Resection and survival in glioblastoma multiforme: an RTOG recursive partitioning analysis of ALA study patients

The benefit of cytoreductive surgery for glioblastoma multiforme (GBM) is unclear, and selection bias in past series has been observed. The 5-aminolevulinic acid (ALA) study investigated the influence of fluorescence-guided resections on outcome and generated an extensive database of GBM patients with optimized resections. We evaluated whether the Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) would predict survival of these patients and whether there was any benefit from extensive resections depending on RPA class. A total of 243 per-protocol patients with newly diagnosed GBM were operated on with or without ALA and treated by radiotherapy. Postoperative MRI was obtained in all patients. Patients were allocated into RTOG-RPA classes III-V based on age, KPS, neurological condition, and mental status (as derived from the NIH Stroke Scale). Median overall survival among RPA classes III, IV, and V was 17.8, 14.7, and 10.7 months, respectively, with 2-year survival rates of 26%, 12%, and 7% (p = 0.0007). Stratified for degree of resection, survival of patients with complete resections was clearly longer in RPA classes IV and V (17.7 months vs. 12.9 months, p = 0.0015, and 13.7 months vs. 10.4 months, p = 0.0398; 2-year rates: 21.0% vs. 4.4% and 11.1% vs. 2.6%, respectively), but was not in the small subgroup of RPA class III patients (19.3 vs. 16.3 months, p = 0.14). Survival of patients from the ALA study is correctly predicted by the RTOG-RPA classes. Differences in survival depending on resection status, especially in RPA classes IV and V, support a causal influence of resection on survival.     

Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis.

PURPOSE: When an initial retrospective review of malignant glioma patients (MG) undergoing brachytherapy was carried out using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) criteria, it revealed that glioblastoma multiforme (GBM) cases benefit the most from implant. In the present study, we focused exclusively on these GBM patients stratified by RPA survival class and looked at the relationship between survival and implanted target volume, to distinguish the prognostic value of volume in general and for a given GBM class. METHODS AND MATERIALS: Between 1991 and 1998, 75 MG patients were treated with surgery, external beam radiation, and stereotactic iodine-125 (I-125) implant. Of these, 53 patients (70.7%) had GBMs, with 52 (98%) having target volume (TV) data for analysis. Stratification by RPA criteria showed 12, 26, 13, and 1 patients in classes III to VI, respectively. For analysis purposes, classes V and VI were merged. There were 27 (51.9%) male and 25 (48.1%) female patients. Mean age was 57.5 years (range 14-79). Median Karnofsky performance status (KPS) was 90 (range 50-100). Median follow-up time was 11 months (range 2-79). RESULTS: At analysis, 18 GBM patients (34.6%) were alive and 34 (65.4%) were dead. Two-year and 5-year survivals were 42% and 17.5%, respectively, with a median survival time (MST) of 16 months. Two-year survivals and MSTs for the implanted GBM patients compared to the RTOG database were as follows: 74% vs. 35% and 28 months vs. 17.9 months for class III; 32% vs. 15% and 16 months vs. 11.1 months for class IV; 29% vs. 6% and 11 months vs. 8.9 months for class V/VI. Mean implanted TV was 15.5 cc (range 0.8-78), which corresponds to a spherical implant diameter of 3.1 cm. Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases. The impact of incremental changes in TV on survival within a given RPA class of GBMs was compared to the RTOG database. Looking at absolute differences in MSTs: for classes III and IV, there was little effect of different TVs on survival; for class V/VI, a survival benefit to implantation was still seen at the target volume cutoff (TV > 25 cc). Within a given RPA class, no significant differences were found within class III; for class IV, the most significant difference was at 10 cc (p = 0.05); and for class V/VI, at 20 cc (p = 0.06). CONCLUSION: For all GBM patients, an inverse relationship between implanted TV size and median survival is suggested by this study. However, when GBM patients are stratified using the RTOG's RPA criteria, the prognostic effect of implant volume disappears within each RPA survival class. At the critical volume of 25 cc, which approximates an implant of 5-cm diameter (upper implantation limit of many CNS brachytherapy protocols), the "poorest" prognosis GBM patients stratified by RPA still demonstrate a survival benefit with implant. We suggest that any GBM patient meeting brachytherapy recognized size criteria be considered for I-125 implant.     

Primary glioblastoma multiforme in younger patients: a single-institution experience

AIMS AND BACKGROUND: To report our experience of patients with primary glioblastoma multiforme of young age by evaluating the characteristics, prognostic factors, and treatment outcomes. PATIENTS AND METHODS: Seventy patients with primary glioblastoma multiforme (GBM) treated at our department between 1996 and 2004 were studied. The male-female ratio was 2.6:1. The median age was 53 (16-74). Sixty-eight patients (97%) were operated on before radiotherapy and 2 patients (3%) underwent only stereotactic biopsy. All patients received radiotherapy. Postoperative chemotherapy as an adjuvant to radiotherapy was given to 9 patients (12%). The patients were divided into 2 groups according to their age (group A < or = 35 years, n = 21 vs group B > 35 years, n = 49). Survival was determined with the Kaplan-Meier method and differences were compared using the log-rank test. Cox regression analysis was performed to identify the independent prognostic factors. Karnofsky performance status (> or = 70 vs < 70), age (< or = 35 vs > 35 years), gender, tumor size (< or = 4 vs > 4 cm), number of involved brain lobes (1 vs more than 1), type of surgery (total vs subtotal), preoperative seizure history (present vs absent), radiotherapy field (total cranium vs partial), total radiotherapy dose (60 vs 66 Gy), and adjuvant chemotherapy (present vs absent) were evaluated in univariate analysis. RESULTS: The median survival was 10.3 months in the whole group, 19.5 months in the younger age group and 5.7 months in the older age group. During follow-up re-craniotomy was performed in 2 patients (3%), and 1 patient (1%) developed spinal seeding metastases and was given spinal radiotherapy. In univariate analysis younger age vs older age: median 19.5 months vs 5.27 months (P = 0.0012); Karnofsky performance status > or = 70 vs < 70: median 15.3 months vs 2.67 months (P < 0.0001), and external radiotherapy dose 60 Gy vs 66 Gy: median 11.6 months vs 3 months (P = 0.02) were found as significant prognostic factors for survival. In regression analysis a worse performance status (KPS <70) was found to be the only independent factor for survival (P = 0.014, 95% CI HR = 0.0043 [0.0001-0.15]). CONCLUSIONS: Younger patients with primary glioblastoma multiforme had a relatively long survival (median, 19.5 months, with a 2-year survival rate of 30%) compared to older patients. This was due particularly to their better performance status.     

Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme

Current therapeutic goals for treatment of Glioblastoma Multiforme (GBM) involve gross total resection followed by multifractionated focal external beam radiation therapy (EBRT). Patients treated with optimal therapy have a median survival of approximately 12-15 months. In the present study, we sought to determine whether a hypofractionated dosing schedule using CyberKnife is at least as effective as multifractionated focal EBRT. A retrospective analysis was conducted on 20 histopathologically confirmed GBM patients treated with CyberKnife at Okayama Kyokuto Hospital in Japan after gross total resection (n=11), subtotal resection (n=8), or biopsy (n=1). Eight patients also received adjuvant ACNU and Vincrisitine chemotherapy according to local protocol; however, no patient received any other form of radiation besides post surgical/biopsy CyberKnife treatment. The treated tumor volumes ranged from 9.62 cm(3)-185.81 cm(3) (mean: 86.08 cm(3)). The marginal dose (D90) ranged from 19.99 Gy-41.47 Gy (mean: 34.58 Gy) with a maximum mean dose of 43.99 Gy (range: 23.33 Gy-56.89 Gy). The prescribed isodose line ranged from 50.38%-85.68% with a mean of 79.25%. Treatment was delivered in 1-8 fractions (mean: 5.65). Patients were followed from 2-36 months (mean: 16.45 months). Overall median survival was 16 months with 55% of patients alive at 12 months and 34% of patients alive at 24 months. Median survival of patients in Recursive Partitioning Analysis (RPA) classes III or IV was 32 months versus 12 months for those in RPA class V. Median survival for patients who received gross total resection was 36 months versus 8 months for those who underwent subtotal resection or biopsy. The results of this study using CyberKnife stereotactic radiosurgery (SRS) and hypofractionated radiotherapy compared favorably to historic data using focal EBRT in newly diagnosed post surgical GBM patients. A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal EBRT is warranted.     

Patients with brain metastases: hope for recursive partitioning analysis (RPA) class 3.

PURPOSE: The objectives of the present study were (a) to validate the prognostic classification derived from recursive partitioning analysis (RPA) of the Radiation Therapy Oncology Group (RTOG); (b) to identify prognostic factors in class 3; (c) to examine the impact of treatment related variables on the prognosis in class 3. PATIENTS AND METHODS: Nine hundred and sixteen patients with brain metastases had resection and whole brain radiotherapy (WBRT, n = 257) or WBRT alone (n = 659) at our institution from 1985 to 2000. Patients were grouped into RPA classes 1, 2, and 3 (n = 67, 441, and 408, respectively). RESULTS: Median survival of the whole group was 3.4 months. Median survival in classes 1, 2, and 3 was 8.2, 4.9, and 1.8 months, respectively. In class 3, age (<65 years vs. > or =65 years, relative risk (RR) 0.75), status of the primary tumor (controlled vs. uncontrolled, RR 0.86), and the number of brain metastases (single vs. multiple, RR 0.76) were independent prognostic variables. We defined three prognostic subgroups: class 3a (n = 51): age <65 years, controlled primary tumor, single brain metastasis; class 3c (n = 44): age > or =65 years, uncontrolled primary tumor, multiple brain metastases; class 3b (n = 313): all other patients. Median survival in classes 3a, 3b, and 3c was 3.2, 1.9, and 1.2 months, respectively (P < 0.0001). Intra-class comparisons showed that resection followed by WBRT yielded significantly better survival compared with WBRT alone. CONCLUSION: Our results validate the RTOG RPA classification for patients with brain metastases. The variables age, status of the primary, and number of brain metastases allow the division of class 3 into prognostic subgroups. Even class 3 patients may benefit from more aggressive treatment strategies.     

High-dose-rate stereotactic brachytherapy for patients with newly diagnosed glioblastoma multiformes

Purpose: To evaluate high-dose-rate (HDR) stereotactic brachytherapy (STBT) for glioblastoma multiforme (GBM). Materials and methods: Between August 1994 and December 1998, 28 patients with newly diagnosed GBM underwent surgery, external-beam radiotherapy (EBRT) and HDR STBT. STBT eligibility criteria included unifocal lesions, residual tumor <6cm in maximum diameter, supratentorial lesions, tumors not crossing the midline, tumors without subependymal spread and Karnofsky performance status (KPS) >60. STBT was delivered over five consecutive days with two fractions per day for a total median dose of 30Gy. Twenty-eight STBT eligible GBM patients treated with surgery and EBRT only over the same period were matched controls. Results: Median survival times for the STBT group and controls were 19.5 versus 12.5 months; one and two year survival rates were 89% versus 42% and 61% versus 28%, respectively (p=0.12). Using multivariate analysis, age, KPS and HDR STBT were significant factors predicting survival. By RPA class, 2-year survival rates for STBT and controls were: III – 78% versus 50%; IV – 40% versus 0%; V – 21% versus 15%, respectively. Corresponding median survival times in months were: 41.6 versus 21.2 (p = 0.39); 16.7 versus 12.1 (p = 0.36); 18.7 versus 10.6 (p = 0.02). No major complications were found in the STBT arm. Conclusions: Because of small patient numbers, median survival time increases were only statistically significant in the RPA Class V patients, but a strong survival time trend emerged favoring patients undergoing HDR STBT. Further prospective study is warranted to fully assess the merits of this technique for GBM management.     

Age as an independent prognostic factor in patients with glioblastoma: a radiation therapy oncology group and American College of Surgeons National Cancer Data Base comparison

Glioblastoma (GBM) is rare in early adulthood and little information is available on this subgroup. We investigated whether young age (18-30 years) had an independent effect on survival. We retrospectively reviewed patients from two large databases: Radiation Therapy Oncology Group (RTOG) and American College of Surgeons National Cancer Data Base (NCDB). In the RTOG evaluation, we analyzed all eligible GBM cases from 17 RTOG studies from 1974 to 2002. All patients with GBM during 1985-1998 in the NCDB were examined for comparison. Patients were divided into three cohorts: ages 18-30, 31-49, and ≥50. Overall survival, as a function of age (discreet and continuous), was assessed. The RTOG review included 3,136 patients: 112 (3.6%) were 18-30, 780 (24.9%) were 31-49, and 2,244 (71.6%) were ≥50. The median survival times of the three groups were 21.0, 13.5, and 9.1 months (P < 0.0001). Significant improvement in survival for younger patients was demonstrated with adjustment for recursive partitioning analysis (RPA) class. Of the 37,260 patients analyzed in the NCDB, 796 (2.1%) were 18-30, 5,711 (15.3%) were 31-49, and 30,753 (82.5%) were ≥50. The median survival times of the three groups were 18.0, 12.8, and 6.3 months (P < 0.0001). Data were not available for RPA class from this series. GBM is rare in young adulthood, comprising 2.1-3.6% of our patients. They have superior survival, even when adjusted for RPA class. More investigations on the unique biologic and clinical characteristics of tumors in this population are needed.     

Two radiation regimens and prognostic factors for brain metastases in nonsmall cell lung cancer patients

BACKGROUND: Nonsmall cell lung cancer (NSCLC) patients with brain metastases usually receive whole-brain radiotherapy (WBRT). Most of these patients survive for only a few months. A short course of WBRT would be preferable to longer regimens if it could provide similar survival. This retrospective study of NSCLC patients compared longer treatment programs with short-course WBRT with 5 x 4 Gy given during 5 days. METHODS: Data from 404 NSCLC patients treated with WBRT for brain metastases were retrospectively analyzed. The 140 patients who received 5 x 4 Gy given in 5 days were compared for survival with 264 patients who received either 10 x 3 Gy given in 2 weeks or 20 x 2 Gy given in 4 weeks. Seven further potential prognostic factors were investigated for survival including age, sex, Karnofsky performance score (KPS), number of brain metastases, extracranial metastases, interval from tumor diagnosis to WBRT, and RPA (recursive partitioning analysis) class. RESULTS: The WBRT regimen was not associated with survival (P = .55). On multivariate analysis, age < 60 years (vs > or =60 years, P = .020), KPS > or =70 (vs KPS < 70, P < .001), interval from tumor diagnosis to WBRT > 12 months (vs < or =12 months, P = .007), no extracranial metastases (P < .001), and RPA class 1 (vs RPA class 2 vs RPA class 3, P = .007) were significantly associated with improved survival. CONCLUSIONS: Short-course WBRT with 5 x 4 Gy appeared preferable for most NSCLC patients, as it was associated with survival similar to longer WBRT programs, and the short course was less time consuming.     

Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases

PURPOSE: To evaluate the usefulness of whole brain radiotherapy (WBRT) and of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) for brain metastases among patients receiving stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A retrospective analysis was performed on 135 patients who underwent linear accelerator (Linac) (n = 73) or Gamma Knife (n = 62) SRS for newly diagnosed brain metastases at the Cleveland Clinic Foundation between 8/89 and 12/98. Univariate and multivariate analyses were performed to evaluate the effects of age, primary site, control of the primary, interval to development of brain metastases (disease-free interval [DFI]), number of brain metastases, presence of extracranial metastases, Karnofsky performance status (KPS), treatment of brain metastases, and RPA class on overall survival. RESULTS: Application of the RPA classification revealed 29 patients fit the criteria for class I, 96 for class II, and 10 for class III. All of the patients underwent SRS. Fifty-seven patients also received WBRT at the time of initial presentation (SRS and immediate WBRT), and 78 patients received WBRT only if CNS relapse occurred (SRS alone). The median survival for all patients was 7.9 months (range: 1.1-90.1), and was 11.2 months for RPA class I compared to 6. 9 months for RPA classes II-III (p = 0.016). Median survival was 10. 5 months following SRS alone compared to 6.4 months following SRS and WBRT (p = 0.07). On univariate analysis, KPS >/= 80% (p = 0.002) and absence of systemic disease (p = 0.013) were also associated with longer survival, whereas control of the primary, DFI, and number of brain metastases did not have an impact. Multivariate analysis revealed only RPA class (p = 0.023) to be an independent predictor for overall survival, whereas treatment group (p = 0.079) was only marginally significant. At 2 years, immediate WBRT improved control at the original site of metastases (80% vs. 52%, p = 0.03) and prevention of new metastatic sites within the brain, 74% vs. 48% (p = 0.06). The 2-year intracranial disease-free survival was 60% following SRS and WBRT compared to only 34% following SRS alone (p = 0.03). CONCLUSIONS: Despite the inherent biases to select more favorable patients for SRS, the RPA class retains its prognostic value. Omission of WBRT from the initial management was not detrimental in terms of overall survival; however, progressive disease occurred in over 50% of patients treated in this manner. Further studies are required to determine which, if any, patients should be considered for SRS with WBRT held in reserve.     

Survival Results from a Phase I Study of Etanidazole (SR2508) and Radiotherapy in Patients with Malignant Glioma

Purpose: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status.Patients and Methods: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS ≥ 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 4–5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (≤ 49 or > 49 years), KPS (≤ 80 or > 80) and implant versus non-implant were also performed.Results: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age ≤ 49 were factors found not to be associated with a statistically improved survival.Conclusion: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.     

Results of whole brain radiotherapy and recursive partitioning analysis in patients with brain metastases from renal cell carcinoma: a retrospective study

PURPOSE: To determine the benefit of whole brain radiotherapy (WBRT) and the use of the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification system in patients with brain metastases from renal cell carcinoma. METHODS AND MATERIALS: We identified 46 consecutive patients with brain metastases from renal cell carcinoma who were treated with WBRT at the Cleveland Clinic Foundation between 1983 and 2000. We reviewed their charts for patient and tumor characteristics and categorized them according to the RTOG RPA classes. RESULTS: The median follow-up and survival time for all 46 patients (15 women and 31 men) was 3.0 months. The median radiation dose was 3000 cGy in 10 fractions. Patients who received higher radiation doses (>3000 cGy) survived longer than those who received 3000 cGy or less than 3000 cGy (8.5 months vs. 2.7 months vs. 0.4 months, p = 0.0289). However, the Karnofsky performance status and RPA class were confounding factors in these data. The median survival for patients by RTOG RPA class was 8.5 months for Class I (n = 2), 3 months for Class II (n = 37), and 0.6 months for Class III (n = 7, p = 0.0834). CONCLUSION: Despite the relatively poor prognosis of patients who receive WBRT alone, it appears that they benefit from this palliative treatment. The RTOG RPA classification system may be a useful tool in assessing prognosis in this patient population.     

Radiation therapy after a partial response to CHOP chemotherapy for aggressive lymphomas

PURPOSE: To analyze the results with involved-field radiotherapy after aggressive lymphomas had decreased in size by 50-99% in response to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. METHODS AND MATERIALS: From 1988 through 1996, 294 previously untreated patients with Working Formulation intermediate-grade or large-cell immunoblastic lymphomas underwent CHOP-based chemotherapy on 2 consecutive protocols at the M. D. Anderson Cancer Center. Forty-four (15%) of these patients achieved, based on international working group guidelines, a partial (50-75%) response (n = 25), or unconfirmed complete (76-99%) response (n = 19) to a median of 6 cycles of chemotherapy. These patients were treated with salvage involved-field radiotherapy (n = 32) or chemotherapy (n = 12), e.g., MINE-ESHAP, without autologous stem-cell rescue (ASCR). RESULTS: Median follow-up was 43 months. Partial responders experienced similar outcomes to unconfirmed complete responders. Local control (4-year rates: 86% vs. 53%, p = 0.009) and progression-free survival (4-year rates: 67% vs. 8%, p < 0.0001), but not overall survival (4-year rates: 70% vs. 50%, p = 0.067) were significantly better in those who received salvage radiotherapy, which was well tolerated. CONCLUSION: Progression-free and overall survival in aggressive lymphoma patients who underwent salvage radiotherapy were similar to results reported for high-dose chemotherapy with ASCR. The role of salvage radiotherapy in partial and unconfirmed complete responders to CHOP chemotherapy justifies examination in a large, cooperative group trial.     

Phase II radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme

PURPOSE: Fractionated external beam radiotherapy (EBRT) +/- carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg/m(2)/3 h/week x 6, during EBRT, with no exacerbation of typical RT-induced toxicities. The Radiation Therapy Oncology Group (RTOG) therefore mounted a Phase II study to determine the feasibility and efficacy of conventional EBRT and concurrent weekly TAX at its MTD. PATIENTS AND METHODS: Sixty-two patients with histologic diagnosis of GBM were enrolled from 8/16/96 through 3/21/97 in a multi-institutional Phase II trial of EBRT and TAX 225 mg/m(2)/3 h (1-3 h before EBRT), administered the first treatment day of each RT week. Total EBRT dose was 60 Gy (200 cGy/fraction), 5 days per week. A smaller treatment field, to include gross disease plus a margin only, was used after 46 Gy. RESULTS: Sixty-one patients (98%) were evaluable. Median age was 55 years (range, 28-78). Seventy-four percent were > or = 50 years. Recursive partitioning analysis (RPA) Classes III, IV, V, VI included 10 (17%), 21 (34%), 25 (41%), and 5 (8%) patients, respectively. Gross total resection was performed in only 16%. There was no Grade 3 or 4 neutropenia or thrombocytopenia. Hypersensitivity reactions precluding further use of TAX occurred in 4 patients. There were 2 instances of late neurotoxicity (4% Grade 3 or 4). Ninety-one percent of patients received treatment per protocol. Seventy-seven percent completed prescribed treatment (6 weeks). Of 35 patients with measurable disease, CR/PR was observed in 23%, MR in 17%, and SD in 43%. Seventeen percent demonstrated progression at first follow-up. Median potential follow-up time is 20 months. Median survival is 9.7 months, with median survivals for RPA classes III, IV, V, and VI of 16.3, 10.2, 9.5, 2.5 months, respectively. Ten patients remain alive. CONCLUSION: Concurrent full-dose EBRT and weekly high-dose TAX is feasible in the majority of GBM patients. Acute toxicity is acceptable; myelosuppression and peripheral sensory neuropathy are surprisingly modest, despite considerably higher overall dose intensity, compared to that achievable in other disease sites. Median survival by RPA class without prolonged adjuvant therapy is comparable to RTOG controls treated with standard EBRT and BCNU (1 year of BCNU).     

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.     

Survival Analysis of Glioblastoma Multiforme

Introduction: To evaluate the survival of Glioblastoma Multiforme (GBM). Material and Methods: Patients witha pathological diagnosis of Glioblastoma Multiforme (GBM) between 1 January 1994 and 30 November 2013, wereretrospectively reviewed. Inclusion criteria: 1) GBM patients with confirmed pathology, 2) GBM patients were treatedby multimodality therapy. Exclusion criteria: 1) GBM patients with unconfirmed pathology, 2) GBM patients with spinalinvolvement, 3) GBM patients with incomplete data records. Seventy-seven patients were treated by multimodalitytherapy such as surgery plus post-operative radiotherapy (PORT), post-operative Temozolomide (TMZ) concurrent withradiotherapy (CCRT), post-operative CCRT with adjuvant TMZ. The overall survival was calculated by the Kaplan-Meiermethod and the log-rank test was used to compare the survival curves. A p-value of ≤ 0.05 was considered to bestatistically significant. Results: Seventy-seven patients with a median age of 53 years (range 4-76 years) showeda median survival time (MST) of 12 months. In subgroup analyses, the PORT patients revealed a MST of 11 monthsand 2 year overall survival (OS) rates were 17.2%, the patients with post-operative CCRT with or without adjuvantTMZ revealed a MST of 23 months and 2 year OS rates were 38.2%. The MST of patients by Recursive PartitioningAnalysis (RPA), classifications III, IV, V, VI were 26.8 months, 14.2 months, 9.9 months, and 4.0 months, (p <0.001).Conclusions: The MST of the patients who had post-operative CCRT with or without adjuvant TMZ was better thanthe PORT group. The RPA classification can be used to predict survival. Multimodality therapy demonstrated the mosteffective treatment outcome. Temozolomide might be beneficial for GBM patients in order to increase survival time.     

Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases

Elderly patients have largely been excluded from randomized trials for glioblastoma multiforme (GBM). We reviewed the results of treatment approaches, which included surgery, chemotherapy, and radiation in this group of patients. Patients were treated during the period 1979-2007 and were 70 years of age and older with histologically confirmed GBM. Overall survival (OS) was the primary endpoint of this retrospective study. Two hundred six patients 70 years of age and older were identified. Median age was 75 years (range 70-90). Median OS time was 4.5 months. Univariate analysis showed that OS was significantly impacted by KPS score (1.8 months for KPS ≤ 50 to 17.2 months for KPS ≥ 90, P < .001), age at diagnosis (5.1 months for age 70-79 versus 3.1 months for age ≥ 80, P < .001), and extent of disease (worse for bilateral disease [P = .003], multifocal disease [P = .005], and multicentric disease [P = .02]). On multivariate analysis, higher KPS score (P = .006), surgical resection (any surgery beyond biopsy) (P < .001), radiation therapy (P < .001), and chemotherapy (P < .001) were all found to be independently associated with improved OS. In this study of newly diagnosed glioblastoma patients over the age of 70 years, aggressive treatment with radiation, chemotherapy, and surgery is associated with OS.     

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial

BACKGROUND: Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. METHODS: Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. FINDINGS: 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. INTERPRETATION: Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. FUNDING: Merck, Lion's Cancer Research Foundation, University of Ume?, and the Swedish Cancer Society.     

Pretreatment factors predict overall survival for patients with low-grade glioma: a recursive partitioning analysis

PURPOSE: Three databases were pooled and analyzed to determine which groupings of prognostic factors best predicted overall survival for patients with low-grade gliomas treated with surgery and immediate or delayed radiotherapy. METHODS AND MATERIALS: Databases of patients with low-grade gliomas compiled at the London Regional Cancer Centre (LRCC), the Norwegian Radium Hospital (NRH), and the University of California, San Francisco (UCSF) were merged. Inclusion criteria for the pooled analysis included: age > or =18 years and histologically confirmed low-grade (World Health Organization Grade II) supratentorial fibrillary astrocytoma, oligodendroglioma or mixed oligoastrocytoma. Factors analyzed for prognostic significance included: age at diagnosis, gender, seizures at presentation, presence of enhancement on computed tomography (CT) or magnetic resonance imaging (MRI), Karnofsky Performance Status (KPS) at diagnosis, histology, extent of surgical resection, timing of radiotherapy, and treating institution. Univariate and multivariate analysis of overall survival for these factors was performed. Recursive partitioning was performed to generate prognostic groups using these factors. RESULTS: From the combined databases, 401 patients were eligible for analysis. Median survival for the entire group was 95 months/7.9 years. On univariate analysis age 18-40, presence of seizures at presentation, KPS > or =70, treating institution, and absence of contrast enhancement were associated with improved overall survival. On multivariate analysis, these factors remained independent predictors of improved overall survival. Recursive partitioning analysis yielded four prognostic groups with statistically different median survivals (MS): Group I (n = 41: KPS <70, age >40) MS 12 months; Group II (n = 34: KPS > or =70, age >40, enhancement present) MS 46 months; Group III (n = 138: KPS <70, age 18-40 or KPS > or =70 age >40, no enhancement) MS 87 months; Group IV (n = 188: KPS > or =70, age 18-40) MS 128 months. CONCLUSION: Clusters of pretreatment prognostic factors described subgroups of low-grade glioma patients with divergent overall survivals. Consideration of these prognostic subgroups may be important when considering timing of interventions for these patients and in the stratification of patients for clinical trials.     

Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution.

PURPOSE: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) performed as reirradiation in 172 patients with recurrent low- and high-grade gliomas. PATIENTS AND METHODS: Between 1990 and 2004, 172 patients with recurrent gliomas were treated with FSRT as reirradiation in a single institution. Seventy-one patients suffered from WHO grade 2 gliomas. WHO grade 3 gliomas were diagnosed in 42 patients, and 59 patients were diagnosed with glioblastoma multiforme (GBM). The median time between primary radiotherapy and reirradiation was 10 months for GBM, 32 months for WHO grade 3 tumors, and 48 months for grade 2 astrocytomas. FSRT was performed with a median dose of 36 Gy in a median fractionation of 5 x 2 Gy/wk. RESULTS: Median overall survival after primary diagnosis was 21 months for patients with GBM, 50 months for patients with WHO grade 3 gliomas, and 111 months for patients with WHO grade 2 gliomas. Histologic grading was the strongest predictor for overall survival, together with the extent of neurosurgical resection and age at primary diagnosis. Median survival after reirradiation was 8 months for patients with GBM, 16 months for patients with grade 3 tumors, and 22 months for patients with low-grade gliomas. Only time to progression and histology were significant in influencing survival after reirradiation. Progression-free survival after FSRT was 5 months for GBM, 8 months for WHO grade 3 tumors, and 12 months for low-grade gliomas. CONCLUSION: FSRT is well tolerated and may be effective in patients with recurrent gliomas. Prospective studies are warranted for further evaluation.     

Stereotactic radiosurgery versus fractionated stereotactic radiotherapy boost for patients with glioblastoma multiforme

The aim of this study is to evaluate the efficacy of stereotactic radiotherapy boost (SRB) in patients with glioblastoma multiforme (GBM) by comparing two different regimens, single dose or fractionated treatment. Between December 1994 and January 2000, 24 patients with GBM were treated with SRB in conjunction with external beam radiotherapy (EBRT). Fourteen patients (58%) were treated with stereotactic radiosurgery (SRS) and 10 patients (42%) with fractionated stereotactic radiotherapy (FSRT). Median interval between EBRT and SRS or FSRT was 1.4 months (range -0.4-3.9 months). Actuarial survival rates of the entire 24 patients at one and two years following SRB were 63% and 34% respectively, with median survival time of 16 months. Variables predicting survival were age, extent of surgery, re-operation and the RTOG (Radiation Therapy Oncology Group) classes based on recursive partitioning analysis (RPA). In comparison to historical controls, improved survival benefit after SRB was observed. The median survival times for the RTOG classes 4, 5, and 6 were 28.3, 10.3, and 6.0 months following EBRT+SRB, respectively. Expected values for these classes after EBRT are 11.1, 8.9, and 4.6 months, respectively. This improvement in survival was seen predominantly for the RTOG class 4. There was no difference in survival between SRS and FSRT treated groups. Late complications developed in 4 patients in the SRS group and 1 patients in the FSRT group. Our retrospective data suggest that SRB in conjunction with EBRT may improve survival in patients with GBM with median survival time of 16 months, when compared to historical controls of the RTOG data following EBRT. The addition of SRB appeared to improve the median survival most demonstrably in RTOG RPA class 4 patients. SRS and FSRT are equally effective with similar median survival, but potentially less late complications associated with FSRT. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.