A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023

PURPOSE: This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense accelerated radiation therapy using weekly fractionated stereotactic radiotherapy (FSRT) boost for patients with glioblastoma multiforme (GBM). METHODS AND MATERIALS: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <60 mm were enrolled. A 50-Gy dose of standard radiation therapy (RT) was given in daily 2-Gy fractions. In addition, patients received four FSRT treatments, once weekly, during Weeks 3 to 6. FSRT dosing of either 5 Gy or 7 Gy per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. After the RT course, carmustine (BCNU) at 80 mg/m(2) was given for 3 days, every 8 weeks, for 6 cycles. RESULTS: A total of 76 patients were analyzed. Toxicity included: 3 Grade 4 chemotherapy, 3 acute Grade 4 radiotherapy, and 1 Grade 3 late. The median survival time was 12.5 months. No survival difference is seen when compared with the RTOG historical database. Patients with gross total resection (41%) had a median survival time of 16.6 months vs. 12.0 months for historic controls with gross total resection (p = 0.14). CONCLUSION: This first, multi-institutional FSRT boost trial for GBM was feasible and well tolerated. There is no significant survival benefit using this dose-intense RT regimen. Subset analysis revealed a trend toward improved outcome for GTR patients suggesting that patients with minimal disease burden may benefit from this form of accelerated RT.     

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.     

Stereotactic radiosurgery and fractionated stereotactic radiotherapy: comparison of efficacy and toxicity in 260 patients with brain metastases

We retrospectively evaluated and compared the efficacy and the toxicity profile of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of patients with brain metastases (BM). Between 2000 and 2009, 260 patients with 1-3 BM were treated using either SRS (median dose 20 Gy; n = 138) or two different FSRT dose concepts: 7 × 5 Gy (n = 61) or 10 × 4 Gy (n = 61). The median survival for SRS, 7 × 5 Gy and 10 × 4 Gy was 8, 7 and 10 months (p = 0.575), respectively, and the overall survival (OS) was 9 months. Follow-up imaging data were available in 214 of the 260 patients. The 1-year local progression-free survival (LPFS) was 73, 75 and 71 %, respectively (p = 0.191). After a mean follow-up of 28 months (range: 2.1-77 months), the rate of complete remission, partial remission, stable disease and progressive disease were 29, 40, 21 and 10 %, respectively. On multivariate analysis, RPA class I was associated with better OS and regional progression-free survival (both p < 0.001). SRS was associated with a higher toxicity rate (grade I-III) compared to the 7 × 5 Gy and 10 × 4 Gy groups (14 vs. 6 vs. 2 %, respectively; p = 0.01). Although FSRT was used for large lesions and/or lesions near critical structures, the LPFS was comparable to SRS. Importantly, FSRT presented low toxicity and appears to be an effective and safe treatment for BM not amenable to SRS. The 10 × 4 Gy fractionation scheme warrants further investigation due to its efficacy and safe toxicity profile.     

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas

Purpose: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy.

Methods and Materials: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35%) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS.

Results: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p < 0.05).

Conclusion: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.     

Does stereotactic eligibility for the treatment of glioblastoma cause selection bias in randomized studies?

The purpose of this study was to evaluate the potential selection bias using stereotactic eligibility as a criteria for participation in studies of glioblastoma multiforme. Radiation Therapy Oncology Group (RTOG) 90-06 comparing 60 Gy in 30 fractions with BCNU and 72 Gy in 60 fractions with BCNU was analyzed based on eligibility criteria used to enter patients on RTOG 93-05 using a stereotactic boost for patients with glioblastoma. Five hundred nine patients with histopathologically confirmed glioblastoma multiforme were analyzed; of these, 137 met criteria for 93-05 and 372 did not. Recursive partitioning analysis (RPA) was used to evaluate for differences. The RPA distribution in stereotactic radiosurgery (SRS)-eligible and -ineligible patients was similar. The median survival for RPA class 3 SRS-eligible patients was 1.4 years and -ineligible patients 1.4 years. For RPA class 4, the median survival was 1.0 years for eligible patients and 0.9 years for ineligible patients (P = 0.0421). For class 5 patients, the median survival was 8.3 months versus 7.2 months (P = 0.09). RPA class 6 patients had a median survival of 1.7 months versus 2.7 months for ineligible patients (P = 0.199). By analyzing previously randomized patients in a study not using a stereotactic boost, there does not appear to be a survival benefit for those patients who fit the criteria for consideration of a stereotactic boost in patients with glioblastoma multiforme.     

Dose escalation beyond 30 grays in 10 fractions for patients with multiple brain metastases

BACKGROUND: Whole-brain radiotherapy (WBRT) to 30 grays (Gy) in 10 fractions is the standard treatment in patients with multiple brain metastases in the majority of treatment centers worldwide. The current study investigated the potential benefit of dose escalation beyond 30 Gy. METHODS: Data regarding 416 patients who were treated with WBRT for multiple brain metastases were evaluated retrospectively. Survival and freedom from recurrent brain metastasis (local control) of 257 patients who were treated with 10 fractions of 3 Gy each for 2 weeks were compared with those of 159 patients treated with 45 Gy in 15 fractions for 3 weeks or 40 Gy in 20 fractions for 4 weeks. Eight additional potential prognostic factors were investigated including age, gender, Karnofsky performance score (KPS), tumor type, interval between tumor diagnosis and RT, number of metastases, extracranial metastases, and Recursive Partitioning Analysis (RPA) class. RESULTS: On multivariate analysis, improved survival was found to be associated with lower RPA class (P < .001), age <60 years (P = .026), KPS >or=70 (P < .001), and absence of extracranial metastases (P = .003). A trend was observed for number of metastases (2-3 vs >or=4; P = .07). Improved local control was associated with a KPS >or=70 (P < .001) and breast cancer (P < .001). A trend was observed for number of metastases (P = .059). The RT schedule did not appear to have any significant impact on survival (P = .86) or local control (P = .61). The subgroup analyses, performed for each of the 3 RPA classes, did not demonstrate a significantly better outcome with dose escalation. CONCLUSIONS: Dose escalation beyond 30 Gy in 10 fractions does not appear to improve survival or local control in patients with multiple brain metastases but does increase the treatment time and cost of therapy.     

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.     

Evaluation of 2 whole-brain radiotherapy schedules and prognostic factors for brain metastases in breast cancer patients

BACKGROUND: The majority of breast cancer patients with brain metastases receive whole-brain radiotherapy (WBRT) and have a survival of only a few months. A short WBRT regimen would be preferable if it provides survival that is similar to that achieved with longer programs. This retrospective study compared survival and local control within the brain resulting from short-course WBRT with longer programs in 207 breast cancer patients. METHODS: Sixty-nine patients treated with 5 fractions of 4 grays (Gy) each given within 5 days were compared with 138 patients treated with 10 fractions of 3 Gy each given over 2 weeks or 20 fractions of 2 Gy each given over 4 weeks. Six additional potential prognostic factors were investigated: age, Karnofsky performance score (KPS), number of brain metastases, the presence of extracranial metastases, interval from tumor diagnosis to WBRT, and recursive partitioning analysis (RPA) class. RESULTS: On univariate analysis, the WBRT regimen was not found to be associated with survival (P=.254) or local control (P=.397). Improved survival was associated with a KPS>70 (P<.001), single brain metastasis (P=.023), the absence of extracranial metastases (P<.001), and lower RPA class (P<.001). On multivariate analysis, which was performed without RPA class because this is a confounding variable, KPS (relative risk [RR] of 4.00; P<.001) and the presence of extracranial metastases (RR of 1.54; P=.024) maintained statistical significance. On univariate analysis, local control was associated with KPS (P<.001) and RPA class (P<.001). On multivariate analysis, local control was found to be associated with a KPS>70 (RR of 5.75; P<.001). CONCLUSIONS: Short-course WBRT with 5 fractions of 4 Gy each resulted in survival and local control that were similar to longer programs in breast cancer patients with brain metastases. The dose of 5 fractions of 4 Gy each appears preferable for the majority of these patients because it is less time consuming and more convenient.     

A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas.

BACKGROUND AND PURPOSE: This phase II study evaluated the efficacy and toxicity of weekly cisplatin along with concomitant boost accelerated radiation regimen in patients with locally advanced unresectable head and neck carcinoma. MATERIAL AND METHODS: A total of 94 patients (median age, 58 years) with UICC stage III (n = 19) and IV (n = 75) cancer of the oropharynx, larynx, hypopharynx and oral cavity were included. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (95%) received both radiation and chemotherapy according to protocol. Toxicity was manageable with grade III mucositis and pharyngeal-oesophageal toxicity in 85 and 50% of patients, respectively. Haematological toxicity was mild. Four patients (4%) died due to complications. With a median follow of 41 months, median overall survival and time to progression were 27 and 25 months, respectively. The estimated overall survival at 4 years was 41%. CONCLUSIONS: Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with locally advanced unresectable head and neck carcinoma, with acceptable toxicity and survival data.     

Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes?

PURPOSE: To determine whether or not Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) derived prognostic classes for patients with brain metastases are generally applicable and can be recommended as rational strategy for patient selection for future clinical trials. Inclusion of time to non-CNS death as additional endpoint besides death from any cause might result in further valuable information, as survival limitation due to uncontrolled extracranial disease can be explored. METHODS: We performed a retrospective analysis of prognostic factors for survival and time to non-CNS death in 528 patients treated at a single institution with radiotherapy or surgery plus radiotherapy for brain metastases. For this purpose, patients were divided into groups with Karnofsky performance status (KPS) <70% and KPS > or =70%, as proposed by the RTOG. RESULTS: Median overall survival was 2.9 months (2.0 months for patients with KPS <70% and 3.6 months for patients with KPS > or =70%, p < 0.001). We did not find other variables splitting patients with KPS <70% in different prognostic groups. However, advanced age, multiple brain metastases, presence of extracranial metastases, and uncontrolled primary tumor each predicted shorter survival in patients with KPS > or =70%. When grouped into the original RTOG RPA classes, our data set split into three subgroups with different prognosis and median survival times of 10.5, 3.5, and 2 months, respectively (p < 0.05). Only 3% of patients fell into the most favorable group. Median time to non-CNS death was 4.1 months (12.9 months in RPA class I, 4.9 months in RPA class II, and 3.8 months in RPA class III, respectively, p > 0.05 for RPA class II versus III). However, it was 8.5 months in RPA class II patients with controlled primary tumor, which was found to be the only prognostic factor for time to non-CNS death in patients with KPS > or =70%. In patients with KPS <70%, no statistically significant prognostic factors were identified for this endpoint. CONCLUSIONS: Despite some differences, this analysis essentially confirmed the value of RPA-derived prognostic classes, as published by the RTOG, when survival was chosen as endpoint. RPA class I patients seem to be most likely to profit from aggressive treatment strategies and should be included in appropriate clinical trials. However, their number appears to be very limited. Considering time to non-CNS death, our results suggest that certain patients in RPA class II also might benefit from increased local control of brain metastases.     

Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and long-term outcome

PURPOSE: To evaluate the effectiveness and toxicity of fractionated stereotactically guided radiotherapy (FSRT) in the management of optic glioma. METHODS AND MATERIALS: Fifteen patients with optic pathway gliomas were treated with FSRT at our institution between 1990 and 2003. A median target dose of 52.2 Gy (range, 45.2-57.6 Gy) was applied using a median fractionation of 5 fractions of 1.8 Gy weekly using a linear accelerator. RESULTS: The median follow-up time was 97 months (range, 8-151 months). Of the 15 patients, 1 died of tumor progression during the follow-up period. The progression-free survival rate at 3 and 5 years was 92% and 72%, respectively. The median overall survival after FSRT was 90 months (range, 8-151 months). The 5-year survival rate after FSRT was 90%. We did not observe secondary malignancies. CONCLUSION: Fractionated stereotactic radiotherapy was safe and well tolerated in all patients. The good tumor control and the potential of sparing normal brain tissue, especially the pituitary gland in lesions involving the optic chiasm, permit effective treatment of patients with optic nerve gliomas. Longer follow-up is needed to assess the incidence of late effects fully.     

器官和病灶联合定义寡转移Ⅳ期NSCLC原发灶三维根治剂量放疗的意义——PPRA-RTOG 003再分析

目的 分析器官和病灶联合定义寡转移Ⅳ期NSCLC原发灶3DRT剂量及其相关因素对生存的影响。方法 定义单器官和2个器官中每器官1个转移病灶为寡转移,共115例,分析剂量及相关因素与总生存的关系, Kaplan-Meier法计算生存并Logrank检验,Cox回归模型行多因素分析。结果 115例中位生存期(MST)为14个月,1、2、3年OS率分别为55.7%、18.3%、11.5%。原发灶剂量≥和<63 Gy的OS比较,全组、2周期化疗获益、放化疗获益MST延长,分别为17个月和13个月(P=0.046)、17个月和13个月(P=0.037)、18个月和14个月(P=0.022);转移灶放疗、原发灶有效有延长生存的趋势,MST均为17个月和13个月(P=0.055和P=0.065);4~6周期化疗的MST为16个月和13个月(P=0.165)。放化疗有效、原发灶体积<120.1 cm³、治疗后KPS改善比无效、大体积、KPS降低患者的MST延长(15个月比12个月,P=0.036;17个月和11个月,P=0.002;14个月和10个月,P=0.031)。多因素分析原发灶剂量和体积(P=0.020和P=0.001)、治疗后KPS变化(P=0.021)显著影响生存。结论 联合器官和病灶定义的寡转移Ⅳ期NSCLC化疗同期原发灶根治剂量放疗的生存期显著延长,原发灶体积、治疗后KPS是影响生存的独立预后因子。     

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.     

Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas

Background To reduce this complication and to enhance the radiation effect to hypoxic cells of high-grade gliomas, the authors performed noninvasive fractionated stereotactic radiotherapy (FSRT) using a Gamma unit combined with hyperbaric oxygen (HBO) therapy for the treatment of recurrent disease. Patients and methods Twenty-five consecutive patients who had previously received radiotherapy with chemotherapy for recurrent high-grade gliomas, including 14 patients with anaplastic astrocytoma (AA) and 11 with glioblastoma multiforme (GBM), underwent Gamma FSRT immediately after HBO therapy (2.5 atmospheres absolute for 60 min). The Gamma FSRT was repeatedly performed using a relocatable head cast. Median tumor volume was 8.7 cc (range, 1.7–159.3 cc), and the median total radiation dose was 22 Gy (range, 18–27 Gy) to the tumor margin in 8 fractions. Results Actuarial median survival time after FSRT was 19 months for patients with AA and 11 months for patients with GBM, which was significantly different (P = 0.012, log-rank test). Two patients underwent subsequent second FSRT for regional or remote recurrence. Seven patients (28%) underwent subsequent craniotomies and resections at a mean of 8.4 months after FSRT treatment, and 4 of them had radiation effects without viable cells and remained alive for 50–78 months. Conclusion Gamma FSRT after HBO therapy appears to confer a survival benefit for patients with recurrent high-grade gliomas and warrants further investigation.     

Whole-brain radiotherapy versus stereotactic radiosurgery for patients in recursive partitioning analysis classes 1 and 2 with 1 to 3 brain metastases

BACKGROUND: The authors investigated whether stereotactic radiosurgery (SRS) alone improved outcomes for patients in recursive partitioning analysis (RPA) Classes 1 and 2 who had 1 to 3 brain metastases compared with whole-brain radiotherapy (WBRT). METHODS: Data regarding 186 patients in RPA Classes 1 and 2 who had 1 to 3 brain metastases and who received either 30 to 40 grays (Gy) of WBRT (n = 91 patients) or 18 to 25 Gy SRS (n = 95 patients) were analyzed retrospectively. Eight other potential prognostic factors were evaluated regarding overall survival (OS), entire brain control (BC), local control (LC) of treated metastases, and brain control distant from treated metastases (distant control [DC]): Those 8 factors were age, sex, performance status, tumor type, number of brain metastases, extracranial metastases, RPA class, and interval from tumor diagnosis to radiotherapy. RESULTS: On multivariate analysis of OS, age ( risk ratio [RR], 1.51; P = .024), Karnofsky performance status (KPS) (RR, 1.98; P = .002), and extracranial metastases (RR, 2.26; P < .001) were significant, whereas the radiation regimen was not significant (P = .89). On multivariate analysis of BC, only the radiation regimen (RR, 1.33; P = .003) was found to be significant. On multivariate analysis of LC, radiation regimen (RR, 1.63; P < .001) and sex (RR, 1.62; P = .022) were significant. On multivariate analysis of DC, KPS (RR, 1.85; P = .049) and extracranial metastases (RR, 1.69; P = .047) were significant. The radiation regimen was not found to be significant even on univariate analysis (P = .80). In RPA class subgroup analyses, BC and LC were better after SRS than WBRT for patients in RPA Classes 1 and 2, whereas OS and DC did not differ significantly. CONCLUSIONS: For patients in RPA Classes 1 and 2 who had 1 to 3 brain metastases, SRS alone was associated with improved BC and LC compared with 30 to 40 Gy WBRT, whereas OS and DC were not significantly different. Similar results were observed in separate subgroup analyses of patients in RPA Class 1 and RPA Class 2.     

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.     

Salvage reirradiation for recurrent glioblastoma with radiosurgery: radiographic response and improved survival

Purpose To determine the radiographic and clinical efficacy of stereotactic single dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) as salvage therapy for glioblastoma (GBM) at recurrence. Methods Thirty-six patients with pathologically proven recurrent GBM were treated with salvage reirradiation by either SRS or FSRT between March of 2001 and August of 2006. Thirty-one patients had an initial diagnosis of GBM. Five patients had a malignant transformation. All patients had received radiotherapy with a dose of 50–60 Gy, a median 13.6 months prior to reirradiation (range: 0.8–119 months). At the time of recurrence, 26 patients were treated with SRS with a median dose of 18 Gy (range: 12–20 Gy). FSRT was performed in ten patients with a dose of 36 Gy in six fractions, twice weekly. Follow-up included MRI and clinical examination every 2 months. Results Median survival time after SRS was 8.5 months, compared to 7.4 months after FSRT (P = 0.81). Of 26 patients treated with SRS, radiographic tumor response or stable disease was observed in eight (35%) patients and tumor progression was seen in 18 (65%) patients. Of 10 patients treated by FSRT, radiographic tumor response or stable disease was observed in four (40%) patients and tumor progression was observed in four (40%) patients (two lost to follow-up). Patients who responded to treatment had statistically improved survival compared to non-responders, with median survival of 15.8 vs. 7.3 months (P < 0.05). Conclusion Salvage reirradiation with SRS or FSRT for recurrent GBM results in radiographic response in a proportion of patients. Survival was significantly improved among patients who either responded or had stable disease after salvage reirradiation, compared to non-responders. Further study is warranted to investigate the method and time of reirradiation for recurrent GBM.     

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).     

A boost in addition to whole-brain radiotherapy improves patient outcome after resection of 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients

BACKGROUND: The current study was conducted to compare 2 treatment regimens including surgical resection and whole-brain radiotherapy (WBRT) for patients with 1 to 2 brain metastases. METHODS: A total of 201 patients with recursive partitioning analysis (RPA) class 1 to 2 disease with 1 to 2 resectable brain metastases were analyzed retrospectively. Patients underwent either resection of the metastases plus WBRT with 10 fractions of 3 grays (Gy) each or 20 fractions of 2 Gy each (99 patients; Group A) or the same treatment plus a WBRT boost to the metastatic site (10 fractions of 3 Gy each plus 5 fractions of 3 Gy each or 20 fractions of 2 Gy each plus 5 fractions of 2 Gy each) (102 patients; Group B). Eight other potential prognostic factors were evaluated with regard to overall survival (OS), brain control (BC), and local control of resected metastases (LC): age, gender, Karnofsky performance status, extent of surgical resection, tumor type, extracranial metastases, RPA class, and interval from tumor diagnosis to WBRT. RESULTS: Group B patients had better 1-year OS (66% vs 41%; P < .001). On multivariate analysis of OS, treatment regimen (relative risk [RR] of 1.94; P < .001), extent of surgical resection (RR of 1.80; P = .001), and interval from tumor diagnosis to WBRT (RR of 1.62; P = .010) were found to be statistically significant. On multivariate analysis of BC, treatment regimen (RR of 2.15; P = .002), extent of surgical resection (RR of 2.78; P < .001), and interval from tumor diagnosis to WBRT (RR of 1.52; P = .034) were found to be statistically significant. On multivariate analysis of LC, treatment regimen (RR of 2.31; P = .002) and extent of surgical resection (RR of 3.79; P < .001) were found to be statistically significant. On RPA class subgroup analyses, outcome was found to be significantly better with a WBRT boost in both RPA class 1 and class 2 patients. A WBRT boost resulted in better outcome after both complete and incomplete surgical resection. However, the results concerning BC and LC were not found to be statistically significant if surgical resection was incomplete. CONCLUSIONS: After surgical resection of 1 to 2 brain metastases, a boost of 10 to 15 Gy in addition to WBRT was found to improve outcome. After incomplete surgical resection, further dose escalation to the metastatic site may be considered.     

Radiotherapy is effective in patients with glioblastoma multiforme with a limited prognosis and in patients above 70 years of age: a retrospective single institution analysis.

BACKGROUND AND PURPOSE: To evaluate the efficacy of radiotherapy in patients with glioblastoma multiforme (GBM) with a limited prognosis and in patients older than 70 years. PATIENTS AND METHODS: Retrospective analysis of 202 patients with GBM treated between 1990 and 2000 in a single institution. Patients (including patients >or=70 years) were assigned to RPA groups and their survival was compared with RTOG data. RESULTS: Median survival was 8.0 months for the total group and 13.9, 10.6, 3.8, 2.1 months for RPA group III (n=17), IV (n=87), V (n=60) and VI (n=38), respectively. Median survival for patients >or=70 years was 3.6 vs. 8.1 months for 50--70 years and 11.0 months for <50. In each separate RPA group, patients >or=70 years had a similar survival compared to patients of 50--70 years. Irradiated patients (66%) survived significantly longer than non-irradiated patients: 10.6 vs. 1.9 months (P<0.0001). In RPA group V the median survival for irradiated patients was 9.4 vs. 2.1 months for non-irradiated patients. In a multivariate analysis, RT remained the only prognostic factor for survival (HR 8.9, P<0.001). CONCLUSIONS: Prognosis for patients above 70 years of age is not different from younger patients, when analyzed for separate RPA groups. For patients with a poor prognosis (i.e. RPA group V), radiotherapy improves survival significantly.