Treatment of brain metastases from lung cancer: chemotherapy

Brain metastases are a frequent complication in patients suffering from Lung cancer, and a significant cause of morbidity and mortality. Brain metastases are found in about 10% of patients at the time of diagnosis, and approximately 40% of all patients with lung cancer develop brain metastases during the course of their disease. The prognosis of these patients is rather poor. The standard treatment for brain metastases, so far, has been whole-brain radiation therapy and surgery focussing on symptom palliation. The use of chemotherapy for the treatment of brain metastases has been limited because of a presumed lack of effectiveness due to the blood-brain barrier. However, the importance of the blood-brain barrier is probably overrated in the case of macroscopic metastases or relapsed disease as the blood-brain barrier has already been disrupted at this stage resulting from the newly developed blood vessels not provided with the physiological properties of the common blood-brain barrier. Chemotherapeutic agents initially lipid-insoluble or liquor-impermeable can also penetrate into the brain and, therefore, trigger action against tumour cells. A number of clinical trials have demonstrated that brain metastases resulting from both small-cell lung cancer and non-small-cell lung cancer are susceptible to systemic chemotherapy. In small-cell lung cancer, cerebral response rates up to 50% were observed even in the second-line situation and were comparable to the response rates observed in the primary tumour. In non-small-cell lung cancer, similar results were achieved. Therefore, it seems justified to further evaluate the significance of chemotherapy compared to whole-brain radiation therapy. Whether chemotherapy alone is superior to whole-brain radiation therapy, or whether the combination of both therapeutic modalities should be preferred for the management of brain metastases, has not yet been proven, and further randomised phase-III studies are clearly needed. Based on the current available data, and the promising response rates in patients with lung cancer, chemotherapy should be considered for the management of brain metastases as part of a multimodality (or "interdisciplinary") treatment concept.     

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.     

The role of topotecan in the treatment of brain metastases

Despite advances in the treatment of systemic malignancies, the prognosis for patients with brain metastases continues to be dismal. Because the majority of cytotoxic agents seem to be unable to penetrate the blood-brain barrier, the role of chemotherapy in the treatment of brain metastases remains controversial. However, growing amounts of both laboratory and clinical data suggest that a few of the newly developed cytotoxic agents can cross the blood-brain barrier and may have a role in the treatment of patients with brain metastases. Topotecan, a novel topoisomerase I inhibitor, freely crosses the blood-brain barrier and may be clinically effective in both the therapeutic and prophylactic settings in patients with brain metastases. Recent studies have demonstrated the antitumor activity of topotecan against brain metastases, with objective response rates ranging from 33%-63% in patients with various solid tumors. The antitumor response in the central nervous system was often greater and occurred more quickly than the systemic antitumor response to topotecan treatment. This result may be explained by the lack of exposure of brain metastases to previous cytotoxic agents, suggesting a role for topotecan in patients with brain metastases. Early studies have also suggested that topotecan, an apparent radiosensitizer, may be particularly effective in combination with radiotherapy, the current standard of care for patients with brain metastases. In addition, preliminary data suggest that topotecan in combination with temozolomide (another cytotoxic agent that can cross the blood-brain barrier) may have synergistic antitumor activity against brain metastases. This review summarizes the available preclinical and clinical evidence for the role of topotecan in the treatment of brain metastases and concludes with three case studies.     

放疗开放血脑屏障及其对化疗的意义

血脑屏障是维持脑组织内环境稳定的重要结构。由于大部分化疗药物难以通过血脑屏障，脑部肿瘤的化疗效果不佳。应用放疗开放血脑屏障有独特的优势，放疗不仅可以杀死肿瘤细胞，而且可以开放血脑屏障，促进化疗药物进入脑肿瘤，提高化疗效果。本文介绍了放疗开放血脑屏障在实验和临床方面的进展，并分析了其对脑肿瘤化疗的意义。     

Endodermal sinus tumor of the pineal region. Metastases through a ventriculoperitoneal shunt

This case report concerns an endodermal sinus tumor (EST) arising in the pineal region of a 16-year-old boy who died 3 months after radiation. He developed extensive abdominal metastases through a ventriculoperitoneal shunt, whereas the primary tumor and a suprasellar metastasis could be controlled by radiotherapy, demonstrated by autopsy. The histologic diagnosis was supported by an elevated level of alpha-fetoprotein in serum and the demonstration of this marker in the tumor tissue by immunoperoxidase method. The poor diagnosis of all previously reported cases with pineal EST requires a combined modality of surgical approach, radiotherapy, and concomitant chemotherapy.     

The response of cerebral metastases in small cell lung cancer to systemic chemotherapy

Although small cell lung cancer (SCLC) is very chemosensitive, cerebral metastases are treated with radiotherapy in the belief that they are protected from chemotherapy by the blood-brain barrier (BBB). The validity of this assumption has not been tested in clinical practice. In a randomised trial of treatment in 610 patients with SCLC, 19 patients who had symptomatic cerebral metastases at presentation were treated initially with chemotherapy, and cranial irradiation withheld. Chemotherapy was cyclophosphamide 1 g m-2 i.v. day 1, vincristine 2 mg i.v. day 1 and etoposide 100 mg tds p.o. days 1-3, repeated every 21 days, with response assessed objectively by computerised tomography (CT) or radionuclide brain scan, and by clinical examination. A post-chemotherapy scan was obtained in 14 patients, eight of whom achieved a partial remission and one a complete remission of the cerebral metastases. The radiologically proven responses were sustained and accompanied by rapid neurological improvement. Of the remaining five patients who were assessed by clinical examination alone, one had improved neurological function after chemotherapy. The response rate for SCLC cerebral metastases treated with chemotherapy was therefore 10/19 (53%). Chemotherapy has the advantage over cranial irradiation of simultaneously treating both cerebral metastases and extracranial disease. The place of chemotherapy in the management of cerebral metastases in this and other chemosensitive tumours should be reconsidered since these findings indicate that the BBB does not prevent response to chemotherapy.     

Lace‐like enhancement pattern of osteosarcoma of rib and liver metastasis in CT scans

The rib is an uncommon site of osteosarcoma. With the use of adjuvant chemotherapy and aggressive surgical resection of the metastatic pulmonary lesions, extrapulmonary metastases are becoming more clinically evident. Primary rib osteosarcoma with extrapulmonary metastasis is exceedingly rare. A case is reported, showing that the pattern of metastasis of rib osteosarcoma is similar to that of primary bone osteosarcoma. The liver metastasis occurred after resection of the metastatic pulmonary lesions. A CT scan of the primary rib lesion and liver metastasis both showed a lace‐like enhancement pattern, its histological appearance corresponding with neoplastic osteoid. With the increasing use of CT abdomen for localization of extrapulmonary metastases, lace‐like enhancement may be seen more readily in the future.     

The role of chemotherapy in brain metastases

Despite the widely held belief of the resistance to chemotherapy of brain metastases, central nervous system metastases of a malignancy are equally sensitive to chemotherapy as its metastases elsewhere in the body. This is due to the fact that the blood-brain barrier is disrupted in contrast enhancing brain metastases, and does not limit the response to chemotherapy. Therefore, the response rate of the primary tumour. Up-front chemotherapeutic treatment instead of radiotherapy of brain metastases should therefore be based on the chemosensitivity of the primary tumor to the used regimen, and not on the question whether the used agent penetrates an intact blood-brain barrier. First-line chemotherapy for brain metastases or with only minor neurological signs and symptoms, and who have an indication for systematic chemotherapy for metastases elsewhere in the body. In contrast, central nervous system micrometastases may hide behind an intact barrier, and this may be clinically relevant in patients that can be cured with chemotherapy (like in small cell lung cancer). Cytochrome P450 3A4 inducing anti-epileptic drugs like phenytoin, carbamazepine and phenobarbital may significantly increase the metabolism of many chemotherapeutic agents like CPT11 and paclitaxel (but also of newer biological agents like many tyrosine kinase inhibitors). These anti-epileptic drugs should be avoided in patients requiring chemotherapy with agents metabolised through the cytochrome P450.     

A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors

There is general agreement that most chemotherapy agents achieve only relatively low concentrations in the normal central nervous system, that the blood-brain barrier is variably disrupted in malignant brain tumors, and that the concentration of chemotherapy drugs in the brain adjacent to tumor is intermediate between concentrations achieved in brain tumors vs normal brain. However, there is substantial controversy regarding the role of the blood-brain barrier in resistance to chemotherapy of intracerebral tumors. Many chemotherapy agents achieve concentrations in brain tumors that are comparable to those in extracerebral tumors, and drugs that cross the intact blood-brain barrier only poorly may be active against intracerebral tumors. Furthermore, the hypothesis that the brain is a pharmacological sanctuary where metastases may grow while tumor is responding in other parts of the body may be flawed: there are only 2 or 3 types of malignancies (out of all those that are sensitive to chemotherapy) in which the risk of isolated central nervous system relapse is moderately high, and even in these 2 or 3, effective central nervous system prophylaxis has minimal or no impact on overall survival. Furthermore, drugs that cross the BBB do not appear to be more effective than other drugs at reducing the risk of brain metastases, and brain metastases at the time of diagnosis do not necessarily convey a worse prognosis than metastases to various other sites.While average drug concentrations in brain adjacent to tumor are lower than those within brain tumors, very small numbers of tumor cells may be capable of inducing local leakiness in blood vessels, and there is little information on drug concentrations achieved in individual tumor cells within the brain adjacent to tumor. Furthermore, any limitation of uptake of drugs into brain tumors could be at least partially due to increased tissue pressure within tumors rather than being due to blood-brain barrier phenomena. This distinction could be important, since strategies that one might use to increase drug delivery to brain tumors might differ depending on whether the reduced delivery were due to barrier phenomena vs blood flow phenomena.The role of the blood-brain barrier in resistance of intracerebral tumors to chemotherapy remains unclear: while it may well play some role (and perhaps even a major one), self-fulfilling prophecies and unintentional bias in data selection and interpretation may have previously made it appear more important than it actually is. The feeling by many investigators that the blood-brain barrier is a major factor in brain tumor resistance to chemotherapy may at times have unnecessarily delayed and limited the exploration of new chemotherapy drugs and strategies in the treatment of human brain tumors. While antineoplastic drug pharmacology is important in the treatment of all malignant tumors, intrinsic drug cytotoxicity may well be a much more important factor in treatment outcome than is any limitation of drug uptake by the blood-brain barrier.     

Complete Remission of Brain Metastases in Non-Small Cell Lung Cancer Patients Harboring an EGFR Mutation Treated with Tyrosine Kinase Inhibitor without Radiotherapy: A Report of 3 Cases

Brain parenchymal metastasis from a solid tumor is a serious clinical condition associated with a poor outcome because systemic chemotherapy is usually ineffective for treating brain metastases (BM) due to the blood-brain barrier. Therefore, radiotherapy such as whole brain radiotherapy (WBRT) and stereotactic radiosurgery have taken on a central role in the management of BM. However, WBRT can delay subsequent systemic treatment or cause neurologic complications such as a decline in cognitive function. Therefore, suspending WBRT is worth considering if there is an effective alternative. Although there have been no large prospective studies, many reports are available about the favorable effect of tyrosine kinase inhibitors (TKIs) for treating BM in patients with non-small cell lung cancer (NSCLC). Here, we report 3 NSCLC cases that showed a complete response in BM after TKI treatment without WBRT. Based on these remarkable response rates of BM to a TKI, the potential toxicity of WBRT can be avoided, particularly in patients with small metastatic nodules and an epidermal growth factor receptor activating mutation.Key words: Non-small cell lung cancer, Tyrosine kinase inhibitor, Brain metastases, Whole brain radiotherapy     

Developments in the diagnosis and treatment of primary CNS lymphoma. A prospective series

Current experience with 12 patients studied prospectively suggests a new approach in the diagnosis and treatment of primary central nervous system (CNS) lymphoma, integrating the techniques of needle brain biopsy, immunohistochemical staining for monoclonal antibody and chemotherapeutic drug delivery in association with blood-brain barrier modification. Computed tomography (CT)-guided needle biopsy of deep parenchymal lesions contributed to the diagnosis in six patients. Immunohistochemical staining methods detected monoclonal immunoglobulins in those patients so tested. Following diagnosis, the patients have been treated with multi-agent chemotherapy in conjunction with osmotic blood-brain barrier modification (five without antecedent cranial irradiation) with an initial complete response rate by CT scan in nine patients, a median follow-up of 19 months from diagnosis, and a 1-year survival of 75%. This experience emphasizes the value of CT-guided stereotaxic or CT-guided needle biopsy, which limits the need for therapy without a diagnosis or the need for a major craniotomy in what are commonly deep, paraventricular lesions. Immunoperoxidase cytochemical stains can detect monoclonal immunoglobulin characteristic of CNS B-cell malignant lymphomas and provide an important diagnostic aid when only modest quantities of tissue or cells are obtained. Finally, chemotherapy administered in conjunction with osmotic blood-brain barrier modification results in a clinical response rate and survival that are at least as effective as radiotherapy as a primary therapeutic modality.     

Brain metastases as preventive and therapeutic targets

The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood-tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood-brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.     

肾上腺皮质癌1例报道并文献回顾

目的:探讨肾上腺皮质癌的临床表现、诊断及治疗方法。方法:报道我科近期收治的1例肾上腺皮质癌患者的临床资料,并检索中国知网、PubMed等数据库,进行文献回顾,对该病的临床特征及诊断要点、治疗方法及最新的研究进展进行归纳总结。结果:本例患者以腹痛为首发临床表现,影像学提示肾上腺肿瘤,行腹腔镜切除,术后20天查PET/CT提示多发转移,给予依托泊苷+顺铂化疗4周期后进展,遂应用吉西他滨联合卡培他滨化疗1周期,出现脑转移后行放疗。结论:肾上腺皮质癌是一种罕见的泌尿系恶性肿瘤,且预后差。诊断应结合临床表现、肾上腺皮质激素水平、影像学检查及病理结果。治疗方面首推多学科会诊（MDT）,早期患者首选手术,术后需根据疾病分期、分级选择辅助治疗,复发转移的患者可给予化疗、放疗、米托坦、免疫治疗等。     

Capecitabine Therapy of Central Nervous System Metastases from Breast Cancer

Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994–2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18–165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.     

A case of multiple liver metastases from rectal cancer in poor performance status successfully treated with hepatic arterial infusion chemotherapy plus CPT-11

Hepatic arterial infusion (HAI) chemotherapy is one of the strategies for cases in poor performance status. This is a case report of multiple liver metastases from rectal cancer in poor performance status successfully treated with HAI plus CPT-11. A 59-year-old man who had rectal cancer, multiple liver metastases and para-aortic LN metastasis underwent a laparoscopic rectal anterior resection. He denied receiving postoperative chemotherapy and selected alternative therapy at another clinic. Four months later, he visited our hospital. His liver metastasis and performance status got worse, so HAI of 5-FU 1250 mg/m2 for 5-hour weekly (weekly high-dose 5-FU: WHF) was started at first. After 3 courses, his status improved, so systemic chemotherapy was added. HAI (WHF: 1000 mg/m2) plus CPT-11 (100 mg/m2) was effective, and liver metastases showed a significant reduction (PR) on abdominal CT. HAI plus CPT-11 was effective for a patient of the poor performance status with unresectable liver metastasis.     

EGFR敏感突变阴性非小细胞肺癌脑转移患者临床特征

除少见的间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)及原癌基因-1受体酪氨酸激酶(c-ros oncogene 1-receptor tyrosine kinase, ROS1)阳性敏感融合外,非表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的非小细胞肺癌(non-small cell lung cancer, NSCLC)脑转移患者目前无有效的全身治疗药物,整体预后较差。由于传统药物血脑屏障透过率低,脑转移的局部治疗尤其是放疗具有非常重要作用。为了更好地认识EGFR突变阴性NSCLC脑实质转移的特点,本文从脑转移的发病率、发病时间、发病部位、病灶数目及大小、发病症状、治疗疗效和病情演变等方面综述了EGFR突变阴性NSCLC脑实质转移的临床特征以及治疗,为脑实质转移局部治疗的介入时机以及局部治疗技术选择提供参考。     

The biology of brain metastases-translation to new therapies

Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood-brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood-tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.     

Eighty-five-year-old patient with recurrent rectal cancer effectively treated with CapeOX chemotherapy

We report a case of a super-elderly patient with recurrent rectal cancer effectively treated with CapeOX chemotherapy. A 85-year-old man who had a low anterior resection was diagnosed with rectal cancer in July 2009. Although peritoneal dissemination near the main tumor was disclosed during the operation, a R0 and Cur B operation was performed. After the operation, an elevation of tumor markers was detected in October. A chest-abdominal-pelvic CT scan revealed multiple liver metastases of the bilateral lobe and a metastasis of the right iliac bone. We attempted CapeOX chemotherapy from November. After 3 courses of CapeOX chemotherapy, the multiple liver metastases shrank and the bone metastasis changed to a consolidation. Although grade 1 chronic peripheral neuropathy appeared after 8 courses of chemotherapy, no other adverse event appeared. After 10 courses of CapeOX chemotherapy, the chemotherapy was changed to capecitabine at the patient's request. A chest-abdominal-pelvic CT scan after 10 courses of CapeOX chemotherapy revealed that the multiple liver metastases were shrinking. As of September 2010, the patient's PS score is 0, and he has been under treatment as an outpatient.     

The role of chemotherapy in the treatment of patients with brain metastases from solid tumors

Chemotherapy for brain metastases has been considered ineffective because the drugs do not penetrate the intact blood brain barrier. Alternate explanations for past failures of chemotherapy include observations that 1) many solid tumors which metastasize to brain are drug-resistant regardless of location, 2) brain metastases often occur following failure of primary chemotherapeutic regimens to control systemic metastases, and 3) previous trials of chemotherapy employed agents other than those known to be most effective against the primary malignancy. Furthermore, laboratory studies have demonstrated that cytoxic levels of many drugs can be measured in tumor tissue from primary and metastatic brain tumors. These clinical and pharmacologic observations suggest that chemotherapy would be expected to have limited value unless known effective combination regimens are employed as first-line therapy in chemosensitive malignancies. Recent reports of chemotherapy for patients with brain metastases from small cell lung carcinoma, gestational choriocarcinoma, germ cell malignancies, and breast carcinoma do describe response rates in the brain similar to those in other organ sites. In conclusion, chemotherapy for cerebral metastases can be expected to be effective only when effective drugs for systemic metastases are available. While the blood-brain barrier may be an additional detriment to successful treatment, other factors may be more important.     

Extracranial metastases in childhood primary intracranial tumors. A report of 21 cases and review of the literature

A clinical and pathologic review of primary intracranial tumors (917 cases in a 62-year period) at The Hospital for Sick Children, Toronto, identified 21 cases with systemic metastases (2.3%). This included 15 cases of medulloblastoma and 1 case each of astrocytoma, meningeal sarcoma, malignant melanoma, ependymoblastoma, teratoma, and endodermal sinus tumor, adding to the pediatric literature of 94 previously reported cases (72 medulloblastoma and 22 cases of other brain tumors). Like adults, children with medulloblastoma tend to develop bone and bone marrow metastases, while those with other brain tumors frequently invade adjacent tissues, and then spread to regional lymph nodes and the lungs. The prognosis is almost uniformly fatal, although prolonged palliation could be achieved with radiation and/or chemotherapy. The pathogenesis of systemic metastases is related to breakage of the blood-brain barrier, whether at surgery, or with tumor invasion into vascular channels, and especially with preoperative systemic-cerebrospinal fluid shunting. Thirteen of 16 patients who developed systemic metastases, including 5 with peritoneal involvement, had ineffective or no millipore filters within their shunts, suggesting their possible prophylactic role against tumor dissemination. A greater understanding of the pathogenesis of systemic metastases may aid the design of future effective preventive measures.