Diagnosis-specific Graded Prognostic Assessment Score Research Articles

Optimal Treatment Strategy of Radiotherapy and Crizotinib for Patients with Brain Metastasis from ALK-Rearranged Non-Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Radiotherapy and anaplastic lymphoma kinase (ALK) inhibitors are treatment options for brain metastasis (BM) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). This study aimed to find the optimal treatment strategy for patients with BM from ALK-rearranged NSCLC. <h3>Materials/Methods</h3> Between 2012 and 2017, consecutive patients with BM from ALK-rearranged NSCLC treated with crizotinib and radiotherapy in our institution were reviewed and enrolled into the study. Patients were treated with sequential radiotherapy and crizotinib (upfront radiotherapy or crizotinib followed by the other at intracranial progression), or concurrent radiotherapy and crizotinib. The cumulative incidence of intracranial progression free survival (iPFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the log-rank test was used to analyze differences between the groups. A two-sided p value ≤ 0.05 were considered statistically significant. <h3>Results</h3> Totally 41 patients were enrolled, including 24 (58.5%) with sequential treatment and 17 (41.5%) with concurrent treatment. The diagnosis-specific graded prognostic assessment (DS-GPA) score was 0-2 in 25 (60.1%) patients and > 2 in 16 (39.0%) patients, respectively. There were 13(31.7%), 17 (41.5%), and 11 (26.8%) patients treated with stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and WBRT with simultaneous in-field boost (SIB), respectively. The median iPFS and OS in all patients were 33.5 (95% CI 30.8-36.2) months and 63.9 (95% CI 46.0-81.9) months, respectively. There was no significant difference of iPFS or OS between the sequential treatment group and the concurrent treatment group. However, in DS-GPA scores of 0-2, the iPFS was longer in the sequential treatment group than concurrent treatment group (67.9 months vs.32.6 months, <i>P</i>=0.045), but the difference of OS was not significant between the two groups (38.9 months vs. 32.6 months, <i>P</i>=0.829). Moreover, the median iPFS of patients receiving SRS, WBRT alone, and WBRT with SIB was 33.5 months, 43.6 months, and 63.9 months (P=0.047). The corresponding median OS was not reached, 26.0 months, and 67.9 months, respectively (<i>P</i><0.001). <h3>Conclusion</h3> For patients with BM from ALK-rearranged NSCLC in our study, sequential crizotinib and brain radiotherapy for patients with DS-GPA score of 0-2 achieve better iPFS. In addition, WBRT with SIB achieves the best iPFS.

Clinicopathological Features and Prognoses in Patients With Brain Metastases From Small-Cell Esophageal Carcinoma: A Retrospective Analysis of 18 Patients.

Objective: This study aims to examine the clinical characteristics of patients with brain metastases (BM) from small-cell esophageal carcinoma (SCEC) and to explore the association of the corresponding factors with overall survival (OS).Methods: The data of 18 patients with brain metastases from SCEC, diagnosed from January 1, 2006, to December 31, 2018, in the Fourth Hospital of Hebei Medical University were analyzed retrospectively.Results: The 18 patients who were included in this study accounted for 6.7% of the patients with SCEC diagnosed from 2006 to 2018. Of the 18 patients, 8 (44.4%) were females. For the entire cohort, the median OS was 7 months, the 1-year OS was 22.2%, and the 2-year OS was 0%. For patients who received whole-brain radiotherapy (WBRT) and for those who did not (13 vs. 5), the median OS was 11.9 and 3 months, respectively, and the 1-year OS was 30.8 and 0%, respectively. When comparing diagnosis-specific Graded Prognostic Assessment (DS-GPA) scores of patients with BM from SCEC ranging from 2.5 to 4 and from 0 to 2, the median OS was 13.1 and 4 months, respectively, and the 1-year OS was 57.1 and 0%, respectively. In the univariable regression, patients who received WBRT had improved OS compared to those who did not (HR = 0.249, p = 0.018), and patients with a DS-GPA score of 2.5–4 were associated with improved OS compared with patients with a DS-GPA score of 0–2 (HR = 0.050, p = 0.005).Conclusion: The incidence of brain metastases in patients with SCEC is low, but the prognosis in those patients is very poor. The DS-GPA score may be a prognostic factor of patients with BM from SCEC. Brain radiotherapy could improve the survival of these patients.

The individual risk of symptomatic radionecrosis after brain metastasis radiosurgery is predicted by a continuous function of the V12Gy

IntroductionBrain metastases are frequently treated with stereotactic radiosurgery (SRS). Radionecrosis (RN) is the late side effect in up to 24% of patients, being symptomatic in 8–10%. Fixed values of the radiosurgical volume receiving 12 Gy or more (V12Gy) are used to roughly predict the global risk. The aim of this retrospective study is to fine-tune the model of individual risk prediction for symptomatic radionecrosis and identify modulating factors. Materials and methodsData of patients treated with SRS for ≤3 BM of solid tumours at CHU-UCL-Namur were retrospectively reviewed. Doses ranging from 15 to 24 Gy were prescribed to the 70% isodose in function of the lesion diameter. Treatment was administered with a stereotactic linear accelerator. Follow-up magnetic resonance imaging was performed 3-monthly for 18 months and 6-monthly thereafter. RN was prospectively diagnosed and confirmed by the tumour board. V12Gy, previous or salvage whole-brain radiotherapy (WBRT), smoking history, diabetes, postoperative SRS, diagnosis-specific graded prognostic assessment score, cerebral lobe location and relative location (superficial versus deep) were retrieved. Univariate and multivariate analyses were performed to assess their predictive values and derive a model. Results128 patients with 220 lesions were analysed. The risk of RN was predicted by a continuous function of the V12Gy (p = 0.005). No other factor had a significant impact, particularly WBRT that did not increase the risk. ConclusionThe risk of symptomatic RN is predicted on an individual basis by a model in function of the V12Gy and must be confirmed in a prospective study.

Evaluation of Prognostic Factors that Affect Survival Outcomes of Breast Cancer Patients with Brain Metastases: A Single Institutional Experience.

This study aimed to evaluate various prognostic factors that play a vital role in stratifying and guiding tailored treatment strategies and survival outcome in breast cancer patients with brain metastases (BM). Data regarding demography, clinical presentation, molecular subtypes, risk-stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event (survival) outcomes were analyzed by Kaplan-Meir method and compared using log-rank test. Univariate and multivariate analysis of relevant prognostic factors were performed and p-values ≤0.05 were considered statistically significant. A total of 88 patients (median age: 50 years) were included for this study. The median follow-up time of all surviving patients was ~20 months. During the follow-up, 82 (93.1%) patients died. The median survival of all patients was 12 months, with 1-year and 2-year overall survival (OS) rate of 51% and 22%, respectively. Based on univariate analysis, statistically significant prognostic factors for OS were molecular subtypes, number of BM, and Karnofsky Performance Status (KPS); however, number of BM and KPS emerged as independent predictors of survival based on multivariate analysis. We conclude that, there are other important prognostic factor, such as number of BM, which may affect the OS of these patients, in addition to variables included in the diagnosis-specific graded prognostic assessment score. Prospective studies evaluating these factors are necessary to further refine the stratification of patients, which will aid the initiation of appropriate treatment to improve the OS of patients.

Hypothyroidism correlates with favourable survival prognosis in patients with brain metastatic cancer

BackgroundSeveral preclinical and epidemiologic studies have indicated tumour-promoting effects of thyroid hormones (THs). However, very limited knowledge exists on the prognostic impact of thyroid function in metastatic cancer. MethodsWe compiled a discovery cohort of 1692 patients with newly diagnosed brain metastases (BMs) of solid cancers treated at the Medical University of Vienna and an independent validation cohort of 191 patients with newly diagnosed BMs treated at the University Hospital Zurich. ResultsHypothyroidism before diagnosis of cancer was evident in 133 of 1692 (7.9%) patients of the discovery, and in 18 of 191 (9.4%) patients of the validation cohort. In the discovery cohort, hypothyroidism was statistically significantly associated with favourable survival prognosis from diagnosis of cancer (31 vs. 21 months; p = 0.0026) and with survival prognosis from diagnosis of BMs (12 vs. 7 months; p = 0.0079). In multivariate analysis including the diagnosis-specific graded prognostic assessment score, primary tumour type and sex, hypothyroidism was an independent factor associated with survival after diagnosis of BMs (hazard ratio: 0.76; 95% confidence interval [CI]: (0.63; 0.91; p = 0.0034). In the validation cohort, the association of hypothyroidism and favourable survival prognosis from diagnosis of cancer (55 vs. 11 months; p = 0.00058), as well as from diagnosis of BMs (40 vs. 10 months; p = 0.0036) was confirmed. ConclusionPre-existing hypothyroidism was strongly and independently associated with prognosis in patients with newly diagnosed BMs, supporting the evidence from preclinical data that THs may indeed have a tumour-promoting effect. Further investigation of the underlying pathobiological mechanism and potential therapeutic implications are required.

Outcome of Omani Women with Breast Cancer-associated Brain Metastases Experience from a University Hospital.

ObjectivesBreast cancer (BC) is the leading cancer among women. Almost 20% of patients develop brain metastases (BM) and die shortly afterward. There is a dearth of data on the survival outcome of BC patients with BM from the Arab world.MethodsConsecutive women diagnosed with BC who developed radiologically-confirmed BM during their illness were identified through the hospital’s electronic patient’s records. Clinicopathological features and treatment outcomes were recorded. Survival was calculated using the Kaplan-Meier method, and factors affecting survival were studied using log-rank analysis.ResultsBetween January 2003 and June 2015, a total of 692 patients were treated for BC at our institute. Forty-eight (6.9%) developed BM. The median age at the diagnosis of BM was 45.2 years. More than half of cohort (54.2%) had HER2 positive disease, while 27.1% had the triple-negative disease. The median time interval between the diagnosis of BC and the development of BM was 21 months, and median survival after development of brain disease was seven months. On univariate analysis, pathological grade, previous systemic treatment, brain as the first site of metastases, brain as the only site of metastases, treatment of BM, systemic treatment after BM, and diagnosis-specific graded prognostic assessment (DS-GPA) score significantly affected survival. On multivariate Cox regression analysis, the brain as the first site of metastases, treatment for brain disease, treatment type, and DS-GPA score significantly affected survival post-BM.ConclusionsOur data indicate that Omani women are diagnosed with BC at a younger age, develop BM earlier, and carry a poor outcome.

External validation of a prognostic score predicting overall survival for patients with brain metastases based on extracranial factors

The aim of our study was an external validation of the extracranial prognostic score predicting survival of patients with brain metastases receiving cranial irradiation on data from a single institution. A retrospective analysis of 524 patients with brain metastases treated with cranial radiotherapy in a single tertiary center was performed. Three predictive scores were calculated and assessed for their ability to discriminate prognostic groups: (i) The Recursive Partitioning Analysis (RPA) score (available for 524 patients); (ii) the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score (464 patients); (iii) the extracranial score (EC-S) developed by Nieder et al. which is based on serum albumin, lactate dehydrogenase (LDH) and the number of extracranial organs involved (157 patients). Discrimination of each score was assessed by Gönen & Heller's concordance probability estimate (CPE). The calibration was checked by comparing median survival estimates of each risk group with the corresponding values of the datasets from which the scores were derived. Finally, a multivariable Cox regression model was built by using the least absolute shrinkage and selection operator on a large number of variables including all three scores. With a CPE = 0.626 ± 0.022, the EC-S had the best discriminatory power. The EC-S also appeared to be better calibrated and had the best ability to separate patients with a very poor prognosis: patients with combination of low albumin, elevated LDH and more than 1 extracranial organ with metastatic involvement had a median survival time of only 0.6 months (CI95% 0.1-1.1) and a hazard ratio for death of 6.36 (2.67-15.14) compared to patients with no extracranial metastases and normal levels of albumin and LDH. In the multivariable Cox model serum albumin, LDH, treatment modality, DS-GPA and EC-S were retained as prognostic factors. An ad hoc combination of both DS-GPA and EC-S into a new score was possible for 134 patients and indicated a slightly better discrimination (CPE = 0.636 ± 0.023) than either DS-GPA or EC-S alone. This study provides an independent validation of the prognostic EC-S which was the best prognostic model for defining the patients who obviously did not benefit from radiation therapy of brain metastases in terms of overall survival. The combination of the EC-S with the established DS-GPA score resulted in a slight increase in discriminatory ability. The new EC-GPA score needs further validation in larger patient cohorts.

Concurrent brain radiotherapy and EGFR-TKI may improve intracranial metastases control in non-small cell lung cancer and have survival benefit in patients with low DS-GPA score.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has intracranial activity in EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). The optimal timing of brain radiotherapy (RT) and appropriate patients who need early brain RT remains undetermined. This is a retrospective study of EGFR-mutant NSCLC patients with newly diagnosed brain metastases (BMs) before EGFR-TKI initiation. Intra-cranial progression free survival (IC-PFS) and overall survival (OS) were measured from the date of EGFR-TKI treatment. A total of 113 patients were eligible, 49 received concurrent early brain RT with EGFR-TKI and 64 were treated with EGFR-TKI alone as initial therapy, including 27 with salvage RT upon BM progression. The patients with early brain RT had superior IC-PFS than those without early brain RT (21.4 vs 15.0 months, P=0.001), which remained significant in multivariate analysis (HR 0.30, P<0.001). The median overall survival (OS) for early RT, EGFR-TKI alone and salvage RT groups was 28.1, 24.5, and 24.6 months, respectively (P=0.604). Similar IC-PFS (23.6 vs 21.4 months, P=0.253) and OS (24.6 vs 28.1 months, P=0.385) were observed between salvage RT and early RT groups. For patients with Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 0 to 2, early brain RT was the independent factor for improved OS (HR 0.33, P=0.025). In conclusion, concurrent early brain RT with EGFR-TKI may improve intracranial disease control in EGFR-mutant NSCLC with BM and have survival benefit in patients with low DS-GPA score. Salvage brain RT upon BM progression may be acceptable in some patients.

Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for Limited Brain Metastases: A Secondary Analysis of the North Central Cancer Treatment Group N0574 (Alliance) Randomized Controlled Trial

To determine whether whole-brain radiation therapy (WBRT) is associated with improved overall survival among non-small cell lung cancer (NSCLC) patients with favorable prognoses at diagnosis. In the N0574 trial, patients with 1 to 3 brain metastases were randomized to receive stereotactic radiosurgery (SRS) or SRS plus WBRT (SRS+WBRT), with a primary endpoint of cognitive deterioration. We calculated diagnosis-specific graded prognostic assessment (DS-GPA) scores for NSCLC patients and evaluated overall survival according to receipt of WBRT and DS-GPA score using 2 separate cut-points (≥2.0 vs <2.0 and≥2.5 vs <2.5). A total of 126 NSCLC patients were included for analysis, with median follow-up of 14.2months. Data for DS-GPA calculation were available for 86.3% of all enrolled NSCLC patients. Overall, 50.0% of patients had DS-GPA score ≥2.0, and 23.0% of patients had DS-GPA scores ≥2.5. The SRS and SRS+WBRT groups were well balanced with regard to prognostic factors. The median survival according to receipt of WBRT was 11.3months (+WBRT) and 17.9months (-WBRT) for patients with DS-GPA ≥2.0 (favorable prognoses, P=.63; hazard ratio 0.86; 95% confidence interval 0.47-1.59). Median survival was 3.7months (+WBRT) and 6.6months (-WBRT) for patients with DS-GPA <2.0 patients (unfavorable prognoses, P=.85; hazard ratio 0.95; 95% confidence interval 0.56-1.62). Outcomes according to the receipt of WBRT and DS-GPA remained similar utilizing DS-GPA ≥2.5 as a cutoff for favorable prognoses. There was no interaction between the continuum of the DS-GPA groups and WBRT on overall survival (P=.53). We observed no significant differences in survival according to receipt of WBRT in favorable-prognosis NSCLC patients. This study further supports the approach of SRS alone in the majority of patients with limited brain metastases.

Outcome appraisal of patients with limited brain metastases (BMs) from non small cell lung cancer (NSCLC) treated with different local therapeutic strategies: a single institute evaluation.

To evaluate the outcome of patients with non-small-cell lung cancer (NSCLC) with limited brain metastases (BMs) treated with local approaches omitting whole-brain radiation therapy (WBRT). Surgery was performed in case of a single, large BM, controlled extracranial disease and Karnofsky Performance Status (KPS) 90-100; stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (HSRS) was performed in all other cases. The prescribed dose was 24 Gy/1 fraction for lesions <2.5 cm, and a median of 30 Gy (24-40 Gy) in 3-5 fractions for lesions >2.5 cm. 156 patients treated for 228 BMs were retrospectively evaluated. The median age was 62 years. The majority of patients had a KPS 90-100, recursive partitioning analysis Class II, diagnosis-specific graded prognostic assessment score 2.5-3 and 1-2 BMs. Surgical resection was performed in 18 cases, and SRS/HSRS was performed in 210 cases. The 1-2-year local control was 87.2 ± 3.0% and 72.8 ± 5.0%; the 1.2-year brain distant failure was 30.8 ± 4.0% and 58.1 ± 6.0%; the 1-2-year overall survival was 60.9 ± 3.9% and 31.4 ± 4.0%. On univariate and multivariate analysis, the following factors influenced survival: age (p = 0.01), the presence of lymph node involvement (p = 0.03), KPS (p << 0.01), the presence of extracranial metastases at the time of BM treatment (p < 0.01), the number of BMs (p = 0.02) and the treatment performed (p < 0.01). The choice of an adequate local treatment can impact on survival in patients with limited BMs from NSCLC. A careful evaluation of prognostic and predictive factors is a pivotal additional aid. Advances in knowledge: Radiosurgery or surgery followed by radiosurgery on the tumour bed in place of WBRT proved to be an effective treatment influencing outcome. Surgical resection followed by SRS on the tumour bed has to be considered for lesions ≥15 mm, in patients with good KPS, age ≤70 years, adenocarcinoma histology and oligometastatic disease.

Comparison of prognostic indices in patients who undergo melanoma brain metastasis radiosurgery

OBJECTIVE The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases. METHODS The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm3 (range 0.3-69.3 cm3), and the median number of metastases was 2 (range 1-32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA). RESULTS The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0-1, n = 67), 4.2 months (Scores 1.5-2.0, n = 143), 6.6 months (Scores 2.5-3.0, n = 111), and 9.4 months (Scores 3.5-4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0-3, n = 56), 5.8 months (Scores 4-7, n = 319), and 12.7 months (Scores 8-10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival. CONCLUSIONS The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

Retrospective study of 229 surgically treated patients with brain metastases: Prognostic factors, outcome and comparison of recursive partitioning analysis and diagnosis-specific graded prognostic assessment.

Background:Metastases are the most frequent tumors in the brain. Most often used scoring systems to predict the outcome are the RPA (Recursive Partitioning Analysis) classification and the DS-GPA (Diagnosis-Specific Graded Prognostic Assessment) score. The goal of our study was to determine prognostic factors which influence outcome in patients who undergo surgery for brain metastases and to compare different outcome scores.Methods:Two hundred and twenty-nine patients who underwent surgery for brain metastases in our institution between January 2005 and December 2014 were included in the study. Patient data were evaluated retrospectively.Results:The mean survival time was 19.2 months (median survival time, MST: 8 months), for patients with a single metastasis (n = 149) 17.6 months (MST: 8 months), and for patients with multiple metastases (n = 80) 17.9 months (MST: 6 months). Significant influence on MST had age <65 years (9 vs. 5 months, P = 0.002), female sex (10 vs. 6 months, P < 0.001), RPA Class I and II (11 vs. 4 months, P < 0.001), Karnofsky score >70% (11 vs. 4 months, P < 0.001), and postoperative radiotherapy (8 vs. 5 months, P < 0.002). To evaluate the diagnostic power of DS-GPA and RPA score in respect of survival, two Cox regressions were modeled, where the RPA classification showed a better predictive power.Conclusion:Favorable factors for prolonged survival were KPS >70%, RPA Class I and II, age <65 years, female sex, a DS-GPA Score of 2.5–3 and 3.5–4, and adjuvant radiotherapy. The RPA Classification was more accurate in predicting the outcome than the DS-GPA score.

Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy.

The purpose of this study was to evaluate the prognostic factors associated with overall survival (OS) in nonsmall cell lung cancer (NSCLC) patients with brain metastasis who received whole-brain radiotherapy (WBRT). This study included 264 consecutive NSCLC patients with brain metastasis who received WBRT. Patients with leptomeningeal metastasis and those who underwent craniotomy or stereotactic radiotherapy before WBRT were excluded. The evaluated prognostic factors for OS included gender, neurological deficit, histology, epidermal growth factor receptor (EGFR) mutation status, previous cytotoxic chemotherapy, previous EGFR-tyrosine kinase inhibitor treatment, recursive partitioning analysis (RPA) class, and diagnosis-specific graded prognostic assessment (DS-GPA) score. All factors with a P < 0.05 in univariate analysis were entered into multivariate analysis using Cox regression and a confidence interval of 99%. Two hundred thirty patients had died, 14 patients were alive, and 20 patients were lost to follow-up. The median follow-up time was 20.9 months. The median survival time was 5.5 months (95% confidence interval; 4.8-6.3). Univariate analysis showed that gender, neurological deficit, histology, EGFR mutation status, RPA class, and DS-GPA score were significant prognostic factors for OS. In multivariate analysis, RPA class and histology were found to be significant prognostic factors for OS, with P values of 0.0039 and 0.0014, respectively. RPA Class I or II (Karnofsky Performance Status ≥70) and adenocarcinoma histology were associated with longer OS. These factors should be taken into account when considering indication for WBRT.

Linear accelerator-based stereotactic radiosurgery in 140 brain metastases from malignant melanoma.

BackgroundTo retrospectively access outcome and prognostic parameters of linear accelerator-based stereotactic radiosurgery in brain metastases from malignant melanoma.MethodsBetween 1990 and 2011 140 brain metastases in 84 patients with malignant melanoma (median age 56 years) were treated with stereotactic radiosurgery. At initial stereotactic radiosurgery 48 % of patients showed extracerebral control. The median count of brain metastases in a single patient was 1, the median diameter was 12 mm. The median dose applied was 20 Gy/80 % isodose enclosing.ResultsThe median follow-up was 7 months and the median overall survival 9 months. The 6-, 12- and 24 month overall survival rates were 71 %, 39 % and 25 % respectively. Cerebral follow-up imaging showed complete remission in 20 brain metastases, partial remission in 39 brain metastases, stable disease in 54 brain metastases, progressive disease in 24 brain metastases and pseudo-progression in 3 brain metastases. Median intracerebral control was 5.3 months and the 6- and 12-month intracerebral progression-free survival rates 48 % and 38 %, respectively. Upon univariate analysis, extracerebral control (log-rank, p < 0.001), the response to stereotactic radiosurgery (log-rank, p < 0.001), the number of brain metastases (log-rank, p = 0.007), the recursive partitioning analysis class (log-rank, p = 0.027) and the diagnosis-specific graded prognostic assessment score (log-rank, p = 0.011) were prognostic for overall survival. The most common clinical side effect was headache common toxicity criteria grade I. The most common radiological finding during follow-up was localized edema within the stereotactic radiosurgery high dose region.ConclusionStereotactic radiosurgery is a well-tolerated and effective treatment option for brain metastases in malignant melanoma and was able to achieve local remissions in several cases. Furthermore, especially patients with controlled extracerebral disease and a low count of brain metastases seem to benefit from this treatment modality. Prospective trials analysing the effects of combined stereotactic radiosurgery and new systemic agents are warranted.

Prognostic Models Predicting Survival of Patients with Brain Metastases: Integration of Lactate Dehydrogenase, Albumin and Extracranial Organ Involvement

AimsTo explore the role of expanded assessment of metastatic extracranial organ involvement, as well as albumin and lactate dehydrogenase (LDH), i.e. surrogates of disease extent, in survival prediction models for patients with brain metastases. Materials and methodsA retrospective analysis of 189 patients treated with whole brain radiotherapy was carried out. Uni- and multivariate analyses included recursive partitioning analysis classes, basic score for brain metastases and diagnosis-specific graded prognostic assessment (DS-GPA). ResultsElevated LDH correlated significantly with extracranial organ involvement, low albumin with primary tumour type and primary tumour control. Elevated LDH, low albumin and a combination of both correlated significantly with overall survival. LDH, albumin and the number of extracranial organs involved (none, one, two or more harbouring metastases) were independent prognostic factors in multivariate analyses (if added to the three established scores mentioned above and also if added to individual parameters such as age, performance status, etc.). A combination of these three new prognostic factors predicted very short survival (median 0.7 months if all three were present). ConclusionWe have previously defined patient groups in whom foregoing radiotherapy was unlikely to compromise survival. These were patients with a DS-GPA score of 0–1.5 points and age ≥75 years or Karnofsky performance status ≤50 or uncontrolled primary tumour with extracranial metastases to at least two organs. Patients with a combination of three new adverse features (elevated LDH plus low albumin plus extracranial metastases to at least two organs) might also be considered for best supportive care. Furthermore, it appears warranted to study whether scores such as DS-GPA can be optimised by integrating information on these three parameters.

Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases

Survival upon diagnosis of brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) is highly variable and established prognostic scores do not include tissue-based parameters. Patients who underwent neurosurgical resection as first-line therapy for newly diagnosed NSCLC BM were included. Microvascular density (MVD), Ki67 tumor cell proliferation index and hypoxia-inducible factor 1 alpha (HIF-1 alpha) index were determined by immunohistochemistry. NSCLC BM specimens from 230 patients (151 male, 79 female; median age 56 years; 199 nonsquamous histology) and 53/230 (23.0%) matched primary tumor samples were available. Adjuvant whole-brain radiation therapy (WBRT) was given to 153/230 (66.5%) patients after neurosurgical resection. MVD and HIF-1 alpha indices were significantly higher in BM than in matched primary tumors. In patients treated with adjuvant WBRT, low BM HIF-1 alpha expression was associated with favorable overall survival (OS), while among patients not treated with adjuvant WBRT, BM HIF-1 alpha expression did not correlate with OS. Low diagnosis-specific graded prognostic assessment score (DS-GPA), low Ki67 index, high MVD, low HIF-1 alpha index and administration of adjuvant WBRT were independently associated with favorable OS. Incorporation of tissue-based parameters into the commonly used DS-GPA allowed refined discrimination of prognostic subgroups. Ki67 index, MVD and HIF-1 alpha index have promising prognostic value in BM and should be validated in further studies.

Best supportive care in patients with brain metastases and adverse prognostic factors: development of improved decision aids

This study aimed to develop a survival prediction model that might aid decision making when choosing between best supportive care (BSC) and brain radiotherapy (RT) for patients with brain metastases and limited survival expectation. A retrospective analysis of 124 patients treated with BSC, whole brain radiotherapy (WBRT), or radiosurgery was conducted. All patients had adverse prognostic features defined as 0-1.5 points according to the diagnosis-specific graded prognostic assessment score (DS-GPA) or GPA if primary tumor type was not among those represented in DS-GPA. Kaplan-Meier survival curves were compared between patients treated with BSC or RT in different scenarios, reflecting more or less rigorous definitions of poor prognosis. If survival was indistinguishable and this result could be confirmed in multivariate analysis, BSC was considered appropriate. Irrespective of point sum examined, DS-GPA by itself was not a satisfactory selection parameter. However, we defined a subgroup of 63 patients (51 %) with short survival irrespective of management approach (only 5 % of irradiated patients survived beyond 6 months; they had newly diagnosed, treatment-naïve lung cancer), i.e., patients in whom foregoing RT was unlikely to compromise survival. These were patients with 0-1.5 points and aged ≥ 75 years, had Karnofsky performance status ≤ 50, or had uncontrolled primary tumor with extracranial metastases to at least two organs. BSC is a reasonable choice in patients with limited life expectancy. After successful external validation of the selection criteria developed in this analysis, identification of patients who are unlikely to benefit from WBRT might be improved.

Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer

Purpose Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Patients and Methods Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. Results Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. Conclusion Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.

Validation of Recursive Partitioning Analysis and Diagnosis-Specific Graded Prognostic Assessment in patients treated initially with radiosurgery alone

Brain metastases present a therapeutic challenge because patients with metastatic cancers live longer now than in the recent past due to systemic therapies that, while effective, may not penetrate the blood-brain barrier. In the present study the authors sought to validate the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), a new prognostic index that takes into account the histological characteristics of the primary tumor, and the Radiation Therapy Ontology Group Recursive Partitioning Analysis (RPA) system by using a single-institution database of patients who were treated initially with stereotactic radiosurgery (SRS) alone for brain metastases. Investigators retrospectively identified adult patients who had undergone SRS at a single institution, MD Anderson Cancer Center, for initial treatment of brain metastases between 2003 and 2010 but excluded those who had undergone craniotomy and/or whole-brain radiation therapy at an earlier time; the final number was 251. The Leksell Gamma Knife was used to treat 223 patients, and a linear accelerator was used to treat 28 patients. The patient population was grouped according to DS-GPA scores as follows: 0-0.5 (7 patients), 1 (33 patients), 1.5 (25 patients), 2 (63 patients), 2.5 (14 patients), 3 (68 patients), and 3.5-4 (41 patients). The same patients were also grouped according to RPA classes: 1 (24 patients), 2 (216 patients), and 3 (11 patients). The most common histological diagnoses were non-small cell lung cancer (34%), melanoma (29%), and breast carcinoma (16%). The median number of lesions was 2 (range 1-9) and the median total tumor volume was 0.9 cm(3) (range 0.3-22.9 cm(3)). The median radiation dose was 20 Gy (range 14-24 Gy). Stereotactic radiosurgery was performed as the sole treatment (62% of patients) or combined with a salvage treatment consisting of SRS (22%), whole-brain radiation therapy (12%), or resection (4%). The median duration of follow-up was 9.4 months. In this patient group the median overall survival was 11.1 months. The DS-GPA prognostic index divided patients into prognostically significant groups. Median survival times were 2.8 months for DS-GPA Scores 0-0.5, 3.9 months for Score 1, 6.6 months for Score 1.5, 12.9 months for Score 2, 11.9 months for Score 2.5, 12.2 months for Score 3, and 31.4 months for Scores 3.5-4 (p < 0.0001). In the RPA groups, the median overall survival times were 38.8 months for Class 1, 9.4 months for Class 2, and 2.8 months for Class 3 (p < 0.0001). Neither the RPA class nor the DS-GPA score was prognostic for local tumor control or new lesion-free survival. A multivariate analysis revealed that patient age > 60 years, Karnofsky Performance Scale score ≤ 80%, and total lesion volume > 2 cm(3) were significant adverse prognostic factors for overall survival. Application of the DS-GPA to a database of patients with brain metastases who were treated with SRS appears to be valid and offers additional prognostic refinement over that provided by the RPA. The DS-GPA may also allow for improved selection of patients to undergo initial SRS alone and should be studied further.

A nomogram for individualized estimation of survival among patients with brain metastasis

An estimated 24%-45% of patients with cancer develop brain metastases. Individualized estimation of survival for patients with brain metastasis could be useful for counseling patients on clinical outcomes and prognosis. De-identified data for 2367 patients with brain metastasis from 7 Radiation Therapy Oncology Group randomized trials were used to develop and internally validate a prognostic nomogram for estimation of survival among patients with brain metastasis. The prognostic accuracy for survival from 3 statistical approaches (Cox proportional hazards regression, recursive partitioning analysis [RPA], and random survival forests) was calculated using the concordance index. A nomogram for 12-month, 6-month, and median survival was generated using the most parsimonious model. The majority of patients had lung cancer, controlled primary disease, no surgery, Karnofsky performance score (KPS) ≥ 70, and multiple brain metastases and were in RPA class II or had a Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 1.25-2.5. The overall median survival was 136 days (95% confidence interval, 126-144 days). We built the nomogram using the model that included primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. The potential use of individualized survival estimation is demonstrated by showing the heterogeneous distribution of the individual 12-month survival in each RPA class or DS-GPA score group. Our nomogram provides individualized estimates of survival, compared with current RPA and DS-GPA group estimates. This tool could be useful for counseling patients with respect to clinical outcomes and prognosis.