Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma.

The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n = 469, 1980-2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n = 596, 1998-2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.

Prognosis in patients with anaplastic oligoastrocytoma is associated with histologic grade.

BACKGROUND: Anaplastic oligoastrocytomas (AOA) are relatively uncommon high-grade gliomas. While oligodendroglial elements are thought to be associated with better outcomes, the magnitude of the difference is not clear. METHODS: Between 1980 and 1999, Mayo Clinic and the NCCTG conducted 10 trials of radiation therapy and chemotherapy in adults with newly-diagnosed high-grade gliomas. All pathology slides were reviewed by one of the authors (BWS or CG). We grouped patients by cell type and grade, compared survival distributions by the log-rank statistic, and performed multiple variable analyses. RESULTS: Of 1368 patients, 68 (5%) had AOA, including 21 Grade 3 (OA3) and 47 grade 4 (OA4), 153 (11%) had anaplastic astrocytoma (AA), and 1147 (84%) had glioblastoma multiforme (GBM). Patients with OA3 survived significantly longer than those with OA4 (P=0.0001) or AA (P=0.0044). Patients with OA4 lived significantly longer than those with GBM (P=0.0005). The same differences were noted for PFS. Prognostic factors for survival identified by multiple variable analysis were histology, age, ECOG performance score, and extent of surgical resection, but not treatment administered. CONCLUSIONS: Patients with anaplastic oligoastrocytoma have distinct outcomes based upon grade (OA3 vs. OA4) and in comparison with pure astrocytoma (AA or GBM). Future trials which include more than one histologic entity need to report results by cell type and grade and account for the varying prognoses in interpreting treatment outcomes.

Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials.

PURPOSE: In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). PATIENTS AND METHODS: After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). RESULTS: Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). CONCLUSION: Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.

Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma): results of North Central Cancer Treatment Group trial 98-72-51.

PURPOSE: To evaluate the efficacy of preradiotherapy (RT) chemotherapy with carmustine, cisplatin, and oral etoposide combined with RT in the treatment of newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Therapy consisted of carmustine (40 mg/m(2)/d) on Days 1-3, oral etoposide (50 mg/d) on Days 1-21 and 29-49, and cisplatin (20 mg/m(2)/d i.v.) on Days 1-3 and 29-31. The regimen was repeated every 8 weeks for three cycles, with conventionally fractionated RT (5000 cGy with a 1000-cGy boost) delivered concurrently with the third cycle. RESULTS: A total of 29 patients were enrolled between December 1999 and March 2001. For varying reasons (e.g., progression, refusal, death, or toxicity), only 48% completed the chemotherapy regimen and 76% completed RT. Grade 3-4 toxicities were observed in 14 patients (48%). The primary study endpoint was the 23-month (700-day) survival, the median survival of patients with anaplastic astrocytoma in a previous North Central Cancer Treatment Group trial. To be considered an active treatment, a maximum of 9 patient deaths (of the first 25) were allowed before 700 days. However, 14 patients had died by 700 days after therapy. CONCLUSION: Our results have demonstrated that pre-RT chemotherapy with this regimen is insufficiently active in patients with anaplastic astrocytoma.

Importance of baseline mini-mental state examination as a prognostic factor for patients with low-grade glioma.

PURPOSE: The outcome and cognitive performance data collected in a prospective, intergroup clinical trial were analyzed to assess the prognostic importance of the baseline (before radiotherapy) Mini-Mental State Examination (MMSE) score in patients with low-grade glioma. METHODS AND MATERIALS: The patients studied were 203 adults with a supratentorial low-grade glioma randomly assigned to low-dose (50.4 Gy in 28 fractions) or high-dose (64.8 Gy in 36 fractions) localized radiotherapy. Folstein MMSE scores and neurologic function scores at baseline in combination with multiple other baseline variables were analyzed. The median follow-up was 7.4 years for the 101 patients still alive. RESULTS: Patients (n = 36) with an abnormal baseline MMSE score (< or =26) had a worse 5-year progression-free survival rate (27% vs. 60%; p <0.001) and overall survival rate (31% vs. 76%; p <0.001) compared with those with a normal score. On multivariate analysis, the baseline MMSE score was a statistically significant predictor of survival. Other factors associated with overall survival were age, tumor size, and tumor histologic type. CONCLUSION: The presence of an abnormal baseline MMSE score was a strong predictor of poorer progression-free and overall survival for patients with a low-grade glioma. The baseline MMSE should be considered in future prognostic scoring systems.

Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial.

PURPOSE: Supratentorial pilocytic astrocytomas in adults are uncommon. A prospective clinical trial was conducted to obtain clinical and outcome data in these patients. METHODS AND MATERIALS: 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, 10 years), 1 patient (5%) had died and 19 patients (95%) were alive. The 5-year progression-free and overall survival rates were 95%. The cause of death in the patient who died (2.1 years after enrollment) was unknown; a radiographic examination obtained shortly before the patient's demise revealed no signs of progression. Progression in 1 patient approximately 1 month after enrollment required injection of (32)P into an enlarging cyst. The patient required RT approximately 18 months later because of further progression. This patient was alive without evidence of progression 9 years after RT. No toxic effects had been recorded at the latest follow-up examinations. CONCLUSION: With follow-up comparable or superior to that in many retrospective studies, the results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. The vast majority of patients remained stable after gross or subtotal resection and no adjuvant therapy. RT need not be offered to adults with supratentorial pilocytic astrocytoma after gross or subtotal resection; instead, close observation is recommended. Because only 3 patients received RT after biopsy, it is difficult to comment on the effect of RT on their outcome as a group.

Immunomodulatory treatment trial for paraneoplastic neurological disorders.

Paraneoplastic neurological disorders are devastating remote effects of malignancy. Despite compelling evidence of an autoimmune pathogenesis, empiric immunomodulatory treatment of these disorders is often ineffective. However, very few systematic studies have been conducted, and the treatment of patients without active malignancy has not been addressed. We conducted a prospective open-label treatment study of plasma exchange plus conventional cancer chemotherapy (10 patients) or plasma exchange plus continuous oral cyclophosphamide (10 patients). All patients had progressive symptoms and at least moderate disability at enrollment (mean Rankin score, 3.4). Patients who had experienced symptoms for more than 12 months were excluded (mean duration of symptoms at enrollment, 3.6 months). The primary outcome measure was change in quantitative disability measures (Rankin and Barthel scores) after 6 months of treatment; a positive response was defined as stability or improvement in disability. Overall, 50% of patients had a positive response at 6 months (6 patients had improved by at least 1 Rankin grade). Patients with good outcome tended to be those with less disability at time of enrollment. Hematologic toxicity was common among those receiving cyclophosphamide. Aggressive immunosuppression early in the clinical course should be considered in patients who have paraneoplastic neurological disorders, even when there is no evidence of active malignancy.

Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination.

PURPOSE: To assess the neurocognitive effects of cranial radiotherapy on patients with low-grade gliomas, we analyzed cognitive performance data collected in a prospective, intergroup clinical trial. METHODS: Patients included 203 adults with supratentorial low-grade gliomas randomly assigned to a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. Folstein Mini-Mental State Examination (MMSE) scores and neurologic function scores (NFS) at baseline and key evaluations were analyzed. Median follow-up was 7.4 years in 101 patients still alive. A change of more than three MMSE points was considered clinically significant. RESULTS: In patients without tumor progression, significant deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively. Most patients with an abnormal baseline MMSE score (< 27) experienced significant increases. Baseline variables such as radiation dose, conformal versus conventional radiotherapy, number of radiation fields, age, sex, tumor size, NFS, seizures, and seizure medications did not predict cognitive function changes. CONCLUSION: In this population, most low-grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE. Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy. Only a small percentage of patients had cognitive deterioration after radiotherapy. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE.

Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia.

Fluorescence in situ hybridization (FISH) was used to detect 6q-, 11q-, +12, 13q-, 17p- and translocations involving 14q32 in interphase nuclei from blood and/or bone marrow from 113 patients with B-cell chronic lymphocytic leukaemia (B-CLL). A total of 87 patients (77%) had a FISH anomaly: 13q- x 1 was most frequent (64%) followed by 13q- x 2 (28%), +12 (25%), 11q- (15%), 17p- (8%) and 6q- (0%). FISH results for blood and bone marrow cells in 38 patients were similar. Purified CD5+/CD19+ cells from blood were studied in eight patients and results indicate that in some patients not all B cells have FISH anomalies. We used a defined set of hierarchical FISH risk categories to compare FISH results by stable versus progressive disease, age, sex, Rai stage, CD38+ expression and IgVH mutational status. Significant differences in FISH risk distributions were associated with Rai stage, disease status and CD38+, but not by age, sex or IgVH mutational status. To look for baseline factors associated with high-risk disease, multivariate analysis of age, sex, Rai stage, CD38+ and disease status versus FISH risk category was performed. Importantly, only CD38+ was significantly associated with high-risk FISH categories (+12, 11q- and 17p-) after adjustment for the effects of other variables.

Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.

Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.

A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases.

PURPOSE: To determine whether neurosurgery (NS) or stereotactic radiosurgery (RS) provided better local tumor control and enhanced patient survival. METHODS AND MATERIALS: Retrospective review of all solitary brain metastases (SBM) patients newly diagnosed at Mayo Clinic Rochester between 1991 and 1999. Eligible patients satisfied tumor size and SBM site criteria to qualify for both NS and RS. RESULTS: There were no significant differences between 74 NS and 23 RS patients in terms of baseline characteristics (age, gender, systemic disease type, systemic disease status, signs/symptoms at SBM presentation) or percent of patients who received whole brain radiotherapy. Median follow-up for alive patients was 20 months (range 0-106 months). There was no significant difference in patient survival (p = 0.15); the 1-year survival rate was 56% for the RS patients and 62% for the NS patients. Multivariate Cox regression analysis found that a significant prognostic factor for survival was a performance score of 0 or 1. There was a significant (p = 0.020) difference in local tumor control between NS and RS for solitary brain metastasis; none of the RS group had local recurrence compared to 19 (58%) of the NS group. CONCLUSION: The need for a Phase III study comparing these two techniques appears to be supported by the data from this study.

Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities.

PURPOSE: The purpose of this article is to determine the response rate and toxicity of PCV administered before radiation therapy in patients with newly diagnosed LGO/LGOA and to explore correlations between response with 1p/19q deletions and aberrant p53 expression. BACKGROUND: Despite prolonged survival of patients with low-grade oligodendroglioma (LGO) and oligoastrocytoma (LGOA), the majority will succumb to progressive disease. Because procarbazine, lomustine (CCNU), and vincristine (PCV) is active in patients with recurrent LGO/LGOA, we hypothesized that it would be beneficial as primary therapy. METHODS: Adult patients with residual tumor on magnetic resonance imaging scan following biopsy or subtotal resection of LGO/LGOA received up to six cycles of PCV. Radiation therapy (59.4 or 54.0 Gy) began within 10 weeks of completing chemotherapy or immediately if there was evidence of tumor progression on PCV. Tumor tissue was analyzed by fluorescent in situ hybridization for 1p and 19q deletion and by immunohistochemistry for p53 expression. RESULTS: Eight of 28 (29%) and 13 of 25 (52%) eligible patients demonstrated tumor regression as assessed by the treating physician and a blinded central neuroradiology reviewer, respectively. Myelosuppression was the predominant toxicity. Loss of 1p and 19q were associated with LGO but not LGOA (P =.009), were inversely associated with p53 detection, and were not associated with response to PCV (possibly because of the small sample size). CONCLUSION: PCV produces tumor regressions in a meaningful proportion of patients with LGO/LGOA. Toxicity, especially myelosuppression, is significant. Loss of 1p and 19q seems limited to patients with pure LGO and is inversely related to p53 alterations.

Triple-dose contrast/magnetization transfer suppressed imaging of 'non-enhancing' brain gliomas.

PURPOSE: Triple-dose (TD) gadolinium contrast administration and magnetization transfer suppression (MTS) in brain magnetic resonance imaging (MRI) have proven to be useful for demonstrating additional enhancing lesions in some diseases. The purpose of this study was to determine if there is a subset of brain tumors that demonstrate contrast enhancement with TD and MTS that do not enhance with standard imaging and standard contrast dose. MATERIALS AND METHODS: Fifteen patients with either newly diagnosed primary brain tumor or brain tumor that had been followed for more than 2 years were enrolled. T1-weighted MTS images without IV contrast, with 0.1 mmol/kg without MTS (single-dose (SD) images), and with additional 0.2 mmol/kg gadolinium and MTS ('TD/MTS') were obtained. RESULTS: None of the patients had enhancement on SD images. Six patients had areas of enhancement on TD/MTS images ('exact' chi-squared p = 0.017). CONCLUSION: A statistically significant increased rate of contrast enhancement was found on TD/MTS images in patients whose tumors did not enhance at single dose without MTS. It is possible that small areas of enhancement seen only with TD/MTS might represent areas of higher-grade tumor.

Prognostic significance of an apoptotic index and apoptosis/proliferation ratio for patients with high-grade astrocytomas.

We evaluated the association of spontaneous apoptosis and an apoptosis/proliferation index with survival to determine the potential of such measures to serve as predictive markers for patients with glioblastoma multiforme (GBM). We examined the extent of spontaneous apoptosis in tumors from newly diagnosed patients, 75 with GBM and 21 with anaplastic astrocytoma, who were entered on treatment protocols of the North Central Cancer Treatment Group. In the group of GBM patients, those with a higher apoptotic index tended to live longer ( P = 0.04; Cox proportional hazards model including performance score, age, and extent of resection in a multivariate model). We found that the apoptotic index values for anaplastic astrocytoma patients tended to be lower than those in the GBM patients, although with small sample sizes, the result was not statistically significant ( P = 0.1). We also examined expression of the Ki-67 cell proliferation antigen immunohistochemically using the MIB-1 monoclonal antibody. Ki-67 expression did not provide additional information regarding the survival of patients with GBM. In this group of GBM patients, those patients with higher apoptotic index/proliferation ratios had a better prognosis than did those with a low ratio ( P < 0.021, same model as above). These findings suggest that both apoptosis and a cell death/cell proliferation ratio are associated with patient survival, and they may be useful for either the clinical evaluation of patients with GBM or the stratification of patients for treatment evaluation.