αv‐Integrin isoform expression in primary human tumors and brain metastases

To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of αvβ3, αvβ5, αvβ6 and αvβ8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of αv integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. Integrin αvβ3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non‐small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p < 0.01). Similarly, integrin αvβ8 expression was increased in brain metastases compared to primary tumors of breast cancer (p < 0.0001), lung cancer (p < 0.01) and renal cancer (p < 0.0001), with a similar trend in metastatic melanoma. Integrin αvβ5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p < 0.05). Also integrin αvβ6 expression was increased in brain metastases compared to primary breast cancer (p < 0.001). Conclusions: The stronger αv‐integrin expression in brain metastases, especially of αvβ3 and αvβ8 integrins, suggests that certain αv integrin are involved in the process of brain metastasis. αv Integrins may be therapeutic targets for patients with metastatic cancer in brain.     

Phase II trial of cisplatinum and etoposide in brain metastases of solid tumors

Fourteen patients with brain metastases (BM) of solidtumors received intravenous cisplatinum, 40 mg/m2/day, and etoposide,150 mg/m2/day, for 3 days every 3 weeks.Primary tumors were lung (8 patients), breast (4),colon (1), and stomach (1). Two patients responded(1 complete response in a poorly differentiated lungcancer patient and 1 partial response in abreast cancer patient). The overall response rate was14%, with a median survival of 6 months.Main toxicity was grade 3–4 neutropenia that occurredin 36% of patients. There were no toxic-relateddeaths. Chemotherapy as a single therapeutic regimen seemsnot to be an effective treatment for BMfrom relatively resistant solid tumors. Moreover, it producesrather high, although not life-threatening, hematologic toxicity.     

Presentation,patterns of care,and survival in patients with brain metastases

BACKGROUND:

It is largely unknown to what extent new oncologic treatment options have improved survival of patients with brain metastasis in recent decades. Therefore, a multi‐institutional time‐staggered analysis was performed.

METHODS:

Two cohorts of 103 patients each were analyzed, one treated between 2005 and 2009 and the other between 1983 and 1989, ie, approximately 20 years earlier. Stratified analyses by prognostic groups were also performed (graded prognostic assessment [GPA] and Radiation Therapy Oncology Group recursive partitioning analysis [RTOG‐RPA]).

RESULTS:

Patterns of care have changed significantly. Contemporary patients received focal treatments such as stereotactic radiosurgery and surgical resection far more frequently. Furthermore, systemic treatment was used more often in contemporary patients, both before and after diagnosis of brain metastasis. Improved survival was observed in the contemporary cohort (P = .03). The 1‐year survival rate increased from 15% (95% confidence interval [CI], 7%‐25%) to 34% (95% CI, 25%‐44%). However, this improvement was largely driven by patients with favorable prognostic features. More than 40% of the patients still belong to unfavorable prognostic groups with limited median survival and little improvement.

CONCLUSIONS:

Contemporary patients were managed on a much more individualized basis, requiring multidisciplinary case discussion and thorough assessment of prognostic features. Progress has been made, but the overall outcome needs to be improved further. Avoiding overtreatment in patients with poor prognosis is as important as aggressive treatment in patients who might survive for several years. Cancer 2011. © 2010 American Cancer Society.     

Melanoma-induced brain metastases

Brain metastases are a common site of metastasis from malignant melanoma, and are associated with a poor prognosis. Diagnosis of brain metastasis may also have significant implications for quality of life, and management can be difficult due to rapid progression of disease and resistance to conventional therapies. In this article, we will review the published evidence for treatment modalities for melanoma-induced brain metastases and outline future directions for research. In brief, surgical management of solitary or acutely symptomatic lesions appears to alleviate symptoms and provide the possibility of local control of disease. Stereotactic radiosurgery is an increasingly utilized technique for patients with a limited number of metastases, and presents a less invasive alternative to craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, though combined chemotherapy with external-beam radiation is being investigated. Future directions include combined-modality therapy, the incorporation of novel agents, and careful consideration of the structure of clinical trials for this disease.     

脑转移瘤发生机制的研究进展

在恶性肿瘤发展的过程中,发生脑转移瘤的概率可达20%~40%,且正在上升。未经治疗的脑转移瘤有着极差的预后,因此,进一步了解其发生机制,并以此为基础优化治疗方案十分重要。本文将对脑转移瘤的形成机制做一综述     

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.     

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.     

Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma

Summary Purpose We performed a retrospective study of patients with diffuse pontine glioma (DPG) who suffered neuraxis metastasis (NM) and characterized the incidence, clinical features, radiologic findings, and patterns of disease dissemination. Methods Magnetic resonance imaging (MRI) of brain and spine was used to assess NM. Some patients also underwent magnetic resonance spectroscopy (MRS) (6 patients) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans (13 patients) to further evaluate areas of metastatic disease. Three patients had histologic confirmation of disease at the site of NM. Results Between 1986 and 2003, 18 of 96 patients (17.3%) with DPG developed NM. The median age at diagnosis was 8 years (range, 4–17). All patients had adjuvant chemotherapy and/or focal radiotherapy at diagnosis. The NM occurred at a median of 15 months from diagnosis of DPG (range, 3–96). Three patterns of NM were seen on MRI of brain and spine in these patients; 8 (39%) had parenchymal (PM), 4 (22%) leptomeningeal (PM), 2 (11%) subependymal, and in 5 a combination of two or more patterns. The MRS and FDG-PET scan of suspected areas of metastatic disease was consistent with tumor in 6 of 6 and 12 of 13 patients who underwent these procedures respectively. Three patients also had histologic confirmation of malignant glioma at the site of NM. Despite salvage therapy, all 18 patients have died of disease at a median of 5 months (range, 0.5–20) from diagnosis of neuraxis spread. Conclusion Our study emphasizes the need for screening patients with DPG for NM at the time of recurrence. ^★Presented in part at the International Society of Pediatric Neuro-Oncology Meeting held in Boston, MA June 13–16, 2004.     

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.     

Biology in prevention and treatment of brain metastases

Brain metastases are common in cancer patients, may significantly diminish neurocognitive function and quality of life and carry a poor prognosis. Brain metastases differ from metastases in other organs such as liver, lung, lymph nodes and bone, both from a pathobiological and from a clinical perspective. Despite the high incidence of brain metastases, only relatively few studies aiming at better understanding of their pathobiology have been performed in the past. However, recently druggable targets have been identified in brain metastases of several tumor types and novel treatment approaches are becoming a feasible option for selected patients. In addition, scientific advances are elucidating some fundamental aspects of brain metastasis formation and may lead to effective strategies of drug-mediated prevention of metastatic brain invasion or inhibition of intracerebral outgrowth.     

Assessment of prognostic scores in brain metastases from breast cancer

Background

Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM.

Methods

We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses.

Results

Median overall survival was 15.1 months (95% CI,11.5–18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%).

Conclusion

The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.     

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.     

X线立体定向放射治疗脑转移瘤的疗效分析

目的观察立体定向放射手术治疗脑转移瘤的疗效。方法X线立体定向放射治疗脑转移瘤患者47例,采用10MV的直线加速器多个非共面弧旋转照射,肿瘤剂量为18～25Gy(平均22.1Gy)。40例患者在术后接受了肿瘤剂量30～40Gy的全脑放疗。结果中位生存期为11个月,1年生存率37.5%,疗后3个月的肿瘤控制率为90.7%,KPS≥70、原发肿瘤已控和无颅外转移患者的预后较好(P<0.05)。结论立体定向放射治疗脑转移瘤是安全和有效的。     

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.     

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。