Recursive Partitioning Analysis Class Research Articles

Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma

ObjectivesRandomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response. Materials and methodsCases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups. ResultsWe identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings. ConclusionWhen treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.

Brain metastases in breast cancer: analysis of the role of HER2 status and treatment in the outcome of 94 patients.

We investigated the impact of human epidermal growth factor receptor 2 (HER2) and prognostic factors in the outcome of patients with breast cancer that developed brain metastases. . The data from 94 patients who received multidisciplinary therapy from 2001 to 2007 were retrospectively reviewed. Patients were assigned according to their HER2 status, and overall survival and time to brain metastases recurrence/progression were evaluated. The prognostic value of age, presence of extracerebral metastases, recursive partitioning analysis class, hormone therapy, systemic therapy and trastuzumab was assessed. The median overall survival and time to brain disease progression were 7.1 and 6.5 months, respectively. HER2 positivity (P = 0.006), treatment with trastuzumab (P = 0.025), chemotherapy (P = 0.011) and recursive partitioning analysis class I-II (P <0.001) were associated with prolonged survival on univariate analysis. On multivariate analysis, only recursive partitioning analysis class I-II (P <0.001) and triple-negative disease (P = 0.04) remained significant for overall survival, whereas time to brain metastases progression was only associated with recursive partitioning analysis class I-II (P = 0.001). The time from the diagnosis of primary disease to brain metastasis was slightly shorter in the HER2+ patients than in HER2- patients (36 vs 39 months). Intensified local treatment of brain metastasis incorporating whole-brain radiotherapy and/or radiosurgery and neurosurgery did not affect survival. Patients with triple-negative disease presented a significantly lower survival than the rest of the cohort (4 vs 8 months; P = 0.012). Recursive partitioning analysis class I-II was found to be the strongest independent predictive factor. Treatment with trastuzumab in HER2+ patients appeared to improve overall survival, probably due to the better control of systemic metastatic disease, but did not maintain significance in multivariate analysis. The dismal prognosis of patients with triple-negative breast cancer highlights the need to develop novel therapies to improve the poor survival.

Survival Analysis of Glioblastoma Multiforme

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

Stereotactic Radiosurgery in the Multimodality Management of Residual or Recurrent Glioblastoma Multiforme.

Management options for residual or recurrent glioblastoma multiforme (GBM) are limited despite advances in surgical, chemotherapeutic, and radiotherapeutic techniques. Stereotactic radiosurgery (SRS) is often beneficial in such cases providing improved survival of patients, but still remains underutilized as part of the multimodality management of malignant gliomas. During the last 20 years, 297 patients with histologically proven residual or recurrent GBM underwent Gamma Knife surgery in the University of Pittsburgh. Retrospective analysis of outcomes revealed median survival after initial diagnosis of 18 months, and 1- and 2-year survival rates of 72.5 and 29.5%, respectively. Median survival from the time of SRS was 9 months. The use of modified RPA (recursive partitioning analysis) classification demonstrated superior survival in our series in comparison with historical data. Important prognostic variables include tumor volume <14 cm3, marginal radiation dose of ≥15 Gy, and younger age of the patients (<60 years). Adverse radiation effects (ARE) were noted in 23% of cases and were mainly controlled with corticosteroids. Combining SRS with bevacizumab resulted in further improvement of the overall and progression-free survival and decreased incidence of ARE. Nevertheless, for future application of SRS in patients with GBM, evaluation of its efficacy in a well-designed prospective controlled clinical trials seems mandatory.

External validity of two nomograms for predicting distant brain failure after radiosurgery for brain metastases in a bi-institutional independent patient cohort.

Patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) are at increased risk of distant brain failure (DBF). Two nomograms have been recently published to predict individualized risk of DBF after SRS. The goal of this study was to assess the external validity of these nomograms in an independent patient cohort. The records of consecutive patients with BM treated with SRS at Levine Cancer Institute and Emory University between 2005 and 2013 were reviewed. Three validation cohorts were generated based on the specific nomogram or recursive partitioning analysis (RPA) entry criteria: Wake Forest nomogram (n = 281), Canadian nomogram (n = 282), and Canadian RPA (n = 303) validation cohorts. Freedom from DBF at 1-year in the Wake Forest study was 30% compared with 50% in the validation cohort. The validation c-index for both the 6-month and 9-month freedom from DBF Wake Forest nomograms was 0.55, indicating poor discrimination ability, and the goodness-of-fit test for both nomograms was highly significant (p < 0.001), indicating poor calibration. The 1-year actuarial DBF in the Canadian nomogram study was 43.9% compared with 50.9% in the validation cohort. The validation c-index for the Canadian 1-year DBF nomogram was 0.56, and the goodness-of-fit test was also highly significant (p < 0.001). The validation accuracy and c-index of the Canadian RPA classification was 53% and 0.61, respectively. The Wake Forest and Canadian nomograms for predicting risk of DBF after SRS were found to have limited predictive ability in an independent bi-institutional validation cohort. These results reinforce the importance of validating predictive models in independent patient cohorts.

Prognostic factors affecting survival after whole brain radiotherapy in patients with brain metastasized lung cancer

Background: Whole-brain radiotherapy (WBRT) has been the standard of care for multiple NSCLC brain metastases but due to its toxicity and lack of survival benefit, its use in the palliative setting is being questioned.Patient and methods: This was a single institution cohort study including brain metastasized lung cancer patients who received WBRT at Karolinska University Hospital. Information about Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) scores, demographics, histopathological results and received oncological therapy were collected. Predictors of overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes were compared by pairwise log rank test. A subgroup OS analysis was performed stratified by RPA class.Results: The cohort consisted of 280 patients. RPA 1 and 2 classes had better OS compared to class 3, patients with GPA <1.5 points had better OS compared to GPA≥ 1.5 points and age >70 years was associated with worse OS (p< .0001 for all comparisons). In RPA class 2 subgroup analysis GPA ≥1.5 points, age ≤70 years and CNS surgery before salvage WBRT were independent positive prognostic factors.Conclusions: RPA class 3 patients should not receive WBRT, whereas RPA class 1 patients should receive WBRT if clinically indicated. RPA class 2 patients with age ≤70 years and GPA ≥1.5 points should be treated as RPA 1. WBRT should be omitted in RPA 2 patients with age >70. In RPA 2 patients with age ≤70 years and GPA <1.5 points WBRT could be a reasonable option.

External Validity of a Nomogram and Recursive Partitioning Analysis to Predict for Distant Brain Failure After Stereotactic Radiosurgery Alone for Brain Metastases: Multi-institutional Analysis

Patients (pts) with brain metastases (BM) treated with stereotactic radiosurgery (SRS) alone are at increased risk of distant brain failure (DBF). A nomogram and recursive partitioning analysis (RPA) designed to predict for DBF at 1 year (yr) after SRS alone from a single institution Canadian tertiary care hospital was recently published (Rodrigues et al., Radio and Oncol 2014). We sought to evaluate the external validity of these tools using a multi-institutional independent validation cohort (VC). The records of consecutive pts with BM treated with SRS alone at 2 tertiary care cancer institutes between 2005-2013 were reviewed. Inclusion criteria were identical to the Canadian study and included pts treated with initial SRS alone, up to 3 BM, and no previous cranial irradiation. The nomogram variables included age, number of BM, largest lesion volume (cc), and WHO performance status (PS) to calculate probability of 1-yr DBF using the Kaplan-Meier method. The RPA defined 3 risk categories (low [LR], intermediate [IR], and high risk [HR]) based on PS, age, and number of BM. Discrimination was assessed using Harrell’s c-index and calibration was assessed using calibration plots and correlation between expected and observed DBF. After exclusions, a total of 282 pts with 390 BM and 303 pts with 416 BM were eligible for the nomogram and RPA VC, respectively. Median age was 60 years old, median tumor volume was 1.35 cc, and median number of BM was 1. Primary disease site was lung 44%, melanoma 20.2%, breast 17.4%, renal 7.8%, GI 2.8%, and other 11.6%. One-year actuarial DBF for the nomogram VC was 50.9% compared to 43.9% in the Canadian study. The Harrell’s c-index for the DBF nomogram using the VC was 0.56 compared to 0.69 in the Canadian study, indicating poor discrimination ability. Calibration plots for the nomogram demonstrated good correlation between predicted and observed DBF (r2=0.92), but with systematic underestimation of DBF risk by an average of 19.6% across all risk levels. RPA risk groups LR, IR, and HR had 1-yr DBF rates of 39%, 62%, and 51.8%, compared to Canadian rates of 25.1%, 45.9%, and 69.1%, respectively. RPA risk groups did demonstrate significantly different actuarial DBF rates (log-rank p=0.0008), but IR had a higher 1-yr DBF rate than HR and would have been categorized as high risk in the Canadian publication (> 40%). The accuracy of the RPA classification was 53% compared with 75% in the Canadian study. In an independent multi-institutional cohort, the Canadian nomogram and RPA classification were not found to be externally valid, had limited ability to accurately differentiate DBF at 1-yr, and generally underestimated risk of DBF. We currently recommend caution in using these tools to predict individualized risk of 1-yr DBF after SRS alone.

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012. To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases. For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review. We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis. We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.

Analysis of survival-and prognosis-related factors of brain metastasis from esophageal cancer

Objective To explore the incidence of brain metastases from esophageal cancer, survival-related factors after brain metastases, and the result of different treatment methods. Methods From January 2000 to October 2016 treated 11 338 cases of esophageal cancer patients, 84 cases of brain metastases, were collected with complete clinical data. Results Eighty four cases of patients with brain metastases included esophageal squamous carcinoma in 74 cases, adenocarcinoma in 6 cases, and small cell undifferentiated carcinoma 4 cases; single brain metastases in 19 cases, 65 cases of multiple brain metastases included 59 cases with brain metastasis symptoms, 58 with extracranial metastases, primary tumors and brain metastases interval time less than 6 months in 31 cases, 24 cases of 6-12, 16 cases for 12-24 months. Prognostic logrank univariate analysis of survival rate found 24-36 months survival for 13 patients. All patients were followed for a median of 19.31 months after brain metastases, the median survival time was 5.43 months. Conclusions About 0.7% of brain metastases from esophageal cancer occurs. Esophageal carcinoma metastatic to the brain: There was no extracranial metastasis, recursive partitioning analysis classification (RPA), Karnofsky (KPS) score, brain metastases different treatment methods is a poor prognostic factor for esophageal cancer brain metastasis. Key words: Stomach neoplasms/ME/DI; Brain neoplasms/SC/EP; Survival rate; Prognosis

Survival improvements with adjuvant therapy in patients with glioblastoma.

Evaluate survival of patients diagnosed with glioblastoma multiforme (GBM) managed with adjuvant intensity modulated radiation therapy and temozolomide since the introduction of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) protocol. All patients with GBM managed between May 2007 and December 2014 with EORTC-NCIC protocol were entered into a prospective database. The primary endpoint was the median survival. Univariate predictors of survival were evaluated with respect to tumour resection, age and Eastern Cooperative Oncology Group (ECOG) performance status using log-rank comparisons. Two hundred and thirty-three patients were managed under the protocol and analysed for outcome. The median age was 57 years; the rate of gross total resection, subtotal resection and biopsy were 47.2%, 35.2% and 17.6%, respectively. At progression, 49 patients had re-resection, and in addition to second-line chemotherapy, 86 patients had Bevacizumab including 26 with re-irradiation. Median survival was 17.0 months (95% CI: 15.4-18.6). On univariate evaluation, extent of resection (P = 0.001), age, ECOG performance status and recursive partitioning analysis class III were shown to significantly improve survival (P < 0.0001). The median survival for gross total resection, age <50 years, ECOG 0-1 and recursive partitioning analysis class III were 21, 27, 20 and 47 months, respectively. This study confirms the significant improvement in median survival in GBM that has occurred in recent years since introduction of the EORTC-NCIC protocol. Further improvements have occurred presumably related to subspecialized care, improved resection rates, sophisticated radiotherapy targeting and early systemic salvage therapies. However, the burden of the disease within the community remains high and the median survival improvements over time have plateaued.

Two-year experience of multi-disciplinary team (MDT) outcomes for brain metastases in a tertiary neuro-oncology centre

Brain metastases (BMs) are the most common intracranial tumour in adults and form a significant proportion of the neuro-oncology workload. Their management has progressed significantly in the last few decades but a gold-standard evidence-based management strategy has not been defined to date and several guidelines based on available evidence exist to support clinical decision-making. This paper evaluates the decision-making process of the neuro-oncology multi-disciplinary team (MDT) in a tertiary neuro-oncology centre over a two-year period. A retrospective review of all patients with BM discussed in the MDT was conducted. Data on patient demographics, tumour characteristics and MDT decision were collected from the MDT database, clinical notes and imaging studies. Patients were stratified into the three recursive partitioning analysis (RPA) classes and according to the graded prognostic assessment (GPA) score. MDT decisions were analysed by RPA class and for GPA score as well as single versus multiple BM. There were 362 patients with BM, representing 22% of the total cases discussed at the MDT. Decision-making was largely consistent with available guidelines. A concrete treatment decision was reached in 77.5% of patients and 32.2% of these received neurosurgical input. More patients with solitary BM underwent surgery compared to multiple BM (p = 0.001), and more patients in RPA classes I and II had surgical resection compared to class III (p = 0.005 and 0.001, respectively). Surgical patients also had higher GPA scores compared to palliative patients (p = 0.005). A greater absolute number and proportion of patients in RPA class II vs. class I underwent neurosurgical intervention. These patients were stratified into class II because of their age but would otherwise have been placed into class I. Survival data were available for 195 patients (53.8%) at 1 year post MDT discussion. A pattern of declining survival was observed along RPA classes which was statistically significant (p = 0.0025). Median survival was 4.7 (0–41), 3.7 (0–23), and 2.5 (range 0–24) months for RPA class I, II and III respectively. A similar pattern that did not reach statistical significance was found between GPA scores (p = 0.101). Median survival was 3 (0–13), 4.6 (range 0–41), and 4.6 (0–35) months for GPA scores 0–1.0, 1.5–2.5 and 3–4.0, respectively. Patient selection was generally in accordance to RPA class and GPA scoring, with the exception of surgery offered to elderly patients: this can be explained by the increasing number of otherwise fit patients as population ages.

Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial

Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5-22·1) in the rindopepimut group versus 20·0 months (18·1-21·9) in the control group (HR 1·01, 95% CI 0·79-1·30; p=0·93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut. Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Celldex Therapeutics, Inc.

Hypofractionated Stereotactic Radiation Therapy to the Resection Bed for Intracranial Metastases

To retrospectively report the outcomes of a large multicenter cohort of patients treated with surgery and hypofractionated stereotactic radiation therapy (HFSRT) to the resection cavities of brain metastases (BMs). Between March 2008 and February 2015, 181 patients with no prior whole-brain radiation therapy (WBRT) were treated by HFSRT to the surgical bed of BM at the dose of 33Gy (3×11Gy). The primary endpoint was local control. Secondary endpoints were distant brain control, overall survival (OS), risk of radionecrosis, and leptomeningeal disease (LMD). Of the 189 resected lesions, 44% were metastatic from a non-small cell lung cancer primary tumor, and 76% of patients had a single BM at the time of treatment. With a median follow-up of 15months, the 6- and 12-month local control rates were 93% and 88%, respectively. On multivariate analysis, planning target volume (P=.005), graded prognostic assessment score (P=.021), and meningeal contact of BM (P=.032) were predictive of local failure. The 6- and 12-month distant brain control rates were 70% and 61%, respectively. Twenty-six patients (14%) developed signs of LMD at a median time of 3.8months. The preoperative tumor volume was predictive of LMD (P=.029). The median OS was 17months. The 6-, 12-, and 24-month OS rates were 79%, 62%, and 39%, respectively. Recursive partitioning analysis class 3 (P=.02), piecemeal resection (P=.017), and an increasing number of BMs (P<.01) were independent unfavorable prognostic factors for OS. Fifty-four patients (30%) were subsequently treated with salvage WBRT at a median time of 6.5months, and 41% were reirradiated with SRT. Radionecrosis occurred in 19% of cases at a median time of 15months and was associated with the infratentorial location of the BM (P=.0025). This study demonstrated the safety and efficacy of a 3×11Gy HFSRT regimen for the irradiation of BMs resection cavities. It was an alternative to adjuvant WBRT.

Predictors of quality of life and survival following Gamma Knife surgery for lung cancer brain metastases: a prospective study.

OBJECTIVE Lung cancer (LC) patients who develop brain metastases (BMs) have a poor prognosis. Estimations of survival and risk of treatment-related deterioration in quality of life (QOL) are important when deciding on treatment. Although we know of several prognostic factors for LC patients with BMs, the role of QOL has not been established. Authors of this study set out to evaluate changes in QOL following Gamma Knife surgery (GKS) for BMs in LC patients and QOL as a prognostic factor for survival. METHODS Forty-four of 48 consecutive LC patients with BMs underwent GKS in the period from May 2010 to September 2011, and their QOL was prospectively assessed before and 1, 3, 6, 9, and 12 months after GKS by using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire. A mixed linear regression model was used to identify potential predictive factors for QOL and to assess the effect of GKS and the disease course on QOL at follow-up. RESULTS Mean QOL as measured by the brain cancer subscale (BRCS) of the FACT-BR remained stable from baseline (score 53.0) up to 12 months post-GKS (57.1; p = 0.624). The BRCS score improved for 32 patients (72.3%) with a total BM volume ≤ 5 cm3. Mean improvement in these patients was 0.45 points each month of follow-up, compared to a decline of 0.50 points each month despite GKS treatment in patients with BM volumes > 5 cm3 (p = 0.04). Asymptomatic BMs (p = 0.01), a lower recursive partitioning analysis (RPA) classification (p = 0.04), and a higher Karnofsky Performance Scale (KPS) score (p < 0.01) at baseline were predictors for a high, stable QOL after GKS. After multivariate analysis, a high KPS score (p < 0.01) remained the only positive predictor of a high, stable QOL post-GKS. Median survival post-GKS was 5.6 months (95% CI 1.0-10.3). A higher BRCS score (p = 0.01), higher KPS score (p = 0.01), female sex (p = 0.01), and the absence of liver (p = 0.02), adrenal (p = 0.02), and bone metastases (p = 0.03) predicted longer survival in unadjusted models. However, in multivariate analyses, a higher BRCS score (p < 0.01), female sex (p = 0.01), and the absence of bone metastases (p = 0.02) at GKS remained significant predictors. Finally, the BRCS score's predictive value for survival was compared with the values for the variables behind well-known prognostic indices: age, KPS score, extracranial disease status, and number and volume of BMs. Both BRCS score (p = 0.01) and BM volume (p = 0.05) remained significant predictors for survival in the final model. CONCLUSIONS Patient-reported QOL according to the BRCS is a predictor of survival in patients with BMs and may be helpful in deciding on the optimal treatment. Gamma Knife surgery is a safe and effective therapeutic modality that improves QOL for LC patients with a BM volume ≤ 5 cm3 at treatment. Careful follow-up and salvage therapy on demand seem to prevent worsening of QOL due to relapse of BMs.

Brain volume reduction after whole-brain radiotherapy: quantification and prognostic relevance.

Recent studies have questioned the value of adding whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) for brain metastasis treatment. Neurotoxicity, including radiation-induced brain volume reduction, could be one reason why not all patients benefit from the addition of WBRT. In this study, we quantified brain volume reduction after WBRT and assessed its prognostic significance. Brain volumes of 91 patients with cerebral metastases were measured during a 150-day period after commencing WBRT and were compared with their pretreatment volumes. The average daily relative change in brain volume of each patient, referred to as the "brain volume reduction rate," was calculated. Univariate and multivariate Cox regression analyses were performed to assess the prognostic significance of the brain volume reduction rate, as well as of 3 treatment-related and 9 pretreatment factors. A one-way analysis of variance was used to compare the brain volume reduction rate across recursive partitioning analysis (RPA) classes. On multivariate Cox regression analysis, the brain volume reduction rate was a significant predictor of overall survival after WBRT (P < 0.001), as well as the number of brain metastases (P = 0.002) and age (P = 0.008). Patients with a relatively favorable prognosis (RPA classes 1 and 2) experienced significantly less brain volume decrease after WBRT than patients with a poor prognosis (RPA class 3) (P = 0.001). There was no significant correlation between delivered radiation dose and brain volume reduction rate (P = 0.147). In this retrospective study, a smaller decrease in brain volume after WBRT was an independent predictor of longer overall survival.

Brain metastases from colorectal cancer: characteristics and management.

Brain metastases (BMs) are the most common intracranial neoplasms in adults, but they rarely arise from colorectal cancer (CRC). The objective of this study was to report an overview of the characteristics and current management of CRC BMs. A systematic review on CRC BMs was performed using Medline database from 1983 to 2015. The search was limited to studies published in English. Review articles, not relevant case report or studies or studies relating to animal and in vitro experiments were excluded. BMs occurred in 0.06-4% of patients with CRC. Most BMs were metachronous and were associated with lung (27-92%) and liver (12-80%) metastases. Treatment options depended on the number of BMs, the general conditions of the patient and the presence of other metastases. Most frequent treatment was whole-brain radiotherapy (WBRT) alone (36%), with median overall survival comprised between 2 and 9 months. Median overall survival was better after surgery alone (from 3 to 16.2 months), or combined with WBRT (from 7.6 to 14 months). After stereotactic radiosurgery alone, overall survival could reach 9.5 months. Many favourable prognostic factors were identified, such as high Karnofsky performance status, low recursive partitioning analysis classes, lack of extracranial disease, low number of BMs and possibility to perform surgical treatment. BMs from CRC are rare. In the presence of favourable prognostic factors, an aggressive management including surgical resection with or without WBRT or stereotactic radiosurgery can improve the overall survival.

Clinical and Molecular Prognostic Factors for Long-Term Survival of Patients with Glioblastomas in Single-Institutional Consecutive Cohort.

The purpose of this study was to clarify the clinical and molecular characteristics associated with long-term survival in patients with glioblastoma. We analyzed the characteristics of 96 glioblastoma patients. Long-term survivors (LTSs) were classified into moderate LTSs (mLTSs), who survived >3 years, and LTSs, who survived >5 years, and compared with short-term survivors (STSs). Clinical and molecular factors were investigated. Younger age, better recursive partitioning analysis class, lack of subventricular zone (SVZ) involvement, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, and loss of 19q were associated with mLTSs as compared with STSs. After adjustment for these factors, younger age and MGMT methylation remained independently associated with mLTSs. Younger age, better recursive partitioning analysis class, lack of SVZ involvement, and loss of 19q were associated with LTSs as compared with STSs. After adjustment, younger age and better preoperative Karnofsky performance scale (KPS) score remained independently associated with LTSs. Kaplan-Meier analyses revealed that younger age (<50 years), better preoperative KPS score (≥70), lack of SVZ involvement, and loss of 19q were associated with longer overall survival. In the multivariate analysis, only age was significantly associated with overall survival. Younger age and better preoperative KPS score were the characteristics associated with LTSs as compared with STSs. MGMT promoter methylation was associated with mLTSs, but not with LTSs. In addition, lack of SVZ involvement and loss of 19q might be prognostic for longer survival.

Refining Patient Selection for Reirradiation of Head and Neck Squamous Carcinoma in the IMRT Era: A Multi-institution Cohort Study by the MIRI Collaborative

The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40Gy) who underwent reirradiation with IMRT (≥40Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60Gy, and the median time between RT courses was 2.4years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2years with unresected tumors or those ≤2years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status.

Estimating prognosis at the time of repeat whole brain radiation therapy for multiple brain metastases: The reirradiation score

PurposeWhole brain radiation therapy (WBRT) remains the standard of care for patients with multiple brain metastases, but more than half of treated patients will develop intracranial progression. Because there is no clear consensus on the optimal therapeutic approach, a prognostic index would be helpful to guide treatment options at progression. We explored whether the recursive partitioning analysis (RPA) score prior to repeat WBRT is predictive of survival. Methods and materialsThis multi-institutional pooled analysis included patients with 2 or more brain metastases from any solid primary tumor that was treated with 2 courses of WBRT. Information on demographics, disease characteristics, and intervals between courses was collected. RPA class was abstracted or retrospectively assigned, and descriptive statistics calculated. Median survival (MS) was determined using the Kaplan-Meier method and compared using log rank tests. Univariate and multivariate analyses were performed via Cox regression analysis. ResultsFor 205 patients, the median age was 55 years (range, 25-83 years), 68% were female, 40.5% had non-small cell lung cancer, and 31.2% had small cell lung cancer. Prior to the second WBRT, 4.9% of patients were RPA class 1, 36.6% were RPA2, and 58.5% were RPA3, with an MS of 7.5 months (95% confidence interval [CI], 4.7-10.3), 5.2 months (95% CI, 3.7-6.7 months), and 2.9 months (95% CI, 2.2-2.9 months), respectively (P = .001). On univariate and multivariate analyses, a Karnofsky Performance Status of <80, extracranial metastases, interval between courses <9 months, small cell lung cancer histology, and uncontrolled primary significantly correlated with shorter MS. By assigning a score of 1 to each of these factors, a new prognostic index was created, the reirradiation (ReRT) score. Survival on the basis of ReRT score grouping ranged from 2.2 to 7.2 months and demonstrated significant differences in MS. ConclusionsIn the largest reported cohort to receive repeat WBRT, application of the RPA score was not predictive of MS. The new ReRT score is a simple tool based on readily available clinical information.

Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy.

The purpose of this study was to evaluate prognostic factors associated with overall survival (OS) and neurological progression free survival (nPFS) in small-cell lung cancer (SCLC) patients with brain metastases who received whole-brain radiotherapy (WBRT). From 2003 to 2015, 229 SCLC patients diagnosed with brain metastases who received WBRT were analyzed retrospectively. In this cohort 219 patients (95%) received a total photon dose of 30Gy in 10 fractions. The prognostic factors evaluated for OS and nPFS were: age, Karnofsky Performance Status (KPS), number of brain metastases, synchronous versus metachronous disease, initial response to chemotherapy, the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class and thoracic radiation. Median OS after WBRT was 6months and the median nPFS after WBRT was 11months. Patients with synchronous cerebral metastases had a significantly better median OS with 8months compared to patients with metachronous metastases with a median survival of 3months (p < 0.0001; HR 0.46; 95% CI 0.31-0.67). Based on RPA classification median survival after WBRT was 17months in RPA class I, 7months in class II and 3months in class III (p < 0.0001). Karnofsky performance status scale (KPS < 70%) was significantly associated with OS in both univariate (HR 2.84; p < 0.001) and multivariate analyses (HR 2.56; p = 0.011). Further, metachronous brain metastases (HR 1.8; p < 0.001), initial response to first-line chemotherapy (HR 0.51, p < 0.001) and RPA class III (HR 2.74; p < 0.001) were significantly associated with OS in univariate analysis. In multivariate analysis metachronous disease (HR 1.89; p < 0.001) and initial response to chemotherapy (HR 0.61; p < 0.001) were further identified as significant prognostic factors. NPFS was negatively significantly influenced by poor KPS (HR 2.56; p = 0.011), higher number of brain metastases (HR 1.97; p = 0.02), and higher RPA class (HR 2.26; p = 0.03) in univariate analysis. In this series, the main prognostic factors associated with OS were performance status, time of appearance of intracranial disease (synchronous vs. metachronous), initial response to chemotherapy and higher RPA class. NPFS was negatively influenced by poor KPS, multiplicity of brain metastases, and higher RPA class in univariate analysis. For patients with low performance status, metachronous disease or RPA class III, WBRT should be weighed against supportive therapy with steroids alone or palliative chemotherapy.