Willem Boogerd

Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9–12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2–235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.

Successful treatment options for cancer result in more young long-term survivors prone for long-term complications. Carotid artery vasculopathy is a potential long-term complication after radiotherapy of the neck, resulting in cerebrovascular events and probably deficits in cognitive and motor functioning. Better insight into the underlying pathofysiology of radiotherapy induced carotid artery vasculopathy is needed for prognostic purposes and to develop preventive strategies.

Reports on the outcome of patients with primary central nervous system lymphoma (PCNSL) are mainly based on results obtained in the context of clinical trials. However, due to poor performance status and cognitive impairment, most patients are actually treated outside clinical studies. The aim of this retrospective study was to get more insight into the outcome of HIV-negative PCNSL patients, treated between 2000-2010 in two hospitals (one academic centre and one categorical cancer centre). Fifty-two patients were identified. Eight patients were treated with corticosteroids only. Sixteen patients received high-dose methotrexate (MTX)-based chemotherapy, ten received radiotherapy and 18 patients were treated with a combination of MTX-based chemotherapy and radiotherapy. At a median follow-up of 63.1 months, the median overall survival for all patients was 24.4 months (95% CI: 11.5-39.8 months), with an event-free survival of 14 months (95% CI: 7.3-24.4 months). Causes of death were progressive PCNSL in 29 patients, MTX toxicity in four patients and epileptic seizures in one patient. These results are comparable with the outcome of prospective clinical trials in this disease, which still has a relatively poor prognosis.

Given the potential toxicity of whole brain radiotherapy, we introduced systemic therapy as possible primary treatment for brain metastases (BM) from breast cancer. This study aims to evaluate the feasibility of this therapeutic approach. Review of 115 breast cancer patients treated for BM with at least 1 year of follow-up. Patients with single BM without extracranial disease were usually treated with surgery, patients with multiple BM and controlled extracranial disease usually with RT, and those with progressive extracranial disease usually with systemic therapy as primary treatment for BM. Primary treatment for BM was surgery in 30 patients, RT in 26 patients, RT combined with systemic therapy in 33 patients, and systemic therapy as single treatment in 27 patients (chemotherapy n = 20; hormonal therapy n = 7). Response rate to surgery was 100 %, to RT 85 %, to RT+systemic therapy 87 %, to chemotherapy 70 %, and to hormonal therapy 14 %. Duration of neurological response and of extracranial response to chemotherapy as single treatment was similar (8 and 7 months, respectively). Patients with single BM and patients without extracranial disease had a better survival but the difference was not significant. Chemotherapy as single treatment for BM from breast cancer is feasible and should not be restricted to salvage treatment.

Pelvic and gastrointestinal tumors are generally considered to have a predilection to metastasize to the posterior fossa rather than to the supratentorial brain. Review of imaging of 100 patients with brain metastases from pelvic and gastrointestinal primary tumors and of 100 patients with brain metastases from other primary tumors did not reveal a difference in distribution of brain metastases between the two groups of patients. So, there is no evidence that pelvic and gastrointestinal tumors metastasize preferentially to the posterior fossa.

In view of recent progressive insight in the diagnosis and treatment of leptomeningeal metastases of solid tumours, a new guideline has been designed on the initiative of the Dutch Association of NeuroOncology and the Netherlands Society of Neurology, with methodological support from the Dutch Institute for Healthcare Improvement (CBO). - There are no neurological symptoms or signs, nor MRI characteristics that are unique to leptomeningeal metastasis. However, clinical suspicion of leptomeningeal metastasis in a patient known to have cancer, in combination with specific MRI characteristics is sufficient to make the diagnosis. If MRI or CT results are negative or inconclusive cerebrospinal-fluid assessment should be conducted. - Management of care of patients with leptomeningeal metastasis without brain metastases can be based on a series of categories that have been developed using prognostic factors such as Karnofsky performance status, serious encephalopathy or neurological dysfunction, systemic disease, sensitivity of the tumour for chemotherapy or hormonal treatment - In the context of meaningful palliation, systemic treatment, if necessary in combination with radiotherapy to clinically relevant sites, is preferable to intrathecal chemotherapy. - Intrathecal chemotherapy combined with local radiotherapy is recommended if effective systemic treatment is not available, and if the tumour is potentially sensitive to methotrexate, cytarabine or thiotepa. The combination of intrathecal methotrexate and whole-brain radiotherapy should be avoided.

BACKGROUND.: The efficacy of radiotherapy (RT) in patients who have brain metastases from melanoma is limited. In this study, the authors evaluated the efficacy of treatment with temozolomide in patients with metastatic melanoma, including small brain metastases, who did not require immediate RT and investigated the feasibility of deferring RT.METHODS.: Patients with brain metastasis were identified from 3 prospective studies of temozolomide (with or without immunotherapy) for metastatic melanoma. Patients with brain metastasis that measured >2 cm, extensive edema, and localization in the brain stem were excluded from the study. For the current analysis, patients with leptomeningeal metastasis and patients who received previous stereotactic RT were excluded. In patients who achieved a systemic response or stabilization to temozolomide, the response of brain metastasis and the necessity for palliative cranial RT were evaluated.RESULTS.: Among 179 patients who received temozolomide for advanced melanoma, 52 patients with brain metastasis were evaluable. Stabilization of systemic metastasis was noted in 7 of 52 patients (13%), and there were 6 responses (5 partial responses and 1 complete response; 11%); thus, in those 13 patients, 6 had stabilization of brain metastasis (11%) and 5 had a response (2 partial responses and 3 complete responses; 9%). Immunotherapy did not influence the neurologic response. The median time to neurologic progression was 7 months (range 2–15, months). RT for cerebral recurrence was required in 2 patients. The median survival of patients with brain metastases was 5.6 months (95% confidence interval, 4.4–6.8 months). Intracranial hemorrhagic complications were not observed.CONCLUSIONS.: The current results indicated that it is feasible to treat patients who have advanced melanoma and small brain metastasis with temozolomide as the single treatment. The small subset of patients with systemic response usually showed durable stabilization or a response of brain metastasis. With this approach, neurologic disease can be controlled, and cranial irradiation may be deferred and even withheld in most of patients. Cancer 2007. © 2006 American Cancer Society.