Systemic chemotherapy,intrathecal chemotherapy,and symptom management in the treatment of leptomeningeal metastasis

Metastasis to the leptomeninges occurs in many common cancers, including leukemia; lung, breast, and gastrointestinal cancers; and tumors of the brain. By way of the flow of cerebrospinal fluid, leptomeningeal metastasis spreads throughout the neuraxis. Consequently, therapy for leptomeningeal metastasis must be directed to the entire central nervous system (CNS). Treatment often consists of involved-field radiotherapy, systemic chemotherapy, and intrathecal chemotherapy. However, because meningeal spread occurs most often in advanced disease, treatment is mainly palliative, except in childhood leukemia, where durable remission has been reported. This article outlines the role of systemic and intrathecal chemotherapy in patients with leptomeningeal metastases. Strategies for symptom management in these patients are also described.     

Systemische Therapie von Hirnmetastasen

Background

Local therapy of brain metastases is frequently effective but not applicable in multiple cerebral metastases and not able to target systemic metastases or the primary tumor. Systemic therapies are advantageous in this respect as they simultaneously treat the systemic disease which is frequently decisive for the prognosis.

Objective

The current role of systemic therapy in the management of brain metastases is presented.

Material and methods

Representative publications, particularly those more recent, on the systemic therapy of brain metastases of solid tumors were assessed and the results critically analyzed.

Results

In general, a substantial improvement in the overall prognosis of patients with brain metastases by treatment with systemic therapy has not yet been achieved; however, in certain entities, as in brain metastases of small-cell lung cancer and germ cell tumors, systemic chemotherapy should be used as first line treatment whenever possible and can be amended during the course of the disease by whole-brain radiotherapy (WBRT) and/or resection. With this treatment long-term survival can be achieved in many patients with germ cell tumors. In other solid tumors systemic chemotherapy should be considered for patients in a good general physical condition with clinically asymptomatic multiple brain metastases, particularly with active systemic disease and when pretreatment with WBRT has already been carried out. For some tumors the spectrum of therapeutic options has been extended by targeted therapy and immunotherapy.

Conclusion

Systemic therapy should often be regarded as a meaningful therapeutic supplement to neurosurgical and radiation therapeutic measures for therapy of brain metastases as a part of a multimodal treatment approach.     

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.     

Therapy and prophylaxis of brain metastases

Metastases of various tumors to the brain account for the majority of brain cancers, and are associated with a poor prognosis. The most common primary sites are lung, breast, skin, kidney and colon; 10–40% of cancer patients develop brain metastases during the course of the disease. The incidence of brain metastasis appears to be rising; reasons may include better therapies for the systemic disease with longer survival of cancer patients but lower efficiency against brain metastases. In this article, we will discuss the conventional treatment with surgery, radiosurgery, radiotherapy and chemotherapy, but also new directions in the management of solid brain metastases. While general therapeutic nihilism should be avoided, it is important to recognize that the number of brain metastases, the extent of the systemic disease and also the tumor type have to be taken into account when choosing individual treatment regimens. Finally, special emphasis will be put on established and future approaches to prevent the disease. We thus aim to provide a framework for treating patients with different presentations of brain metastases, and to highlight important avenues for research.     

Therapy and prophylaxis of brain metastases

Metastases of various tumors to the brain account for the majority of brain cancers, and are associated with a poor prognosis. The most common primary sites are lung, breast, skin, kidney and colon; 10-40% of cancer patients develop brain metastases during the course of the disease. The incidence of brain metastasis appears to be rising; reasons may include better therapies for the systemic disease with longer survival of cancer patients but lower efficiency against brain metastases. In this article, we will discuss the conventional treatment with surgery, radiosurgery, radiotherapy and chemotherapy, but also new directions in the management of solid brain metastases. While general therapeutic nihilism should be avoided, it is important to recognize that the number of brain metastases, the extent of the systemic disease and also the tumor type have to be taken into account when choosing individual treatment regimens. Finally, special emphasis will be put on established and future approaches to prevent the disease. We thus aim to provide a framework for treating patients with different presentations of brain metastases, and to highlight important avenues for research.     

Treatment of brain metastases from germ cell tumors

Brain metastases occur in approximately 10% of patients with advanced metastatic germ cell tumors. Patients with nonseminomatous histology, lung metastases, and high β-human chorionic gonadotropin levels are at higher risk for synchronous brain metastases at first diagnosis and for relapsing with brain metastases after successful cisplatin-based chemotherapy. Patients with brain metastases should undergo multimodal treatment strategies, including cisplatin-based combination chemotherapy plus radiotherapy or surgery. However, the optimal combination and sequence of these strategies remain unclear and may differ between subgroups. But in all cases, chemotherapy must be part of treatment, even in patients with isolated cerebral relapse without systemic disease.     

Identification and treatment of aggressive thyroid cancers. Part 2: risk assessment and treatment

Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radio-iodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article, which appeared in March, described in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, treatment, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2 covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.     

Identification and treatment of aggressive thyroid cancers. Part 1: subtypes

Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radioiodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article describes in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2, which will appear in next month's issue, covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and the value of treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.     

Brain Metastases of Her2-Positive Breast Cancer: A Case of 34 Months’ Remission with Lapatinib plus Capecitabine

Breast tumors overexpressing Her2 (15% of breast cancers) are particularly at risk for central nervous system parenchymal metastases. Whole-brain irradiation (WBI) is the standard of care of brain metastases (BM), and secondarily, systemic treatment is used in case of progression. We report the case of a patient with Her2-positive breast tumor with BM developed 10 months after the initial diagnosis of cancer. The BM were initially treated with WBI then trastuzumab before a recurrence occurred, which was controlled during 34 months with lapatinib and capecitabine. The treatment was regularly adjusted according to the tolerance and the efficacy in order to obtain the control of systemic and neurological disease and to maintain the patient''s quality of life. Studies on new targeted agents and/or new combinations with chemotherapy are ongoing. This suggests a better efficacy of treatment and an increased survival of patients. However, these patients are sometimes in a very poor general condition. In this case, we show that a good evaluation of efficacy and toxicities may allow an adaptation of the sequence and dose of treatment in order to preserve the response to treatment and the quality of life. Indeed, systemic treatments are available in addition to WBI. Therefore, the objective of the management of BM is twofold: survival and quality of life.Key words: Breast cancer, Brain metastases, Her2-positive tumors, Lapatinib, Capecitabine     

Recent advances in the treatment of pediatric brain tumors

Central nervous system (CNS) cancers are the second most frequent malignancy (and the most common solid tumor) in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment. Advances in the understanding of the nature of the blood-brain/tumor barrier, chemotherapy resistance, tumor biology, and the role of angiogenesis in tumor progression and metastases have led to the advent of newer therapeutic strategies that circumvent these obstacles or target specific receptors that control signal transduction and/or angiogenesis in tumor cells. Ongoing clinical trials will determine whether these novel treatment modalities will improve outcomes for children with brain tumors.     

Überwindung der Blut-Hirn-Schranke

The penetration of cytostatic agents into the brain parenchyma is inhibited by the blood-brain-barrier (BBB). However, brain metastases of solid tumors are generally amenable to systemic chemotherapy due to the absence of an intact barrier. Only small tumor cell conglomerates are protected by a presumably intact BBB. Furthermore, systemic treatment of brain metastases is limited by chemoresistance and a poor performance status in the majority of patients. Novel cytostatic agents with different biochemical properties often show improved penetration into the brain parenchyma. Moreover, targeted drugs, such as tyrosine kinase inhibitors exhibit a more selective mode of action with a favorable therapeutic index and potentially act synergistically in combination with chemotherapy. Their efficacy in the treatment of brain metastases is currently being explored in clinical trials.     

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient’s disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS.

Implications for Practice:

Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.     

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

Brain metastases are the most frequent cancer in the central nervous system, being ten times more common than primary brain tumors. Patients generally have a poor outcome with a median survival of 4 months after diagnosis of the metastases. Therapeutic options include surgery, stereotactic, radiosurgery, whole-brain radiotherapy (WBRT), and chemotherapy. Patients with a limited number of brain metastases and well-controlled systemic cancer benefit from brain metastases-specific therapies, including surgery, radiosurgery, and conventional radiation. The role of chemotherapy for brain metastases remains limited. There is concern about drug delivery because of the blood-brain barrier. However, higher response rates are noted with initial therapies, suggesting that part of the poor response rate may be related to the late onset of brain metastases and the use of second- and third-line regimens. Recent studies have demonstrated objective responses with systemic therapy in a variety of cancer types, especially when combined with WBRT. Individual therapeutic strategies for central nervous system metastases must be chosen based on performance status, the extent of intracranial disease, and the chemosensitivity of the underlying tumor, as well as the control of the systemic cancer. In this article we review important prognostic factors and challenges in using chemotherapy. We specifically review recent advances in the treatment of brain metastases from breast and lung cancer as well as melanoma. Future treatment advances will require a multidisciplinary approach integrating surgical, radiation, and chemotherapeutic options to improve neurological function and quality of life, rather than just focusing on survival endpoints.     

Growth rate of newly developed metastatic brain tumors after thoracotomy in patients with non-small cell lung cancer

Among 1372 lung cancer patients without brain metastasis that underwent resection of lung cancer at our center from 2001 to 2007, brain metastases developed in 72 patients (5.2%) during their hospital course. We hypothesized that there were micro-metastases in the brain at the time of lung surgery in these patients, even though there were no detectable brain metastases on the MRI. The purpose of this study was to evaluate the growth rates of metastatic brain tumors in this unique subset of patients, and to compare the findings with our previous study that calculated the growth rate of brain metastases during chemotherapy. Among 72 patients, 23 with cystic or hemorrhagic metastases were excluded. Seventy-six metastatic brain tumors in 49 patients were reviewed. Twenty-five patients underwent adjuvant or neoadjuvant chemotherapy; however, for the rest of the patients, chemotherapy was not added after lung cancer surgery. The tumor volume was determined using V-works software (v. 4.0) (Cybermed, Seoul, Korea) and T1 gadolinium enhanced MR images. The overall median tumor growth rate was 11.7 mm³/day (interquartile range, 4.9-26.8). There were no statistically significant differences in the tumor growth among the lung cancer stages and the growth rate was similar regardless of the use of chemotherapy. The growth rate reported in this study shows consistency with that of our previous report (12.1 mm³/day). These findings may help optimize patient management during follow up.     

Chemotherapy and the treatment of brain metastases

Brain metastases have traditionally been treated with a surgical or radiotherapeutic approach. Chemotherapy is used occasionally as salvage therapy. The blood-brain barrier excludes most chemotherapeutic agents, rendering many systemic options ineffective within the CNS. Intrathecal chemotherapies do not penetrate into brain tissue or bulky parenchymal tumors, so are ineffective in treatment of brain metastases. However, some patients with brain metastases benefit from chemotherapy, and temozolomide or targeted therapies like gefitinib have demonstrated activity. A better understanding of the biological behavior of brain metastases may lead to development of effective treatments for this common complication of systemic cancer. The review discusses the biology of brain metastases and provides an update on current chemotherapeutic strategies.     

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.     

Diagnosis and treatment of metastatic disease to the liver

A number of cancers present with synchronous or metachronous hepatic metastases. Historically, many of these patients were considered unresectable and were treated with either systemic chemotherapy or supportive care. Today, a variety of options exist for the management of hepatic metastases. Newer agents for systemic therapy continue to be introduced and are providing improved progression-free and overall survival and increased resectability of liver metastases. However, complete surgical resection of isolated hepatic metastases remains the optimal management for these patients. Surgical interventions can be offered to patients with hepatic-only metastases. Hepatic artery chemotherapy represents an adjunct for those patients undergoing resection and can improve survival. This benefit may be even more pronounced when combined with systemic chemotherapy. Newer generation biologic agents can improve results. New therapeutic modalities to treat lesions that are unresectable include ablative techniques such as radiofrequency ablation (RFA) and cryoablation. This article will examine modalities of diagnosis of hepatic metastases and highlight the data regarding hepatic resection for metastases of several types of primary cancers, the rationale for, and efficacy of, hepatic arterial chemotherapy, in both the postoperative adjuvant setting and in unresectable liver disease, and review the current literature for ablative techniques in the treatment of liver metastases.     

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.     

Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

BackgroundThe dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases.Experimental designPaired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ² or Fisher's exact test were used for analysis.ResultsWe analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009).ConclusionsWe identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.     

Multidisciplinary management of brain metastases

Metastatic brain tumors are the most common intracranial neoplasms in adults. The incidence of brain metastases appears to be rising as a result of superior imaging modalities, earlier detection, and more effective treatment of systemic disease. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Treatment decisions must take into account clinical prognostic factors in order to maximize survival and neurologic function whilst avoiding unnecessary treatments. The goal of this article is to review important prognostic factors that may guide treatment selection, discuss the roles of surgery, radiation, and chemotherapy in the treatment of patients with brain metastases, and present new directions in brain metastasis therapy under active investigation. In the future, patients will benefit from a multidisciplinary approach focused on the integration of surgical, radiation, and chemotherapeutic options with the goal of prolonging survival, preserving neurologic and neurocognitive function, and maximizing quality of life.