The prognostic factors of lung cancer patients with brain metastases treated with radiotherapy

Purpose: To analyze the prognostic factors of lung cancer with brain metastases (BM) and evaluate the role of cranial irradiation on survival. Methods and materials: From 1987 to 1994, 159 lung cancer patients with CT scan documented BM were reviewed. All of them underwent cranial irradiation (median radiation dose: 30 Gy). Chemotherapy and surgery of BM were performed in 21 and 10 cases, respectively. Results: Overall median survival was 3.5 months and one year survival rate was 10.69%. Univariate analysis showed that the significant factors were performance status, age, total radiation dose to brain, BM as the first metastasis, neurosurgery, symptoms of urine/stool incontinence, and synchronous BM. Multivariate analysis indicated that (1) performance status (p=0.0002), (2) total radiation dose (p=0.0032), (3) BM as the first metastasis (p=0.0449), (4) neurosurgery (p = 0.0233), (5) symptoms of urine/stool incontinence (p = 0.0002), and (6) the presence of a midline shift on cranial CT scans (p = 0.0063) were significant prognostic factors. Conclusion: The prognosis of BM in lung cancer patients is extremely poor. Radiotherapy appears as an effective means of palliation with 75% overall symptomatic response rate. Higher radiation dose ( 30 Gy) and neurosurgery are associated with longer survival. Good performance status, BM as the first metastasis, absence of sphincter dysfunction, and midline shift on CT scans are favorable prognostic predictors. The role of midline shift is very interesting and needs to be explored further.     

Prognostic factors for survival in melanoma patients with brain metastases

BACKGROUND:

One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS).

METHODS:

An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS.

RESULTS:

Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded.

CONCLUSIONS:

The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials. Cancer 2011. © 2010 American Cancer Society.     

28例脑转移瘤放射治疗疗效分析

目的:探讨脑转移瘤放疗疗效及预后因素。方法:从2000年5月～2002年5月对28例脑转移瘤进行放射治疗。采用6MV-X线,两侧平行相对野作全脑照射,(1.8～2)Gy/次,(36～40)Gy后缩野针对转移灶加量(14～20)Gy。结果:影像学有效率64.3%。中位生存期5.6个月,6个月生存率46.4%,1年生存率21.4%。结论:影响预后的因素主要有:KPS评分、脑转移数目、颅外有无转移和原发灶是否控制。     

Brain metastases in lung cancer

Brain metastases secondary to primary non-small cell and small cell lung cancer have become an important area of research. The brain is one of the most common sites of failure following treatment for locally advanced non-small cell lung cancer, often as the only site. Treatment strategies and the outcome for brain metastases from lung cancer may differ from brain metastases arising from other primary cancers. This article reviews the prognostic factors associated with brain metastases from lung cancer, as well as current treatment approaches with chemotherapy, surgery and radiation therapy.     

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.     

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases

Introduction Whole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma in terms of symptom palliation, especially when extracranial systemic disease is present. Temozolomide (TMZ) has shown efficacy in the treatment of metastatic melanoma. The objective was to evaluate the potential benefit in survival of two different schedules of total dose and fractionation (20 Gy/5 fractions vs 30 Gy/10 fractions) and further TMZ based chemotherapy. Materials and method We have conducted a retrospective study in a group of twenty-one patients (RTOG Recursive Partitioning Analysis class II) of the use of WBRT with 20 Gy/5 fractions (n=11) and 30 Gy/10 fractions (n=10). All patients received further TMZ based chemotherapy administered as a single chemotherapeutic agent or in combination with chemo-immunotherapy. Results Prognostic variables such as: age, Karnofsky performance status, extracranial metastases and number of brain metastases, were analyzed in both groups of treatment without statistically significant differences. The median survival time (MST) for WBRT 20 Gy group was 4 months (CI 95%: range 2–6 months) and for WBRT 30 Gy group was 4 months (CI 95%: range 0–7 months) without statistically significant differences (Log rank p=0.74). There was one complete response and two partial responses. Conclusions The results suggest that MST was not significantly affected by the total dose/fractionation schedule.     

Radiotherapy and chemotherapy of brain metastases

Summary The authors have reviewed the results, the indications and the controversies regarding radiotherapy and chemotherapy of patients with newly diagnosed and recurrent brain metastases. Whole-brain radiotherapy, radiosurgery, hypofractionated stereotactic radiotherapy, brachytherapy and chemotherapy are the available options. New radiosensitizers and cytotoxic or cytostatic agents are being investigated. Adjuvant whole brain radiotherapy, either after surgery or radiosurgery, and prophylactic cranial irradiation in small-cell lung cancer are discussed, taking into account local control, survival, and risk of late neurotoxicity. Increasingly, the different treatments are tailored to the different prognostic subgroups, as defined by Radiation Therapy Oncology Group RPA Classes.     

Excision of solitary brain metastases: Effect on survival

Retrospective analysis of 88 patients treated for brain metastases at Veterans Administration and Erie County Medical Centers, Buffalo, New York, between January 1975 and August 1980 is presented. Patients were followed until January 1981. They were classified into three groups: Group I—15 patients with solitary brain metastases treated by surgical excision followed by radiotherapy (SBM-S). Group II—32 patients with solitary brain metastases treated by radiotherapy alone (SBM-RT). Group III—41 patients with multiple brain metastases treated by radiotherapy (MBM-RT). The average survival was 216 days for the first group versus 80 and 106 days for the second and third groups, respectively. Three patients in the first group were still living at five, eighteen, and twenty-one months versus one patient each in the second and third group at five months. When brain metastases appeared either at time of presentation or within two months from the diagnosis of the primary disease, excision of solitary brain metastases did not prolong survival. Survival periods were 114, 53, and 81 days for Group I, II, and III, respectively. When brain metastasis appeared after a minimum of two months from the treatment of the primary lesion, excision of solitary brain metastasis did prolong patient survivals for 286 days versus 128 and 94 days for Groups I, II, and III, respectively. When the primary site of origin was inoperable lung cancer or unknown primary cancer no difference in survival between the three groups, survival was 80, 50, and 70 days for Groups I, II, and III, respectively. Percentage survival at 2, 6, and 12 months was 67%, 53%, and 27% in the first group versus 32%, 16%, and 3% for the second group and 41%, 15%, and 5% for the third group. We conclude that excision of solitary brain metastasis might prolong survival in selected patients.     

Prognostic index to identify patients who may not benefit from whole brain radiotherapy for multiple brain metastases from lung cancer

Palliative whole brain radiotherapy (WBRT) is often recommended in the management of multiple brain metastases. Allowing for WBRT waiting time, duration of the WBRT course and time to clinical response, it may take 6 weeks from the point of initial assessment for a benefit from WBRT to manifest. Patients who die within 6 weeks (‘early death’) may not benefit from WBRT and may instead experience a decline in quality of life. This study aimed to develop a prognostic index (PI) that identifies the subset of patients with lung cancer with multiple brain metastases who may not benefit from WBRT because of ‘early death’. The medical records of patients with lung cancer who had WBRT recommended for multiple brain metastases over a 10-year period were retrospectively reviewed. Patients were classified as either having died within 6 weeks or having lived beyond 6 weeks. Potential prognostic indicators were evaluated for correlation with ‘early death’. A PI was constructed by modelling the survival classification to determine the contribution of these factors towards shortened survival. Of the 275 patients recommended WBRT, 64 (23.22%) died within 6 weeks. The main prognostic factor predicting early death was Eastern Cooperative Oncology Group (ECOG) status >2. Patients with a high PI score (>13) were at higher risk of ‘early death’. Twenty-three per cent of patients died prior to benefit from WBRT. ECOG status was the most predictive for ‘early death’. Other factors may also contribute towards a poor outcome. With further refinement and validation, the PI could be a valuable clinical decision tool.     

全脑放疗联合替莫唑胺治疗肺癌脑转移疗效观察

目的:探讨全脑放疗（WBRT）联合替莫唑胺（TMZ）治疗非小细胞肺癌（NSCLC）脑转移的疗效。方法:回顾分析本院2010年-2014年收治的37例接受WBRT联合TMZ同步治疗及TMZ辅助治疗的NSCLC脑转移患者疗效。WBRT剂量30Gy,TMZ放疗同步口服75mg/(m2·d),序贯给予TMZ 150~200mg/(m2·d),连续5天,28天为1周期,3~6周期。结果:完全缓解10.8%(4/37),部分缓解40.5%(15/37)。中位无进展生存时间和中位生存时间分别为8和10个月。最常见不良反应恶心、呕吐,中性粒细胞减少和血小板减少的发生率分别为59.5%（22/37）,32.4%（12/37）,35.1%（13/37）。结论:WBRT联合TMZ同步治疗及TMZ辅助化疗治疗NSCLC脑转移癌安全有效,耐受性良好,不良反应轻,可作为脑转移癌放化疗综合治疗模式之一进行深入研究。     

Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases

Background:

Synchronous metastases of colorectal cancer (CRC) are considered to be of worse prognostic value compared with metachronous metastases, but only few and conflicting data have been reported on this issue.

Methods:

We retrospectively investigated patient demographics, primary tumour characteristics and overall survival (OS) in 550 advanced CRC patients with metachronous vs synchronous metastases, who participated in the phase III CAIRO study. For this purpose only patients with a prior resection of the primary tumour were considered.

Results:

The clinical and pathological characteristics associated with poor prognosis that we observed more often in patients with synchronous metastases (n=280) concerned an abnormal serum lactate dehydrogenase (LDH) concentration (P=0.01), a worse WHO performance status (P=0.02), primary tumour localisation in the colon (P=0.002) and a higher T stage (P=0.0006). No significant difference in median OS was observed between patients with synchronous metastases and metachronous metastases (17.6 vs 18.5 months, respectively, P=0.24).

Conclusion:

Despite unfavourable clinicopathological features in patients with synchronous metastases with a resected primary tumour compared to patients with metachronous metastases, no difference in the median OS was observed. Possible explanations include a (partial) chemoresistance in patients with metachronous disease because of previous adjuvant treatment, whereas differences between the two groups in screening procedures resulting in a lead time bias to diagnosis or in prognostic molecular markers remain speculative.     

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

Background:

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.

Methods:

Performance of the msGPA was assessed in Cohort I (1997–2008, n=231) and Cohort II (2008–2013, n=162) using Kaplan–Meier methods and Harrell''s c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.

Results:

The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.

Conclusions:

An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care.     

基于不同部位评估脑转移癌患者全脑放疗后近期认知功能动态变化

目的 通过动态监测不同部位脑转移癌患者全脑放疗后认知功能变化,探讨全脑放疗对脑认知功能的影响及与颅内转移灶部位的关系.方法 选取行全脑放疗脑转移癌患者88例为研究对象,按照颅内病灶主要部位分为A1组(31例,小脑、脑干)、A2组(57例,额叶、颞叶),在放疗前1周、放疗后1~3个月采用简易精神状态量表(MMSE)、词汇流畅性试验(VFT)、数字广度试验(DS)评估患者总体认知功能.结果 放疗前1周A2组MMSE评分24~26分所占比例高于A1组,A2组MMSE、DS、VFT评分明显低于A1组(P<0.05);入组患者放疗后1个月内复查MRI,A1组总有效率为32.26%,A2组为70.18%,两组比较差异有统计学意义(Z=3.044,P=0.002);A1组患者放疗前与放疗后1~3个月MMSE无明显变化(P>0.05),A2组患者放疗后MMSE高于放疗前(P<0.05),且放疗后1~3个月有逐渐升高趋势.结论 全脑放疗对不同部位脑转移癌患者近期总体认知功能的影响不同,其中额叶、颞叶部位脑转移癌患者放疗后认知功能有明显改善,认知功能障碍可能与额叶、颞叶结构及功能改变相关.     

腋窝淋巴结1～3个转移的早期乳腺癌根治术后局部复发和生存预后因素的研究

背景与目的：腋窝淋巴结1—3个阳性的早期乳腺癌进行辅助放射治疗的指征尚未明确,本研究探讨这部分患者根治术后的局部／区域复发以及生存的危险预后因素。方法：回顾性分析1998年3月至2002年3月在中山大学肿瘤防治中心接受标准或改良根治手术的217例乳腺癌病例的资料,原发肿瘤病理分期pT1期71例,pT2期146例,其中202例接受辅助化疗,51例接受辅助放疗,116例接受术后内分泌治疗。结果：中位随访时间69个月,全组的5年无局部复发生存率、无瘤生存率和总生存率分别为85．2％、81．8％和90．2％。44例出现肿瘤复发,其中21例局部／区域复发。生存分析表明,局部／区域复发患者的5年总生存率明显低于局部／区域控制的患者（61．9％vs93．6％,P〈0．0001）,患者年龄≤35岁、原发肿瘤pT2期和腋窝淋巴结转移比例≥30％是影响无局部复发生存率、无病生存率和总生存率的不良预后因素。根据这3项预后影响因素设立评分系统,发现不同分值病例的5年无局部／区域复发生存率差异具有统计学意义（P=0．0072）。在辅助化疗≥5疗程的159例患者中,接受辅助放疗的35例患者的各项生存率指标均优于未作放射治疗的患者。结论：对于腋窝淋巴结1～3个阳性的早期乳腺癌患者,年龄≤35岁、pT2期原发肿瘤和腋窝淋巴结转移比例≥30％提示术后局部／区域复发危险较高．应考虑辅助放疗。     

Survival with brain metastases following radiation therapy

The onset of intracranial metastases is a common development during the course of malignancy. The treatment of these patients represents a significant workload in any radiation oncology department. Much debate has occurred regarding the most appropriate fractionation schedules employed given the perception of limited life expectancy and symptomatic relief following cranial radiation. The aim of this study was to identify the spectrum of primary sites in patients developing intracranial metastases and to assess survival postradiation for the group overall and for selected subgroups. The records of 378 patients undergoing palliative cranial radiation in the years 1993?1998 at Sydney's Mater and Royal North Shore hospitals were analysed retrospectively. Major primary sites were lung (42%), breast (18%), colorectal (9%), melanoma (7%), and unknown primary (7%). Overall median survival post‐treatment was 3 months. Lung cancer patients showed a median survival of 6 months, breast 5 months, colorectal 4 months and melanoma 3 months. Long‐term survivors were noted with up to 15% of certain groups alive beyond 12 months and 2% alive at 24 months. Multivariate analysis revealed improved survival in patients undergoing resection, and those receiving higher dose radiation justifying a more aggressive approach in selected patients.     

Prognostic factors and a scoring system for survival after radiotherapy for metastases to the spinal column: a review of 544 patients at Shizuoka Cancer Center Hospital

BACKGROUND: To optimize selection of a radiotherapy schedule for patients with spinal metastases, the authors analyzed prognostic factors and developed a scoring system to predict survival in such patients. METHODS: Five-hundred forty-four patients with spinal metastases received radiotherapy at Shizuoka Cancer Center Hospital between September 2002 and November 2006. Prognostic factors for survival were studied using a Cox proportional hazards model, and a scoring system was developed based on regression coefficients: Three points were given for an unfavorable tumor type and bad performance status (> or =3); 2 points were given for hypercalcemia, visceral metastases, and previous chemotherapy; and 1 point was given for multiple bone metastases and age > or =71 years. RESULTS: The overall survival rates after 6 months, 12 months, and 24 months were 49%, 32%, and 19%, respectively, and the median survival was 5.9 months (95% confidence interval, 4.9-6.8 months). In total, 503 patients (93%) were followed for > or =12 months or until death. These patients were separated into Groups A, B, and C based on scores of 0 to 4, 5 to 9, and 10 to 14, respectively. These groups included 24%, 57%, and 19% of patients, respectively; and the mean median survival for Groups A, B, and C was 27.1 months, 5.4 months, and 1.8 months, respectively. Overall survival rates after 6 months, 12 months, and 24 months were 89%, 77%, and 54% in Group A; 46%, 22%, and 9% in Group B; and 7%, 4%, and 0% in Group C, respectively (P < .001). CONCLUSIONS: The scoring system was able to predict the survival of patients with spinal metastases and may be useful for selecting an optimal radiotherapy schedule.     

X射线立体定向放射治疗多发脑转移瘤的价值

目的　探讨X射线立体定向放射治疗多发脑转移瘤的疗效。方法　在 4种预后因素(年龄、治疗前卡氏评分、有无其他部位转移及转移灶数目 )相同或相似的条件下 ,配对选择两组病例。X射线立体定向放射治疗加常规放射治疗组 (研究组 )和常规放射治疗组 (对照组 )各 53例。在研究组中 ,X射线立体定向放射治疗采用单次照射 40例 ,分次照射 1 3例 ;单次靶区平均周边剂量为 2 0Gy,分次照射剂量为 4～ 1 2Gy/次 ,2次 /周 ,总剂量为 1 5～ 30Gy。X射线立体定向放射治疗结束后即开始全脑放射治疗。对照组采用全脑照射 30～ 40Gy,3～ 4周。结果　研究组和对照组中位生存期分别为1 1 .6、6 .7个月 (P <0 .0 5) ;1年生存率分别为 44 .3 %、1 7.1 % (P <0 .0 1 ) ;1年局部控制率分别为50 .9%、1 3 .2 % (P <0 .0 5) ;治疗后 1个月卡氏评分增加者分别占 69.8%、30 .2 % (P <0 .0 1 ) ;治疗后 3个月影像学上的有效率分别为 82 .0 %、55 .0 % (P <0 .0 1 )。在死因分析中 ,研究组死于脑转移的占2 3 .3 % ,比对照组的 51 .0 %低 (P <0 .0 5)。两组病例放射并发症的发生率相似。结论　对于多发脑转移瘤 ,X射线立体定向放射治疗加常规放射疗在提高局部控制率、延长生存期和提高生存质量方面均优于单纯放射治疗。     

脑转移瘤的治疗

随着恶性肿瘤患者病情的发展,发生脑转移瘤的概率可达到20%-40%。因此,脑转移瘤治疗方案的优化对延长患者的生存期和改善生存质量具有重要意义。本文综述了近年来国内外手术、放疗、化疗等治疗脑转移瘤相关的临床研究,对脑转移瘤的规范化治疗进行探讨。     

Hypofractionated stereotactic radiotherapy in combination with whole brain radiotherapy for brain metastases

BACKGROUND: The efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) in combination with whole brain radiotherapy (WBRT), for the treatment of 1-4 brain metastases, using a non invasive fixation of the skull, was investigated. METHODS: Between 04/2001 and 01/2006 30 patients with 44 brain metastases underwent irradiation. Every patient received WBRT (10 x 3 Gy); 41/44 lesions received HSRT boost with a median dose fraction of 6 Gy, the fractionation schemes were 3 x 6 Gy and 4 x 8 Gy; a median total dose of 18 Gy was delivered to the tumor isocenter. RESULTS: The median survival period was 9.15 months, the actuarial 1-year overall survival and freedom from new brain metastases were 36.6% and 87.9%, respectively; at univariate analysis Karnofsky Performance Status (KPS) was statistically significant (P = 0.05); the actuarial 1-year local control for the 41/44 lesions was 86.1%. No patient had acute or late complications. CONCLUSIONS: HSRT as a concomitant boost during WBRT is a safe and well tolerated treatment for selected patients with brain metastases.     

Population-based estimates of survival among elderly patients with brain metastases

BackgroundPrognostic estimates for patients with brain metastases (BM) stem from younger, healthier patients enrolled in clinical trials or databases from academic centers. We characterized population-level prognosis in elderly patients with BM.MethodsUsing Surveillance, Epidemiology, and End Results (SEER)–Medicare data, we identified 9882 patients ≥65 years old with BM secondary to lung, breast, skin, kidney, esophageal, colorectal, and ovarian primaries between 2014 and 2016. Survival was assessed by primary site and evaluated with Cox regression.ResultsIn total, 2765 versus 7117 patients were diagnosed with BM at primary cancer diagnosis (synchronous BM, median survival = 2.9 mo) versus thereafter (metachronous BM, median survival = 3.4 mo), respectively. Median survival for all primary sites was ≤4 months, except ovarian cancer (7.5 mo). Patients with non-small-cell lung cancer (NSCLC) receiving epidermal growth factor receptor (EGFR)– or anaplastic lymphoma kinase (ALK)–based therapy for synchronous BM displayed notably better median survival at 12.5 and 20.1 months, respectively, versus 2.8 months exhibited by other patients with NSCLC; survival estimates in melanoma patients based on receipt of BRAF/MEK therapy versus not were 6.7 and 2.8 months, respectively. On multivariable regression, older age, greater comorbidity, and type of managing hospital were associated with poorer survival; female sex, higher median household income, and use of brain-directed stereotactic radiation, neurosurgical resection, or systemic therapy (versus brain-directed non-stereotactic radiation) were associated with improved survival (all P < 0.05).ConclusionsElderly patients with BM have a poorer prognosis than suggested by prior algorithms. If prognosis is driven by systemic and not intracranial disease, brain-directed therapy with potential for significant toxicity should be utilized cautiously.