"I cannot suppose any situation more distressing than for a woman of sensibility with an improving mind to be bound to such a man as I have described." Mary Wollstonecraft's response to one of her ...early critics points to the fact that fiction has long been employed by authors to cast a vision for social change. Less acknowledged, however, has been the role of the Christian faith in such works. In this Studies in Theology and the Arts volume, literary scholar Dalene Joy Fisher explores the work of four beloved female novelists: Jane Austen, Anne Brontë, Elizabeth Gaskell, and Mary Wollstonecraft. Each of these authors, she argues, appealed to the Christian faith through their heroines to challenge cultural expectations regarding women, especially in terms of marriage. Although Christianity has all too often been used to oppress women, Fisher demonstrates that in the hands of these novelists and through the actions of their characters, it could also be a transformative force to liberate women. The Studies in Theology and the Arts? series encourages Christians to thoughtfully engage with the relationship between their faith and artistic expression, with contributions from both theologians and artists on a range of artistic media including visual art, music, poetry, literature, film, and more.
Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could affect the design and ...conduct of clinical trials substantially.
Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled onto 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the New Approaches to Brain Tumor Therapy CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors.
Factors associated with an increased risk of death were increased age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk RR = 2.01), 10-year increase in age (RR = 1.23), KPS less than 80 (RR = 1.54), and corticosteroid use (RR = 1.49). RPA resulted in seven classes. Median survival time was poorest in non-GBM patients with KPS less than 80 or GBM patients, age 50 years, corticosteroid use (4.4 months; 95% CI, 3.6 to 5.4 months); median survival was best in patients with initial histology other than GBM with KPS 80 and tumor confined to the frontal lobe (25.7 months; 95% CI, 18.7 to 52.5), and was 7.0 months (95% CI, 6.2 to 8.0 months) for all patients.
Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across phase II trials, enrollment criteria may need to be restricted.
This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in ...patients with recurrent malignant glioma.
Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration.
A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy.
Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.
AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated ...objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma.
In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS).
A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM.
AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent data suggest that the glutamatergic system is important in the proliferation and migration of glioblastoma. Talampanel is a well-tolerated, oral ...alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker that could be beneficial in this disease.
This trial was designed to estimate overall survival in adults with newly diagnosed glioblastoma treated with talampanel in addition to standard radiation (RT) and temozolomide (TMZ). A secondary purpose was to evaluate talampanel toxicity in this setting. Talampanel was initiated with RT + TMZ and discontinued for toxicity or disease progression. Survival was compared with historical controls.
Seventy-two patients were enrolled from December 2005 to July 2006. Their median age was 60 years (range, 37 to 85 years, with 17% > 70 years), median Karnofsky performance score was 90 (range, 70 to 100), and 77% had a debulking procedure. With a median follow-up time of 18 months, 55 patients (76%) have died, yielding a median survival time of 18.3 months (95% CI, 14.6 to 22.5 months). When the 60 patients who were 18 to 70 years old were compared with the European Organisation for Research and Treatment of Cancer (EORTC) RT + TMZ data, the median survival (20.3 v 14.6 months, respectively) and percentage of patients surviving at 24 months (41.7% v 26.5%, respectively; P = .02) seemed superior. The percentage of patients methylated at O(6)-methylguanine-DNA methyltransferase was lower than on the EORTC study (29% v 43%, respectively). Talampanel was well tolerated and did not increase the known hematologic or nonhematologic toxicities of TMZ.
Talampanel can be added to RT + TMZ without significant additional toxicity. The encouraging survival results in methylated and unmethylated patients suggest that blocking AMPA receptors may be a useful strategy in newly diagnosed glioblastoma.
Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed ...mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG.
Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB.
Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB.
MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.
ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six ...patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.
Purpose: 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 ≥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.
Results: 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 × 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan
was distinctly dose dependent in the patients receiving EIAs, decreasing from ∼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.
Conclusions: 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.
Quantitative 3'-deoxy-3'-
F-fluorothymidine (
F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these ...quantitative data, we evaluated the repeatability of
F-FLT PET as part of a multicenter trial involving patients with high-grade glioma.
F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after
F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUV
), gradient-based segmentation (SUV
), the maximum pixel (SUV
), and a 1-mL sphere at the region of highest uptake (SUV
). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d.
RCs for tumor SUVs were 22.5% (SUV
), 23.8% (SUV
), 23.2% (SUV
), and 18.5% (SUV
) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUV
(RC, 16.5%).
SUV quantification of
F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after
F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUV
Although changes in
F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.
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