Radiation Therapy Oncology Group Recursive Research Articles

Risk stratification of pediatric high-grade glioma: a newly proposed prognostic score.

High-grade glioma (HGG) is a clinical challenge. Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG-RPA) for HGG remains the standard for assessing the prognosis of adult HGG. This study assesses the validity of the RTOG-RPA to be applied to pediatric HGG. A retrospective study was conducted on 59 pediatric HGG treated in the Children's Cancer Hospital, Egypt (CCHE) between 2007 and 2016. Several factors were studied as predictors for the disease survival, including age, gender, increased intracranial hypertension, tumor characteristics and pathology, CSF seeding, performance status, post-surgical residual, and radiation dose. The statistically significant results were integrated into a Cox-regression model to develop a prognostic risk score. Kaplan-Meier statistics identified 13 factors that impacted the overall survival. However, Cox model showed that the histological grade IV [HR 14.2, 95%CI; (3.5-57), P < 0.0001], thalamic infiltration [HR 8.7; 95%CI; (2.9-25.9), P < 0.0001], PS ≥ 60 [HR 0.317; 95%CI; (0.13-0.776); P = 0.012], and maximum tumor dimension > 3.3cm [HR 10.2; 95%CI; (1.58-65.89); P = 0.015] were the independent variables that predicted the overall survival. A risk score was proposed based on the presence of one or more of these factors. The median OS for the low risk (score 0-1), the intermediate-low risk (score 2), the intermediate-high risk (score 3), and the high risk (score 4) were 40, 18.5, 9.5, and 2.5months, respectively, (P < 0.0001). The proposed model and risk score could stratify pediatric patients as the RTOG-RPA do for the adults.

Risk factors for synchronous brain metastases: A National Cancer Database analysis.

e13591 Background: Brain metastases (BM) are a significant source of disability and mortality in cancer patients. Investigations on the risk factors for their development are limited. We provide risk factors assessment using the largest cancer database. Methods: We analyzed the National Cancer Database from 2010-2014, for risk factors and survival outcomes in all patients with BM. Results: 4,650,963 tumor records were analyzed of which 88,274 were BM. Lung cancer accounted for 82.2%, breast cancer for 4.2%, melanoma for 3.5%, and urinary system tumors for 3.1% of cases. The majority of patients were males (51.6%), and whites (84.2%) with a median age of 65 years. A high index of comorbidities [Charlson-Deyo score (CDS) ≥3] was reported in 3.5% of patients. Lung primaries had the highest risk of BM (OR of 17.867), followed by melanoma (OR 1.946). Patients diagnosed at 70 years or older were less likely to present with BM, while patients diagnosed between 40 and 60 years were at increased risk. Other and unknown race were associated with an increased risk of BM compared to whites. Patients with a CDS of one or two had a decreased risk of presenting with BM compared to patients with scores greater or equal to three. Median overall survival was 5 months, with a 5-year survival rate of 5.2%. There was a decreasing risk of mortality, and increasing risk of receiving surgery, radiation, or chemotherapy per advancing year of diagnosis. Older age, white race, Hispanic origin, and higher CDS were risk factors for mortality. Conclusions: Higher number of comorbidities, younger age at diagnosis, and other races were associated with an higher risk of synchronous BM. The risk of mortality is decreasing, with a higher risk of receiving radiation, surgery, and/or chemotherapy. Median overall survival has increased in comparison to the Radiation Therapy Oncology Group Recursive Partitioning Analysis RPA studies (4.4 months).

Prognostic Value of Metabolic Tumor Volume on (11)C-Methionine PET in Predicting Progression-Free Survival in High-Grade Glioma.

C-11 methionine (MET) PET is commonly used for diagnosing high-grade glioma (HGG). Recently, volumetric analysis has been widely applied to oncologic PET imaging. In this study, we investigated the prognostic value of metabolic tumor volume (MTV) on MET PET in HGG. A total of 30 patients with anaplastic astrocytoma (n = 12) and glioblastoma multiforme (n = 18) who underwent MET PET before treatment (surgery followed by chemo-radiotherapy) were retrospectively enrolled. Maximal tumor-to-normal brain ratio (TNRmax, maximum tumor activity divided by mean of normal tissue) and MTV (volume of tumor tissue that shows uptake >1.3-fold of mean uptake in normal tissue) were measured on MET PET. Adult patients were classified into two subgroups according to Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) classification. Prognostic values of TNRmax, MTV and clinicopathologic factors were evaluated with regard to progression-free survival (PFS). Median PFS of all patients was 7.9months (range 1.0-53.8months). In univariate analysis, MTV (cutoff 35cm(3)) was a significant prognostic factor for PFS (P = 0.01), whereas TNRmax (cutoff 3.3) and RTOG RPA class were not (P = 0.80 and 0.61, respectively). Treatment of surgical resection exhibited a borderline significance (P = 0.06). In multivariate analysis, MTV was the only independent prognostic factor for PFS (P = 0.03). MTV on MET PET is a significant and independent prognostic factor for PFS in HGG patients, whereas TNRmax is not. Thus, performing volumetric analysis of MET PET is recommended in HGG for better prognostication.

The shifting landscape of metastatic breast cancer to the CNS

The improved survival following the diagnosis of breast cancer has potentially altered the characteristics and course of patients presenting with CNS involvement. We therefore sought to define our current cohort of breast cancer patients with metastatic disease to the CNS in regard to modern biomarkers and clinical outcome. Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases. There were 88 women analyzed who were treated over the period of January 2003 to February 2010, average age 56.9years. At the time of initial presentation of CNS disease, 68% of patients had multiple brain metastases, 17% had a solitary metastasis, and 15% had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0months, and 9.7months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor-positive pathology (57.6 v. 38.2months, p = .02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p = .004, HR = 3.1, Cox regression) and triple-negative hormonal/HER2 status (p = .02, HR = 2.3, Cox regression). Patients with either had a median survival of 3.1months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26%) subsequently developed LMD in the course of their disease (median 10.4months), following which survival was grim (1.8months median). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33). The recently described Graded Prognostic Assessment (GPA) tumor index stratified median survival at 2.5, 5.9, 13.1, and 21.7months, respectively, for indices of 1-4 (p = .004, log-rank), which contrasted with the nonsignificant survival difference between Radiation Therapy Oncology Group Recursive Partitioning Analysis classes one and two. (13.1 v. 13.2, p = .8, log-rank). Treatment of patients with metastatic brain disease from breast cancer should be tailored to the patient's hormonal status and GPA index. Practitioners must be vigilant for the development of LMD, especially as it often presents with nondescript complaints such as back pain.

Population-based outcomes after whole brain radiotherapy and re-irradiation in patients with metastatic breast cancer in the trastuzumab era

PurposeThis study examined the population-based use and outcomes of brain radiotherapy (BRT) for brain metastases (BM) from breast cancer with a focus on repeat BRT in the trastuzumab era.Methods and materialsAll women with breast cancer diagnosed from 2000-2007 and treated with BRT were retrospectively identified from a provincial database.ResultsA total of 441 women with BM from breast cancer were identified. The median age was 55 years and 40% (176/441) had human epidermal growth factor receptor 2 (HER2) positive disease. The median survival (MS) from the initial BRT for all 441 women was 4.5 months. The MS by Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) class was: 1 (14.5 months), 2 (6.4 months) and 3 (1.8 months). For the 37 cases receiving repeat BRT, 27% (10/37) had stereotactic radiosurgery (SRS) and 70% (26/37) had HER2 positive disease, of which, 81% (21/26) received trastuzumab in the metastatic setting. For repeat BRT, the median survival by RPA class was: 1 (9.8 months), 2 (7.4 months) and 3 (2.0 months). For RPA class 1 and 2, the one-year overall survival (OS) was 45%.ConclusionThe proportion of cases with HER2 positive disease was increased at repeat BRT compared to initial BRT. RPA class 1 and 2 patients should be considered for repeat BRT.

Validation and Simplification of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification for Glioblastoma

Previous recursive partitioning analysis (RPA) of patients with malignant glioma (glioblastoma multiforme [GBM] and anaplastic astrocytoma [AA]) produced six prognostic groups (I-VI) classified by six factors. We sought here to determine whether the classification for GBM could be improved by using an updated Radiation Therapy Oncology Group (RTOG) GBM database excluding AA and by considering additional baseline variables. The new analysis considered 42 baseline variables and 1,672 GBM patients from the expanded RTOG glioma database. Patients receiving radiation only were excluded such that all patients received radiation+carmustine. "Radiation dose received" was replaced with "radiation dose assigned." The new RPA models were compared with the original model by applying them to a test dataset comprising 488 patients from six other RTOG trials. Fitness of the original and new models was evaluated using explained variation. The original RPA model explained more variations in survival in the test dataset than did the new models (20% vs. 15%) and was therefore chosen for further analysis. It was reduced by combining Classes V and VI to produce three prognostic classes (Classes III, IV, and V+VI), as Classes V and VI had indistinguishable survival in the test dataset. The simplified model did not further improve performance (explained variation 18% vs. 20%) but is easier to apply because it involves only four variables: age, performance status, extent of resection, and neurologic function. Applying this simplified model to the updated GBM database resulted in three distinct classes with median survival times of 17.1, 11.2, and 7.5 months for Classes III, IV, and V+VI, respectively. The final model, the simplified original RPA model combining Classes V and VI, resulted in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. This classification will be used in future RTOG GBM trials.

Supratentorial Glioblastoma Treated with Radiotherapy: Use of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Grouping for Predicting Survival

This study aimed to evaluate the usefulness of recursive partitioning analysis model established by the Radiation Therapy Oncology Group for predicting the survival of patients with supratentorial glioblastoma treated with radiotherapy and to determine prognostic factors for the subgroups of this prognostic model. A total of 108 glioblastoma patients treated with radiotherapy between January 1987 and December 2005 were retrospectively reviewed. Recursive partitioning analysis classes III, IV, V and VI included 8, 29, 32 and 39 patients, respectively. These classes were divided into two subgroups: a good prognostic group containing classes III-IV and a poor prognostic group containing classes V-VI. The median radiation dose was 60 Gy. Seventy-five patients received chemotherapy and/or immunotherapy. The overall survival differed significantly among classes III, IV, V and VI, with median survival times of 34, 15, 11 and 7 months, respectively. Among the good prognostic group, patients with basal ganglia invasion showed poorer survival outcomes than patients without basal ganglia invasion. Among the poor prognostic group, patients with tumor sizes of <5 cm and patients treated with nimustine hydrochloride showed better survival outcomes than those with tumor sizes of > or =5 cm and those without treatment with nimustine hydrochloride, respectively. This study confirms the prognostic value of the recursive partitioning analysis grouping. Basal ganglia invasion could be a useful predictive factor for survival in the good prognostic group, whereas tumor size and treatment with nimustine hydrochloride could be useful predictive factors in the poor prognostic group.

Prospective evaluation of the palliative effect of whole-brain radiotherapy in patients with brain metastases and poor performance status

Background/Purpose. The benefit of whole brain radiotherapy (WBRT) for RTOG RPA (Radiation Therapy Oncology Group Recursive Partitioning Analysis) class 3 patients with brain metastases is not well established. The aim of this study was to determine whether WBRT has any benefit in terms of symptoms palliation in such patients. Evaluation of patients’ preferences for WBRT, changes in performance and neurological status were secondary aims. Methods. Ninety-one RTOG RPA class 3 patients were included. All patients received WBRT (20 Gy in 5 fractions) and were asked to complete a questionnaire about their symptoms before and one month after WBRT. The patient's symptom checklist comprised 17 items scored from 0 to 3; a higher score meant a greater symptom intensity. The mean scores at baseline and after treatment were compared. Karnofsky performance status (KPS) and neurological status before and one month after WBRT were also recorded. Patients were asked to express their preference as to the WBRT undergone. Results. Forty-three (47%) patients completed both symptom checklists. The mean scores on the symptom checklist were 18.21 and 21.09 at baseline and one month after WBRT, respectively (p = 0.02). The KPS was estimated after WBRT in 42 patients: 57% of patients improved, 26% worsened, and 17% did not change from the baseline KPS score (p = 0.06). Neurological status did not change from baseline to one month after WBRT (p = 0.44). Only 7% of respondents would not have consented to the WBRT undergone. Conclusion. Our results challenge the palliative value of the WBRT in RPA class 3 patients.

Gender, Race, and Survival: A Study in Non–Small-Cell Lung Cancer Brain Metastases Patients Utilizing the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification

To explore whether gender and race influence survival in non-small-cell lung cancer (NSCLC) in patients with brain metastases, using our large single-institution brain tumor database and the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) brain metastases classification. A retrospective review of a single-institution brain metastasis database for the interval January 1982 to September 2004 yielded 835 NSCLC patients with brain metastases for analysis. Patient subsets based on combinations of gender, race, and RPA class were then analyzed for survival differences. Median follow-up was 5.4 months (range, 0-122.9 months). There were 485 male patients (M) (58.4%) and 346 female patients (F) (41.6%). Of the 828 evaluable patients (99%), 143 (17%) were black/African American (B) and 685 (83%) were white/Caucasian (W). Median survival time (MST) from time of brain metastasis diagnosis for all patients was 5.8 months. Median survival time by gender (F vs. M) and race (W vs. B) was 6.3 months vs. 5.5 months (p = 0.013) and 6.0 months vs. 5.2 months (p = 0.08), respectively. For patients stratified by RPA class, gender, and race, MST significantly favored BFs over BMs in Class II: 11.2 months vs. 4.6 months (p = 0.021). On multivariable analysis, significant variables were gender (p = 0.041, relative risk [RR] 0.83) and RPA class (p < 0.0001, RR 0.28 for I vs. III; p < 0.0001, RR 0.51 for II vs. III) but not race. Gender significantly influences NSCLC brain metastasis survival. Race trended to significance in overall survival but was not significant on multivariable analysis. Multivariable analysis identified gender and RPA classification as significant variables with respect to survival.

Clinical analysis of novalis stereotactic radiosurgery for brain metastases.

The authors analyzed the effectiveness and therapeutic response of Novalis shaped beam radiosurgery for metastatic brain tumors, and the prognostic factors which influenced the outcome. We performed a retrospective analysis of 106 patients who underwent 159 treatments for 640 metastatic brain lesions between January 2000 and April 2008. The pathologies of the primary tumor were mainly lung (45.3%), breast (18.2%) and GI tract (13.2%). We classified the patients using Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) and then analyzed the survival and prognostic factors according to the Kaplan Meier method and univariate analysis. The overall median actuarial survival rate was 7.3 months from the time of first radiosurgery treatment while 1 and 2 year actuarial survival estimates were 31% and 14.4%, respectively. Median actuarial survival rates for RPA classes I, II, and III were 31.3 months, 7.5 months and 1.7 months, respectively. Patients' life spans, higher Karnofsky performance scores and age correlated closely with RPA classes. However, sex and the number of lesions were not found to be significantly associated with length of survival. This result suggests that Novalis radiosurgery can be a good treatment option for treatment of the patients with brain metastases.

Evaluation of Different Score Index for Predicting Prognosis in Gamma Knife Radiosurgical Treatment for Brain Metastasis

To assess the utility of the Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) and Score Index for Radiosurgery (SIR) stratification systems in predicting survival in patients with brain metastasis treated with Gamma Knife radiosurgery (GKRS). A total of 185 patients were included in the study. Patients were stratified according to RPA and SIR classes. The RPA and SIR classes, age, Karnofsky Performance Status (KPS), and systemic disease were correlated with survival. Five patients were lost to follow-up. Median survival in patients in RPA Class 1 (30 patients) was 17 months; in Class 2 (140 patients), 10 months; and in Class 3 (10 patients), 3 months. Median survival in patients in SIR Class 1 (30 patients) was 3 months; in Class 2 (135 patients), 8 months; and in Class 3 (15 patients), 20 months. In univariate testing, age younger than 65 years (p = 0.0004), KPS higher than 70 (p = 0.0001), RPA class (p = 0.0078), SIR class (p = 0.0002), and control of the primary tumor (p = 0.02) were significantly associated with improved outcome. In multivariate analysis, KPS (p < 0.0001), SIR class (p = 0.0008), and RPA class (p = 0.03) had statistical value. This study supports the use of GKRS as a single-treatment modality in this selected group of patients. Stratification systems are useful in the estimation of patient eligibility for GKRS. A second-line treatment was necessary in 30% of patients to achieve distal or local brain control. This strategy is useful to control brain metastasis in long-surviving patients.

LINEAR ACCELERATOR STEREOTACTIC RADIOSURGERY FOR METASTATIC BRAIN TUMORS

To review one of the largest single-institution experiences treating metastatic brain disease with stereotactic radiosurgery. We performed a retrospective analysis of 619 patients who underwent linear accelerator-based stereotactic radiosurgery for 1569 brain metastases between May 1989 and February 2006. Patient characteristics and treatment parameters were obtained prospectively. Patients were followed up at regular intervals clinically and with imaging studies to document local control, regional control, and survival. Cox proportional hazards analysis was performed using SAS version 9.1 software (SAS Institute, Cary, NC). Median actuarial survival was 7.9 months. 1- and 2-year actuarial survival probabilities were 0.36 and 0.14, respectively. Radiation Therapy Oncology Group Recursive Partitioning Analysis Class I or II was associated with improved survival, but the difference between the two was insignificant. Female sex, younger age, higher Karnofsky performance status, controlled primary tumor, absence of systemic metastases, asynchronous presentation of brain metastasis, fewer brain metastases, smaller total volume of brain metastases, surgery prior to radiosurgery, and multiple radiosurgical treatments were also associated with improved survival. Melanoma metastasis was associated with impaired survival. Local control was achieved in 84.3% of all lesions treated. 1- and 2-year actuarial local control probabilities were 0.82 and 0.72, respectively. Whole brain radiation therapy prior to radiosurgery was associated with improved regional control. Linear accelerator-based stereotactic radiosurgery is a safe and effective treatment for patients with metastatic brain tumors. Selection of patients who are likely to benefit most from radiosurgery is complex and treatment decisions should be based on the entire clinical picture.

Brain Metastases From Breast Carcinoma: Validation of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification and Proposition of a New Prognostic Score

To validate the Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) classification and determine independent prognostic factors, to create a simple and specific prognostic score for patients with brain metastases (BM) from breast carcinoma treated with whole-brain radiotherapy (WBRT). From January 1998 through December 2003, 132 patients with BM from breast carcinoma were treated with WBRT. We analyzed several potential predictors of survival after WBRT: age, Karnofsky performance status, RTOG-RPA class, number of BM, presence and site of other systemic metastases, interval between primary tumor and BM, tumor hormone receptor (HR) status, lymphocyte count, and HER-2 overexpression. A total of 117 patients received exclusive WBRT and were analyzed. Median survival with BM was 5 months. One-year and 2-year survival rates were 27.6% (95% confidence interval [CI] 19.9-36.8%) and 12% (95% CI 6.5-21.2%), respectively. In multivariate analysis, RTOG RPA Class III, lymphopenia (< or =0.7 x 10(9)/L) and HR negative status were independent prognostic factors for poor survival. We constructed a three-factor prognostic scoring system that predicts 6-month and 1-year rates of overall survival in the range of 76.1-29.5% (p = 0.00033) and 60.9-15.9% (p = 0.0011), respectively, with median survival of 15 months, 5 months, or 3 months for patients with none, one, or more than one adverse prognostic factor(s), respectively. This study confirms the prognostic value of the RTOG RPA classification, lymphopenia, and tumor HR status, which can be used to form a prognostic score for patients with BM from breast carcinoma.

Combined Razoxane and Radiotherapy for Melanoma Brain Metastases. A Retrospective Analysis

We retrospectively compared the efficacy of razoxane and radiotherapy with radiotherapy alone or in combination with a non-razoxane based medication in patients with melanoma brain metastases. From 19 assessable patients receiving whole brain irradiation with or without a boost (mean total dose 40.5 Gy) for measurable brain metastases, 8 patients underwent an additional razoxane therapy with 125 mg per os twice daily started 5 days before radiotherapy and given throughout the whole radiation period. The median razoxane dose was 6.25 g (range 3.2-8.0 g). Endpoints included radiation response rates, median survival time and 1-year survival rates. To generate reliable prognostic parameters for this non-randomized study population, the Score Index for Stereotactic Radiosurgery and the Radiation Therapy Oncology Group Recursive Partitioning Analysis score were applied. Radiotherapy with razoxane led to higher response rates (62% vs. 27%) and a lower percentage of progressive disease (12.5% vs. 36%) if compared with radiotherapy alone or with a non-razoxane based medication. This combination was associated with a longer median survival (5 months vs. 2.2 months; P=0.052) and a 1-year survival rate of 37.5% vs. 0% (P=0.027). Both treatment groups belonged to similar prognosis subsets. The treatment was well tolerated. Taken together our data support the therapeutic concept of a combined razoxane radiation therapy in melanoma patients with brain metastases. The favorable treatment effects are probably due to the radiosensitizing and the cytorallentaric mode of action of razoxane. Since the patient numbers are low, confirmatory studies are certainly necessary.

Radiosurgery for brain metastases at the Royal Adelaide Hospital: are we treating the right patients?

Although non-randomized data strongly suggest improved outcome from radiosurgery (RS) for brain metastases relative to whole brain radiotherapy (WBRT) alone, selection factors account for much of the observed differences. This retrospective review of the 16 brain metastases patients treated so far with RS at the Royal Adelaide Hospital confirms a median survival of 10.1 months, consistent with recent multi-institutional pooled results and significantly longer than the median survival of 3-6 months typically reported for WBRT alone. The emerging randomized trials comparing surgery, RS and WBRT for brain metastases are reviewed in the context of the Radiation Therapy Oncology Group Recursive Partitioning Analysis prognostic Class concept in order to assess whether we are using this resource intensive technique to treat the 'right' patients. We conclude that it is reasonable to continue our current policy of considering RS primarily for patients of good performance status with solitary brain metastases. We have a flexible approach to adjuvant WBRT which appears to decrease brain relapse, but not improve survival.