bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents
Authors: Bode U. , Buchen S. , Warmuth-Metz M. , Pietsch T. , Bach F. , Fleischhack G. 
Published: March 2020

2006 Background: Despite multimodal therapy most children with high grade gliomas (HGG), including glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and intrinsic pontine glioma (PG) have an infaust prognosis if they relapse or are refractory to the primary treatment. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (nimotuzumab) in the treatment of these patients. Patients and Methods: Pediatric patients with GM, AA or PG with radiologically proven progressive disease following primary or relapse treatment and a life expectancy of less than 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for six weeks, and in case of non-PD a consolidation therapy of 4 infusions in a 3 week interval. The response was documented by MRI in week 8 and 21 and only clinically in rapidly progresssive disease. Results: Between June 2004 and April 2006 47 patients aged 4 to 17 years (median 11 years) were enrolled in this study. 46 patients were evaluable for response. According to RECIST 14 out of 46 patients showed objective responses (PR n=4, SD n=10) in the MRI as the best response with a median change in the largest diameter of the index lesion of -11% (-50% to +16%). The PR/SD were seen in 2/13 patients with GM, 2/11 with AA and 10/22 with PG. Thirteen patients continued with the consolidation therapy and showed 4 PR, 3 SD and 6 PD in week 21. The median overall survival was 4.4 months (0.3–25.4 months) and was significantly better for repsonders (median 10 months) than for nonresponders (median 4.0 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of nimotuzumab is well tolerated and safe. Nimotuzumab has cytotoxic efficacy in heavily pre- treated relapsed HGG. Based on this data a phase III trial with nimotuzumab in newly diagnosed diffuse intrinsic pontine gliomas concomittent with radiotherapy was introduced in first quarter 2006. No significant financial relationships to disclose.
Iatrogenic immunosuppression in patients with newly diagnosed high-grade gliomas
Authors: Grossman S. A. , Desideri S. , Ye X. , Szajna K. , Chamberlain M. , Lesser G. 
Published: March 2020

2012 Background: Vaccines and other immunologic interventions hold promise for patients (pts) with high grade gliomas (HGG). However, a prior report noted that CD4 counts dropped significantly during the 6 weeks of radiation (RT) in patients receiving only RT and dexamethasone (Dex). This is the first study to follow CD4 counts in HGG treated with RT, Dex, and temozolomide (TMZ) and to obtain serial CD4 counts for 12 months. Methods: 70 pts with newly diagnosed HGG were accrued before they started RT and TMZ. CD4 counts were obtained before therapy and monthly thereafter for one year. Information on hospitalizations, infections, steroid doses, and survival is also being collected. Descriptive statistics were used. Results: Data is available on 60 pts: 54% are female and 97% are Caucasian. The median age of the pts was 57 (range 30–77) and 78% had a diagnosis of glioblastoma. The median CD4 count before RT was 640 (range 145–1445) which fell to 363 (32–1055), 272 (8–558), and 250 (44–845) in 1, 2, and 3 months respectively. The median CD4 counts during months 4, 6, 8, 10 and 12 were 373, 319, 329, 395, and 269. CD4 counts <200 were recorded in 34 pts (57%) and CD4 <100 in 13 pts (22%) during the study period. Conclusions: This study demonstrates that CD4 counts: 1) are relatively normal prior to radiation, 2) nadir to a median of 250 during the first three months of therapy, and 3) generally remain depressed following the completion of radiation. Severe iatrogenic immunosuppression as evident by CD4 counts is common in this population. Correlations with outcome and steroid doses are underway. These findings have implications for the recommended duration of PCP prophylaxis, the optimal design for therapeutic interventions that require a relatively intact immune system, and studies seeking to increase the intensity or duration of TMZ. No significant financial relationships to disclose.
What is the role of whole brain radiation therapy (WBRT) and high-dose cytarabine (Ara-C) as consolidation treatment after initial chemotherapy for primary CNS lymphoma (PCNSL)?
Authors: Ekenel M. , Iwamoto F. M. , Porat L. S. Ben , Panageas K. S. , Yahalom J. , DeAngelis L. M. , Abrey L. E. 
Published: March 2020

2013 Background: Optimal management of PCNSL is not defined. To date the best outcomes have been achieved by combined modality therapy using methotrexate (MTX)-based chemotherapy and WBRT. However, WBRT carries a significant risk of neurotoxicity and may not be required in all patients. Methods: We retrospectively analyzed the data of 122 patients who had complete response (CR) after initial chemotherapy, from a total of 338 PCNSL patients treated in our institution since 1986. Descriptive variables including sex, age, KPS at diagnosis, histology, and extent of CNS involvement were reported. We specifically studied the benefit of consolidation therapy with WBRT and/or high dose Ara-C on OS and PFS. Results: The median age was 60 (19–89) years and a median KPS was 70. Men constituted 57% of the patients. Median follow up was 30 months. Histologically, 83% had diffuse large B cell lymphoma. Ocular and CSF involvements were 13%, and 27%, respectively. Most patients received MTX-based regimens (96%). Five-year OS was 43% and five-year PFS was 50% for all patients. There was no significant difference in OS, between patients who received consolidation therapy with Ara-C (n=35), WBRT (n=12), Ara-C + WBRT (n=28), or no consolidation (n=42) [data from 5 patients are missing]. There was a trend towards improved disease control for patients treated with WBRT; however, these patients were also younger than the other groups. Risk of neurotoxicity was significantly higher in patients who received WBRT (p=0.005). Conclusions: Consolidation therapy does not clearly improve survival in PCNSL patients with a CR to initial treatment. However other important prognostic factors including age and KPS may have been used in the decision making related to consolidation therapy. [Table: see text] No significant financial relationships to disclose.
Temozolomide as a vaccine adjuvant in GBM
Authors: Sampson J. H. , Aldape K. D. , Gilbert M. R. , Hassenbusch S. J. , Sawaya R. , Schmittling B. , Archer G. E. , Mitchell D. , Bigner D. D. , Reardon D. A. , Heimberger A. B. 
Published: March 2020

2020 Background: Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide (TMZ) is an effective chemotherapeutic for patients with glioblastoma multiforme (GBM), but it induces significant lymphopenia. Methods: In a Phase II trial, patients with newly-diagnosed, completely resected GBM are vaccinated with an EGFRvIII-specific peptide q2 weeks X 3 after radiation (XRT)(∼60Gy) and TMZ (75mg/m2/d) and then monthly with 5 day TMZ cycles (200mg/m2/d). Results: TMZ induces transient, Grade 3 lymphopenia (< 500 cells/uL) in 70% of patients after the first TMZ cycle with nadirs occurring 14–21 days after treatment (n=10). Regulatory T cell (TReg) (CD4+CD25++CD45RO+FOXP3+) levels increased from 5.2+1.5% (3.3 - 7.5) to 11.8+2.6% (6.9 - 13.8)(P=0.0004; paired t-test) with TMZ and XRT and averaged 12.2+4.0% (6.4 - 18.1) after the second TMZ cycle (P=0.007) (n=6). Despite these findings, in patients assayed, both humoral and cellular EGFRvIII-specific immune responses appear to be enhanced with TMZ. Median survival and TTP after vaccination is 26.2 weeks with no patients progressing (n=8). Conclusions: Despite conventional dogma, we demonstrated that both chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. TMZ-induced lymphopenia may prove to be synergistic with a peptide vaccine. No significant financial relationships to disclose.
Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM)
Authors: Sathornsumetee S. , Rich J. N. , Vredenburgh J. J. , Desjardins A. , Quinn J. A. , Gururangan S. , Egorin M. J. , Salvado A. J. , Friedman H. S. , Reardon D. A. 
Published: March 2020

2027 Background: Recent studies have demonstrated promising anti-glioma activity of imatinib mesylate (IM) and hydroxyurea (H). Angiogenesis is one of the hallmarks of GBM with VEGF as a key regulator. This study attempts to extend the efficacy of IM and H by adding a VEGF receptor inhibitor, vatalanib (V; PTK787/ZK22584). Methods: We employ a ‘3+3‘ dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IM and V when administered with fixed dose of H in adult recurrent GBM patients with < 3 prior recurrences, KPS = 70% and adequate organ function. Patients are stratified based on concurrent enzyme-inducing anticonvulsant (EIAC) administration, and both strata (A- not on EIAC and B- on EIAC) are independently dose-escalated. Initial dose levels for stratum A: IM - 400 mg/day; H - 500 mg bid; V- 250 mg bid and for stratum B: IM- 500 bid; H-500 mg bid; V- 500 mg bid. Patients are given only V on day 1–7 of cycle 1 and then IM+H+V daily thereafter. Only cycle 1 is 35 days with subsequent cycles of 28 days. Response is evaluated every other cycle. Pharmacokinetic (PK) studies are performed on days 7 and 35 of cycle 1. Results: Thirty-five recurrent GBM patients have enrolled. The median age is 51.5 (range 31 to 75), 66% are male, and 51% are on EIAC. One DLT (grade 3 thrombocytopenia) occurred in a stratum A patient on dose level three . For stratum B, two DLTs (grade 3 hypertension and ALT elevation) occurred in a patient on dose level two and one DLT (grade 3 fatigue) occurred in a patient on dose level three. MTDs for each stratum have not been reached and accrual is ongoing. PK results are pending. Ten partial responses (29%) have been observed and nine patients remain on study including three who have received more than 6 cycles of therapy. Conclusions: Combination of imatinib, hydroxyurea and vatalanib is safe and well-tolerated with an encouraging rate of radiographic response. Further accrual is in progress to define the MTD. No significant financial relationships to disclose.
An analysis of two different schedules of radiochemotherapy with concomitant temozolomide in high grade gliomas
Authors: D’Agostino G. R. , Balducci M. , Anile C. , Manfrida S. , Di Lella G. , Fiorentino A. , Mantini G. , Apicella G. , Pompucci A. , Cellini N. 
Published: March 2020

2035 Background: We compared two different schedules of temozolomide (TMZ) concomitant therapy in terms of toxicity and outcome. Methods: 70 patients (median age 61 years, range 27–80) affected by high grade gliomas were treated with concomitant chemoradiation. Conformal radiotherapy (5,940 cGy, 180 cGy/day; CTV2: tumor bed + residual tumor if present + oedema, 3,960 cGy; CTV1: tumor bed + residual tumor if present + margins, 1,980 cGy) was associated with one of the following TMZ schedules: TMZ1: (75 mg/m2 × 5 days, first and last week of radiotherapy); TMZ2 (75 mg/m2, 7 days/week, from the first to the last day of radiotherapy); Toxicities were graded according to RTOG criteria. Survival analysis based on the Kaplan-Meier model. Results: From October, 2000 to March, 2006, 54 patients high grade gliomas were evaluated. 41 patients (29 GBL, 70.7%; 12 AA, 29.3%) were treated between October 2003 and March 2006 with TMZ2, and compared to an historical series of 29 patients (25 GBL, 86.2%; 4 AA, 13.%) treated in our Institution before 2003 with TMZ1. All patients received adjuvant chemotherapy with TMZ for 6 cycles or until disease progression. Hematological toxicity was mild in both group, whereas neurological toxicity (seizures) was higher in TMZ2 group, with a grade > 2 toxicity registered in 11/41 pts (26.8%) compared to 1/29 of the TMZ1 group (3.5%), even if this difference failed to achieve statistical significance (p=0.06). The overall survival did not significantly differ among the 2 schedules (p=0.60). In fact, at a median follow-up of 21 months (range 3- 68), median survival time was 21 months and 19 months, for TMZ1 and TMZ2 groups, respectively, with a 1-year and 2-year overall survival of 73.1% in the TMZ1 group and 75.3% in the TMZ2 group, respectively. Conclusions: In our experience, the concomitant administration of TMZ at the daily dose of 75 mg/m2 given continuously or only in the first and the last week of radiotherapy obtained comparable results in terms of outcome, with a heavier neurological toxicity when given 7 days per week, from the first to the last day of radiotherapy. These data suggest that, in selected cases, the TMZ1 schedule can be considered as a safe, alternative strategy, which does not impact significantly on patient outcome, compared to the standard TMZ2. No significant financial relationships to disclose.
Phase II trial of Gliadel plus O6-benzylguanic (O6-BG) for patients with recurrent glioblastoma multiforme
Authors: Quinn J. A. , Vredenburgh J. J. , Rich J. N. , Reardon D. A. , Desjardins A. , Gururangan S. , Friedman A. H. , Carter J. H. , Threatt S. , Friedman H. S. 
Published: March 2020

2036 Background: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O6- position of guanine. O6-BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous phase III randomized, placebo- controlled trial has shown that Gliadel wafer (G) significantly prolongs 6-month survival (55.5% for G vs. 35.6% for placebo) and median survival (28 weeks for G vs. 20 weeks for placebo) in patients with recurrent glioblastoma multiforme (GBM) (Brem et al 1995). Despite the success of G in prolonging survival we may be able to improve on this success by depleting AGT. Methods: Thus, we have designed a phase 2 trial where we define the activity and the toxicity of G in combination with a 5-day infusion of O6-BG in patients with recurrent GBM. In a prior study the O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days after G placement, this O6-BG bolus was repeated on days 3 and 5 while continuing the infusion. Results: To date, 47 patients have been enrolled out of a planned accrual of 50 patients. The 6-month survival is 80% and the median survival is 47 weeks. The adverse events include the following: 3 episodes of grade 3 CSF leak (6%), 7 episodes of grade 3 wound infection at craniotomy site (15%), 6 episodes of hyponatremia (13%), 3 episodes of hydrocephalus (6%), 1 episode of hygroma (2%), 1 episode of infectious meningitis (2%), 1 episode of arachnoiditis (2%), 1 episode of grade 3 fever (2%). Conclusions: Thus far, this data demonstrates an increase in the efficacy of G when combined with O6-BG. Three additional patients will be enrolled for a total accrual of 50 patients. [Table: see text]
Identification of occult brain metastases amenable to stereotactic radiosurgery by motexafin gadolinium (MGd) based treatment planning MRI: Results of a phase II trial of MGd and whole brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS)
Authors: Mehta M. P. , Dagnault A. , Chabot P. , Suh J. , Chang E. , Fortin M. , Timmerman R. , Grecula J. , Eubank L. , Renschler M. F. 
Published: March 2020

2037 Background: Motexafin gadolinium (MGd) is a novel anti-cancer agent that selectively localizes in tumors and is detectable by MRI. Previous studies of patients (pts) with brain metastases (BM) demonstrated the detection of occult lesions after MGd administration not visible with gadolinium MRI contrast. The purpose of this study was to evaluate if MRI scanning after MGd improves SRS treatment-planning and treatment outcome by identifying and better defining lesions that can be treated with the SRS boost. Methods: Pts with 1–4 BM (< 4 cm diameter, or, if multiple, < 3cm) received WBRT (37.5 Gy) and MGd, 5 mg/kg/day during weeks 2–3 of WBRT, plus MGd, 5 mg/kg prior to treatment planning MRI and prior to SRS (21 Gy for lesions = 2 cm, 18 Gy for lesions 2.1–3.0 cm, and 15 Gy for lesions 3.1–4.0 cm). MRI was obtained within 4 weeks prior to enrollment with standard contrast, and after WBRT for SRS treatment planning with MGd and standard contrast. Patients were followed for neurologic progression and survival. Results: 45 patients with either lung cancer (76%), breast cancer (11%), melanoma (7%), or other cancers (7%), a median age of 58 years (range 42–74), and a median of 2 BM (range 1–4) were evaluable. In 9 of 42 patients (21%) with MRI data available, the MGd-based treatment planning MRI demonstrated at least one occult lesion not visualized on the screening MRI. The MGd-based treatment planning MRI detected 1 occult lesion in 6 pts, 2 occult lesions in 1 patient, and 3 occult lesions in 2 patients. Median survival for evaluable pts is 10 months; median time to neurologic progression or radiologic progresssion is not reached at 15 months. Grade 3+ neurotoxicity was limited to 1 pt with tumor necrosis and 1 pt with motor weakness. Most common Grade 3+ adverse events were pneumonia (9%) and DVT (9%). Conclusions: MGd-based treatment planning MRI for SRS identified occult BM that are amenable to SRS and are undetected with standard gadolinium contrast agents in 21% of the pts enrolled in this phase II trial. Treatment with MGd, WBRT and SRS to all lesions visualized resulted in improved survival and local control compared with historical results. [Table: see text]
Evaluation of clinical markup with CT simulation in whole brain radiation therapy
Authors: Wang Y. , Makhani N. , Tsao M. 
Published: March 2020

2043 Background: Two types of clinical markup have been used for whole brain radiation therapy (WBRT), but the extent of dose coverage and sparing of the lens is unknown. This study is designed to evaluate clinical markup with CT simulation. Methods: CT simulation images of the brain from 20 random adult patients were included in this study. Two types of inferior field borders were generated to mimic the 2 types of clinical markup of WBRT: from superior orbital ridge (SOR) to tragus, and from SOR to inferior tragal notch (ITN). A field margin of 1 cm from contoured brain (along base of skull) was used in CT simulation, except near the orbital globe where 0.5 cm margin to eye shielding was used. Two opposed lateral fields with 6 MV photon were used to generate 3 WBRT plans in each patient: clinical markup with SOR to tragus, SOR to ITN, and CT simulation. Dose volume histograms of the brain and lens were generated. The primary end point was dose coverage of whole brain with clinical markup. The secondary end point was sparing of the lens. Results: Patients with clinical markup using SOR to tragus or SOR to ITN had significantly larger median brain volume receiving less than 95% of the prescribed dose, 37.0 mL and 7.8 mL (respectively) compared to CT simulation 0 mL (P < 0.001). All patients with SOR to tragus and most patients (95%) with SOR to ITN clinical markup had underdosing in the regions of inferior frontal lobe, temporal lobe and posterior fossa. There was no significant difference in the dose to the lens between CT simulation and clinical markup using SOR to tragus (P = 0.18) or SOR to ITN (P = 0.90). Conclusions: Whole brain radiation therapy with clinical markup using either SOR to tragus or SOR to ITN results in underdosing at the inferior frontal lobe, temporal lobe and posterior fossa. Sparing of the lens is adequately achieved with clinical markup. No significant financial relationships to disclose.
Phase III study of paclitaxel (Pac) versus pegylated liposomal doxorubicin (PLD) for the treatment of advanced human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS): An Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium
Authors: Von Roenn J. H. , Lee S. , Cianfrocca M. , Tulpule A. , Scadden D. , Aboulafia D. , Sparano J. 
Published: March 2020

20503 Background: PLD (doxorubicin HCL liposome injection, Doxil®, Tibotec Therapeutics, Raritan, NJ) and paclitaxel (Taxol®, Bristol Myers, Inc, New York, NY) are active in the treatment of HIV-associated KS; however, optimal therapy is undefined. Methods: A randomized phase III, multicenter trial was initiated to compare the efficacy of Pac (100 mg/m2) every 2 weeks to PLD (20 mg/m2) every 3 weeks for chemotherapy-naïve AIDS-related KS. Treatment continued until disease progression or unacceptable toxicity; concurrent antiretrovirals were permitted. 216 pts were required to detect at least a 3-month improvement in median progression free survival (PFS) for Pac compared with PLD (80% power, 2-sided alpha 0.05). Response was assessed using KS response and clinical benefit criteria, and global assessment of quality of life (QOL) using the Functional Assessment of Health Index (FAHI; version 3) plus 3 supplemental questions concerning pain, swelling, and satisfaction with physical appearance (measured at baseline and during/after treatment). Results: The trial was terminated early due to poor accrual; 46 pts were randomized to PLD, 43 to Pac. 11 pts were ineligible, 4 never started therapy and 6 lacked disease assessment or progression data, resulting in 68 pts for the efficacy analysis (34 in each arm) and 82 in the toxicity analysis. After a median follow-up of 35.8 months (mo.), there was no significant difference in PFS, response rate, or overall survival. Due to early termination, the study was not adequately powered to detect the hypothesized difference in PFS. There was no significant difference in QOL between the two arms. Grade 3–4 toxicity was comparable, including grade 4 neutropenia (34% vs. 27%) and infection (13% vs. 11%). Conclusions: Paclitaxel and PLD have comparable efficacy and toxicity in patients with HIV-associated KS. [Table: see text] [Table: see text]