patients (51 adult, 6 pediatric) with newly diagnosed supratentorial GBM or AA were treated with temozolomide (200 mg/m ( 2 ) per day for 5 consecutive days every 28 days) for a maximum of 4 cycles. All patients were then treated with external beam radiotherapy. Twenty-two patients (39%) achieved objective response, including 6 (11%) with complete response (CR) and 16 (28%) with partial response (PR). Additionally, 18 (32%) patients had stable disease (SD). Of 21 patients (18 adult, 3 pediatric) with AA, 2 (10%) achieved CR, 5 (24%) achieved PR, and 8 (38%) had SD. Among adult patients with AA, the median progression-free and overall survival rates were 7.6 and 23.5 months, respectively. Among 36 patients (33 adult, 3 pediatric) with GBM, 4 (11%) had CR, 11 (31%) had PR, and 10 (28%) had SD. The median progression-free and overall survival rates among adult patients with GBM were 3.9 and 13.2 months, respectively. Temozolomide was safe and well tolerated in adult and pediatric patients. Grades 3 and 4 adverse events were reported in 16 (28%) and 7 (12%) patients, respectively. Temozolomide was safe and effective in treating newly diagnosed GBM and AA before radiotherapy. This pre-irradiation treatment approach appears promising, but will require additional evaluation in comparative studies.
This study was conducted to investigate the incidence of ERBB1 amplification and overexpression in samples of diffusely infiltrative (WHO grades II-IV) pediatric brain stem glioma (BSG) and determine the relationship of these abnormalities to expression and mutation of TP53 and tumor grade.
After central pathology review, the incidence of ERBB1 amplification and overexpression was determined in 28 samples (18 surgical biopsy and 10 postmortem specimens) of BSG using quantitative PCR and immunohistochemistry, respectively. Mutation and expression of TP53 were also determined in these same samples by direct sequence analysis of microdissected tumor material and immunohistochemistry, respectively. All experimental procedures were performed blind to tumor grade.
Twelve, 9, and 7 tumors were classified as WHO grades II, III, and IV, respectively. A significant increase in ERBB1 expression was observed with increasing tumor grade (P < 0.001). Two grade IV tumors displayed intense membranous ERBB1 expression in 90% of tumor cells in association with high-level ERBB1 gene amplification. One grade III tumor also contained low-level amplification of ERBB1. Six tumors demonstrated TP53 nuclear immunoreactivity, and six contained a mutation in TP53. No correlation was observed between abnormalities in TP53 and either tumor grade or amplification and overexpression of ERBB1.
These data suggest that ERBB1 signaling is important for the development of childhood BSG and is worthy of study as a therapeutic target in this disease. Our data also indicate that the genetics of childhood BSG are complex and include both grade-dependent amplification and overexpression of ERBB1 and grade-independent expression and mutation of TP53.
Learning Objectives
After completing this course, the reader will be able to:
Describe the known genetic alterations associated with pediatric supratentorial high-grade astrocytomas and diffuse brainstem gliomas. Discuss the clinical and biologic prognostic factors for children with supratentorial high-grade astrocytomas and diffuse brainstem gliomas. Explain the roles played by surgery, radiation therapy, and chemotherapy in the treatment of children with supratentorial high-grade astrocytomas and diffuse brainstem gliomas.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at http://CME.TheOncologist.com
Pediatric high-grade gliomas represent a heterogeneous group of tumors that accounts for 15%–20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons, in which case the tumors are usually called diffuse brainstem gliomas. The diagnosis of supratentorial neoplasms is dependent on their histologic appearance. The maximum possible surgical resection is always attempted since the degree of surgical resection is the main prognostic factor for these patients. Older children (>3 years) with supratentorial neoplasms undergo a multimodality treatment comprised of surgical resection, radiation therapy, and chemotherapy. The addition of chemotherapy seems to improve the survival of a subset of these children, particularly those with glioblastoma multiforme. However, 2-year survival rates remain poor for children with supratentorial neoplasms, ranging from 10%–30%.
The diagnosis of a diffuse brainstem glioma is based upon typical imaging, dispensing with the need for surgery in the majority of cases. Radiation therapy is the mainstay of treatment for children with diffuse brainstem gliomas. The role of chemotherapy for these children is not clear, and it is, in general, employed in the context of an investigational study. Less than 10% of children with diffuse brainstem gliomas survive 2 years.
Because the outcome for patients with either type of tumor is poor when standard multimodality therapy is used, these children are ideal candidates for innovative treatment approaches.
PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.
PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m²/d × 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy × 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m²/d × 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival.
RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome.
CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.
: Glioblastoma multiforme is a rare neoplasm in children and is often located infratentorially, particularly in the brainstem. Pediatric glioblastomas arise frequently (here 60%) outside the cerebral hemispheres. We investigated 20 pediatric glioblastomas for mutational inactivation of the p53 tumor suppressor gene, loss of p16 protein expression and overexpression of the epidermal growth factor receptor (EGFR). Mutations in the p53 gene were identified in 5/20 (25%) glioblastomas, 4 of which occurred in primary glioblastomas with a clinical history of less than 4 months and neither clinical nor histologic evidence of a less malignant precursor lesion. Loss of p16 expression was detected in 11/18 (61%) glioblastomas. Overexpression of the EGFR was infrequent (2/19, 11%) and included 1 tumor with a p53 mutation. Of 4 secondary glioblastomas that progressed from histologically diagnosed lower grade tumors, one contained a p53 mutation. Our results are at variance with similar studies in adult patients in which primary and secondary glioblastomas are characterized by EGFR overexpression and p53 mutations, respectively, suggesting that the evolution of pediatric glioblastomas follows different genetic pathways.
(C) 1997 American Association of Neuropathologists, Inc
Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The camptothecin derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin’s lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1–5 and 8–12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (PPCPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.
In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed.
For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has \(0 \leqslant t_1^\prime \leqslant t_2^\prime \leqslant \cdots \leqslant t_N^\prime .\) Then \(\hat P\left( t \right) = \Pi r\left[ {\left( {N - r} \right)/\left( {N - r + 1} \right)} \right]\), where r assumes those values for which \(t_r^\prime \leqslant t\) and for which \(t_r^\prime\) measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations.
Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
Brain stem gliomas are pediatric astrocytomas that histologically resemble adult supratentorial astrocytomas such as glioblastomas multiforme (GBM). Our molecular genetic studies have suggested that adult GBM can be divided into two genetic subsets: tumors with p53 tumor suppressor gene mutations and chromosome 17p loss that occur more commonly in younger patients; and tumors with epidermal growth factor receptor (EGFR) gene amplification that occur more commonly in older patients. Brain stem gliomas have not been studied since biopsies of these tumors are rare and extremely small. We investigated the molecular genetic composition of seven brain stem glioblastomas (two small biopsies, five autopsies) using polymerase chain reaction (PCR) assays for chromosomal loss, gene mutation and gene amplification. Four cases lost portions of chromosome 17p that included the p53 gene. These four cases and one additional case had mutations in the p53 gene. None of the cases showed amplification of the EGFR gene. Allelic losses of the long arm of chromosome 10 were noted in four cases. These results suggest similarities between pediatric brain stem glioblastomas and those GBM that occur in younger adult patients, and confirm the utility of PCR-based means of studying small and archival brain tumor specimens.
Using polymerase chain reaction-single strand polymorphism(PCR-SSCP) and nucleotide analyses, p53 gene mutation was examined in 13 pontine gliomas many of which were of juvenile onset. A total of 15 mutations were detected in 8 cases, of which 5 revealed multiple or tandem mutations. The mutations included 6 G:C-A:T and 4 A:T-G:C transitions and 4 G:C-T:A and 1 A:T-T:A transversions. There was only 1 transition at the CpG site. Normal tissues of the same patients revealed no mutation, suggesting that these mutations were somatic, but not of germ line, in nature. The pattern of mutation characterized by frequent multiple or tandem occurrence, predominancy of transition at non-CpG sites and relatively frequent transversions suggested that pontine glioma might be related with some mutagenic or carcinogenic agents.
To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma.
Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients.
All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment.
Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.
To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse.
This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle.
Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients.
Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.
To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients.
Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses.
Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5.
Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.
High-grade astrocytomas are tumors that are uncommon in children. Relatively few studies have been performed on their molecular properties and so it is not certain whether they follow different genetic pathways from those described in adult diffuse astrocytomas. In this study, we evaluated 24 pediatric high-grade astrocytomas (11 anaplastic astrocytomas and 13 glioblastomas) all of which were sporadic and primary. We studied mutations of p53, phosphatase and tensin homolog (PTEN), loss of heterozygosity (LOH) of chromosomes 17p13, 9p21 and 10q23-25, amplification of epidermal growth factor receptor (EGFR), and overexpression of EGFR and p53 protein. In addition, we searched for microsatellite instability (MSI) by using MSI sensitive and specific microsatellite markers. p53 mutations were found in 38% (9/24) of the high-grade astrocytomas and all brain stem tumors except 2 (71%, 5/7) had p53 mutations. PTEN mutations were found in 8% (2/24) of high-grade astrocytomas. However, no EGFR amplification was found in any of them. LOH was found at 17p13.1 in 50% (3/6 informative tumors), 9p21 in 83% (5/6 informative tumors), and 10q23-25 in 78% (7/9 informative tumors). Four tumors showed MSI, and 2 of them that showed widespread MSI were regarded as tumors with replication error (RER+) phenotype. All 4 tumors with MSI showed concurrent LOH of 9p21 and 10q23-25. Combining gene alterations, LOH, MSI, and gene mutations, inactivation of both alleles of PTEN and p53 was found in 57% (4/7 informative tumors) and 50% (3/6 informative tumors) of the cases respectively. We conclude that development of pediatric high-grade astrocytomas may follow pathways different from the primary or secondary paradigm of adult glioblastomas. In a subset of these tumors, genomic instability was also implicated.
A Phase I trial of irinotecan was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the incidence and severity of other toxicities in children with refractory solid tumors. Thirty-five children received 146 courses of irinotecan administered as a 60-min i.v. infusion, daily for 5 days, every 21 days, after premedication with dexamethasone and ondansetron. Doses ranged from 30 mg/m2 to 65 mg/m2. An MTD was defined in heavily pretreated and less-heavily pretreated (i.e., two prior chemotherapy regimens, no prior bone marrow transplantation, and no radiation to the spine, skull, ribs, or pelvic bones) patients. Myelosuppression was the primary DLT in heavily pretreated patients, and diarrhea was the DLT in less-heavily pretreated patients. The MTD in the heavily pretreated patient group was 39 mg/m2, and the MTD in the less-heavily pretreated patients was 50 mg/m2. Non-dose-limiting diarrhea that was well controlled and of brief duration was observed in approximately 75% of patients. A partial response was observed in one patient with neuroblastoma, and in one patient with hepatocellular carcinoma. Stable disease (4-20 cycles) was observed in seven patients with a variety of malignancies including neuroblastoma, pineoblastoma, glioblastoma, brainstem glioma, osteosarcoma, hepatoblastoma, and a central nervous system rhabdoid tumor. In conclusion, the recommended Phase II dose of irinotecan administered as a 60-min i.v. infusion daily for 5 days, every 21 days, is 39 mg/m2 in heavily treated and 50 mg/m2 in less-heavily treated children with solid tumors.
Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.
Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival.
Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome.
Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.
Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood-brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem.
Three primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 microl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and midbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94), with a Vd/Vi ratio of 8.7 +/- 1.2 (mean +/- standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal gliosis that was limited to the region immediately surrounding the cannula track.
First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes.
To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide.
A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans.
Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication.
Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.
To assess the antitumour activity and safety profile of irinotecan and its pharmacokinetic interactions with anticonvulsants in patients with glioblastoma multiforme.
This multicentre phase II and pharmacokinetic study investigated the effects of irinotecan 350 mg/m(2) given as a 90-min infusion every 3 weeks either prior to (group A) or after relapse following radiotherapy (group B) in chemotherapy-naïve patients with glioblastoma. Preferred concomitant medication for seizure prevention was valproic acid. Pharmacokinetic analysis of irinotecan and its main metabolites (SN-38, SN-38-G, APC and NPC) was performed during cycle 1. An independent panel of experts reviewed the activity data.
Fifty-two patients (25 patients in group A and 27 patients in group B) received a total of 191 cycles of irinotecan. Forty-six patients (22 patients in group A and 24 patients in group B) were evaluable and externally reviewed for activity. According to external review, one partial response (group B), seven minor responses (three in group A and four in group B), 12 disease stabilisations (seven in group A and five in group B) were observed. This resulted in an overall response rate of only 2.2% (95% confidence interval 0.2% to 6.5%). The median time to tumour progression was 9 weeks in group A and 14.4 weeks in group B. Six-month progression-free survival rates were 26% in group A and 43% in group B. Grade 3-4 toxicities (percentage of patients in groups A and B) consisted of neutropenia (12.5% and 25.9%), diarrhoea (8.3% and 7.4%), asthenia (12.5% and 7.4%) and vomiting (0% and 7.4%). The clearance of irinotecan was 12.4 and 14.4 l/h/m(2) in two patients who received no anticonvulsant. In patients receiving valproic acid, the clearance of irinotecan was 17.2 +/- 4.4 l/h/m(2).
Irinotecan given at the dose of 350 mg/m(2) every 3 weeks has limited clinical activity as a single agent in patients with newly diagnosed and recurrent glioblastoma after radiotherapy. The toxicity profile and plasma disposition of irinotecan and SN-38 were not strongly influenced by anticonvulsant valproic acid therapy. Although the response rate of irinotecan as a single agent was limited, it remains an attractive drug for combination studies in patients with glioblastoma.
A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs). Experimental Design: Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of >/==" BORDER="0">3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose.
Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients.
The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.
A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors.
Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts.
One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean +/- standard deviation (SD) CPT-11 plasma clearance was 20.7 +/- 9.5 L/h/m2 (range, 5 to 54). The mean +/- SD SN-38 metabolic ratio was 1.5% +/- 1.1% (range, 0.15% to 5.55%).
The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.
Purpose:
To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors.
Methods:
We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling.
Results:
The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies.
Conclusions:
This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.
Nonparametric estimation from incomplete observations 138 CANCER January 1, 2005 / Volume 103 / Number 1 11 Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design
- El Kaplan
- P Meier
- Pike
- Mc
- P Armitage
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457– 481. 138 CANCER January 1, 2005 / Volume 103 / Number 1 11. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976;34:585– 612.