Chemotherapy for breast cancer brain metastases

Breast cancer is the second most common cause of brain metastases, and 10-15% of patients develop clinically overt central nervous system disease. Radiotherapy is the standard treatment for patients with brain metastases. Surgical resection should be considered in patients with isolated brain metastasis and no extracranial disease. The role of chemotherapy in breast cancer brain metastases is not clearly defined; the results of the 8 trials found in the literature are reported. Most experience has been gained with the CMF (cyclophosphamide, methotrexate and fluorouracil) and PE (cisplatin and etoposide) regimens; here the median survival of 6 months is similar to radiotherapy. The blood-brain barrier, maintained by tight endothelial junctions and active transport mechanisms, is a major reason for the lower activity of most chemotherapeutic agents compared to other sites of metastatic disease. Most substances with good penetration of the blood-brain barrier have limited activity against breast cancer and some of the most active substances in breast cancer - including doxorubicine, the taxanes and trastuzumab - appear not to reach the central nervous system in sufficient concentrations. Approaches to overcome the blood-brain barrier are still experimental, and more research is clearly needed to identify chemotherapeutic agents both active in breast cancer and with good penetration of the blood-brain barrier. With the exception of patients with resectable brain metastases, danger of cranial herniation or poor general condition, chemotherapy should be offered to breast cancer patients with brain metastases that have progressive extracranial metastatic disease or relapse after radiotherapy.     

Chemotherapy is the cornerstone of the combined surgical treatment of lung cancer with synchronous brain metastases

BACKGROUND: Lung cancer accounts for about 50% of brain metastases, of which nearly 25% are eligible for neurosurgery, providing a neurological control rate of up to 70% when followed by whole brain radiation therapy. How to manage the primary lung carcinoma remains elusive. METHODS: We undertook a retrospective study of consecutive patients who underwent surgical resection for synchronous brain metastases from non-small cell lung cancer in a single institution, to determine overall survival and prognostic factors, with particular attention to the treatment of the primary lung tumor. RESULTS: Fifty-one patients underwent surgical resection of synchronous brain metastases from non-small cell lung cancer. Median survival was 13.2 months. Prognosis mainly depended of the treatment of the lung tumor, with a marked survival advantage in the 29 patients receiving a focal treatment (thoracic surgery or radiotherapy), compared to the 22 other patients: median, 1-year, and 2-year survival were 22.5 months, 69%, and 42%, versus 7.1 months, 33%, and 5%, respectively (p<0.001); response to pre-operative chemotherapy before focal treatment was the main favorable prognostic factor (p=0.023), and further identified patients who had benefit from resection of the lung tumor, with a significantly better outcome. CONCLUSIONS: Chemotherapy, by its therapeutic and prognostic value, may be considered as the cornerstone of the combined medical and surgical therapeutic sequence whereby brain metastasectomy is followed by chemotherapy and further focal treatment of the primary lung tumor in responders to chemotherapy.     

Chemotherapy for brain metastases in small-cell lung cancer

PURPOSE: Brain metastasis occurs commonly in patients with small-cell lung cancer (SCLC). Herein, we report the efficacy of irinotecan and carboplatin in the treatment of brain metastases from SCLC. In addition, we review the existing data on chemotherapy for brain metastases in SCLC. PATIENTS AND METHODS: Eighty patients with metastatic or relapsed SCLC were enrolled in a phase II trial of irinotecan and carboplatin. Patients naive to chemotherapy were treated with irinotecan 200 mg/m2 and carboplatin AUC of 5, and patients previously treated with chemotherapy received irinotecan 150 mg/m2 and carboplatin AUC of 5, every 21 days for 6 cycles. RESULTS: Among the 80 patients, 15 (19%) presented with brain metastases. An analysis of 14 assessable patients with brain metastases revealed an overall response rate of 65% after 2 cycles of chemotherapy and a median survival of 6 months (range, 1-24 months). Upon review of the literature, 8 studies were identified as having > 10 patients who received chemotherapy for brain metastases from SCLC. Based on these studies, the response rate of brain metastases from SCLC to a variety of chemotherapy and median survival of patients ranged from 22% to 85% and 3 months to 9 months, respectively. CONCLUSION: Chemotherapy, including the regimen of irinotecan and carboplatin, is an effective treatment for SCLC brain metastases.     

Chemotherapy induces regression of brain metastases in breast carcinoma

This study improves treatment options and ultimately survival by using systemic chemotherapy in brain metastases from breast carcinoma, since most of these patients have disseminated disease and a dismal prognosis when treated by conventional brain irradiation alone. One hundred consecutive patients with symptomatic brain metastases documented by radionuclide and/or computerized tomography scan were treated with systemic chemotherapy. Fifty of 100 patients demonstrated an objective response of brain metastases which was similar for extracranial metastases. There were 10 complete responders (CR), 40 partial responders (PR), 9 stable, and 41 nonresponders. Median duration of remission was 10+ months for CR and 7 months for PR (range, 2-72 months). Primary chemotherapy of brain metastases yielded responses in 27 of 52 patients (52%) treated with Cytoxan (cyclophosphamide) (C), 5-fluorouracil (F) and prednisone (P); 19 of 35 (54%) receiving CFP-methotrexate (M) and vincristine (V); 3 of 7 (43%) treated with MVP, and 1 of 6 (17%) receiving Cytoxan plus Adriamycin (doxorubicin) (CA). Thirteen of 35 patients (37%) who subsequently had relapse of brain metastases were retreated successfully with secondary chemotherapy. The median survival for CR and PR was 39.5 months and 10.5 months, respectively, in contrast with nonresponder patients who had a median survival of 1.5 months. Thirty-one percent of all treated patients survived more than 12 months. These findings suggest that the chemotherapeutic agents used penetrate the blood-brain barrier inducing regression of brain metastases. This approach offers a significant benefit by simultaneously controlling extracranial disease, improving the response and prolonging survival.     

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。     

Adjuvant treatment of brain metastases

With an incidence of 15/10(5) in the general population, brain metastases constitute a serious, debilitating complication in cancer patients. The majority of those patients suffer from more than one metastasis, but up to 30% to 40% present with a solitary lesion. Whole-brain radiotherapy (WBRT) extends median survival from 1 to 2 months for treatment with steroids only, to 4 to 6 months in most series. However, long-term survival (>1-2 years) is observed in up to 10% of patients with favorable prognostic factors, such as solitary lesions, good Karnofsky performance status, and absence of extracranial disease. For those patients, individually optimized treatment is worthwhile. For good-prognosis patients with controlled extracranial disease, surgery in combination with postoperative WBRT should be considered, especially when fast relief of symptoms is mandated. For surgically inaccessible solitary lesions below a size threshold of approximately 30 ccm, stereotactic radiosurgery (RS), although never compared to surgery in a randomized fashion, seems to yield comparable results and is the treatment of choice for more than one lesion in appropriately selected patients. Nevertheless, a number of questions concerning the optimal treatment regimens for brain metastases remain. These mainly concern the radiation dose, need for a combination of RS and WBRT, relative timing of different treatment modalities, and maximum number of brain metastases that can reasonably be treated with RS when long-term progression-free survival is the goal. However, RS is definitely an excellent option for salvage and palliation in patients with short life expectancy, as it is simultaneously noninvasive and cost-effective, with short hospitalization times.     

Chemotherapy for brain metastases of lung cancer: A review

In lung cancer patients brain metastases develop with a high frequency. For years radiotherapy has been the standard treatment for these patients. Here we review the experience with chemotherapy for brain metastases in lung cancer patients. The concept of the brain as pharmacological sanctuary site when brain metastases are present is challenged and it is argued that chemotherapy does play a role in this situation. Recent clinical trials indicate that the combination of chemotherapy and radiotherapy may become the standard treatment for lung cancer patients with brain metastases. It is unclear whether for micrometastatic disease to the brain, blood brain barrier function is of importance for the outcome of chemotherapy in lung cancer patients with respect to the development of overt brain metastases. Areas of improvement of delivery of cytotoxic agents to the brain when brain metastases have not yet developed are discussed.     

Whole brain radiotherapy for the treatment of multiple brain metastases

BACKGROUND： Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies. OBJECTIVES： To assess the effectiveness and adverse effects of whole brain radiotherapy （WBRT） in adult patients with multiple metastases to the brain. SEARCH STRATEGY： CENTRAL （The Cochrane Library）, MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched. SELECTION CRITERIA： Randomized controlled trials （RCTs） in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis. DATA COLLECTION AND ANALYSIS：     

Chemotherapy for the treatment of metastatic brain tumors

Metastatic brain tumors are the most common complication of systemic cancer and affect 20-40% of all adult cancer patients. Whole-brain radiotherapy and surgical resection of accessible, solitary lesions have been the mainstay of treatment. Recently, chemotherapy has become a more viable treatment option for metastatic brain tumors. Many different drugs and administrative approaches have been shown to be clinically active. Traditional chemotherapy given before or during irradiation can be effective with agents such as cyclophosphamide, cisplatin and etoposide. Nontraditional approaches, such as tempozolomide and intra-arterial administration of carboplatin, have demonstrated activity against recurrent metastatic disease. In early clinical trials of interstitial chemotherapy, biodegradable polymers have shown some clinical efficacy and have been well-tolerated. Molecular approaches are also under investigation in response to new information regarding the metastatic phenotype. Potential targets include growth factor receptors and other protein tyrosine kinases, internal signal transduction pathways, ras activation and matrix metalloprotease activity. New clinical trials will be needed to investigate these new molecular-based therapeutics, alone and in combination with currently available treatment options, to determine the optimal application of chemotherapy to metastatic brain tumors.     

Chemotherapy for the treatment of metastatic brain tumors

Metastatic brain tumors are the most common complication of systemic cancer and affect 20–40% of all adult cancer patients. Whole-brain radiotherapy and surgical resection of accessible, solitary lesions have been the mainstay of treatment. Recently, chemotherapy has become a more viable treatment option for metastatic brain tumors. Many different drugs and administrative approaches have been shown to be clinically active. Traditional chemotherapy given before or during irradiation can be effective with agents such as cyclophosphamide, cisplatin and etoposide. Nontraditional approaches, such as temozolomide and intra-arterial administration of carboplatin, have demonstrated activity against recurrent metastatic disease. In early clinical trials of interstitial chemotherapy, biodegradable polymers have shown some clinical efficacy and have been well-tolerated. Molecular approaches are also under investigation in response to new information regarding the metastatic phenotype. Potential targets include growth factor receptors and other protein tyrosine kinases, internal signal transduction pathways, ras activation and matrix metalloprotease activity. New clinical trials will be needed to investigate these new molecular-based therapeutics, alone and in combination with currently available treatment options, to determine the optimal application of chemotherapy to metastatic brain tumors.     

多发性脑转移瘤的优化治疗

目的探讨多发性脑转移瘤患者应用伽玛刀及全脑放疗的最佳治疗方式。方法将2003年5年至2011年2月收治的KPS评分≥70分的179例多发性脑转移患者随机分为两组,甲组88例,其中男性42例,女性46例,年龄26～67岁,平均44.2岁;采用伽玛刀治疗,1周后配合全脑放疗,如发现转移瘤进展,再行伽玛刀治疗。乙组91例,其中男性43例,女性48例,年龄28～66岁,平均43.1岁;采用伽玛刀治疗,如发现转移瘤进展,再行伽玛刀治疗,1周后配合全脑放疗。两组患者在病种、年龄、性别上差异无统计学意义。结果甲组中位疾病进展时间为4.6个月,乙组中位疾病进展时间为3.4个月,差异有统计学意义(P<0.05)。甲组中位生存时间为8.9个月,乙组中位生存时间为8.5个月,差异无统计学意义(P>0.05)。亚组分析,甲组小细胞肺癌多发性转移患者的中位疾病进展时间及中位生存时间均长于乙组小细胞肺癌患者,差异有统计学意义(P<0.05)。结论伽玛刀与全脑放疗具有协同治疗作用,对小细胞肺癌多发性脑转移患者伽玛刀治疗后应及早联合全脑放疗。     

Stereotactic radiosurgery for the treatment of brain metastases

Background: The objective of this systematic review was to summarise the current evidence concerning radiosurgical treatment (SRS) of newly diagnosed brain metastasis and to compare SRS as a single or additional treatment to treatment alternatives with regard to medical effectiveness and safety.Methods: A structured search of electronic databases was performed to identify relevant publications from 2002 through 2007. Studies targeting patients with brain metastases were included. Standardised quality assessment and data extraction were performed.Results: Of 1496 publications, 16 studies were included. The mean survival in most studies was less than 12 months. There was evidence that SRS plus WBRT was associated with improved local tumour control and neurological functioning compared to either treatment alone. Only in patients with single metastasis, this resulted in improved survival. There was inconclusive evidence when comparing SRS to WBRT, Neurosurgery (NS) or Hypofractionated Radiotherapy (HCSRT). The Quality of life (Qol) was not investigated.Conclusion: SRS plus WBRT was associated with improved local tumour control and neurological functioning compared to either treatment alone. Only in certain patients, this resulted in improved survival. Methodologically rigorous studies are therefore warranted to investigate further treatment options, and in view of the poor prognosis, to investigate Qol and neurological functioning.     

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.     

脑转移瘤立体定向放射外科治疗

立体定向脑放疗放射外科(SRS)可治疗单发或多发脑转移瘤,与全脑放射治疗(WBRT)相比,能延长生存时间、提高生活质量.用于全身肿瘤控制或稳定、直径≤3.5cm单发脑转移瘤患者,具有与手术配合WBRT相似的疗效.SRS加WBRT与单纯SRS治疗相比,能提高颅内无进展生存期,但未能延长生存时间.脑转移瘤复发后SRS治疗能取得较好疗效.     

放化综合治疗在脑转移癌治疗中的临床应用研究

目的:观察放化综合治疗脑转移癌的近期疗效与安全性。方法:62例脑转移癌患者随机分为放化疗组与单纯放疗组。其中化疗联合组31例,非小细胞肺癌脑转移患者入组替莫唑胺联合放疗组、乳腺癌脑转移患者入组卡培他滨联合放疗组;31例为单纯放疗组。替莫唑胺联合放疗组给予替莫唑胺[75mg/(m2·d)]至放疗结束,卡培他滨组给予[625mg/(m2·d),2次/d,连用4周]。两组均联合2周三维适形头部放疗,总剂量42Gy(3Gy,5f/w),其中全脑30Gy/10f,病灶区补量12Gy/4f;单纯放疗组仅予42Gy三维适形头部放疗,其中全脑30 Gy,病灶区补量12 Gy。联合放化疗组放疗结束后继续给予2个周期替莫唑胺[每周期150mg/(m2·d)],连续服用5d,28d为1个周期;卡培他滨组给予[每周期825mg/(m2·d),2f/d,d1-14],连续服用14d,28d为1个周期。结果:联合放疗组与单纯放疗组的客观有效率分别为80.63%、64.5%,差异无统计学意义(P>0.05);骨髓抑制发生率分别为70.96%、54.84%,胃肠道毒副反应发生率分别为61.29%、41.94%,差异均无统计学意义(P>0.05)。结论:替莫唑胺联合放疗以及卡培他滨联合放疗治疗非小细胞肺癌及乳腺癌脑转移安全、有效,但是近期疗效对比单纯放疗差异不显著。