bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM)
Authors: Stupp R. , Goldbrunner R. , Neyns B. , Schlegel U. , Clement P. , Grabenbauer G. G. , Hegi M. E. , Nippgen J. , Picard M. , Weller M.
Published: March 2020

2000

Background: To evaluate safety, toxicity, and efficacy of the combination of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, in addition to standard temozolomide (TMZ) and radiotherapy (RT). Methods: 52 pts (PS 0–1: 92%, 2: 8%; median age 57 yrs) after tumor resection (n=43/83%) or biopsy (n= 9/17%) were treated with standard TMZ/RT (Stupp et al. NEJM 2005). In addition cilengitide (500 mg i.v., 2x/week) was started one week before TMZ/RT and given throughout for the duration of chemotherapy or until progression. The primary endpoint was progression free survival rate at 6 months (target: 65%). Pts were followed with MRI every 2 months. Histopathologic diagnosis and MRI imaging were independently reviewed, O6-Methylguanine- DNA methyltransferase (MGMT) promotor methylation status was assessed in 45 (86.5%) pts. Results: 46 pts (92%) completed RT, = 90% of concomitant TMZ was received by 42 pts and cilengitide by 45 pts. 20 pts (3 ongoing) completed 6 cycles of maintenance TMZ and cilengitide. Observed hematological grade 3 and 4 toxicities were: lymphopenia (28/52, 53.8%), thrombocytopenia (7/52 pt. 13.4%) and neutropenia (5/52, 9.6%). Treatment related non-hematologic grade 3/4 toxicities were reported for n=3/52 (5.7%) patients: constitutional symptoms (asthenia, fatigue, anorexia, n=3); elevated liver function tests (n=1), deep venous thrombosis and pulmonary embolism (n=1). One patient with a history of sigmoid diverticulosis experienced sigmoid perforation (grade 2). In total, 34/52 (65.4% [95% CI, 50.9–78.0%]) of the pts were progression free at 6 months. Pts with MGMT gene-promotor methylation in the tumor were more likely to reach 6 months PFS endpoint. Conclusions: The study reached its primary endpoint. The combination of the integrin inhibitor RGD peptide Cilengitide and TMZ/RT was well tolerated, PFS at 6 months is encouraging. MGMT gene promoter methylation correlates with outcome. At the time of ASCO, updated results and survival estimates after a minimum follow-up of at least 1 year will be available.

[Table: see text]
The role of EGFR trafficking in neuroblastoma
Authors: Zage P. E. , Yan Q. , Zeng L. , Bean A. J.
Published: March 2020

20003

Background: Signaling through growth factor receptors is important in neuroblastoma pathogenesis. Chromosome 1p36 is commonly deleted in neuroblastoma tumors and is associated with a poor prognosis. UBE4B, a gene in 1p36, has been reported mutated in high- risk neuroblastoma. We have found a direct interaction between UBE4B and hrs, a protein required for epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. We have analyzed the role of UBE4B in the EGFR pathway in neuroblastoma cell lines. Methods: The expression of UBE4B, hrs and EGFR were analyzed by quantitative Western blot in a panel of 7 human neuroblastoma cell lines (SHEP, SKNAS, SKNSH, KCNR, SY5Y, LA155N, NGP). EGFR degradation rates were determined by examining the kinetics of cellular EGFR depletion following a pulse of ligand. Results: UBE4B levels were lowest in SKNAS and highest in NGP cells. Hrs levels were lowest in SKNSH cells and higher in other cell lines. EGFR levels were lowest in NGP and KCNR and highest in SKNAS cells. UBE4B levels were correlated with known 1p deletions. EGFR degradation rates were slowest in SKNAS cells and therefore correlated with cellular UBE4B levels. The low degradation rates were correlated with high cellular levels of EGFR. Conclusions: Expression levels of UBE4B are correlated in neuroblastoma cell lines with chromosome 1p deletions. Cell lines with lower levels of UBE4B degrade EGFR at a markedly slower rate, correlated with higher cellular EGFR levels. We hypothesize that UBE4B affects cell growth by interacting with hrs, directing EGFR for degradation. In its absence the ability of a cell to sort growth factor receptors for degradation is inhibited, resulting in growth factor receptor overabundance and uncontrolled cell growth. These results support the testing of EGFR inhibitors in a future phase I trial for children with neuroblastoma.

No significant financial relationships to disclose.
Chemotherapy plus cyclosporine A for the treatment of intraocular retinoblastoma: The University of Miami Miller School of Medicine experience
Authors: Fernandes C. E. , Schefler A. C. , Murray T. G. , Davis J. A. , Alvarez O. A. , Podda A. , Barredo J. C. , White E. , Lewis N. , Toledano S. R.
Published: March 2020

20005

Background: In the past decade chemotherapy and focal control became the standard of care in retinoblastoma. The ideal chemotherapy regimen has not yet been determined. We analyzed the results of treatment at the University of Miami Miller School of Medicine using the regimen carboplatin (20 mg/kg, day 1), vincristine (0.05 mg. /kg, day 1), etoposide (5 mg / kg, days 1 and 2) with or without cyclosporine A (10 mg. /kg over 2 hours followed by 45 mg/kg over 31 hours) every 3–4 weeks. We attempted to maintain peak CSA levels between 2,400 and 6,000 and steady state levels between 2,400 and 4,200 ng/ml. When CSA was given, vincristine was started at 0.0125 mg /kg. The dose was escalated by 25% with each cycle of therapy, as tolerated. Methods: A retrospective analysis was performed in 41 patients diagnosed with bilateral retinoblastoma from Dec 1996 to Jan 2006. Only eyes with intraocular disease (76 eyes) were included in this analysis. Before each cycle of chemotherapy ophthalmologic examination under anesthesia was performed and active tumor and seeding were treated with local ablation using laser therapy. Eyes in which enucleation was planned at diagnosis were excluded from this analysis. Results: Most patients received 9 cycles of chemotherapy. Sixty percent (46/76) of the eyes were treated with chemotherapy and CSA. The eye salvage rate for eyes classified by the International Classification of Retinoblastoma (ICRB) as groups A, B, C and D was 100%. The eye salvage rate for the 21 eyes classified as ICRB group E was 29%. No difference in salvage rate was observed in eyes treated with or without CSA. One patient died from disease progression. Only one patient required radiation therapy to both eyes. To date there have been no reports of development of secondary malignancies. Conclusion: The addition of CSA to the treatment of the eyes classified as ICRB groups A, B, C and D made no difference in the eye salvage rate. Also, we were not able to demonstrate any benefit from the addition of CSA in patients with stage E eyes- although our sample size was quite small. Aggressive focal control and chemotherapy beginning at diagnosis may be the reason for the excellent EFS in group A, B, C and D eyes.

No significant financial relationships to disclose.
Radiographic tumor response in pediatric patients with newly diagnosed localized (LOC) or metastatic (MET) Ewing’s sarcoma (EWS) following neoadjuvant chemotherapy
Authors: Chuk M. K. , Balis F. M. , Mackall C. , Hawkins D. , Avila N. , Widemann B. C. , Helman L. J. , Fox E.
Published: March 2020

20008

Background: Standard treatment for EWS includes vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE). Using this therapy, overall survival is 70% in patients with LOC EWS and 30% in patients with MET EWS. We compared the radiographic response to VDC and IE in patients with LOC or MET EWS. Methods: We conducted a randomized trial comparing pegfilgrastim to filgrastim in patients treated with VDC (cycles 1, 2, 5, 9, 11, 13) and IE (cycles 3, 4, 6–8, 10, 12, 14). Local control with radiation or surgery was initiated after cycle 5. We assessed radiographic response after VDC (C1,2) and IE (C3,4) using 1-dimensional (RECIST) and 2-dimensional (WHO) criteria. Measurements were performed using MEDx. Results: Twenty-one patients with EWS, median age 20y (6–25y), were enrolled; 16 were evaluable for this analysis. Primary tumors were in extremity (n=5) or central axis (n=11). Eight patients had MET disease (pulmonary only, n=4). Median (range) decrease in tumor size by WHO after C4 was 61% (40–92%) for LOC and 83% (47–94%) for MET. Decrease by treatment is presented in the table . Overall responses after 4 cycles for LOC patients were 5 PR, 3 SD using RECIST, and 6 PR, 2 SD using WHO. For MET patients, overall responses were the same using RECIST and WHO, 7 PR, and 1SD. Conclusion: Patients with MET EWS responded as well as those with LOC EWS after 4 cycles of neoadjuvant chemotherapy. Similar overall response was demonstrated using RECIST or WHO. Tumor response after VDC was greater than after IE, possibly due to sequence of administration, but patients had continued tumor response with IE.

[Table: see text]

No significant financial relationships to disclose.
A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma
Authors: Batchelor T. , Sorensen A. G. , Ancukiewicz M. , Duda D. G. , Louis D. N. , Plotkin S. R. , Ivy P. , Wen P. Y. , Loeffler J. S. , Jain R.
Published: March 2020

2001

Background: AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients treated with daily doses of AZD2171. Normalization has rapid onset, is reversible and is associated with alleviation of brain edema [Cancer Cell 2007; 11: 83]. Methods: In this phase II study of 30 recurrent glioblastoma subjects the primary endpoint was the proportion of patients alive and progression-free at 6 months (APF6). Secondary endpoints include radiographic response proportion; progression-free survival; overall survival and toxicity. At this time we are presenting radiographic response data and toxicity on the first 16 consecutive patients and APF6, PFS and OS on all 30 patients. Complete information will be available on all 30 patients at the time of presentation. Results: Twenty-eight patients have experienced disease progression and two patients remain in follow-up without progression. The primary and secondary endpoints are tabulated below: Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities of hypertension, fatigue and diarrhea were observed in 9/16 patients. There were no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in the first 16 patients enrolled. Blood biomarkers were serially assessed and elevated levels of bFGF, SDF1a and viable circulating endothelial cells correlated with disease progression. Conclusions: AZD2171 has activity in patients with recurrent glioblastoma. Combination studies of AZD2171 with radiation and chemotherapy are planned.

[Table: see text]

[Table: see text]
Valproic acid enhances etoposide induced cytotoxicity in neuroblastoma cells
Authors: Aguilera D. G. , Das C. , Wolff J. , Zage P. , Gopalakrishnan V.
Published: March 2020

20010

Background: Metastastic neuroblastoma is resistant to treatment and prolonged response is difficult to achieve therefore new therapies are necessary. Etoposide, a topoisomerase II inhibitor is often used for its treatment. Valproic acid (VPA) has histone deacetylase inhibitor (HDI) activity. Epigenetic alterations described in neuroblastoma tumors make VPA a good candidate to evaluate for potentiation of etoposide-mediated cytotoxicity. We evaluate the effects of VPA in combination with etoposide in neuroblastoma cells. Methods: Human neuroblastoma cell lines SKNAS and SKNSH were incubated with 1.5 mM VPA and increasing concentrations of etoposide from 1x10-6 to 1 mM. Cell viability assay were measured with MTT assays. Results: We observed that VPA and etoposide independently decreased cell viability in a time and concentration dependent manner. The co-incubation with both drugs greatly enhanced the cytotoxicity of etoposide. IC50 for SKNSH cells treated with etoposide were approximately 1x10–3, 1.8x10–4, and 3x10- 5mM at 24, 72 and 96 hours, respectively. With the addition of VPA we found that cell viability was reduced approximately by 10 fold at each time point. At 72 and 96 hours 100 percent cell death was achieved at 0.1 mM of etoposide. IC50 for SKNAS cells treated with etoposide were approximately 1.8x10–3 mM and 6x10–4 mM at 72 and 96 hours, respectively. With the addition of VPA, IC50s were reduced by approximately 5 fold at the same exposure times. Further confirmation of synergistic activity was demonstrated with the use of the fraction product method of Webb formula. Conclusions: Our results demonstrate that VPA potentiates the cytotoxic effects of etoposide on neuroblastoma cells. by altering gene expression and rendering the cells more sensitive to etoposide induced cell death. Finally, since these agents have a proven track record of safety and efficacy in patients with neuroblastoma, this data supports the use of this combination in a phase I trial in patients with neuroblastoma.

No significant financial relationships to disclose.
Result of childhood acute lymphoblastic leukemia protocol (INCTR) from a developing country
Authors: Mukhopadhyay D. , Gupta P. , Mukhopadhyay S. , Chitalkar P. , Banavali S. D. , Advani S. H. , Adde M. , Magrath I.
Published: March 2020

20015

Background: Acute Lymphatic Leukemia in children is a curable disease in the range of 80–90 % in developed Countries by aggressive protocol like BFM, St. Judes’. In developing Countries like ours, patients can’t tolerate those aggressive protocol because of Socio- economic and nutritional factors. The less aggressive Protocol like INCTR (International Network for Cancer Treatment & Research) are suitable in developing Countries like ours. The aim of our study was to see outcome of childhood ALL patient with INCTR protocol and tolerability of the protocol in Indian-asian population. Methods: We treated 480 Children (age range 1–25 years, median age of 11 yrs) with INCTR Protocol at Netaji Subhash Chandra Bose Cancer Research Institute, Kolkata, India, a tertiary cancer centre from Eastern India during period from April ’99 to Dec ’06. There was female preponderance in the study. Fever 283 (58.9%), lymphadenopathy 211 (43.9%) and haepatosplenomegaly 153 (31.8%) were the major clinical presentation. Forty-three (8.9%) patients were present with hyper Leukocytosis. C-ALL phenotype were the largest group though the incidence of the T-ALL were quite high (27.9%). Results: Remission induction were seen in 446 (92.9%) of the patient. In a follow-up period of 88 months (with an average of 54 months) the disease-free survival ( DFS) was 66.8% (321 patients) with an overall survival of 73.9% (355 patients). The isolated bone marrow relapse was seen in majority of the cases 40 (8.33%) and the major relapse was in maintenance and first 6 months of completion of therapy. The major cause of morbidity was infection 316 (65.8%) followed metabolic complications 81 (16.8%), hemorrhage 52 (10.8%), neurologic 10 (2.08%), hepatitis 6 (1.25%) and pancreatitis 5 (1.04%). The major cause of the mortality was infection 75%(360 patients) followed progressive disease 7.91% (38 patients) and Hemorrhage 5.83%( 28 patients). Conclusions: The data of acute lymphatic leukemia from a developing country is encouraging. The protocol was well tolerated by India- asian population.

No significant financial relationships to disclose.
Radiation induced lung injury in survivors of childhood cancer
Authors: Stegner M. M. , Luckett P. M. , Fitzgerald J. E. , Eshelman D. , Cochran C. , Leavey P. J.
Published: March 2020

20017

Background: The purpose of this study was to examine survivors of childhood cancer, treated with whole lung irradiation (WLI), for signs of pulmonary insufficiency and to correlate pulmonary function test (PFT) results to symptoms of pulmonary dysfunction as detected using the St. George’s Respiratory Questionnaire (SGRQ). Methods: A cross-sectional study was conducted on eligible patients (>2 years from WLI and <18 years at time of diagnosis) who are followed in our institution’s cancer survivor program. Participating patients had a history and physical examination and PFTs performed pre and post bronchodilator challenge. Patients (or their guardians) also completed the SGRQ. The SGRQ, validated for patients 17 to 80 years, generates four values that define respiratory dysfunction: a Symptoms score, an Activity Score, an Impact score, and a Total score. Results: Twenty eligible patients were identified, 12 of whom consented to participate in this study (11 Wilms, 1 Ewing sarcoma). The median current age was 18.4 years (7.5 to 43 years; n=6 < 14 yrs), while patients received WLI (1,200 cGy n=10, 1500 cGy n=2) at a median age of 4.4 years of age (1.7 to 8.7 years). The median time from radiation therapy was 12.6 years (4.7 to 34.3 years). All patients denied smoking, 4 had a history of asthma and all had a normal lung exam. Ten patients had PFTs, 5 of whom (4/5 adults and 1/5 children) had a restrictive pattern noted by PFTs. One further patient (7.5 yrs of age) had a total lung volume 70% predicted but a forced vital capacity 86% predicted. In the pediatric patients (<14 years currently) the FEF 25–75 (4/5) and SGaw (5/5) were increased following treatment with bronchodilator. Twelve participants completed the SGRQ, 4 had elevated total scores (22, 32, 37 and 64). 1 patient with echocardiographic evidence of a dilated cardiomyopathy had an elevated total score but normal symptom score. One patient with a recorded acute pneumonitis after WLI, now 18 years later had normal PFTs and normal SGRQ scores. No correlation was seen between PFT results and SGRQ scores. Conclusions: A restrictive lung function pattern is more common at a later age following WLI in childhood. Mid-expiratory flow and airway conductance following bronchodilator were increased in children. The functional significance of these findings requires further study.

No significant financial relationships to disclose.
Results of cisplatin-based chemotherapy in inoperable hepatoblastoma during last two years at a single institute
Authors: Patel K. M. , Shah S. A. , Patel A. A. , Shah P. M. , Shukla S. N. , Parikh B. J. , Anand A. S. , Talati S. S. , Srivastav R. K. , Dave R. I.
Published: March 2020

20027

Background: Total surgical excision and adjunctive chemotherapy are cornerstones of treatment of hepatoblastoma in children. But many are unsuitable for radical surgery at diagnosis due to extensive intrahepatic and/or extra hepatic disease. We assessed 18 consecutive cases during the last two years, all of whom presented with unresectable tumor, treated in our center with neoadjuvant chemotherapy,in order to analyze the clinical profile and response to treatment. Methods: A retrospective analysis of patients who presented to our institute during January 2004 to January 2006 was carried out. All patients were biopsy proven hepatoblastoma. One patient was operated without anterior chemotherapy outside our institute .Two patients had lung metastasis. Rest all had stage 3 disease. All the patients were given cisplatin [90 mg/m2] and continuous infusion doxorubicin [80 mg/m2 over 4 days]. The response to therapy was assessed. Results: Mean age of presentation was 3 years and 4 months [range 1 year to 11 year]. M:F ratio was 4:1. Most common presenting complaint was an asymptomatic abdominal mass felt by the parent. All the patients had tumour in right lobe. Mean alpha fetoprotein level was 0.14 million and the range was from normal to 1.24 million. None of the patients were positive for hepatits B or hepatitis C. After three cycles of chemotherapy, seven of the seventeen patients had adequate down staging of the disease so as to undergo successful resection. There was one post operative mortality. All of them completed total of six cycles of chemotherapy. Ten patients had unresectable tumour even after six cycles of chemotherapy. All of them had reduction in the size of primary tumor and decreased alpha fetoprotein level .There was no chemotherapy related grade 3 or grade 4 toxicity. Conclusions: Hepatoblastoma occurs at a later age in Indian patients as compared to that seen in western countries. Cisplatin and adriamycin are quite effective in downstaging hepatoblastoma. Since these agents are cheap and have minimal toxicity they should be used frequently.

No significant financial relationships to disclose.
N047B: NCCTG phase II trial of vorinostat (suberoylanilide hydroxamic acid) in recurrent glioblastoma multiforme (GBM)
Authors: Galanis E. , Jaeckle K. A. , Maurer M. J. , Reid J. M. , Ames M. M. , Giannini C. , Hardwick J. S. , Moore D. F. , Zwiebel J. A. , Buckner J. C.
Published: March 2020

2004

Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported.

No significant financial relationships to disclose.
Motexafin gadolinium (MGd) combined with whole brain radiation therapy prolongs time to neurologic progression in non- small cell lung cancer (NSCLC) patients with brain metastases: Pooled analysis of two randomized phase III trials
Authors: Shapiro W. R. , Mehta M. P. , Langer C. , Bezjak A. , Timmerman R. , Brachman D. , Suh J. , Smith J. A. , Phan S. , Renschler M. F.
Published: March 2020

2010

Background: In 2 randomized trials, whole brain radiation therapy (RT) plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM). In this report, results of a pooled analysis from both trials are presented. Methods: In trial 9801, 401 pts with BM from solid tumors were randomized to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10 days. The subgroup of 251 pts with NSCLC is included in this analysis. In trial 0211, 554 pts with BM from NSCLC were randomized to the same treatments. In both trials, eligibility included a KPS = 70, no liver metastases, and = 1 site of extracranial metastasis. In both trials, a primary endpoint was time to neurologic progression determined by a blinded events review committee (ERC), incorporating data from neurologic exams, neurologic symptom collection, and neurocognitive tests. Results: 805 pts received RT (N=403) or RT+MGd (N=402). Most pts had multiple BM (80%), extracranial metastases (47%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with 93.3% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4.6%), and fatigue (2.8%). TNP in the RT+MGd group was 15.4 mo, significantly longer than the 9.0 mo for the RT alone group, p=0.016, HR=0.74 (95% CI 0.57–0.95). The results of both studies are consistent, as shown in the table below. Similar results were observed in time to investigator-determined neurologic progression (p=0.015, HR=0.76) and time to neurocognitive progression (memory: HR=0.80, p=0.047, executive function: HR=0.74, p=0.028, all tests combined: HR=0.78, p=0.020). Conclusions: Motexafin gadolinium significantly prolonged time to neurologic progression and neurocognitive progression in NSCLC patients with brain metastases undergoing whole brain radiation therapy in a pooled analysis of 2 randomized phase III trials.

[Table: see text]

No significant financial relationships to disclose.
Should adult medulloblastoma patients at low risk receive adjuvant chemotherapy? Long-term results of a prospective study
Authors: Franceschi E. , Tosoni A. , Ermani M. , Blatt V. , Amistà P. , Sotti G. , Bartolini S. , Grosso D. , Pasetto L. M. , Brandes A. A.
Published: March 2020

2018

Background: Due to the rarity of medulloblastoma (MB) in adults, the few studies available on this condition are retrospective, and the follow-up tends to be short. Furthermore, the different therapeutic strategies used in these patients makes it difficult to assess survival rates and prognostic factors. Methods: Between January 1989 and February 2001, a prospective phase II trial was performed to evaluate the efficacy of treatment for adults with medulloblastoma. Patients were completely staged with a neuroradiological examination of the brain and neuraxis and by CSF cytology, according to Chang’s staging system. Low risk patients received radiotherapy alone, while high risk patients were given 2 cycles of upfront chemotherapy followed by radiotherapy and adjuvant chemotherapy. The results of the preliminary analysis of this study at a median follow-up of 3.7 years are reported elsewhere. The present papers reports on the long- term results of the same trial. Results: After a median follow up of 7.6 years, among a total of 36 enrolled adults with medulloblastoma, overall progression free survival (PFS) and overall survival (OS) at 5 years were 72% (range 59% to 84%) and 75% (62% to 91%), respectively. No difference was found between low and high risk patients in terms of PFS and OS at 5 years: in low-risk patients the 5-year PFS was 80% (range, 59–100%) and the 5-year OS, 80% (range, 58 - 100%); in high-risk patients the 5-year PFS was 69% (range, 54 -89%) and the 5-year OS, 73% (range, 58 - 92%). Conclusions: A long-term follow-up is essential to evaluate the real impact of treatments in adult patients with MB. Since there is no significant difference between low-risk and high-risk patients for PFS and OS, the use of chemotherapy is also questionable in low-risk patients.

No significant financial relationships to disclose.
Biochemical evidence of tumor response and measurable levels of the drug in glioblastoma tissue from patients treated with imatinib
Authors: Razis E. , Selviaridis P. , Fletcher J. , Labropoulos S. , Caprioli R. , Karkavelas G. , Zhu M. , Kalebic T. , Norris J. , Fountzilas G.
Published: March 2020

2023

Background: Glioblastoma multiforme (GBM) carries a grave prognosis. There are phase I-II studies indicating that imatinib is active in GBM in pre-treated patients. To better understand the molecular basis of imatinib’s activity in this disease we performed a pharmacodynamic neoadjuvant study with imatinib in GBM. Methods: Patients underwent CT guided biopsy of their brain tumors. If diagnosed with GBM they were immediately treated with 7 days of imatinib 400mg po BID followed by either definitive surgery or, if that was not feasible, followed by re-biopsy. Corticosteroid dose was stable during this period and valproic acid was the only anti-epileptic drug allowed in order to avoid pharmacokinetic interaction with imatinib. Treatment after recovery was as per usual institutional policy. Pre and post treatment tissue specimens were analyzed by immunohistochemistry, proteomic technology and molecular biological methods. Pharmacokinetic studies were also performed. Results: Twenty patients were enrolled in 2 institutions with a median age of 64, of which 14 were male and 6 female. PS was 0 in 2, 1 in 9 and 2 in 9. Seventeen patients had pure GBM, 2 had mixed GBM with astrocytoma and one had anaplastic astrocytoma. Eighteen patients had stable disease on pre and post treatment MRI, one had progressed and one was not evaluable. Median survival was 6.2 months (1.1–18mo). Intact imatinib was quantified in the post treatment tissue specimens and correlations were made with serum imatinib levels per patient. No correlation was seen. Tissue specimens were analyzed by in situ MALDI mass spectroscopy and differential protein expression profiles were detected, when pre and post treatment specimens were compared. The identification of candidate proteins is ongoing. In 11 patients with evaluable, high-quality, matched pre and post imatinib biopsies, 4 had biochemical evidence of tumor response (decreased AKT or MAPK, or increased p27). In addition, 2 patients showed high-level EGFR activation, and one patient had high-level PDGFR activation. Conclusions: Treatment of GBM patients with imatinib results in measurable levels of the drug in the tumor. Potential indicators of biochemical response in a subset of patients were identified.

No significant financial relationships to disclose.
EORTC Study 26041–22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with or without PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma—Results of a phase I trial
Authors: Brandes A. A. , Stupp R. , Hau P. , Sleijfer S. , Lacombe D. , Gorlia T. , Yun H. , Tosoni A. , Mirimanoff R. , van den Bent M. J.
Published: March 2020

2026

Background: VEGF is an essential mediator of angiogenesis. PTK/ZK is an orally available tyrosine kinase inhibitor of all known VEGF receptors. The EORTC has initiated a randomized phase I/II study in which PTK/ZK is being investigated in combination with standard RT and concomitant TMZ. The results of the safety and dose-finding run-in of the triple combination are reported here. Methods: Escalating doses of PTK/ZK QD continuously (using classical 3+3 design) and concomitant RT (60 Gy) and TMZ (75 mg/m2/day) during 6–7 weeks were to be administered. During the adjuvant/maintenance part, PTK/ZK was prescribed at a fixed standard dose of 750mg bid until progression. Dose limiting toxicities (DLT) were defined as >G3 toxicity occurring during RT + 2 weeks. Results: 18 GBM pts (M/F: 11/7, median age: 53 years, PS 0/1) have been enrolled and complete data for 15 pts are currently available. DL1 (500 mg): 4 pts; no DLT; DL2 (1000 mg): 6 pts: 1 DLT: G3, liver enzyme (ALAT) elevation and hyponatremia DL3 (1250 mg); 8 pts: 3 DLTs: G3 hepatic toxicity (2 pts) and G3 platelets and G4 neutrophil (1 pt). In a 4th patient a G3 diarrhea and hepatic DLT leading to PTK/ZK interruption was doubtful therefore it was decided to extend DL3. Frequently observed possibly related non-dose limiting drug adverse events of all grades included: abdominal pain/cramping (2 pts), ALAT/ASAT elevation (10 pts), creatinine elevation (2 pts), allergic reaction (2 pts), constipation (4 pts), diarrhea (5 pts), fatigue (11 pts), hypertension (6 pts), nausea (8 pts), vomiting (3 pts), and weight loss (4 pts). All toxicities were reversible. Conclusions: MTD has been reached at 1250 mg and the recommended dose of PTK/ZK in combination with RT and TMZ is 1000 mg/day. A randomized 3-arm phase II will start accrual in January 2007. Patients will receive standard TMZ/RT alone or with PTK/ZK starting at the beginning of radiotherapy or at the beginning of adjuvant therapy 4 weeks after the end of radiotherapy.

[Table: see text]
One week on/one week off regimen of temozolomide: Phase II trial in recurrent glioma
Authors: Wick W. , Wick A. , Schuth J. , Platten M. , Reifenberger G. , Weller M.
Published: March 2020

2032

Background: Evaluation of toxicity and efficacy of a one week on/one week off temozolomide regimen in patients with recurrent gliomas. Methods: Ninety adult patients (median Karnofsky performance score 90; median age 51 years) with recurrent gliomas (9 patients with low-grade gliomas, 11 with anaplastic gliomas, 64 with GBM, and 6 with other brain tumors) accrued in one center received chemotherapy with temozolomide at 150 mg/m2/d (days 1–7 and 15–21 every four weeks) with individual dose adjustments according to hematological toxicity. Results: A total of 906 treatment weeks was delivered. Grade 4 hematotoxicity according to the common terminology criteria for adverse events (CTCEA v 3.0) was observed in 24 treatment weeks (2.6%). CTCEA grade 4 lymphopenia eventually developed in 11 patients (12%). There were no cumulative lymphopenia or opportunistic infections. The progression-free survival (PFS) rate at 6 months for the patients with GBM was 43.8%. The median PFS was 24 weeks (95% CI, 17 to 26 weeks), the median survival time (MST) from diagnosis of progression was 38 weeks (95% CI, 30 to 46 weeks), the 1-year survival rate from progression was 23%. O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was not associated with longer PFS (p=0.37, log-rank test). Conclusions: This data imply that the one week on/one week off schedule is feasible, safe and effective and clearly warrant investigation in randomized studies. In contrast, protracted low-dose temozolomide at 75 mg/m2 has been shown to be toxic, resulting in cumulative lymphopenia and opportunistic infections. Compared with protracted low-dose temozolomide 1 the one week on/one week off schedule was far less toxic. In addition this dosing schedule may circumvent the disadvantage of an unmethylated MGMT gene promoter by depleting MGMT.

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Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)
Authors: Jauch T. , Hau P. , Bogdahn U.
Published: March 2020

2034

Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG. Methods: A retrospective review of pt with recurrent HGG who were rechallenged with TMZ between Jan 2000 and Oct 2006 was conducted. Standard criteria for rechallenge were as follows: if pts relapsed=8 wks after discontinuation of FL-TMZ, they were treated with the same or an alternative regimen of TMZ; however, if they progressed while still receiving TMZ, they were treated with an alternative regimen. Results: Of a total 81 pts identified, 54 intra-institutional pts were evaluable, 23 glioblastoma (GBM), 22 anaplastic glioma (AG). Median age was 44 yr with median KPS of 80. The response rate (RR) to FL-TMZ was 65% in GBM and 95% in AG using Macdonald criteria. At rechallenge, pts received one of four TMZ regimens: 150–200 mg/m2/d for 5/28 days (n=35), 150 mg/m2/d for 7/14 days (n=7), 75 mg/m2/d for 21/28 days (n=4), or continuous 50 mg/m2/d (n=7). All pts had progressed during FL-TMZ or after initial discontinuation of TMZ. Discontinuation during rechallenge TMZ was due to progressive disease in 36 pts and patient request in 6 pts. None of the pts discontinued due to toxicity. The response rates were 66% and 70% in GBM and AG, respectively. 8/12 non-responders to FL-TMZ responded to alternate regimens of TMZ. Median time to progression (TTP) was 20 weeks and 22 weeks, respectively. Six-month progression-free survival was 41% in GBM and 43% in AG. Conclusions: TMZ was well tolerated without major toxicities and had a good RR in pts who had previously failed TMZ. Durable responses were observed in patients who had not initially responded to front-line TMZ. These data suggest that rechallenge with TMZ in previous responders and non-responders warrants further investigation in a prospective study.

No significant financial relationships to disclose.
Phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with temozolomide (TMZ) in patients with malignant gliomas (NABTC 04–03)
Authors: Wen P. Y. , Puduvalli V. , Kuhn J. , Reid J. , Cloughesy T. , Yung W. A. , Chang S. M. , Robbins H. I. , McGovern R. , Ames M. , Prados M. D.
Published: March 2020

2039

Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, > 18 yrs old, life expectancy > 8 weeks, KPS > 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. PKs were determined on cycle 1 for TMZ, V and its metabolites. Results: To date, 19 eligible patients have been enrolled (15 GBM; 4 AG). Patients’ characteristics are 11 male, 8 female; median age 54 yrs (36–78); median KPS 90 (70–100). DLTs were encountered at 300 mg bid of vorinostat (1 grade 3 thrombocytopenia; 1 grade 3 fatigue in 3 patients), 200 mg tid (1 grade 3 nausea, 1 grade 4 thrombocytopenia in 3 patients) and 200 mg twice daily (grade 3 fatigue in 2/6 patients). No DLTs were encountered in 6 patients receiving 300 mg daily. TMZ PKs included [n=16: Cmax 5.2 (± 1.55) μg/ml; AUC 20.1 (±4.66) μg x hr/ml; t1/2 1.9 (±0.32)/hr]. Vorinostat PKs (300mg dose level) were [n=4; Cmax 267 (±174) ng/ml; AUC0–8 603 (±197) ng x hr/ml]. The t1/2 for V and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Conclusions: The MTD of vorinostat in combination with TMZ is 300 mg daily on days 1–14 every 28 days. Final PK results, and toxicities from an additional 10 patients enrolled at the MTD will be presented.

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Clinical results of continuous intrathecal or intracavitary administration of sodium butyrate for patients with recurrent and progressive malignant glioma: Experience with 23 cases
Authors: Nakagawa H. , Yoshida M. , Motozaki T. , Yoshioka K. , Itoh K.
Published: March 2020

2040

Background: We evaluated the clinical potential of intrathecal use of sodium butyrate (NaB) for malignant glioma in experimental research. Based on the results of experimental research, continuous intrathecal or intracavitary administration of NaB for recurrent and progressive malignant glioma was clinically attempted. We evaluated the efficacy and therapeutic safety of this treatment. Methods: A total of 23 patients (pts)(glioblastoma:GB,19; anaplastic astrocytoma: AN, 4) were enrolled in this study between Oct. 2001 and Feb. 2006 and followed until Oct. 2006. Five patients showed CSF dissemination of tumor cells. Sixty milimolar NaB was administered to all pts after dose-escalation study using a simple balloon pump system and continued as long as possible by changing the pump containing NaB weekly. The primary end point was radiographic response, and the secondary end points were progression-free survival (PFS), overall survival, and therapeutic safety. Results: Nineteen of 23 pts (GB, 16; AN,3) were evaluable. Nine pts showed regression of the tumor, 5 showed stable disease, and 5 showed growth of the tumor. The overall median PFS of the pts was 6.0 months (mos) and that of pts with GB was 5.5 mos, while the 6-month PFS was 53.3.% and that of GB was 50%. The overall median survival time was 11.0 mos and that of GB was also 11.0 mos. The overall 1-year survival rate was 42 % and that of GB was 29.4%. Four of 5 pts with CSF tumor cell dissemination showed therapeutic response, including temporary negative cytological conversion. Various adverse effects and complications have been encountered to date, including bacterial meningitis, temporary bradycardia and convulsions. Conclusions: The present therapy was well tolerated and resulted in long-term inhibition of the growth of the tumor in some pts, and showed therapeutic safety.

No significant financial relationships to disclose.
Intra-arterial chemotherapy and osmotic blood-brain barrier disruption for primitive neuroectodermal tumors
Authors: Jahnke K. , Kraemer D. F. , Fortin D. , Bell S. , Doolittle N. D. , Knight K. R. , Muldoon L. L. , Neuwelt E. A.
Published: March 2020

2046

Background: The blood-brain barrier (BBB) may, in part, contribute to the poor outcome in primitive neuroectodermal tumors (PNETs) treated with chemotherapy. Intra-arterial chemotherapy and osmotic BBB disruption (IA/BBBD) increases drug delivery to the central nervous system while preserving neurocognitive functioning and minimizing systemic toxicity. Methods: The study aims were evaluation of efficacy and toxicity in patients with PNETs other than medulloblastoma treated with IA/BBBD. A chart review of patients from 3 centers treated on various protocols was conducted. Study outcomes included overall survival (OS) and time to progression (TTP, from date of first study treatment). Times to events were estimated using Kaplan-Meier product limit method. Results: Twenty-nine patients (median age 20.5 years, median Karnofsky performance status 90%) were identified. Pathologic diagnoses included pineoblastoma (n = 13 patients), atypical pineocytoma (n = 2), neuroblastoma (n = 3), and other supratentorial or disseminated PNETs (n = 11). Thirteen patients were pretreated before IA/BBBD: 5 with only chemotherapy, 4 with radiotherapy alone, and 4 with both. Intraarterial chemotherapy included carboplatin (n = 24), methotrexate (n = 3), or a combination of both (n = 2). Six patients had a complete and 11 a partial response to IA/BBBD (response rate 58.6%). Ten patients received adjuvant radiotherapy. Twenty (69%) patients relapsed. Median TTP was 1.1 (95% confidence interval 0.8 to 8.4) years, and 9/28 (32.1%) evaluable patients have not yet progressed. Median OS was 2.5 (1.2–11.7) years, 40% survived 4.0 years, and 30% survived 8.7 years. Nine out of 29 (31%) patients are alive, and 6/29 (20.7%) are alive 11+ years after first treatment. Twenty patients have died: 16 due to disease progression, 3 due to toxicity, and 1 due to other reasons. No deaths or permanent neurologic or vascular sequelae related to the IA/BBBD procedure were observed. Conclusions: Survival in PNETs treated with IA/BBBD appears favorable as compared to the literature, especially when considering that 11 patients received IA/BBBD as salvage treatment. A plateau in survival suggests that select patients may be cured.

No significant financial relationships to disclose.
A phase II study of radiosurgery and temozolomide for patients with one to four brain metastases
Authors: Fiveash J. B. , Sawrie S. M. , Guthrie B. L. , Spencer S. A. , Meredith R. F. , Markert J. M. , Nordal R. A. , Conry R. M. , Nabors L. B.
Published: March 2020

2048

Background: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1–4 brain metastases treated with radiosurgery without whole brain radiation therapy. Methods: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase II trial of radiosurgery (15–24 Gy) and adjuvant temozolomide. Temozolomide was started within 14 days of radiosurgery and was administered 150–200 mg/m2 p.o. q day x 5 days in 28 day cycles. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. If more than 4 metastases were identified on the MRI performed on the day of radiosurgery, then the patient could still be treated on the clinical trial if all tumors could be treated with radiosurgery. In addition to clinical and radiographic follow-up, QOL was assessed utilizing the FACT-Br questionnaire. Results: Twenty-five patients were enrolled 2002–2005; three were not evaluable for determining DBF. Of the remaining twenty-two patients, tumor types included NSCLC (n=8), melanoma (n=7), other (n=7). Extracranial disease was present in ten (45%) patients. The median number of tumors was 3 (range 1–6). The median overall survival was 31 weeks. The median radiographic follow-up for patients that did not develop DBF was 33 weeks. Six patients developed DBF. The one year actuarial risk of DBF was 37%. Patients with melanoma had a higher risk of DBF than other patients (p<0.001, log-rank). Only 1/15 patients without melanoma vs. 5/7 patients with melanoma developed DBF. 15 serious adverse events (SAEs) occurred in 10 of the patients, but none of the SAEs were judged to be likely related to temozolomide. Among patients that experienced DBF, no significant differences were seen in QOL when pretreatment FACT-Br and time of distant brain failure FACT-Br scores were compared. Conclusions: Adjuvant temolozomide after radiosurgery is associated with a low risk of distant brain failure in non-melanoma patients. Larger clinical trials should examine the relative efficacy and QOL of WBRT and temozolomide in non-melanoma brain metastases patients.

No significant financial relationships to disclose.