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W J Curran

Publications and source records attributed to W J Curran.

At least 37 records · Page 2Linked to original sources
PubMed2000

Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme.

PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model. PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered. RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level. CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Adult↗
PubMed1999

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Repair of DNA double-strand breaks and radiosensitivity to killing in an isogenic group of p53 mutant cell lines.

PURPOSE: Accumulation of the p53 protein can result in G1 arrest that may facilitate DNA repair, or alternatively, it may lead to apoptosis. Mutations that alter p53's ability to mediate these responses are expected to alter cell radiosensitivity to killing. However, the relationship between p53 status and cell radiosensitivity has proven to be complex. Several studies have suggested that p53 mutations are associated with increased radioresistance to killing, while others have shown no such correlation. These differences may be derived from the fact that different mutations of p53 exert different effects on cell radiosensitivity. METHODS AND MATERIALS: To address this question, we examined a group of isogenic cell lines that express different "hot spot" mutant forms of p53. These cells were generated from human osteosarcoma (SAOS) cells, a p53 null cell line, by transfection with vectors expressing different p53 mutants. Vectors with the following p53 mutations were utilized: 143Ala, 175His, 248Try, 273His, and 281Gly. As controls, we used the original SAOS cells and cells transfected with the vector alone. Results were compared to those obtained with a cell line expressing wild-type p53 (wt p53). Radiosensitivity to killing was determined in the exponential phase of growth by measuring loss of colony-forming ability. Induction and repair of DNA double-strand breaks (dsb) was measured in irradiated cells using pulsed-field gel electrophoresis. Apoptosis was assessed using morphologic evaluation of DAPI-stained cells after treatment either with radiation or paclitaxel. RESULTS: Transfected SAOS-2 cell lines expressed a mutant form of p53 that could not be induced by radiation, and which was transcriptionally inactive. Among the 7 cell lines studied, we observed no difference in cellular radiosensitivity to killing (p = NS). When examining DNA repair, no difference in either the induction or repair of DNA dsb was noted in any of the cell lines studied (p = NS). Also, induction of apoptosis, either after exposure to radiation or paclitaxel, was low, and similar in all cell lines (p = NS). Non-isogenic cells expressing wt p53 were more radioresistant to killing by radiation, but showed similar kinetics of dsb rejoining. CONCLUSION: The results suggest that expression of different p53 mutants does not alter the yields of radiation-induced dsb, or the ability of cells to repair this type of lesion. In addition, the same p53 mutants do not affect cellular radiosensitivity to killing, or the induction of apoptosis after exposure to radiation or paclitaxel.

Apoptosis↗
PubMed1999

Immediate side effects of stereotactic radiotherapy and radiosurgery.

PURPOSE: Despite increased utilization of fractionated stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS), the incidence and nature of immediate side effects (ISE) associated with these treatment techniques are not well defined. We report immediate side effects from a series of 78 patients. MATERIALS AND METHODS: Intracranial lesions in 78 adult patients were treated with SRT or SRS, using a dedicated linear accelerator. Those lesions included 13 gliomas, 2 ependymomas, 19 metastatic tumors, 15 meningiomas, 12 acoustic neuromas, 4 pituitary adenomas, 1 optic neuroma, 1 chondrosarcoma, and 11 arteriovenous malformations (AVM). SRT was used in 51 and SRS in 27 patients. Mean target volume was 9.0 cc. Eleven patients received prior external-beam radiation therapy within 2 months before SRT/SRS. Any side effects occurring during and up to 2 weeks after the course of radiation were defined as ISE and were graded as mild, moderate, or severe. The incidence of ISE and the significance of their association with several treatment and pretreatment variables were analyzed. RESULTS: Overall, 28 (35%) of 78 patients experienced one or more ISE. Most of the ISE (87%) were mild, and consisted of nausea (in 5), dizziness/vertigo (in 5), seizures (in 6), and new persistent headaches (in 17). Two episodes of worsening neurological deficit and 2 of orbital pain were graded as moderate. Two patients experienced severe ISE, requiring hospitalization (1 seizure and 1 worsening neurological deficit). ISE in 6 cases prompted computerized tomography of the brain, which revealed increased perilesional edema in 3 cases. The incidence of ISE by diagnosis was as follows: 46% (6 of 13) for gliomas, 50% (6 of 12) for acoustic neuromas, 36% (4 of 11) for AVM, 33% (5 of 15) for meningiomas, and 21% (4 of 19) for metastases. A higher incidence of dizziness/vertigo (4 of 12 = 33%) was seen among acoustic neuroma patients than among other patients (p< 0.01). There was no significant association of dizziness/vertigo with either a higher average and maximum brainstem dose (p = 0.74 and 0.09, respectively) or with 2-Gy equivalents of the average and maximum brainstem doses (p = 0.28 and 0.09, respectively). Higher RT dose to the margin and higher maximum RT dose were associated with a higher incidence of ISE (p = 0.05 and 0.01, respectively). However, when RT dose to the margin was converted to a 2-Gy dose-equivalent, it lost its significance as predictor of ISE (p = 0.51). Recent conventional external-beam radiation therapy, target volume, number of isocenters, collimator size, dose inhomogeneity, prescription isodose, pretreatment edema, dose of prior radiation, fraction size (2.0-7.0 Gy with SRT and 13.0-21.0 Gy with SRS), fractionation schedule, and dose to brainstem were not significantly associated with ISE. ISE occurred in 26% (8) of 31 patients taking corticosteroids prior to SRT/SRS and in 20 (42%) of 47 patients not taking them (p = 0.15). CONCLUSION: ISE occur in one third of patients treated with SRT and SRS and are usually mild or moderate and self-limited. Dizziness/vertigo are common and unique for patients with acoustic neuromas and are not associated with higher brainstem doses. We are unable to detect a relationship between ISE and higher margin or maximum RT doses. No specific conclusion can be drawn with regard to the effect of corticosteroids, used prior to SRS/SRT, on the occurrence of ISE.

Adult↗
PubMed1999

A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma.

PURPOSE: A phase I dose escalation of hypofractionated stereotactic radiotherapy (H-SRT) in recurrent or persistent malignant gliomas as a means of increasing the biologically effective dose and decreasing the high rate of reoperation due to toxicity associated with single-fraction stereotactic radiosurgery (SRS) and brachytherapy. MATERIALS AND METHODS: From November 1994 to September 1996, 25 lesions in 20 patients with clinical and/or imaging evidence of malignant glioma persistence or recurrence received salvage H-SRT. Nineteen patients at the time of initial diagnosis had glioblastoma multiforme (GBM) and one patient had an anaplastic astrocytoma. All of these patients with tumor persistence or recurrence had received initial fractionated radiation therapy (RT) with a mean and median dose of 60 Gy (44.0-72.0 Gy). The median time from completion of initial RT to H-SRT was 3.1 months (0.7-45.5 months). Salvage H-SRT was delivered using daily 3.0-3.5 Gy fractions (fxs). Three different total dose levels were sequentially evaluated: 24.0 Gy/3.0 Gy fxs (five lesions), 30.0 Gy/3.0 Gy fxs (10 lesions), and 35.0 Gy/3.5 Gy fxs (nine lesions). Median treated tumor volume measured 12.66 cc (0.89-47.5 cc). The median ratio of prescription volume to tumor volume was 2.8 (1.4-5.0). Toxicity was judged by RTOG criteria. Response was determined by clinical neurologic improvement, a decrease in steroid dose without clinical deterioration, and/or radiologic imaging. RESULTS: No grade 3 toxicities were observed and no reoperation due to toxicity was required. At the time of analysis, 13 of 20 patients had died. The median survival time from the completion of H-SRT is 10.5 months with a 1-year survival rate of 20%. Neurological improvement was found in 45% of patients. Decreased steroid requirements occurred in 60% of patients. Minor imaging response was noted in 22% of patients. Using Fisher's exact test, response of any kind correlated strongly to total dose (p = 0.0056). None of six lesions treated with 21 Gy or 24 Gy responded, whereas there was a 79% response rate among the 19 lesions treated with 30 or 35 Gy. Tumor volumes < or =20 cc were associated with a higher likelihood of response (p = 0.053). CONCLUSIONS: H-SRT used in this cohort of previously irradiated patients with malignant glioma was not associated with the need for reoperation due to toxicity or grade 3 toxicity. This low toxicity profile and encouraging H-SRT dose-related response outcome justifies further evaluation and dose escalation.

Brain Neoplasms↗
PubMed1999

Evaluation of the spatial accuracy of magnetic resonance imaging-based stereotactic target localization for gamma knife radiosurgery of functional disorders.

PURPOSE: This study was undertaken to determine the impact of geometric distortions on the spatial accuracy of magnetic resonance imaging (MRI)-guided stereotactic localization for gamma knife functional radiosurgery. METHOD: The spatial accuracy of MRI was evaluated by comparing stereotactic coordinates of intracranial targets, external fiducials, and anatomic structures defined by computed tomographic and MRI studies of the Radionics skull phantom (Radionics, Inc., Burlington, MA), the Rando head phantom, and 11 patients who underwent gamma knife functional radiosurgery. The distortion in MRI was assessed from computed tomographic and MRI fusion studies for these patients, as well as from MRI studies acquired by swapping the direction of the magnetic field gradients for five patients who underwent gamma knife radiosurgery and three patients who underwent MRI-guided frameless surgery. A follow-up program to compare the location of the created lesion with the intended target complemented the analysis. RESULTS: The average difference between computed tomographic and MRI stereotactic coordinates of external fiducials, intracranial targets, and anatomic landmarks was of the order of 1 pixel size (0.9 x 0.9 x 1 mm3) along the x, y, and z axes. The average linear scaling along these axes as determined by fusion studies was approximately 0.8% and consistent with a single pixel. The follow-up studies, available for seven patients, revealed good agreement between the location of the created lesion and the intended target. CONCLUSION: The spatial accuracy of an MRI-based localization system can be comparable to computed tomography-based localization with the added benefit of MRI resolution. Both machine- and object-related MRI distortions can be reduced to an acceptable level with contemporary scanners, optimized scanning sequences, and distortion-resistant stereotactic instruments.

Artifacts↗
PubMed1999

Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation--preliminary experience.

PURPOSE: To evaluate the temporal evolution and appearance of a radiosurgical lesion at magnetic resonance (MR) imaging and the clinical response in patients undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma knife. MATERIALS AND METHODS: Seventeen patients with medically refractory movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or thalamotomy (n = 15). A single dose of 120-140 Gy was administered to a target in the globus pallidus interna or ventralis intermedius thalamic nucleus. Postprocedure gadolinium-enhanced MR imaging and clinical assessment were performed at 1 month and 3 months. RESULTS: At 3 months, the radiosurgical lesion most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in diameter surrounded by vasogenic edema that extended less than 7 mm in radius beyond the target. Five patients had ring-enhancing lesions 7 mm or more in diameter; four of these developed symptomatic perilesional edema at 3 (n = 2) or 8 (n = 2) months after the procedure. Onset of therapeutic effect began approximately 4 weeks after treatment. In the 15 patients with tremor, there was a mean decline of 2.1 on the Tremor Rating Scale. CONCLUSION: Findings in this pilot study suggest that radiosurgical thalamotomy is a promising treatment for medically refractory tremor. Three-month follow-up MR studies show a ring-enhancing lesion surrounded by a variable amount of vasogenic edema. Visualization of the radiosurgical lesion and the clinical response are delayed compared to that with radio-frequency procedures.

Adult↗
PubMed1999

Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy.

PURPOSE: To determine any differences in outcome for patients with anaplastic astrocytoma (AA) treated with adjuvant carmustine (BCNU) versus procarbazine, lomustine, and vincristine (PCV) chemotherapy. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) database was reviewed for patients with newly diagnosed AA treated according to protocols that included either BCNU or PCV adjuvant chemotherapy. All patients were treated with radiation therapy. The outcome analysis included overall survival, taking into account patient age, extent of resection, Karnofsky performance status (KPS), and treatment group (BCNU v PCV). Stratified and nonstratified Cox proportional hazards models were used, as well as an analysis using matched cases between the groups. RESULTS: A total of 257 patients were treated with BCNU according to RTOG protocols 70-18, 83-02, and 90-06; 175 patients were treated with PCV according to RTOG protocol 94-04. All pretreatment characteristics except KPS were well balanced by treatment group; 61% of the BCNU group had a KPS of 90 to 100 compared with 73% of the PCV group (P =.0075). No statistically significant difference in survival was observed in any age group or by KPS or extent of surgery. The stratified analysis also showed no trends for improved survival by treatment group (P =. 40). The Cox model identified only age, KPS, and extent of surgery as important variables influencing survival, not treatment group. Matching cases between groups using age, KPS, and surgery resulted in 133 matched pairs. No difference in survival was observed (P =. 41). In a Cox model in which each matched pair is a strata, there was no difference between groups (P =.20). CONCLUSION: Using this retrospective analysis, there does not seem to be any survival benefit to PCV chemotherapy. Future phase III studies for patients with AA may need to consider whether BCNU or PCV is used in the control arm.

Adult↗
PubMed1999

Apoptosis as a predictor of paclitaxel-induced radiosensitization in human tumor cell lines.

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06.

PURPOSE: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes. PATIENTS AND METHODS: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I-VI from RTOG 90-06, respectively. RESULTS: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms. CONCLUSION: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.

Dose Fractionation, Radiation↗
PubMed1998

Waldenström's macroglobulinemia resulting from localized gastric lymphoplasmacytoid lymphoma.

A patient with a high level serum monoclonal IgM lambda paraprotein (3,850 mg/dL) was found to have a mass infiltrating the gastric mucosa. Gastric biopsy with immunohistochemical stains showed a B-cell lymphoplasmacytoid infiltrate expressing IgM lambda, consistent with Waldenström's macroglobulinemia. The patient's response to gastric radiation indicated that the primary source of the macroglobulinemia was the stomach. This is an extremely rare presentation, with only six other reported cases of this entity with gastric involvement.

Female↗
PubMed1998

Atypical and malignant meningiomas: an outcome report of seventeen cases.

Limited data are available concerning the outcome of patients with atypical and malignant meningiomas. We therefore analyzed the outcome of seventeen patients with meningiomas (9 atypical; 8 malignant) at Thomas Jefferson University Hospital between 1973 and 1996. Strict adherence to the 1993 WHO criteria for the typing of CNS tumors was maintained. The median potential follow-up period for all patients was 87 months. The age at diagnosis ranged from 22 to 72 (mean 51.8 years). There were 5 males and 12 females. The mean tumor diameter was 4.45 cm. Of the 16 cases where the extent of surgical resection was known, 4 were partial and 12 were complete resections. Six patients (35%) had dural or cortical invasion by tumor. Fifteen patients received postoperative megavoltage photon irradiation (mean 61 Gy). One of these fifteen pts. received an additional 20 Gy with Au-198 implantation and 1 received post-radiation chemotherapy for recurrent disease. The overall survival rate for all patients at 5 and 10 years were 87% and 58% respectively. The 5- and 10-year survival rates for atypical meningiomas were 87% and 58%; for malignant meningiomas the survival rates were 60% and 60% respectively. Five patients (30%) have died. Three of these 5 patients initially received less than 54 Gy to the tumor bed and have died of recurrent disease. Local disease progression was documented in 11 patients (65%) after surgery and in 3 patients (18%) after radiation. There was an improvement in performance status in 3 (18%) patients with a decline and no change seen in 1 (6%) and 13 (77%) respectively after receiving radiation. There appeared to be no difference in survival in patients as a function of dural or cortical invasion. Long term survival is possible for patients with atypical and malignant meningiomas treated with surgery and post-operative radiation. We are unable to distinguish a difference in outcome between these two pathological entities. Dural and cortical invasion were not associated with a decrease in survival. In addition, improved tumor control and survival may be associated with increased radiation dose.

Adult↗