Chemotherapy For Brain Metastases Research Articles

Radiotherapy for brain metastases from small-cell lung cancer in distinct clinical indications and scenarios.

Management of brain metastases (BM) from small-cell lung cancer (SCLC) is complex and not supported by a strong evidence from prospective clinical trials. Owing to the different clinical and pathological characteristics of SCLC, patients with this histology were not included in the prospective studies on the value of whole-brain radiotherapy (WBRT) and local surgical or ablative radiation treatment like stereotactic radiosurgery (SRS). Chemotherapy also represents a major part of the armamentarium against BM from SCLC due to the well-recognized chemoresponsiveness of this cancer and the frequent presentation of BM with extracranial progression. WBRT in combination with chemotherapy has long been a standard approach in this setting. However, data on the neurocognitive toxicity and the lack of documented impact on overall survival of WBRT in the management of BM from other solid tumors, as well as the increasing availability of the stereotactic radiotherapy technologies, has led to the increasing use of SRS with omission of WBRT also in SCLC. In the current review the use of different modalities of radiotherapy and ways of combining radiotherapy with chemotherapy for BM from SCLC will be presented for distinct clinical situations: presentation of BM synchronous with primary, metachronous presentation of BM—without previous prophylactic cranial irradiation (PCI) vs. after PCI, and asymptomatic BM found at the staging before PCI.

Chapter 11 - Systemic therapy for brain metastases

Central nervous system metastases cause grave morbidity in patients with advanced malignancies. Lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases. Although the exact incidence of brain metastases is unclear, there appears to be an increasing incidence which has been attributed to longer survival, better control of systemic disease, and better imaging modalities. Until recently surgical resection of solitary or symptomatic brain metastases, and radiation therapy (either whole-brain radiation therapy or stereotactic radiation) were the mainstay of treatment for patients with brain metastases. The majority of traditional chemotherapies have shown limited activity in the central nervous system, which has been attributed to the blood-brain barrier and the molecular structure of the used agents. The discovery of driver mutations and drugs targeting these mutations has changed the treatment landscape. Several of these targeted small-molecule tyrosine kinase inhibitors do cross the blood-brain barrier and/or have shown activity in the central nervous system. Another major advance in the care of brain metastases has been the advent of new immunotherapeutic agents, for which initial studies have shown intracranial activity. In this chapter, we will review the unique challenges in the treatment of brain metastases. The pertinent clinical studies of chemotherapy in brain metastases will be discussed. The currently reported clinical trials and evidence for use of targeted therapies and immunotherapeutic agents will be emphasized.

Chemotherapy for brain metastases from small cell lung cancer

Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate early in the course of its natural history and to grow quickly. Approximately 10% to 18% of patients present with brain metastases (BM) at the time of initial diagnosis, and an additional 40% to 50% will develop BM some time during the course of their disease. The aim of this review was to evaluate the effectiveness and toxicity of systemic chemotherapy for the treatment of BM from SCLC. We searched the Cochrane Lung Cancer Review Group Specialised Register (July 2011), CENTRAL (2011, Issue 5), PubMed (1966 to July 2011), EMBASE (2005 to July 2011), LILACS (1982 to July 2011) and the International Clinical Trial Registry Platform (ICTRP). Randomized controlled trials (RCTs) comparing systemic chemotherapy (single agent or combination chemotherapy) with another chemotherapy regimen, palliative care, whole brain radiotherapy or any combination of these interventions for the treatment of BM as the only site of progression. Data extraction and 'Risk of bias' assessment were carried out independently by two review authors. As the included studies evaluated three different treatment modalities meta-analysis was not possible. Three RCTs, involving 192 participants, met inclusion criteria for this review. No significant differences for overall survival (OS) were reported in any of the trials: in the first trial, 33 patients received whole brain radiation therapy and no significant difference was found between patients treated with topotecan and those not treated with topotecan. In a second trial, in which 120 patients were randomized to receive teniposide with or without brain radiation therapy, the authors reported that the median progression-free survival (brain-specific progression-free survival (PFS)) was 3.5 months in the combined modality arm and 3.2 in the teniposide alone arm. In a third trial, comparing sequential and concomitant chemoradiotherapy (teniposide plus cisplatin) in 39 participants, the survival difference between the two groups was not statistically significant. While the first trial reported no significant difference in PFS, the second RCT found a significant difference favoring combined therapy group. The second trial also found that patients receiving chemoradiotherapy (teniposide plus whole brain radiotherapy) had a higher complete response rate than those receiving only the topoisomerase inhibitor. Given the paucity of robust studies assessing the clinical effects of treatments, available evidence is insufficient to judge the effectiveness and safety of chemotherapy for the treatment of BM from SCLC. Published studies are insufficient to address the objectives of this review. According to the available evidence included in this review, chemotherapy does not improve specific brain PFS and OS in patients with SCLC. The combined treatment of teniposide and brain radiation therapy contributed to outcome in terms of increased complete remission and shorter time to progression (though not OS).

Research progress on chemotherapy for brain metastasis of lung cancer

Brain metastases from lung cancer is a significant cause of morbidity and mortality,whichis lack of effective treatment.Because chemotherapeutic drugs are thought to not cross the blood-brain barrier(BBB), the role of chemotherapy in the treatment of brain metastases remains controversial. For yearsradiotherapy has been the standard treatment for brain metastases.However, recent studies have confirmedthat the BBB in patients with brain metastases tumors are broken down.At the same time,researchers havefound some new methods for chemotherapeutic drugs to reach the brain metastases.Chemotherapy will play amore and more active role in the treatment of brain metastases tumors. Key words: Lung neoplasms; Drug therapy,combination; Blood-brain barrier; Neoplasm metastasis

P4-17-10: Insights into Mechanisms Involved in the Accumulation of Nanovectors within the Breast Cancer Brain Metastasis.

Abstract Systemic chemotherapy for brain metastasis of breast cancer (BMBC) is considered to be inefficient. It is widely accepted in the literature that blood-brain-barrier (BBB) is responsible for clinical failures with the conventional chemotherapy. We hypothesized that nanovectors, therapeutic carriers with submicron dimensions, can be delivered to the brain tissue through a different pathway than molecular therapeutics. The objective of this study was to examine the accumulation of various intravenously injected nanovectors into the brain metastasis of breast and other cancers loci and to explore possible mechanisms involved. Both human (MDAMB231) and mouse (4T1) breast cancer brain metastasis were evaluated. We also tested lung (3LL) and colon (CT26) originated cancers. Orthotopic brain tumors were produced either by intracarotid injection or stereotactic brain injection of cancer cells. When the animals became moribund, they were injected intravenously with one of the following nanovectors including fluorescently labeled PEGylated (100nm) and non-PEGylated (100nm, 250nm, 500nm) liposomes, disc-shape silicon particles (600, 1000nm in diameter). The accumulation of the nanovectors was compared to an unencapsulated fluorescent molecule. The accumulation of the nanovectors in the brain tumor tissue was evaluated through live animal imaging (IVIS) and immunohistochemical analysis. Immunohistochemical staining of endothelial cells and basal membrane markers was performed to determine the integrity of the tumor associated vasculature and the co-localization of the fluorescent nanovectors/molecules with tumor associated vasculature. Interestingly, we have found that brain metastasis of different tumors (originated form breast, lung and colon cancers) possess dissimilar accumulation profiles for intravenously administered nanovectors. For example when comparing various tumor origins, 4T1 breast cancer originated brain tumors enabled the highest accumulation of the nanovectors as compared to CT26 and 3LL. On the other hand, free molecule accumulated into the 4T1 brain metastasis model to a much lower extend than in nanovector. Finally, the observed brain distribution of nanovectors corresponded well with impairment in vascular endothelium and basal membrane integrity shown in immunohistochemical analysis. The results of our study point toward a possibility to treat specific patients with impaired BBB function with nanovector encapsulated chemotherapeutics based on the fact that their transport, accumulation and retention in the brain tissue are governed by different biological mechanisms, such as Enhanced Permeation and Retention (EPR) effect. These studies indicate that it is possible to cross the blood brain barrier, thus giving hope to patients with brain metastasis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-10.

Brain metastases: a medical neuro-oncology perspective

Brain metastases (BMs) are the most common neurological complication related to cancer. A review of recent and relevant literature relating to BMs was performed and found that the therapy of BMs remains controversial, notwithstanding numerous randomized clinical trials. Surgical resection of a solitary BM when possible, followed by whole-brain irradiation (WBI) is an established standard of care. More controversial is the substitution of stereotactic radiosurgery for surgery in the treatment of solitary BM. Treatment with WBI following local therapy remains controversial, with advocates for and against WBI. At present, systemic chemotherapy for BMs offers only very modest palliation. In summary, treatment of BMs remains contentious with respect to the utilization and timing of surgical resection, application of WBI and stereotactic radiosurgery, notwithstanding numerous randomized trials, as the range of interpretation of these trials has resulted in differing treatment perspectives.

Medical management of brain metastases from lung cancer (Review)

Brain metastases are a frequent complication in patients with lung cancer and a significant cause of morbidity and mortality. The prognosis of these patients is poor. Medical therapies for brain metastases are neither well-studied nor established. This review analyzes the impact of medical treatment on survival by reviewing recent articles of the management of brain metastases from lung cancer patients. Chemotherapy for brain metastases from lung cancer is effective for both small cell and non-small cell lung cancer. Since brain metastases are part of systemic progression, chemotherapy should always be considered for the therapeutic management of brain metastases. Available data and response rates in lung cancer patients indicated that medical treatment for the management of brain metastases should be part of a multimodality treatment.

Metastatic Melanoma With Multiple Small Bowel Intussusceptions

Abstract: A 53-year-old man with a history of melanoma resected from the left ear 2 years ago that subsequently metastasized to brain, liver, and lung presented with new onset of fever, anemia, and emesis. He had a history of headaches, weakness and seizures status postradiation, and chemotherapy for brain metastasis. Abdomen and pelvis CT was obtained to further evaluate the fever, nausea, vomiting, and anemia. This revealed nonobstructive small bowel intussusceptions in the right and left lower quadrants. The patient continued to have worsening abdominal pain and FDG PET CT was obtained 1 month later to further evaluate the metastatic lesions. The PET CT revealed multiple new small bowel intussusceptions throughout the abdomen and pelvis that are intensely hypermetabolic, most consistent with small bowel metastatic lesions serving as lead points for the intussusceptions.

Chemotherapy in patients with brain metastases

The development of brain metastases is still considered as a "terminal complication" of a cancer disease. The potential for CNS metastases appears to be greatest in tumours of neuroectodermal origin like melanoma or SCLC, very high in patients with tumours of ectodermal origin like breast cancer and NSCLC, whereas tumours arising from other embryonic origin develop brain metastases less often. Neovacularisation with upregulated VEGF Expression by the tumour cells facilitates their transmigration through the BBB. Temozolomide and "small molecules" are currently under investigation in solid tumours as farnesyltransferase inhibitors and tyrosin kinase inhibitors are able to cross BBB and thus should be active within the brain. Although studies on chemotherapy of brain metastases are usually small and include mostly a small number of patients, responses and prolongations of survival have been recorded. More studies are needed to evaluate the potential of the new therapeutics agents which increased therapeutic ratio and reduced side effects from chemotherapy.

Chemotherapie von Hirntumoren bei Erwachsenen

Chemotherapy has become a third major treatment option for patients with brain tumors, in addition to surgery and radiotherapy. The role of chemotherapy in the treatment of gliomas is no longer limited to recurrent disease. Temozolomide has become the standard of care in newly diagnosed glioblastoma. Several ongoing trials seek to define the role of chemotherapy in the primary care of other gliomas. Some of these studies are no longer only based on histological diagnoses, but take into consideration molecular markers such as MGMT promoter methylation and loss of genetic material on chromosomal arms 1p and 19q. Outside such clinical trials chemotherapy is used in addition to radiotherapy, e.g., in anaplastic astrocytoma, medulloblastoma or germ cell tumors, or as an alternative to radiotherapy, e.g., in anaplastic oligodendroglial tumors or low-grade gliomas. In contrast, there is no established role for chemotherapy in other tumors such as ependymomas, meningiomas or neurinomas. Primary cerebral lymphomas are probably the only brain tumors which can be cured by chemotherapy alone and only by chemotherapy. The chemotherapy of brain metastases follows the recommendations for the respective primary tumors. Further, strategies of combined radiochemotherapy using mainly temozolomide or topotecan are currently explored. Leptomeningeal metastases are treated by radiotherapy or systemic or intrathecal chemotherapy depending on their pattern of growth.

Chemotherapy for Brain Metastases in Small-Cell Lung Cancer

PURPOSEBrain 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 METHODSEighty 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. RESULTSAmong 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. CONCLUSIONChemotherapy, including the regimen of irinotecan and carboplatin, is an effective treatment for SCLC brain metastases.

転移性脳腫瘍に対する化学療法の役割(<特集>転移牲脳腫瘍治療の現状と展望)

転移性脳腫瘍は,癌患者の増加に伴って増加している.無治療での平均生存期間は1〜2カ月であり,全脳照射に加えて局所コントロールの目的で,手術やガンマナイフなどの定位放射線照射が施行されているが,生存期間の延長への寄与は小さい.脳転移に対する化学療法はこれまであまり重要視されてこなかったが,癌薬物療法の進歩に伴い,肺癌,乳癌などの脳転移症例に対して化学療法の積極的な施行が試みられ,化学療法未施行例においては全身の頭蓋外病変と奏効率に差がないことが明らかになってきた.また,脳転移患者の死亡原因の約半数は原発巣の悪化によるものであるため,生存期間延長には脳転移の局所コントロールに加え,全身の転移病巣のコントロールが重要である.

Chemotherapy in Brain Metastases

The use OF chemotherapy to treat patients with brain metastases has been viewed historically with skepticism. To date, a survival benefit has not been demonstrated with the use of systemic chemotherapy in patients with brain metastases. However, the introduction of novel agents and delivery techniques warrants a reexamination of the role of systemic chemotherapy in the management of brain metastases. Temozolomide has shown encouraging results in patients with nonsmall cell lung cancer, and implanted carmustine wafers have demonstrated excellent local tumor control rates. This review discusses clinical data from the past decade with emphasis on trial design, tumor histology, available agents, and multimodality strategies. In addition, delivery techniques that circumvent the blood-brain barrier are reviewed. Although chemotherapy is usually used as a salvage therapy, it may be considered for use in selected patients with newly diagnosed brain metastases. To better evaluate chemotherapy in brain metastases, future trials should evaluate novel agents in the preirradiation setting. Enhanced regional delivery methods warrant further investigation, and Phase III trials of current regimens stratified by histology and by prognostic factors will establish the role of specific chemotherapy regimens in the treatment of patients with brain metastases.

Radiotherapy and chemotherapy of brain metastases

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.

Chemotherapy in brain metastases of lung and breast cancer

Brain metastases are the most common intracranial tumors and their incidence is increasing. Results of a recent analysis have confirmed that good performance status, control of the primary tumor, absence of extracranial disease and age less than 65 years are predictive of survival. Without treatment, patients with brain metastases survive approximately 1 month after diagnosis. Currently, chemotherapy has a limited role in the treatment of most brain metastases. Several regimens and new therapies, with a good penetration through the blood–brain barrier, such as Temozolomide (Temodar®, Shering Plough Corp.), have been used in brain metastases with different results depending on the histology of the primary tumor and on the administration schedule. A better understanding of the complex processes underlying the development of brain metastasis will enable us to develop more satisfactory targeted treatments.

Chemotherapy in brain metastases of lung and breast cancer

Brain metastases are the most common intracranial tumors and their incidence is increasing. Results of a recent analysis have confirmed that good performance status, control of the primary tumor, absence of extracranial disease and age less than 65 years are predictive of survival. Without treatment, patients with brain metastases survive approximately 1 month after diagnosis. Currently, chemotherapy has a limited role in the treatment of most brain metastases. Several regimens and new therapies, with a good penetration through the blood–brain barrier, such as Temozolomide (Temodar®, Shering Plough Corp.), have been used in brain metastases with different results depending on the histology of the primary tumor and on the administration schedule. A better understanding of the complex processes underlying the development of brain metastasis will enable us to develop more satisfactory targeted treatments.

The role of chemotherapy in brain metastases

Despite the widely held belief of the resistance to chemotherapy of brain metastases, central nervous sytem 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 metastasess 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 sytem 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 fenytoin, carbamazepin 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.

Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1

To determine if the timing of whole brain radiotherapy (WBRT) with respect to chemotherapy with cisplatin and vinorelbine would influence survival in patients with non-small-cell lung cancer (NSCLC) and concurrent brain metastasis. One hundred seventy-six patients with brain metastasis from NSCLC were included in the study between July 1995 and October 1997. All patients received chemotherapy with cisplatin 100 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1, 8, 15, 22. Cycles were repeated every four weeks. Evaluation of response was performed after two, four or six cycles. After two cycles, chemotherapy was administered to the responders to a maximum of six cycles. Patients were randomised to receive WBRT 30 Gy/10 fx/12 days and delayed corticosteroids. (arm A) for the intracranial nonresponders, or early on day 1 to 12 during the first cycle of chemotherapy (arm B). One hundred seventy-one patients were eligible: eighty-six in arm A and eighty-five in arm B; none had received prior chemotherapy; seventy-six and seventy-three, respectively, were assessable for response. There was a 21% overall objective response rate (OR) (with 1 complete response and 17 partial responses) after two cycles of chemotherapy alone (arm A) and a 20% OR (with 17 partial responses) to chemotherapy and early WBRT (arm B). The intracranial OR was 27% and 33%, respectively (P = 0.12). The six months survival rate (46% and 40%) and the median survival duration (24 and 21 weeks, respectively) were not significantly different between the two arms (P = 0.83, log-rank test). The major toxicity was severe or life-threatening neutropenia (grade 4), which occurred in 35% of arm A patients and 36% of arm B patients. There were thirteen treatment-related deaths (six in arm A and seven in arm B). There was no difference between the arms for haematological and neuro-toxicities. These results confirm the efficacy of chemotherapy in brain metastases of NSCLC and suggest that the timing (early or delayed) of WBRT did not influence survival of NSCLC with brain metastasis treated with concurrent chemotherapy.

Chemotherapy of brain metastases.

Chemotherapy of brain metastases.

Treatment of small cell lung cancer. Recent experience of the EORTC lung cancer cooperative group : Van Zandwik N. Department of Chest Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam. Anticancer Res 1994;14: B 313-5

In this paper an overview of the activities since 1982 of the EORTC Lung Cancer Cooperative Group is given. Although the last decade has brought only small improvements, several important questions have been answered. Prognostic factors, optimal duration of chemotherapy, retreatment policies, non-cross resistant combinations and chemotherapy of brain metastases have been the subject of cooperative effort during the last ten years, allowing better choices to be made in the treatment of individual patients. Currently the place and timing of radiotherapy and the efficacy of several new drugs are under study. In order to assess reliably the relatively small gains of different treatment options, cooperative groups like the EORTC LCCG will continue to play an important role in the future.