piperidines and Brain-Stem-Neoplasms

Assessing the response to treatment in infiltrative brain tumors by using lesion volume-based response criteria is challenging. We hypothesized that in such tumors, volume measurements alone may not accurately capture changes in actual tumor burden during treatment. We longitudinally evaluated volume changes in both normal-appearing supratentorial white matter and the brain stem lesions in patients treated for diffuse intrinsic pontine glioma to determine to what extent adjuvant systemic therapies may skew the accuracy of tumor response assessments based on volumetric analysis.. The anatomic MR imaging and diffusion tensor imaging data of 26 patients with diffuse intrinsic pontine glioma were retrospectively analyzed. Treatment included conformal radiation therapy in conjunction with vandetanib and dexamethasone. Volumetric and diffusion data were analyzed with time, and differences between time points were evaluated statistically.. Normalized brain stem lesion volume decreased during combined treatment (slope = -0.222,. Longitudinal changes in brain stem lesion volume are robust; less pronounced but measurable changes occur in the supratentorial white matter. Volume changes in nonirradiated supratentorial white matter during the disease course reflect the effects of systemic medication on the water homeostasis of normal parenchyma. Our data suggest that adjuvant nontumor-targeted therapies may have a more substantial effect on lesion volume changes than previously thought; hence, an apparent volume decrease in infiltrative tumors receiving combined therapies may lead to overestimation of the actual response and tumor control.

Topics: Antineoplastic Agents; Brain Stem; Brain Stem Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Dexamethasone; Diffusion Tensor Imaging; Disease Progression; Disease-Free Survival; Female; Glioma; Humans; Magnetic Resonance Imaging; Male; Piperidines; Prospective Studies; Quinazolines; Steroids; Vascular Endothelial Growth Factor A; White Matter

We previously reported the cases of 3 children with diffuse intrinsic pontine glioma (DIPG) in whom noncontiguous treatment-related abnormalities (NCTRAs) developed in the brain after expanded-field radiation therapy (RT). To investigate the occurrence and putative mechanism of NCTRAs, we reviewed brain magnetic resonance imaging studies of patients with DIPG treated in 2 consecutive phase I clinical trials (trials 1 and 2).. The 55 children included in these trials received small-molecule inhibitors: vandetanib in trial 1 (n=32; mean age 6.4 years) and vandetanib and dasatinib in trial 2 (n=23; mean age 5.8 years). The patients also received conformal 3-dimensional RT (cumulative dose 54 Gy). For patients enrolled in trial 1, the clinical target volume (CTV) was expanded by 1 cm from the gross tumor volume. In trial 2, the expansion to form the CTV was 2 to 3 cm. A review of imaging studies was performed from the initial diagnosis through the end of progression-free survival. The imaging findings were grouped into 5 categories according to the presence, absence, location, extent, and putative mechanism of NCTRAs. Statistical analysis was performed to evaluate the association between covariates and NCTRA, cohort characterization, and survival comparisons.. Overall survival was similar in both studies (P=.74). NCTRAs developed in 9 patients (39%) treated in trial 2 but in none treated in trial 1. The NCTRAs included T2-weighted hyperintensities with (n=3; radiation necrosis) or without (n=5) contrast uptake, supratentorial leukoencephalopathy (n=2), and ischemic stroke (n=1). All NCTRAs, except for 1, occurred within the CTV. Compared with nonaffected patients, patients with a NCTRA were younger (P=.003) and had had larger relative brain volumes exposed to doses >20 Gy.. The imaging features of NCTRAs suggest that their development is secondary to synergistic steno-occlusive vascular effects induced by the combination of RT, an expanded CTV, potent antiangiogenic therapy, young age, and, in 1 case, a genetic predisposition.

Topics: Adolescent; Angiogenesis Inhibitors; Antineoplastic Agents; Brain; Brain Stem Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Dasatinib; Disease-Free Survival; Female; Glioma; Humans; Leukoencephalopathies; Magnetic Resonance Imaging; Male; Piperidines; Quinazolines; Radiotherapy, Conformal; Stroke; Tumor Burden

DIPG is among the most devastating brain tumors in children, necessitating the development of novel treatment strategies and advanced imaging markers such as perfusion to adequately monitor clinical trials. This study investigated tumor perfusion and 3D segmented tumor volume as predictive markers for outcome in children with newly diagnosed DIPG.. Imaging data were assessed at baseline, during, and after RT, and every other month thereafter until tumor progression for 35 patients (ages 2-16 years) with newly diagnosed DIPG enrolled in the phase I clinical study, NCT00472017. Patients were treated with conformal RT and vandetanib, a vascular endothelial growth factor receptor 2 inhibitor.. Tumor perfusion increased and tumor volume decreased during combined RT and vandetanib therapy. These changes slowly diminished in follow-up scans until tumor progression. However, increased tumor perfusion and decreased tumor volume during combined therapy were associated with longer PFS. Apart from a longer OS for patients who showed elevated tumor perfusion after RT, there was no association for tumor volume and other perfusion variables with OS.. Our results suggest that tumor perfusion may be a useful predictive marker for the assessment of treatment response and tumor progression in children with DIPG treated with both RT and vandetanib. The assessment of tumor perfusion yields valuable information about tumor microvascular status and its response to therapy, which may help better understand the biology of DIPGs and monitor novel treatment strategies in future clinical trials.

Topics: Adolescent; Antineoplastic Agents; Blood Volume; Brain Stem Neoplasms; Child; Child, Preschool; Cohort Studies; Disease Progression; Echo-Planar Imaging; Female; Follow-Up Studies; Glioma; Humans; Image Enhancement; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Neoadjuvant Therapy; Neuroimaging; Piperidines; Prospective Studies; Quinazolines; Radiotherapy, Conformal; Receptors, Vascular Endothelial Growth Factor; Survival Rate; Treatment Outcome

To evaluate the growing skeleton for potential altered skeletalgenesis associated with antiangiogenesis therapy.. Knee radiographs and magnetic resonance imaging (MRI) were prospectively obtained on patients enrolled on two consecutive clinical trials using vandetanib, a potent oral (VEGF receptor 2) VEGFR-2 inhibitor alone or combined with dasatinib, a multiple tyrosine kinase inhibitor, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).. Fifty-nine patients (32 females) underwent 119 MRIs; 51 patients underwent 89 radiographs of the knees. The median age at enrollment was 6.2 years (range, 2.4-17.6 years). The dose of vandetanib ranged from 50 to 145 mg/m(2) /day. The median treatment duration was 205 days. Only two patients have not experienced disease progression after 18 and 60 months from diagnosis. MRI identified clinically significant premature physeal fusion in both knees of one patient, focal physeal thickening in one, osteonecrosis in eight patients (present at enrollment in one), and bony spicules crossing the physis in two patients (bilateral in one). MRI follow-up period averaged 5.3 months (range, 0-25.5 months; median, 3.5 months). Radiographs delineated normally fused physes in two patients but no cases of premature physeal fusion, osteonecrosis or bony spicules.. As MRI provided greater information than radiographs, and thus would be a more sensitive test to assess skeletalgenesis in pediatric patients.

Topics: Adolescent; Adult; Angiogenesis Inhibitors; Brain Stem Neoplasms; Child; Child, Preschool; Dasatinib; Female; Follow-Up Studies; Glioma; Humans; Infant; Knee Joint; Magnetic Resonance Imaging; Male; Osteonecrosis; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Quinazolines; Radiography; Thiazoles; Vascular Endothelial Growth Factor Receptor-2

Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.. Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.. Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.. The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Stem Neoplasms; Child; Child, Preschool; Dasatinib; Female; Glioma; Humans; Male; Piperidines; Pyrimidines; Quinazolines; Thiazoles; Treatment Outcome

To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma.. Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy.. Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039).. The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

Topics: Adolescent; Antineoplastic Agents; Brain Stem Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Disease-Free Survival; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Glioma; Humans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Piperidines; Quinazolines; Radiotherapy, Adjuvant; Treatment Outcome; Young Adult

Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines. Survival benefit of niraparib was examined in an orthotopic xenograft model of pHGA. About 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP1. Six of 8 primary cell lines highly expressed PARP1. Interestingly, across multiple cell lines, some PARP1 protein expression was required for response to PARP inhibition; however, there was no correlation between protein level or PARP1 activity and sensitivity to PARP inhibitors. Niraparib was the most effective at reducing cell viability and proliferation (MTT and Ki67). Niraparib induced DNA damage (γH2AX foci) and induced growth arrest. Pretreatment of pHGA cells with a sublethal dose of niraparib (1 μmol/L) before 2 Gy of ionizing radiation (IR) decreased the rate of DNA damage repair, colony growth, and relative cell number. Niraparib (50 mg/kg) inhibited PARP1 activity in vivo and extended survival of mice with orthotopic pHGA xenografts, when administered before IR (20 Gy, fractionated), relative to control mice (40 vs. 25 days). Our data provide in vitro and in vivo evidence that niraparib may be an effective radiosensitizer for pHGA and DIPG.

Topics: Animals; Astrocytoma; Benzimidazoles; Blotting, Western; Brain Stem Neoplasms; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Child; Combined Modality Therapy; Glioma; Humans; Indazoles; Kaplan-Meier Estimate; Linear Models; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Microscopy, Confocal; Phthalazines; Piperazines; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Pons; Radiotherapy; Xenograft Model Antitumor Assays