Radiation Therapy Oncology Group Recursive Partitioning Analysis Class Research Articles

A Prospective Study of Intensity-modulated Radiation Therapy Using a Standard Radiation Dose for High-grade Glioma.

We evaluated the treatment outcomes of intensity-modulated radiation therapy (IMRT) using a standard radiation dose in patients with high-grade glioma (HGG). We conducted a prospective, single-institutional, single-arm trial. Patients aged 20-75 years with histologically proven HGG were enrolled. Surgical procedures and chemotherapy regimens were not regulated. The prescribed dose of postoperative IMRT was 60 Gy in 30 fractions over six weeks. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), completion rate of IMRT, and Grade 3 or higher non-hematological toxicity. Between 2016 and 2019, 20 patients were enrolled. According to the World Health Organization 2016 Classification, glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma were present in nine, six, and five of the recruited patients, respectively. Gross total resection, partial resection, and biopsy were performed in four, nine, and seven patients, respectively. All patients received concurrent and adjuvant chemotherapy using temozolomide with or without bevacizumab. The completion rate of IMRT was 100%. The median follow-up period was 29 months (range=6-68 months). Median OS and PFS were 30 and 14 months, respectively. No patients experienced Grade 3 or higher non-hematological toxicity. The 2-year OS rates were 100%, 57%, and 33% in Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) classes I/II, IV, and V, respectively (p=0.002; log-rank test). IMRT using the standard radiation dose in patients with HGG can be carried out safely. RTOG-RPA class appears to be useful to estimate patient prognoses.

Clinical and Molecular Recursive Partitioning Analysis of High-grade Glioma Treated With IMRT

Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables. Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (P<0.001, χ=584) with median survival ranging from 96.4 to 2.9 months based on age, histology, O6-methylguanine-DNA methyltransferase methylation status, radiation fractions, tumor location, radiation dose, temozolomide status, and resection status. Our second RPA of our genetic subset generated 5 significantly different survival classes (P<0.001, χ=166) with survival ranging from 65.3 to 5.6 months based on age, isocitrate dehydrogenase 1 mutation status, O6-methylguanine-DNA methyltransferase methylation status, neurological functional classification, hospitalization during IMRT, temozolomide status, and Karnofsky performance status. The RTOG-RPA retains partial prognostic significance, however, should be updated to reflect recent advancements. This series represents a large RPA analyzing both clinical and genetic factors and generated 7 distinct survival classes. Further assessment of patients with fully available genetic markers generated 5 distinct survival classes. These survival classifications need to be validated by a prospective data set and compared against the RTOG-RPA to determine whether they provide improved prognostic power.

Whole brain irradiation with simultaneous integrated boost in treatment of oligometastatic brain disease

Background/Aim. Brain metastases occur in 20%?30% of all patients with systemic cancer. We aimed at investigating whether patients with oligometastatic brain disease treated with whole brain radiotherapy (WBRT) and simultaneous integrated boost of brain metastases (SIBmets) improved overall survival (clinical outcomes) compared with patients from the Radiation Therapy Oncology Group (RTOG) 9508 database, treated with WBRT and sequential stereotactic radiosurgery (SRS) boost. Methods. WBRT with SIBmets, using the RapidArc (RA) (Varian Medical Systems, Palo Alto, CA) volumetric modulated arc technique (VMAT), was delivered to 15 patients with computed tomography/ magnetic resonance imaging (CT/MRI) findings of 1?3 brain metastases with a diameter less than 40 mm for the largest lesion. Radiotherapy (RT) plans consisted of WBRT, with a prescribed dose of 20 Gy in 5 fractions, with SIBmets which was also 20 Gy (gray units) in 5 fractions. Results. A group of 15 patients included 8 males and 7 females with the mean age of 56.3 years. Three patients were in the RTOG Recursive Partitioning Analysis (RPA) Class I and other 12 patients in RPA Class II. Four patients had one metastasis and 11 patients had two metastases. Calculated mean survival time (MST) was 7.49 ? 4.36 months with no statistically significant difference compared to RTOG 9508 results (MST = 6.5 months) (p = 0.197). The local control rate for 7 patients after three months was 85.7%. Conclusion. WBRT with SIBmets and WBRT + SRS are clinically equivalent treatment options for the patients with oligometastatic brain disease. In comparison to the WBRT + SRS, the treatment by WBRT + SIBmets technique reduces the treatment time and improves the patient?s treatment comfort.

Role of Recursive Partitioning Analysis and Graded Prognostic Assessment on Identifying Non-Small Cell Lung Cancer Patients with Brain Metastases Who May Benefit from Postradiation Systemic Therapy.

Background:The role of postradiation systemic therapy in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) was controversial. Thus, we explored the role of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) and graded prognostic assessment (GPA) in identifying population who may benefit from postradiation systemic therapy.Methods:The clinical data of NSCLC patients with documented BM from August 2007 to April 2015 of two hospitals were studied retrospectively. Cox regression was used for multivariate analysis. Survival of patients with or without postradiation systemic therapy was compared in subgroups stratified according to RTOG-RPA or GPA.Results:Of 216 included patients, 67.1% received stereotactic radiosurgery (SRS), 24.1% received whole-brain radiation therapy (WBRT), and 8.8% received both. After radiotherapy, systemic therapy was administered in 58.3% of patients. Multivariate analysis found that postradiation systemic therapy (yes vs. no) (hazard ratio [HR] = 0.361, 95% confidence interval [CI] = 0.202–0.648, P = 0.001), radiation technique (SRS vs. WBRT) (HR = 0.462, 95% CI = 0.238–0.849, P = 0.022), extracranial metastasis (yes vs. no) (HR = 3.970, 95% CI = 1.757–8.970, P = 0.001), and Karnofsky performance status (<70 vs. ≥70) (HR = 5.338, 95% CI = 2.829–10.072, P < 0.001) were independent factors for survival. Further analysis found that subsequent tyrosine kinase inhibitor (TKI) therapy could significantly reduce the risk of mortality of patients in RTOG-RPA Class II (HR = 0.411, 95% CI = 0.183–0.923, P = 0.031) or with a GPA score of 1.5–2.5 (HR = 0.420, 95% CI = 0.182–0.968, P = 0.042). However, none of the subgroups stratified according to RTOG-RPA or GPA benefited from the additional conventional chemotherapy.Conclusion:RTOG-RPA and GPA may be useful to identify beneficial populations in NSCLC patients with BM if TKIs were chosen as postradiation systemic therapy.

The prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases

ObjectiveThe median survival of leptomeningeal metastases is short despite therapy and is sometime associated with hydrocephalus. We investigated the prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases. Materials and methodsBetween December 2005 and November 2012, 1343 patients had brain metastases from systemic solid tumors. Of these, 71 patients (5.3%) experienced leptomeningeal metastases from 45 lung cancers, 14 breast cancers, 4 gastric cancers and 8 other cancers. The mean age was 60 years (range 37–89). The clinical symptoms presented in the cerebral hemisphere and cerebellum in 58 patients, cranial nerve in 7 patients and spinal cord and nerves in 6 patients. Twenty-nine (40.8%) patients were Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class II and 42 (59.2%) were class III. Hydrocephalus was associated in 18 (25.4%) patients and 7 patients underwent ventriculoperioneal shunt. The primary cancer, clinical symptoms, RTOG-RPA class, surgically treated hydrocephalus and systemic chemotherapy were analyzed as the prognostic factors for overall survival. ResultsThe overall incidence of leptomeningeal seeding was 5.0% of the brain metastases. The median duration of leptomeningeal metastases from first brain metastasis was 4.0 months and 24 (33.8%) patients showed leptomeningeal metastases as the first form of brain metastasis. The median overall survival (OS) was 2.1 months. Based on the univariate and multivariate analyses, RTOG-RPA class II patients, treatment of leptomeningeal metastases (such as radiotherapy or intrathecal chemotherapy) and systemic chemotherapy improved OS with statistical significance. Surgically untreated hydrocephalus (median OS, 1.7 months) showed poor OS compared with surgically treated hydrocephalus (median OS, 5.7 months) and no hydrocephalus (median OS, 2.3 months) without statistical significance. ConclusionsThe leptomeningeal metastases were often associated with hydrocephalus and the surgical treatment was helpful in limited patients. The prognosis was related with RTOG-RPA class and treatment of local and systemic treatment.

Abstract A110: EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial.

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.

The prognosis of anaplastic astrocytoma with radiologic necrosis mimicking glioblastoma

Anaplastic astrocytoma (AA) sometimes shows a rapid poor course like glioblastoma. In this study, we investigated the prognosis of AA with radiologic necrosis which is the representative radiologic finding of glioblastoma. From 1995 to 2010, we operated on 26 patients who were confirmed to have AA. The male:female ratio was 13:13, and the median age was 47.23 years. The mean follow-up period was 3 years. We analyzed the prognostic significance of radiologic necrosis with age, sex, KPS, tumour location, radiologic findings, extent of removal and radiation therapy oncology group recursive partitioning analysis (RTOG-RPA) classification. The median progression-free survival (PFS) was 0.5 (± 0.17) years and the median overall survival (OS) was 1.6 (± 0.40) years. In univariate analysis, the clinical variables of younger age (p = 0.030) and RTOG-RPA class III (p = 0.043) correlated with longer PFS, and KPS (p = 0.038), radiologic necrosis (p = 0.013) and the extent of removal (p = 0.041) correlated with OS. The median OS was 1.0 (± 0.21) year in AA with radiologic necrosis compared to AA without radiologic necrosis, which showed 2.1 (± 0.29) years median OS. On multivariate analysis, there was no statistically significant prognostic factor. However, Cox's regression model revealed that gross total removal was associated with a longer OS (hazard ratio = 0.136; 95% CI, 0.018 to 1.046; p = 0.055) compared to partial removal or biopsy. Gross total resection was associated with good prognosis, and AA with radiologic necrosis had poor prognosis like glioblastoma.

Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma

Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan-Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis.

Tumour-infiltrating T-cell subpopulations in glioblastomas

This study was designed to determine the incidence and prognostic value of various populations of tumour-infiltrating T cells in glioblastomas. We also evaluated the difference in T-cell populations after conventional treatment. Sixty-seven patients with glioblastomas underwent surgery between 2003 and April 2009. Immunohistochemical staining was performed for CD3, CD4, CD8 and FoxP3, and the average number and percentage of positive cells were calculated. In eight patients, the average number of subpopulations was compared between the specimens obtained during the first and second operations. Age, gender, Karnofsky performance status, Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) classes, extent of removal, treatment modality, O-6-methylguanine-DNA methyltransferase (MGMT) methylation status and immunopositivity for CD4, CD8 and FoxP3 were analyzed as prognostic factors. There was an average of 12.8 ± 1.8 CD31 T cells, 1.5 ± 0.5 CD41 T cells, 6.8 ± 1.3 CD81 T cells and 0.6 ± 0.2 FoxP3 cells. The percentage of positive T-cell subpopulations was 89.6%, 22.4%, 77.6% and 34.3% for CD3, CD4, CD8 and FoxP3, respectively. In eight patients, there was no difference in the subpopulations between the first and second operations. The median progression-free survival was 7.0 months (95% CI, 5.2–8.9 months) and the overall survival was 14.8 months (95% CI, 11–18.7 months). Univariate analysis showed a statistically significant difference in progression-free survival for CD8 (p = 0.02) and overall survival for RTOG-RPA classes (p = 0.003), the extent of removal (p = 0.01) and MGMT promoter methylation status (p = 0.005). Based on multivariate analysis, RTOG-RPA classes were significantly associated with longer overall survival. The intratumoural immune response occurred frequently in glioblastomas and there was a consistent response, even after conventional treatment. There was a statistically significant difference in progression-free survival for CD81 T cells in immunologically privileged central nervous system.

Treatment outcomes for patients with glioblastoma multiforme and a low Karnofsky Performance Scale score on presentation to a tertiary care institution

The object of this study was to determine the benefit of surgery, radiation, and chemotherapy for patients with glioblastoma multiforme (GBM) and a low Karnofsky Performance Scale (KPS) score. The authors retrospectively evaluated the records of patients who underwent primary treatment for pathologically confirmed GBM and with a KPS score ≤ 50 on initial evaluation for radiation therapy at a tertiary care institution between 1977 and 2006. Seventy-four patients with a median age of 69 years (range 19-88 years) and a median KPS score of 50 (range 20-50) were retrospectively grouped into the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Classes IV (11 patients), V (15 patients), and VI (48 patients). Patients underwent biopsy (38 patients) or tumor resection (36 patients). Forty-seven patients received radiation. Nineteen patients also received chemotherapy (53% temozolomide), initiated concurrently (47%) or after radiotherapy. The median survival overall was 2.3 months (range 0.2-48 months). Median survival stratified by RPA Classes IV, V, and VI was 6.6, 6.6, and 1.8 months, respectively (p < 0.001, log-rank test). Median survival for patients receiving radiation (5.2 months) was greater than that for patients who declined radiation (1.6 months, p < 0.001). Patients in RPA Class VI appeared to benefit from radiotherapy only when tumor resection was also performed. The median survival from treatment initiation was greater for patients receiving chemotherapy concomitantly with radiotherapy (9.8 months) as compared with radiotherapy alone (1.7 months, p = 0.002). Of 20 patients seen for follow-up in the clinic at a median of 48 days (range 24-196 days) following radiotherapy, 70% were noted to have an improvement in the KPS score of between 10 and 30 points from the baseline score. On multivariate analysis, only RPA class (p = 0.01), resection (HR = 0.37, p = 0.001), and radiation therapy (HR = 0.39, p = 0.02) were significant predictors of a decreased mortality rate. Patients with a KPS score ≤ 50 appear to have increased survival and functional status following tumor resection and radiation. The extent of benefit from concomitant chemotherapy is unclear. Future studies may benefit from reporting that utilizes a prognostic classification system such as the RTOG RPA class, which has been shown to be effective at separating outcomes even in patients with low performance status. Patients with GBMs and low KPS scores need to be evaluated in prospective studies to identify the extent to which different therapies improve outcomes.

Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of Radiation Therapy Oncology Group-Recursive Partitioning Analysis in the IMRT and temozolomide era

Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ (n = 154) or adjuvant TMZ only (n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other (P < 0.01, χ2 statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set.

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.

Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma

The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class. The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40-negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Malignant Supratentorial Astrocytoma Treated with Postoperative Radiation Therapy: Prognostic Value of Pretreatment Quantitative Diffusion-weighted MR Imaging

To retrospectively evaluate whether the minimum apparent diffusion coefficient (ADC) of the tumor seen on pretreatment magnetic resonance (MR) images is of prognostic value in patients with malignant supratentorial astrocytoma. The study was approved by the institutional review board; the requirement for informed patient consent was waived. Between June 1996 and November 2003, 79 patients (44 male, 35 female; age range, 16-76 years) with malignant supratentorial astrocytoma underwent pretreatment MR imaging. Patient age, symptom duration, neurologic function, mental status, Karnofsky performance scale (KPS) score, extent of surgery, histopathologic diagnosis, tumor component enhancement, and minimum ADC were assessed at factor analysis of survival. Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) criteria were used to validate the prognostic value of the minimum ADC. Kaplan-Meier survival curves, the log-rank test, and the multivariate Cox proportional hazards model were used to evaluate the prognostic factors. Twenty-nine patients had anaplastic astrocytoma, and 50 had glioblastoma multiforme. The minimum ADC was significantly lower in patients with glioblastoma multiforme than in those with anaplastic astrocytoma (P < .001). The two-year survival rates associated with low (<or=1.0 x 10(-3) mm(2)/sec) and high (>1.0 x 10(-3) mm(2)/sec) minimum ADCs were 14% (six of 42 patients) and 84% (31 of 37 patients), respectively (P < .001). The minimum ADC was the most important prognostic factor (hazard ratio = 10.459; 95% confidence interval: 5.113, 21.396) and could be used to assign patients to different prognostic groups in each RTOG-RPA class. The minimum ADC at pretreatment MR imaging is a useful clinical prognostic biomarker for survival in patients with malignant supratentorial astrocytoma.

Validation of the RTOG recursive partitioning analysis (RPA) classification for small-cell lung cancer–only brain metastases

The Radiation Therapy Oncology Group (RTOG) developed a prognostic classification based on a recursive partitioning analysis (RPA) of patient pretreatment characteristics from three completed brain metastases randomized trials. Clinical trials for patients with brain metastases generally exclude small-cell lung cancer (SCLC) cases. We hypothesize that the RPA classes are valid in the setting of SCLC brain metastases. A retrospective review of 154 SCLC patients with brain metastases treated between April 1983 and May 2005 was performed. RPA criteria used for class assignment were Karnofsky performance status (KPS), primary tumor status (PT), presence of extracranial metastases (ED), and age. Median survival was 4.9 months, with 4 patients (2.6%) alive at analysis. Median follow-up was 4.7 months (range, 0.3-40.3 months). Median age was 65 (range, 42-85 years). Median KPS was 70 (range, 40-100). Number of patients with controlled PT and no ED was 20 (13%) and with ED, 27 (18%); without controlled PT and ED, 34 (22%) and with ED, 73 (47%). RPA class distribution was: Class I: 8 (5%); Class II: 96 (62%); Class III: 51 (33%). Median survivals (in months) by RPA class were: Class I: 8.6; Class II: 4.2; Class III: 2.3 (p = 0.0023). Survivals for SCLC-only brain metastases replicate the results from the RTOG RPA classification. These classes are therefore valid for brain metastases from SCLC, support the inclusion of SCLC patients in future brain metastases trials, and may also serve as a basis for historical comparisons.

Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404

Purpose This study was an open-label, randomized Phase III trial in newly diagnosed patients with anaplastic glioma other than glioblastoma multiforme comparing external beam radiotherapy (EBRT) plus adjuvant procarbazine, cyclohexylchloroethylnitrosurea (lomustine), and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-h infusion each week of RT. Methods and materials Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible. A central pathology review was accomplished for most patients, but was not mandated before registration. The study had initially opened as a Northern California Oncology Group trial in 1991, becoming an Intergroup Radiation Therapy Oncology Group (RTOG), Southwestern Oncology Group and the North Central Cancer Treatment Group study in July 1994. A total accrual of 293 patients was planned for the sample size, using survival as the primary end point. The experimental arm (RT/BUdR + PCV) was to be compared with the control arm (RT + PCV) using a one-sided α = 0.05, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after enrollment completion. Results Between July 1994 and August 1996, 134 patients were randomized to EBRT + PCV (non-BUdR patients) and 134 to EBRT/BUdR + PCV (BUdR patients). The study was closed before the full-anticipated accrual on the basis of an interim analysis that predicted no survival benefit for the BUdR arm. Of the 268 patients, 41 and 37, respectively, were ineligible or canceled primarily on the basis of the central pathology review findings. Thus, 93 patients and 97 patients were eligible/analyzable in the non-BUdR and BUdR arms, respectively. Patient characteristics were well balanced in both arms, with most <50 years old and in the RTOG recursive partitioning analysis (RPA) Class I category. The minimal potential follow-up was 4.6 years. The median survival for non-BUdR patients was 4.1 years compared with 4.6 years for the BUdR patients ( p = 0.61). The 4-year overall survival rate was 51% in both arms. For RPA Class I patients (the best prognostic class), the median survival had not been reached for non-BUdR patients (4-year survival rate 61%) and was 5.6 years for BUdR patients (4-year survival rate 64%; p = 0.91). Each arm was also compared with the RTOG historical database for RPA Class I patients with no statistically significant difference found in overall survival (BUdR vs. historical, p = 0.31 and non-BUdR vs. historical, p = 0.48). Grade 4 toxicity occurred in 15 and 17 patients in the non-BUdR and BUdR arms, respectively, with one treatment-related death in the BUdR group. Conclusion No survival advantage was noted by adding BUdR to EBRT and PCV in this patient population

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.

Long-term survival in patients with brain metastases.

The aims of this study are: (a) to determine long-term survival in patients with brain metastases who underwent whole brain radiation therapy; (b) to evaluate whether long-term survival can be predicted by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA); and (c) to review the literature on long-term survival. The records of 916 patients with brain metastases who underwent whole brain radiation therapy at our hospital from 1985 to 2000 were analyzed retrospectively. By July 2001, 891 patients had died. Median survival of the whole group was 3.4 months. Overall survival was 5.6% at 2 years (at risk: n=48), 2.9% at 3 years ( n=25), 1.8% at 5 years ( n=12), and <1% at 10 years ( n=1). Survival for 2 years or more was observed in RTOG RPA class 1, but also in class 2 patients. Within both classes, survival was significantly better for patients with a single brain metastasis compared with those patients having multiple metastases. A survey of the literature revealed that in rare instances survival of 10 years or more was seen in patients with brain metastases. The majority of these patients had a single brain metastasis treated by radical resection and whole brain radiation therapy. Even in patients with favorable characteristics, survival for 2 years or more after the diagnosis of brain metastases is considerably low. Aggressive therapy in RPA class 1 and class 2 patients with a single brain metastasis occasionally permits long-term survival.

Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma: a retrospective study.

In a population of patients with brain metastases from melanoma, the authors sought to determine whether various therapies provided any benefit at all, whether local therapy was better than whole brain radiotherapy (WBRT), and whether combined local therapy and WBRT provided any advantage over local therapy alone. They also analyzed survival according to a Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) to determine how well the RTOG RPA classes predicted survival in this patient population and whether treatments varied in effectiveness from category to category. A total of 74 patients with brain metastases from melanoma were treated at The Cleveland Clinic Foundation between 1984 and 1998. For this study, the authors reviewed patient charts and confirmed survival status. Survival was compared by treatment modality (surgical resection, WBRT, stereotactic radiosurgery, or WBRT combined with local therapy). Survival also was compared according to the RTOG RPA prognostic classes (Class 1, Class 2, or Class 3), which has not been validated previously in patients with malignant melanoma. The median survival was 5.5 months for all patients. Survival varied significantly by RTOG prognostic class; The median survival was 10.5 months (range, 2.2-99.2 months) for patients in Class 1, 5.9 months (range, 0.2-43.9 months) for patients in Class 2, and 1.8 months (range, 0.1-6.9 months) for patients in Class 3 (P < 0.0001). Survival analysis showed that combined treatment offered significantly better survival (P < 0.0001; combined vs. other). The median survival was 8.8 months (range, 1.8-99.2 months) for the combined therapy group, 4.8 months (range, 1.2-27.8 months) for the local therapy alone group, 2.3 months (range, 0.2-9.6 months) for the WBRT alone group, and 1.1 months (0.1-3.0 months) for the group that received no therapy. Adding WBRT to local therapy may improve survival in this group of patients: Combined therapy was superior to WBRT alone. The RPA classification scheme likely has prognostic value for patients with brain metastases from malignant melanoma. Prospective studies are required to overcome selection bias and confirm these results.

Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases

Purpose: The Radiation Therapy Oncology Group (RTOG) previously developed three prognostic classes for brain metastases using recursive partitioning analysis (RPA) of a large database. These classes were based on Karnofsky performance status (KPS), primary tumor status, presence of extracranial system metastases, and age. An analysis of RTOG 91-04, a randomized study comparing two dose-fractionation schemes with a comparison to the established RTOG database, was considered important to validate the RPA classes. Methods and Materials: A total of 445 patients were randomized on RTOG 91-04, a Phase III study of accelerated hyperfractionation versus accelerated fractionation. No difference was observed between the two treatment arms with respect to survival. Four hundred thirty-two patients were included in this analysis. The majority of the patients were under age 65, had KPS 70–80, primary tumor controlled, and brain-only metastases. The initial RPA had three classes, but only patients in RPA Classes I and II were eligible for RTOG 91-04. Results: For RPA Class I, the median survival time was 6.2 months and 7.1 months for 91-04 and the database, respectively. The 1-year survival was 29% for 91-04 versus 32% for the database. There was no significant difference in the two survival distributions ( p = 0.72). For RPA Class II, the median survival time was 3.8 months for 91-04 versus 4.2 months for the database. The 1-year survival was 12% and 16% for 91-04 and the database, respectively ( p = 0.22). Conclusion: This analysis indicates that the RPA classes are valid and reliable for historical comparisons. Both the RTOG and other clinical trial organizers should currently utilize this RPA classification as a stratification factor for clinical trials.