Buckner, Jan C.

Abstract Background Pilocytic astrocytoma is a rare tumor in adults. This report is of a prospective clinical trial with long-term follow-up. Methods Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. Results At the time of analysis (median follow-up, 20.8 years), 2 patients (10%) have died and 18 patients (90%) are alive. Neurologic and cognitive function were stable or improved over time for the majority of patients. No toxic effects of treatment or malignant transformations have been recorded at last follow-up. For the entire cohort the 20-year time to progression and overall survival rates are 95% and 90% respectively. The cause of death (2.2 and 16.1 years after enrollment) in both patients was unrelated to tumor although both were biopsy-only patients. One subtotally resected tumor progressed 1 month after enrollment requiring P32 injection into an enlarging cyst. Because of further progression this patient required RT 18 months later. This patient is alive without evidence of progression 18 years after RT. Conclusion The long-term follow-up results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. Close observation is recommended for adults with pilocytic astrocytomas, reserving RT for salvage, as the majority remain stable after gross or subtotal resection and no adjuvant therapy.

AbstractThe population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme‐inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m2, and plasma samples were collected and analyzed for irinotecan and its APC, SN‐38, and SN‐38G metabolites. Nonlinear mixed‐effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN‐38, and SN‐38G but not APC. SN‐38 clearance was 2‐fold higher with concomitant EIAED use, resulting in 40% lower SN‐38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7‐fold increase in irinotecan dose may compensate for decreases in SN‐38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

The authors conclude that single-item measures of pain, fatigue, and QOL can be incorporated into oncology clinical practice with positive implications for patients and physicians without increasing duration of visits or work burden.

Purpose Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. Patients and Methods Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. Results IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. Conclusion IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.

Purpose The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. Patients and Methods A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini–Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. Results Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. Conclusion The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.

Abstract Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1–5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5–24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7–8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P &lt; 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell–derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation. Clin Cancer Res; 19(17); 4816–23. ©2013 AACR.

Object Optimum management for elderly patients with newly diagnosed glioblastoma (GBM) in the temozolomide (TMZ) era is not well defined. The object of this study was to clarify outcomes in this population. Methods The authors retrospectively reviewed 105 consecutive cases involving elderly patients (age ≥ 65 years) with newly diagnosed GBM who were treated at the Mayo Clinic between 2003 and 2008. Results The patients' median age was 74 years (range 66–87 years), and the median Karnofsky Performance Status (KPS) score was 80 (range 40–90). Half of the patients underwent biopsy and half underwent resection. Patients with deep-seated lesions (19 patients [18%]) or multifocal lesions (34 patients [32%]) were more likely to have biopsy than resection (p = 0.0001 and 0.0009, respectively). New persistent neurological deficits developed in 7 patients (6.7%). Postoperative hemorrhage occurred in 6 patients (5.7%), all of whom underwent biopsy. Complete follow-up data regarding adjuvant treatment was available in 84 patients. Forty-one (49%) were treated with chemotherapy (mostly TMZ) and radiation therapy (RT), and 23 (27%) with RT alone. Nineteen (23%) received only palliative care after surgery (more common with biopsy, p = 0.03). Chemotherapy complications occurred in 28.6% (Grade 3 or 4 hematological complications in 11.9%). The median values for progression-free survival (PFS) and overall survival (OS) were 3.5 and 5.5 months. In a multivariate analysis, younger age (p = 0.03, risk ratio [RR] 0.34, 95% CI 0.13–0.89), single lesion (p = 0.02, RR 0.51, 95% CI 0.30–0.89), resection (p = 0.04, RR 0.54, 95% CI 0.31–0.94), and adjuvant treatment (p = 0.0001, RR 0.24, 95% CI 0.11–0.49) were associated with better OS. Only adjuvant treatment was significantly associated with prolonged PFS (p = 0.0007, RR 0.27, 95% CI 0.13–0.57). With combined therapy with resection, RT, and chemotherapy, the median PFS and OS were 8 and 12.5 months, respectively. Conclusions The prognosis for GBM worsens with increasing age in elderly patients. With important risks, resection and adjuvant treatment are associated with prolonged survival. Although selection bias cannot be excluded in this retrospective study, advanced age alone should not necessarily preclude optimal resection followed by adjuvant radiochemotherapy.