Central Nervous System Metastatic Disease Research Articles

NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA

Abstract Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.

Interactive music therapy for chronic pain management in people with advanced cancer: A mechanistic study.

e24119 Background: Chronic pain is one of the most feared symptoms in people with cancer. Although music therapy is frequently used for pain management in cancer care, there is a lack of knowledge of underlying mechanisms. Yet, it is well accepted that knowledge of mediators is essential for optimization of psychosocial treatment interventions. We conducted a multi-site randomized controlled trial to examine mediators hypothesized to account for the pain-reducing effects of interactive music therapy (IMT) in adults with advanced cancer. Methods: This study included adults with advanced cancer (stage III/IV) who had moderate to severe chronic pain caused by 1) locally advanced cancer that had extended to other organs/soft tissue or was impinging on/eroding the bone, 2) bone metastasis, or 3) soft tissue metastasis. We excluded adults with primary central nervous system (CNS) tumor, CNS metastatic disease, or hematologic malignancies. We randomized 92 participants to 6 individual IMT ( n = 45) or social attention control (SAC) ( n = 47) sessions. The mediators (anxiety, mood, pain-related self-efficacy and emotional support) and pain outcomes (pain intensity and pain interference) were measured at baseline, week 4, and week 6 using self-report measures. We included treatment expectancy, music reward, and adult playfulness as moderators. Follow-up interviews were conducted to examine congruence between the hypothesized mediation model and participants’ explanations of how IMT impacted their pain experience. Our target sample size was 100 to achieve 80% power to detect a medium effect at α = 0.05 and 28% attrition. We used ITT analyses and the mediation model per Preacher and Hayes to estimate the total and specific indirect effects of each hypothesized mediator individually. Interview transcripts were analyzed using thematic analysis. Results: Participants were 56±12 years old. Most were female (72%), white (44%) or Black (39%), and had stage IV cancer (75%). The most common types of cancer were breast (46%) and lung (13%). Self-efficacy was found to be a significant mediator for the effect of IMT on pain intensity (indirect effect ab = 0.79, 95% CI 0.01 to 1.82) and pain interference (indirect effect ab = 1.16, 95% CI 0.02 to 2.51), while anxiety, mood, and perceived support were not. The quantitative results were supported by the qualitative findings. None of the proposed moderators were found to be significant. However, we found that the mediating effect of pain-related self-efficacy on pain intensity and pain interference was significantly moderated by baseline pain interference. Conclusions: This study suggests that the impact of music therapy on chronic pain management is mediated through self-efficacy. This knowledge can help further optimize music therapy interventions for chronic pain management in people with advanced cancer by capitalizing on teaching music-based self-management techniques. Clinical trial information: NCT03432247 .

Abstract A019: Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma

Abstract Background: CDK9 blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as MCL1 and MYC. TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. The anti-tumor activity of alvocidib has previously been shown in vitro in a Ewing sarcoma cell line and in vivo in a mouse Ewing sarcoma xenograft model. TP-1287 is being investigated in a phase 1 dose escalation and dose expansion study in patients with solid tumors (escalation) and sarcoma (expansion) (NCT03604783). The design of the expansion part of the phase 1 study in patients with sarcoma is herein described. Methods: Thirty patients with sarcoma will be enrolled. Key eligibility criteria are age ≥18 years (≥16 years if ≥40 kg); histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma, dedifferentiated liposarcoma, or synovial sarcoma (10 patients each); 1–3 prior lines of therapy (including an anthracycline); Eastern Cooperative Oncology Group performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status. Exclusion criteria include a history of certain cardiovascular diseases (including heart failure and myocardial infarction [≤6 months]); seizure disorder requiring anticonvulsant therapy; presence of symptomatic central nervous system metastatic disease or disease that requires local therapy ≤2 weeks; severe chronic obstructive pulmonary disease with hypoxemia; active infections; or treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives (whichever occurs first). Patients will be treated at the recommended phase 2 dose established during dose escalation (11 mg twice daily orally, continuous dosing) and will continue to receive treatment with the same dose/schedule if they successfully complete a 28-day treatment cycle without significant treatment-related toxicity or progressive disease. Assessments will be performed on Day 1 and Day 15 of each cycle. Assessments for response and tumor burden will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objective is objective response rate; secondary objectives are progression-free survival at 16 and 24 weeks and safety; and exploratory objectives are systemic exposure, antitumor activity (by objective radiographic assessment), and pharmacodynamics. Tumor tissue concentrations may be measured in patients who consent to optional tumor biopsies. Statistical analysis for all safety and efficacy parameters will be primarily descriptive in nature; time-to-event variables will be summarized via Kaplan-Meier. The dose expansion cohort is currently recruiting in the United States. Results: N/A. Conclusions: N/A. Citation Format: Andrew J. Wagner, Gregory M. Cote, Donald Richards, Nicholas J. Vogelzang, William J. Edenfield, Mitchell E. Gross, Lynn Mar, Gil D. Fine, Edward Dow, John A. Charlson. Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A019.

Leptomeningeal carcinomatosis and breast cancer: a systematic review of current evidence on diagnosis, treatment and prognosis.

Leptomeningeal carcinomatosis (LC) is a rare but challenging manifestation of advanced breast cancer with a severe impact on morbidity and mortality. We performed a systematic review of the evidence published over the last two decades, focusing on recent advances in the diagnostic and therapeutic options of LC. Lobular histology and a triple-negative intrinsic subtype are well-known risk factors for LC. Clinical manifestations are diverse and often aspecific. There is no gold standard for LC diagnosis: MRI and cerebrospinal fluid cytology are the most frequently used modalities despite the low accuracy. Current standard of care involves a multimodal strategy including systemic and intrathecal chemotherapy in combination with brain radiotherapy. Intrathecal chemotherapy has been widely used through the years despite the lack of data from randomized controlled trials and conflicting evidence on patient outcomes. No specific chemotherapeutic agent has shown superiority over others for both intrathecal and systemic treatment. Although endocrine therapy was heuristically considered unable to exert significant control on central nervous system metastatic disease, retrospective data suggest a favourable toxicity profile and even a possible positive impact on survival. In recent years, encouraging data on the use of targeted agents has emerged but further research in this field is required. Palliative treatment in the form of whole brain or stereotactic radiotherapy is associated with improvement in clinical manifestations and quality of life, with no proven impact on survival. The most investigated prognostic factors include performance status, non-triple-negative disease and multimodal treatment. Validation of prognostic scores is necessary to aid clinicians in the identification of patient subgroups that are most likely to benefit from an intensive therapeutic approach.

OTHR-04. Gynecological Malignancies With Metastasis To The Central Nervous System: A Case Series and Systematic Review of the Literature

IntroductionGynecologic malignancies are an increasingly common proportion of central nervous system metastatic disease. As genetic sequencing technology improves and becomes more accessible, mutations associated with CNS metastasis are easier to elucidate. The aims of this case series and systematic literature review are to describe the patient population with CNS metastatic disease from a gynecologic primary, and to investigate why the proportion of CNS metastasis from gynecologic malignancies is increasing. Ultimately, we hope to improve understanding of this subset of metastatic CNS malignancies and improve management strategies.MethodsA literature review of articles describing patients from 1990–2020 who were diagnosed with CNS metastasis from a known gynecologic primary malignancy was performed. Demographics, cancer type, mutation characteristics, management for metastatic disease, progression free survival, number of CNS metastases, and location of metastatic disease were assessed. Inclusion criteria were age>18 years, diagnosis of primary ovarian, uterine, or cervical cancer with confirmed metastatic disease to the CNS, including brain parenchyma, leptomeninges, or intradural spinal cord or dural metastases. Exclusion criteria included pediatric population and bony metastases (e.g., bony spine metastases without evidence of meningeal/parenchymal invasion).ResultsOur review showed that patients with gynecological metastasis to the CNS generally have worse outcomes regarding overall survival, progression free survival, and quality of life than patients without CNS metastasis.DiscussionOur results infer that the reported increase in incidence of CNS metastasis from gynecologic malignancies is a reflection of improvement of detection given advances in technology, improved patient follow up, and increased overall survival of patients with gynecologic malignancies. Further characterization of mutations from gynecologic malignancies associated with brain metastasis could result in development of more treatment options for patients in the future and help determine factors that contribute to developing metastasis to the CNS of various degrees, thus, potentially inform treatment strategies.

An overview of osimertinib as a treatment of non-small cell lung cancer (NSCLC): an update

ABSTRACT Introduction: Osimertinib is a third-generation anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), that irreversibly binds to mutant EGFR, specifically to the T790M EGFR mutant non-small cell lung cancer (NSCLC). Since its approval, osimertinib has been tested in multiple scenarios, including the first-line and adjuvant setting of EGFR-mutant disease. Areas covered: The authors summarize the most recent evidence about osimertinib in NSCLC, covering its use as a first-line therapy, its activity on central nervous system metastatic disease, and in elderly patients. Moreover, the authors focus on resistance to this drug and on the therapeutic strategies that may be used to overcome this issue. Expert opinion: Osimertinib is a key player in the treatment ofEGFR mutant NSCLC and will probably be used in earlier clinical settings in the future, giving rise to an emerging variety of resistance mechanisms. These could be potentially overcome in several ways: e.g. as an oligo-progressive disease local therapy, maintaining osimertinib might be a reasonable option; however, for widespread progressive disease, a switch to chemotherapy should be considered. Finally, either liquid biopsy or tissue biopsy might be considered in patients progressing to osimertinib, as they can lead to the identification of potentially targetable resistance mechanisms.

Neuro-oncology Multidisciplinary Clinic and Improvements in Patient Outcome.

Neuro-oncology care is becoming increasingly complex and patients often see multiple specialists. Multidisciplinary clinic (MDC) is a patient-centric option to allow multiple specialists to be involved where patients see multiple providers on the same day. The objective of this study was to evaluate the role of a neuro-oncology MDC on patient outcomes. Retrospective study was performed on consecutive patients who received radiosurgery for central nervous system (CNS) disease. We evaluated patients 2 years before and 2 years after the implementation of a MDC. A total of 351 patients were analyzed, 163 patients before MDC and 188 after implementation of MDC. Before MDC the median follow-up was dependent on which department ordered follow-up radiographic imaging. This discrepancy decreased after the MDC. Overall survival for patients with CNS metastatic disease improved in the MDC cohort (median survival of 248 before MDC and 315 d after, P<0.027). We found that neuro-oncology MDC improved follow-up across disciplines and improved overall survival for patients with CNS metastatic disease.

Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease.

While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need.

2568 Pembrolizumab for patients with leptomeningeal disease from advanced solid tumors

OBJECTIVES/SPECIFIC AIMS: Pembrolizumab is an anti-PD-1 immune checkpoint antibody that has demonstrated promising anti-tumor activity in patients with solid tumor malignancies, including patients with brain metastases from malignant melanoma and non-small cell lung cancer. Leptomeningeal disease (LMD) is a rare form of malignant spread to the central nervous system (CNS), that occurs in 2%–10% of patients with solid tumors, most commonly in breast cancer and non-small cell lung cancer. We propose an open-label phase II study of pembrolizumab in patients with LMD from advanced solid tumors (NCT03091478). This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a &gt;4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status &lt;1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically +/− cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.

Mania and Psychosis in a Woman Receiving Interferon

The patient is a 36-year-old married woman diagnosed 7 months ago with stage III malignant melanoma. Following her initial diagnosis, she was started on intravenous interferon-alpha. She subsequently presented to outpatient psychiatry complaining of 3 weeks of psychosis and racing thoughts. After 5 months of ongoing treatment with interferon, the patient reported visual hallucinations, worsening paranoia, confusion, racing thoughts, and increased anxiety. She noted “obsessions” regarding her 2-year-old daughter’s safety. During this period, she also suffered from significant insomnia, reporting no sleep for 3 days at a time. A prescription for zolpidem 10 mg nightly provided little relief. An MRI ruled out the possibility of central nervous system metastatic disease as an etiology

Stereotactic radiosurgical treatment of brain metastasis of primary tumors that rarely metastasize to the central nervous system

We evaluated the local control of gamma knife stereotactic radiosurgery (GKSRS) in the treatment of cerebral metastases from primary tumors that rarely metastasize to the central nervous system (CNS). There is little published data on this subject with very few series on specific primary tumors. We present our experience treating these lesions with GKSRS combined with a review of the salient literature. A retrospective study of 36 patients who collectively underwent 44 GKSRS procedures for CNS metastatic disease was undertaken. Our series includes four patients with sarcoma, two with prostate cancer, three with thyroid cancer, five with endometrial cancer, seven with ovarian cancer, two with cervical cancer, six with esophageal cancer, two with bladder cancer, one with liver cancer, one with pancreatic cancer, and three with testicular cancer. With 44 gamma knife sessions treating 74 tumors, 63 tumors showed no radiographic evidence of progression, and 13 tumors demonstrated radiographic progression between one and 12 months after gamma knife treatment. In six patients in the population, further treatment with GKSRS was necessary due to enlargement of untreated lesions or new metastatic disease. GKSRS for uncommon CNS metastases is appears to be efficacious in controlling the treated tumor. The majority of tumors treated in our study did not progress post gamma knife.

High‐dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma

Stage 4b retinoblastoma (central nervous system metastatic disease) has been lethal in virtually all cases reported. Here we describe a series of eight patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy with autologous hematopoietic stem cell rescue. Induction chemotherapy included cyclophosphamide and/or carboplatin with a topoisomerase inhibitor. High-dose chemotherapy regimens were carboplatin and thiotepa with or without etoposide (n = 3) or carboplatin, etoposide, and cyclophosphamide (n = 2). Seven patients had leptomeningeal disease and one patient had only direct extension to the CNS via the optic nerve. Three patients had stage 4b disease at the time of original diagnosis of the intra-ocular retinoblastoma; five had later onset at a median of 12 months (range 3-69 months). One patient died of toxicity (septicemia and multi-organ system failure) during induction and two had disease progression prior to high-dose chemotherapy. Five patients received high-dose chemotherapy at a median of 6 months (range 4-6) post-diagnosis of stage 4b disease. Two patients survive event-free at 40 and 101 months; one was irradiated following recovery from the high-dose chemotherapy. Intensive multimodality therapy may be beneficial for some patients with stage 4b retinoblastoma. Longer follow-up will determine whether it has been curative.

Treatment of Invasive Retinoblastoma in a Murine Model Using an Oncolytic Picornavirus

Retinoblastoma, the most common intraocular malignancy of childhood, metastasizes by initial invasion of the choroid and the optic nerve. There is no effective treatment for metastatic retinoblastoma, especially when the central nervous system (CNS) is involved, and prevention of this complication is a treatment priority. Seneca Valley Virus (SVV-001) is a conditionally replication-competent picornavirus that is not pathogenic to normal human cells but can kill human retinoblastoma cells in vitro with an IC(50) of <1 viral particle (vp) per cell. A xenograft murine model of metastatic retinoblastoma was used to examine the therapeutic potential of SVV-001. Histopathologic analysis of ocular and brain tissues after a single tail vein injection of SVV-001 (1 x 10(13) vp/kg) showed effective treatment of choroid and ocular nerve tumor invasion (1 of 20 animals with invasive disease in the treated group versus 7 of 20 animals with invasive disease in the control group; P = 0.017) and prevention of CNS metastasis (0 of 20 animals with CNS metastatic disease in the treated group versus 4 of 20 animals with CNS disease in the control group; P = 0.036). There were no observed adverse events due to the virus in any of the treated animals. SVV-001 may be effective as a treatment of locally invasive and metastatic retinoblastoma.

Helical TomoTherapy in the treatment of central nervous system metastasis

In this report the authors review the use of radiotherapy in the treatment of central nervous system (CNS) metastasis. They comment on different treatment methods for both intracranial and extracranial CNS metastasis and discuss some of the evidence supporting the use of radiotherapy in these settings. Recent advancements in radiation oncology technology are briefly reviewed with a focus on the advantages and disadvantages of helical TomoTherapy-based treatment strategies. A review of pertinent current literature was performed. TomoTherapy research currently underway at the University of Virginia Health System is discussed and a representative case is presented. Radiotherapy for CNS metastasis is an effective treatment that provides palliation of symptoms and confers a survival advantage on selected patients. Advances in radiotherapy techniques continue to improve the therapeutic ratio for patients with CNS metastases. Helical TomoTherapy offers distinct advantages for patients with CNS metastatic disease by sparing normal tissue when intracranial or extracranial disease is targeted.

Brain metastases as isolated site of relapse in patients with epithelial ovarian cancer previously treated with platinum and paclitaxel-based chemotherapy

Brain metastases in patients with epithelial ovarian cancer (EOC) have an estimated incidence of 0.3-1.9% and are isolated in up to 50% of these patients. The risk factors and the prognostic significance of isolated central nervous system (CNS) relapse in patients with EOC who received primary treatment with platinum and paclitaxel have not been identified. We conducted a retrospective study in patients with EOC who relapsed with isolated brain metastases and report our experience. Two hundred sixty-seven patients with stages III and IV EOC, in clinical complete remission after first-line treatment with platinum and paclitaxel, were included in our analysis. After a median follow-up of 65 months, 150 patients had relapsed. Eight patients (5%) had isolated brain metastases. Patient and disease characteristics did not differ among patients who relapsed with isolated brain metastases and those with relapse outside the CNS. Median time to first disease relapse, overall survival, and survival after relapse did not differ significantly between patients with brain metastases and those with relapse outside the CNS. Two patients have died 6 and 12 months after the diagnosis of brain metastases, and 5 patients are alive 4-35 months after the diagnosis of isolated brain metastases. Three patients remain free of disease 4-18 months after treatment with radiotherapy and systemic chemotherapy for their CNS metastatic disease. Patients with isolated brain metastases have comparable survival to patients with relapse outside the CNS, and long-term remission can be achieved in some cases, provided that systemic chemotherapy is added to local treatment.

Optic neuropathy from metastatic squamous cell carcinoma of the cervix: An unusual CNS presentation

Background. Central nervous system (CNS) metastases from cervical carcinoma are uncommon events. Leptomeningeal involvement from cervical squamous cell carcinoma has not been extensively described. Case. A 43-year-old woman with initial diagnosis of stage IB squamous cervical carcinoma at age 30 was treated with hysterectomy and left salpingo-oophorectomy. She recurred with nodal disease at age 39 and went into a clinical complete remission after chemotherapy and radiation treatment. Three years later, she presented with symptoms of optic neuropathy. Cerebral spinal fluid (CSF) was positive for squamous cells consistent with primary cervical squamous cell carcinoma. No measurable disease was evident outside of the CNS. Conclusion. Meningeal carcinomatosis from cervical squamous cell carcinoma involving optic nerves has not been reported. Rapid progression of this patient's CNS metastatic disease suggests this form of metastases may be more aggressive and carry extremely poor prognosis.

Brain metastases as isolated site of relapse in patients with epithelial ovarian cancer previously treated with platinum and paclitaxel-based chemotherapy

Brain metastases in patients with epithelial ovarian cancer (EOC) have an estimated incidence of 0.3–1.9% and are isolated in up to 50% of these patients. The risk factors and the prognostic significance of isolated central nervous system (CNS) relapse in patients with EOC who received primary treatment with platinum and paclitaxel have not been identified. We conducted a retrospective study in patients with EOC who relapsed with isolated brain metastases and report our experience. Two hundred sixty-seven patients with stages III and IV EOC, in clinical complete remission after first-line treatment with platinum and paclitaxel, were included in our analysis. After a median follow-up of 65 months, 150 patients had relapsed. Eight patients (5%) had isolated brain metastases. Patient and disease characteristics did not differ among patients who relapsed with isolated brain metastases and those with relapse outside the CNS. Median time to first disease relapse, overall survival, and survival after relapse did not differ significantly between patients with brain metastases and those with relapse outside the CNS. Two patients have died 6 and 12 months after the diagnosis of brain metastases, and 5 patients are alive 4–35 months after the diagnosis of isolated brain metastases. Three patients remain free of disease 4–18 months after treatment with radiotherapy and systemic chemotherapy for their CNS metastatic disease. Patients with isolated brain metastases have comparable survival to patients with relapse outside the CNS, and long-term remission can be achieved in some cases, provided that systemic chemotherapy is added to local treatment.

Posterior Fossa Metastases: Risk of Leptomeningeal Disease When Treated with Stereotactic Radiosurgery Compared to Surgery

Leptomeningeal disease (LMD) represents a diffuse form of central nervous system metastatic disease that is often associated with poor quality of life and prognosis. Our objective was to compare the incidence of LMD in patients with posterior fossa metastases (PFM) following stereotactic radiosurgery (SRS) versus surgical resection. The medical records of 93 patients aged 57.9 +/- 10.8 years (mean +/- SD) with PFM treated at the Cleveland Clinic from 1995 to 2001 were analyzed retrospectively. Treatments consisted of surgery with whole brain radiation therapy (WBRT) or SRS with or without WBRT. The impact of age, Karnofsky performance status (KPS) at presentation, Radiation Therapy Oncology Group, recursive partitioning analysis (RPA) class, status of extracranial disease, number, size, volume, pathology of brain metastases and steroid use were studied using univariate and multivariate analyses. There were 80 evaluable patients (10 lost to follow-up and three excluded for supratentorial surgery with subsequent LMD). LMD occurred after the surgical removal of the PFM in 9 of 18 patients (50%), whereas LMD occurred after SRS in 4 of 62 patients (6.5%) (p = 0.0028). Multivariate analysis also showed that patients who had surgery were more likely to develop LMD compared to patients treated with SRS (p = 0.0024). Patients had a median KPS decline of 30 points after LMD was diagnosed. There was no statistically significant difference in survival of patients with LMD and the rest of the patients (13.5 vs. 11.7 months, p = 0.7659). Patients treated surgically had significantly larger lesions (3.43 +/- 0.74 vs. 1.96 +/- 0.95 cm maximum diameter, p < 0.0001). All surgical patients belonged to RPA class II at diagnosis. Their survival was not different from the RPA class II patients in the SRS group. Surgery and SRS had comparable complication rates (8.1% vs. 5.6%, p = 0.99), although the surgical complications were more serious (e.g. hemorrhage, CSF leak). The duration of steroid use was longer after SRS compared to surgery (2.1 +/- 3.6 vs. 1.3 +/- 2.4 months); however, the difference was not statistically significant. Myopathy and psychosis in one patient after SRS, were the only steroid-related complications. There was no statistically significant association between the primary tumor type and the presence of LMD. In this retrospective analysis of patients with PFM, SRS was associated with a lower incidence of LMD than was surgery. Although LMD was associated with rapid and considerable decline in the quality of life, it did not influence the overall survival. SRS was associated with less serious complications than surgery. Surgery in this study was performed on patients with larger lesion sizes and a trend toward poorer initial performance status, which could bias these results. A prospective study directly comparing surgery and SRS and further evaluating the significance of LMD in PFM is warranted.

Neoplasms involving the central nervous system in the older old

Geriatric cancer patients present special challenges for clinicians. Few large series have been published in the last 20 years on the types of neoplasms that involve the central nervous system (CNS) in older individuals. To review types of neoplasms involving the central CNS that are currently being encountered by pathologists and neurosurgeons, we identified from our databases for the years 1992–2002, inclusive, patients 75 years or older who had symptomatic lesions requiring neurosurgical interventions. Retrospective characterization of tumors by immunohistochemistry, in situ hybridization, and fluorescence in situ hybridization was performed whenever possible and relevant to tumor type. Neurosurgical procedures (n = 125) on 119 patients were identified; 90 patients were diagnosed as having neoplasms, with clot evacuation or infections being the most frequent non-neoplastic conditions necessitating surgery. Tumor types included glioblastomas (36 patients), meningiomas (16), pituitary adenomas (12), lymphomas or other hematological malignancies (8), anaplastic gliomas (5), metastases (6), head and neck malignancies with direct intracranial extension (3), and other miscellaneous tumor types (4). Compared with older literature series, we encountered a larger number of elderly patients with CNS lymphomas and fewer who came to surgery for CNS metastatic disease. In the “older old”, glioblastomas are the most frequent symptomatic tumors necessitating surgical intervention. Glioblastomas in this aged cohort display the signature features of the small cell phenotype (62%), high cell cycle labeling indices (mean MIB-1—labeling index = 25.1%), and either amplification of epidermal growth factor receptor or gain of chromosome 7 by fluorescence in situ hybridization (93% of assessable cases).

Thirty-Seventh Annual Meeting of the American Society of Hematology

The 37th annual meeting of the American Society of Hematology was held in Seattle, Washington, from December 1-5, 1995. This paper will briefly highlight a number of important clinical reports relevant to malignant hematology and high dose chemotherapy programs from among the more than 4000 abstracts submitted to this important international meeting. S. Forman (Duarte, California) presented an evaluation of the survival of adults with acute lymphocytic leukemia treated with either an allogeneic transplantation (from a histocompatible sibling donor) or continued consolidation chemotherapy, after attaining a complete remission following induction therapy. In this analysis, there was no significant difference in disease-free survival or overall survival between the two therapeutic strategies. R Rowlngs (Milwaukee, Wisconsin) reported the results of an analysis of prognostic factors among > 1000 women undergoing autologous bone marrow transplantation for metastatic breast cancer. Features predicting for a poorer outcome following treatment with high dose chemotherapy, included: age >45 years; the presence of "refractory disease"; a short time interval between diagnosis and the performance of the transplant; the presence of visceral or central nervous system metastatic disease; and the absence of estrogen receptor positivity on the tumor. B. Bolwell (Cleveland, Ohio) reported the experience of the Cleveland Clinic Foundation Bone Marrow Transplantation program with salvage treatment of Iymphoma employing bone marrow transplantation. While transplanted patients with low-grade lymphomas continued to relapse > 2 years after the procedure, no patient with a high grade lymphoma in a continuous remission after this 2 year time point has relapsed.