Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy

Leptomeningeal meningitis occurs in approximately 5% of metastatic breast cancers, and there is no standard treatment for this complication. We retrospectively analyzed the clinical data and cerebrospinal fluid of 24 patients treated with high-dose intrathecal methotrexate for breast cancer leptomeningeal meningitis (BLM). Cytologic response (CSF cytology without neoplastic cells after treatment) was observed in 11 patients (46%) and related to survival (P = 0.005). In addition, clinical symptoms improved in all 11 patients who had a cytologic response and in 7 patients (54%) without cytologic response (P = 0.02). The predictive value of cytologic response needs further confirmation. Cytologic response could be helpful in the management of intrathecal chemotherapy in patients with BLM.     

Current diagnosis and treatment of leptomeningeal metastasis

Meningeal metastasis occurs in 3–8% of all cancer patients, producing neurologic morbidity and a high mortality. Diagnosis is best established by the demonstration of malignant cells in the cerebrospinal fluid. However, in patients with known cancer, MR scan with gadolinium may be diagnostic when subarachnoid nodules can be demonstrated in the head or spine. Therapy usually involves radiotherapy to symptomatic sites, often followed by intrathecal chemotherapy. Intrathecal chemotherapy is best delivered by an intraventricular reservoir system but can also be delivered by repeated lumbar puncture. Methotrexate, cytarabine and thiotepa are the most common agents instilled into the subarachnoid space. Their limited efficacy can be explained by their restricted spectrum of antitumor activity. Patients with leptomeningeal metastasis from leukemia, lymphoma or breast cancer tend to respond best and this may, in part, be attributed to the relative sensitivity of these primary tumor types to the agents administered intrathecally. Systemic chemotherapy may prove a more attractive alternative to intrathecal drugs since it can penetrate into bulky disease, reach all areas of the subarachnoid space, and not be restricted by CSF bulk flow. The prognosis for patients with leptomeningeal metastasis is poor, most individuals surviving a median of only about four months. Occasional patients do have prolonged survival and improvement of their neurologic function.     

Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis

Introduction

The prognosis for leptomeningeal metastasis (LM) remains extremely poor regardless of intrathecal chemotherapy with various drugs, and thus, new treatments are necessary. Butyrate is an endogenous 4-carbon saturated fatty acid, has been investigated as an anti-tumor agent because of its multiple suppressive effects on several tumors. In this study, we investigated the cellular basis of sodium butyrate (SB), a sodium salt compound of butyrate, in vitro and evaluated the clinical potential of intrathecal SB administration for LM in vivo.

Methods

We examined SB’s effects on Walker 256 rat mammary tumor cells with regard to cytotoxicity, cell morphology, colony formation, migration, and invasion. We also examined SB’s neurotoxicity for primary neurons and primary astrocytes. We finally evaluated the potency of continuous intrathecal SB administration in rats with intrathecally transplanted breast tumors as an LM model.

Results

Physiological SB concentrations (2–4 mM) induced growth suppression, morphological changes, and inhibition of migration and invasion, but did not exhibit neurotoxic effects on primary neurons and astrocytes. Continuous intrathecal SB administration in a rat LM model significantly increased survival periods with little neurotoxicity.

Conclusions

Continuous intrathecal SB administration significantly improved prognoses in a rat LM model, which suggests that SB is a promising therapy for LM.

     

Successful treatment of intracranial ependymoma with leptomeningeal spread with systemic chemotherapy and intrathecal liposomal cytarabine in a two-year-old child

Ependymoma is the third most common CNS tumor in children. Neuraxis dissemination at the time of diagnosis is rare and occurs in fewer than 10% of patients. Recent advances in neuroimaging, neurosurgery, and radiation therapy have improved disease control and functional outcomes for children with ependymoma. However, children under the age of 3 years with ependymoma and leptomeningeal spread historically have had worse outcomes. It is not clear if age alone, or a combination of risk factors such us unfavorable location, which may prevent gross total resection, and withholding radiation therapy may have contributed to poor outcomes in younger age groups. The reason for attempting GTR is based on results from retrospective and prospective studies, where the most important prognostic factor is extent of resection. These patients are not candidates for craniospinal irradiation. Therefore, new therapeutic approaches must be attempted. This is a case report of a posterior fossa ependymoma with leptomeningeal dissemination in a two-year-old child, successfully treated with dose intensive chemotherapy and intrathecal liposomal cytarabine.     

Phase I study of intrathecal chemotherapy with NS-101 for leptomeningeal carcinomatosis in Japan

Intrathecal administration of MTX and/or Ara-C through the Ommaya system placed in a ventricle has been accepted as a standard therapy for leptomeningeal carcinomatosis. Recently, sustained-release cytosine arabinoside, a depot cytosine arabinoside liposomal injection: DepoCyt, has been reported to be useful for the treatment of leptomeningeal carcinomatosis in Canada, Europe, and the USA. Phase I study of NS-101, DepoCyt in Japan, was performed in patients with leptomeningeal carcinomatosis from solid tumors using the continuous reassessment method (CRM). NS-101 was administered twice through the Ommaya system placed in the lateral ventricle with an interval of 2 weeks. A dose of 25 mg was initially tried in a patient and then a dose of 50 mg was administered in 8 patients. The recommended dose of NS-101 was estimated from pharmacodynamics and tolerance from CRM, and the clinical effectiveness of NS-101 was also assessed. We also compared the present data with the reported data from Europe and the USA. As a result, free Ara-C was maintained over the estimated effective concentration for 2 weeks, and no pharmacodynamic differences were confirmed among Japan, Europe and the USA. Maximum tolerated dose was determined to be 50 mg. Complete cytological response of cerebrospinal fluid (CSF) was obtained in a patient, and CSF cytological conversion of either ventricle or lumbar CSF from positive to negative was observed in four patients. Neurological improvements in 3 pts and no sign of worsening in one patient were observed, and grade IV toxicity based on National Cancer Institute-Common Toxicity Criteria was not encountered. In conclusion, NS-101 was effective for leptomeningeal carcinomatosis from solid tumors and the estimated maximum tolerated dose was 50 mg as approved in Europe and the USA.     

乳腺癌脊髓转移患者多重放化疗5例报告

目的探讨乳腺癌脊髓转移患者的临床特点及综合治疗效果。方法选取2008年7月至2018年6月间解放军307医院和北京丰台右安门医院收治的5例乳腺癌脊髓转移患者,脊髓病变局部治疗包括常规放疗及立体定向放疗,脊髓转移后的药物治疗包括拉帕替尼、卡培他滨、培美曲塞、替莫唑胺及氨甲蝶呤,分析患者的临床疗效和不良反应。结果患者中4例行常规放疗,2例行立体定向放疗。脊髓转移后,2例Her-2阳性患者均采用拉帕替尼。2例患者用卡培他滨,1例用替莫唑胺,2例用培美曲塞,2例用鞘内注射氨甲蝶呤。脊髓病变治疗后,4例患者用核磁评价疗效:2例完全缓解,1例部分缓解,1例稳定,1例未评价。3例去世者脊髓转移后生存时间分别为1、5和7个月,2例存活者分别为8和129个月。结论乳腺癌脊髓转移患者综合治疗有效,有的患者可能长期生存。     

Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study

Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of systemic cancer with limited survival. Randomized trials comparing single agent intrathecal methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. We hypothesized that combination intrathecal chemotherapy would be a safe and tolerable option in solid tumor LM. We conducted a retrospective cohort study of combination IT chemotherapy in solid tumor LM at a single institution between April 2010 and July 2012. In addition to therapies directed at active systemic disease, each subject received IT liposomal cytarabine plus IT methotrexate with dexamethasone premedication. Patient characteristics, survival outcomes and toxicities were determined by systematic chart review. Thirty subjects were treated during the study period. The most common cancer types were breast 15 (50 %), glioblastoma 6 (20 %), and lung 5 (17 %). Cytologic clearance was achieved in 6 (33 %). Median non-glioblastoma overall survival was 30.2 weeks (n = 18; range 3.9–73.4), and did not differ significantly by tumor type. Median time to neurologic progression was 7 weeks (n = 8; range 0.9–57), with 10 subjects (56 %) experiencing death from systemic disease without progression of LM. Age less than 60 was associated with longer overall survival (p = 0.01). Six (21 %) experienced grade III toxicities during treatment, most commonly meningitis 2 (7 %). Combination IT chemotherapy was feasible in this small retrospective cohort. Prospective evaluation is necessary to determine tolerability, the impact on quality of life and neurocognitive outcomes or any survival benefit when compared to single agent IT chemotherapy.     

Animal models of leptomeningeal metastasis

Animal models of leptomeningeal metastasis (LM) should give insight into pathophysiological mechanisms and allow to evaluate new treatments including their neurotoxicity. Syngeneic models use tumor cells of mouse, rat, rabbit or guinea pig origin. Allogeneic models usually rely on human tumor cells injected into nude mice or rats. A review of the literature revealed 2 (4) different glioma, 3 medulloblastoma, 3 (3) carcinoma, 3 (1) melanoma, 1 rhabdomyosarcoma, 2 (8) leukemia and 2 (2) non-Hodgkin's lymphoma allogeneic (syngeneic) models of LM. These models have been used to study the evolution of LM and to evaluate systemic or intrathecal chemotherapy, intrathecal immunotherapy (interleukin-2, interferon-beta, uncoupled, toxin- or radionuclide-conjugated antibodies), and recently gene therapeutic approaches. On the whole, pathophysiological, therapeutic and neurotoxic findings have been well transferable to the clinical situation. Therefore, it seems rational to preclinically test new treatments in an appropriate animal model of LM before using them in patients.     

Systemic chemotherapy for advanced colorectal cancer with liver metastasis

We report the progress of systemic chemotherapy for advanced colorectal cancer with liver metastasis. It must be noted that the purpose of this treatment is to prolong the symptom-free period. Review of hepatic arterial infusion (HAI) compared with systemic chemotherapy for the treatment of unresectable liver metastases from colorectal cancer showed that was attained with HAI a much higher response rate and survival benefit than systemic chemotherapy. However, systemic chemotherapy has shown progress since that time. Regarding administration methods, continuous injection is better than bolus injection for 5-FU. New modulators of 5-FU have also became available, such as leucovorin, CPT-11, and I-OHP. Futhermore, many studies of 5-FU-based combination therapy have shown that the mean survival time (MST) and response rate (RR) are now close to those of HAI. Finally, the combination with HAI with systemic chemotherapy using CPT-11 resulted in the highest RR of 74%. Further trials of such combination therapy will be performed in the future.     

Systemic chemotherapy in the management of malignant peritoneal mesothelioma.

AIM: To review available evidence on the efficacy of chemotherapy in malignant mesothelioma of any origin. METHODS: All original research and review papers related to the role of systemic chemotherapy in the treatment of malignant mesothelioma, published from 1966 through February 2005, were identified through a MEDLINE search of the literature using the following search terms: "mesothelioma", "peritoneal", "chemotherapy", "antifolates", "cancer therapy". This search was supplemented by a manual search of the Proceedings of the Annual Meetings of the American Association for Cancer Research, American Society of Clinical Oncology, and the American Association for Cancer Research (AACR)-European Organization for Research and Treatment of Cancer (EORTC)-National Cancer Institute (NCI) Symposium on New Anticancer Drugs. RESULTS: Pemetrexed in combination with cisplatin is the first treatment regimen that demonstrates a survival improvement in patients with unresectable malignant pleural mesothelioma. Data from uncontrolled studies suggest similar antineoplastic efficacy in patients with mesothelioma of peritoneal origin. Preliminary results also suggest a possible survival advantage for a combination of cisplatin and raltitrexed as compared to cisplatin alone. Other cytotoxic agents that have shown to be active in this setting include vinorelbine and gemcitabine, either alone or combined with platinum compounds. CONCLUSION: The pemetrexed-cisplatin combination has become the new standard of care for patients with unresectable malignant mesothelioma. Future strategies shall incorporate these novel agents into multimodality approaches at earlier stages of the disease. Given the low incidence of this disease, encouraging physicians to refer these patients to specialized centers and patients to participate in clinical trials is of utmost importance.     

Systemic chemotherapy and its implications for resection of colorectal liver metastasis

Background

Liver resection remains the only chance of cure for patients with colorectal liver metastasis. Modern chemotherapy can play a role in the management of these patients but is not without risk.

Methods

The online databases Medline and Pubmed were searched to identify relevant articles. Keywords used in these searches were “colorectal cancer”, “liver metastasis”, “chemotherapy”, “liver resection”, “monoclonal antibody”, “steatohepatitis”, “sinusoidal obstruction” and “liver regeneration”. Databases were searched for the period January 1970 to September 2009 inclusively. In addition hand referencing of retrieved articles was performed.

Results

Modern chemotherapy regimens can effectively downstage initially unresectable disease such that surgical resection can be performed with the prospect of long term cure. There is insufficient evidence however to recommend its use in either the neoadjuvant or adjuvant setting in those with resectable disease from the outset.

Conclusion

Chemotherapy can be associated with significant changes to the hepatic parenchyma with subsequent increased risk of morbidity and mortality in the perioperative period. Much work needs to be done to understand the molecular mechanisms underlying these changes to make extended resections safer in patients who are at risk.     

Current concepts in leptomeningeal metastasis.

Leptomeningeal metastasis is a common neurologic disorder affecting the entire neuraxis in patients with metastatic systemic cancer and primary brain tumors. The clinical presentation of leptomeningeal metastasis is pleomorphic and commonly affects the cerebral hemispheres, cranial nerves, or spinal cord and its roots. Diagnosis is confirmed by the presence of malignant cells in the cerebrospinal fluid or by clinical and neuroradiographic pattern compatible with leptomeningeal metastasis. Treatment is palliative and is directed at the entire neuraxis combining involved-field radiotherapy and intra-cerebrospinal fluid drug administration. Regional chemotherapy pharmacokinetically is best administered by intraventricular instillation employing frequent drug administration, thereby insuring prolonged cytotoxic drug exposure. Chemotherapeutic drug distribution is dependent on bulk flow of cerebrospinal fluid. This review will summarize current information regarding the incidence, clinical presentation, laboratory findings, pathology, pathophysiology, staging, treatment, and survival of patients with leptomeningeal metastasis.     

The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study

To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n = 17) or to non-intrathecal (non-IT) treatment (n = 18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) −5.5 to +34.3 weeks; P = 0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P = 0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.     

Systemic chemotherapy for the treatment of metastatic melanoma

The role of systemic chemotherapy in the treatment of patients with metastatic melanoma remains of questionable benefit. Despite encouraging phase II data from multiple institutions that suggested an improved overall response rate for patients treated with the Dartmouth regimen, recently completed phase III trials have failed to demonstrate a significant benefit in survival. Of concern is the fact that there have been relatively few new chemotherapeutic agents in the past several years that have demonstrated any activity in this disease. More recently there has been a shift away from combination chemotherapy to biochemotherapy. However, this approach has yet to be clearly defined as superior. The basis for optimism in the future in this field resides in the realm of molecular oncology. As mechanisms of resistance are identified, new molecules such as antisense oligonucleotides may provide the basis for increasing the sensitivity of melanoma to chemotherapeutic and/or immunotherapeutic treatments.     

Therapy of leptomeningeal metastasis in solid tumors

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM + parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.     

Resolution of extensive leptomeningeal metastasis and clinical spinal cord compression from breast cancer using weekly docetaxel chemotherapy

Metastatic breast cancer to the leptomeninges is a late event in the disease course and is associated with significant morbidity and a grave prognosis. Treatment typically involves direct intrathecal injection of chemotherapy into the cerebrospinal fluid compartment since systemic chemotherapy penetrates poorly to the central nervous system. Here we report an interesting clinical observation involving a patient presenting with leptomeningeal spread of breast cancer causing extensive spinal cord compression with obliteration of the subarachnoid space, thus precluding the use of direct intrathecal chemotherapy. We administered systemic chemotherapy using weekly docetaxel with complete radiographic resolution of her disease and recovery from clinical spinal cord compression. While this is a single clinical observation, weekly administration of docetaxel in this circumstance may have been associated with improved drug “escape” into the central nervous system and better antitumor effect. Because leptomeningeal disease is typically a late event in metastatic breast cancer, resistance to therapeutic intervention may reflect intrinsically resistant disease in the setting of extensive prior therapy rather than a routine problem with systemic drug delivery to the CNS. Studying patterns of disease relapse in patients who had received adjuvant weekly taxanes may provide insights into this hypothesis.     

New aspects of immunotherapy of leptomeningeal metastasis

Immunotherapeutic approaches to leptomeningeal metastasis (LM) include the intrathecal application of cytokines such as interleukin-2 (IL-2) and interferon- (IFN-), and lymphokine-activated killer cells (LAK cells). Results in a rodent model of leptomeningeal gliomatosis with intrathecal IL-2 application are discouraging, but some clinical improvement and clearance of neoplastic cells from CSF have been seen in patients with LM from melanoma treated with intrathecal IL-2 alone, and in patients with LM from primary brain tumors and squamous cell carcinoma of the tongue treated with intrathecal LAK cells and IL-2. The neurotoxicity of this therapy, mainly increased intracranial pressure, has been considerable but generally manageable. However, IFN- caused severe neurotoxicity in form of an only partly reversible progressive vegetative state in the majority of patients. Considering the small number of patients treated with IL-2 and LAK cells, its value for the treatment of LM could only be stated by further investigation. In future, the application of recently discovered cytokines such as Fas-ligand, the continuous paracrine cytokine release by genetically modified cells, or vaccination strategies using genetically modified tumor cells might offer new immunotherapeutic approaches in LM.