All right. Our next presentation will be by Samer Zamar on multi-agent versus single-agent interventricular chemotherapy for patients with neoplastic meningitis, changing the reputation of a fearsome disease. Good afternoon. My name is Samer Zamar. I'm a second-year resident at Penn State Neurosurgery. So I'm going to discuss multi-agent versus single-agent interventricular chemotherapy for patients with neoplastic meningitis. So a little bit of background. I think everyone knows that neoplastic meningitis is still regarded as an end-stage disease with dismal survival ranging from two to six months. Its incidence is around 110,000 cases per year. And 1 to 8 percent of patients with malignancies will be diagnosed with neoplastic meningitis at some point in time. And this number gets higher with patients with lymphoma and melanoma as compared to primary brain tumors and solid tumors. And we should keep in mind that neoplastic meningitis is dramatically underdiagnosed. Some literature report as many as 19 percent of people with recurrent solid tumor develop neoplastic meningitis, and the number is significantly higher in leukemia and lymphoma patients. So we know survival is linked to younger age, Karnovsky scale more than 70, longer duration of symptoms, absence of neurological deficits, absence of encephalopathy on presentation, and low protein levels in CSF. Treatment consists of radiation. It's mainly reserved for symptomatic and bulky disease areas. Systemic chemotherapies has also shown some benefits, primarily in controlling the primary disease. And IT chemotherapy is mainly used as single agent, and this has been the standard of care for many years. Now, although there were some reports about biological agents, mainly case reports, case series, and only one formal phase one trial, the use of biological agents has not been done because the concerns about toxicity. So these are the common cytotoxic, targeted, and biological agents that we classically use for neoplastic meningitis. So our treatment approach consists of giving two sets of chemotherapy agents, set A and set B, and alternating these two sets depending on the tumor histology. For example, patients with leukemia will receive methotrexate and topotecan alternating with etoposide and deposit or liposomal citerabine. And a drug labeled C is a drug that is used in substitution of another chemotherapy agent that was not tolerated by the patient. Our treatment protocol consists of induction chemotherapy, five to six cycles, one cycle per week, and after that we test the CSF. If the CSF is negative, the patient would go to maintenance chemotherapy and we spread out the chemotherapy cycles. Otherwise, if the CSF still has malignant cells, then we give another two to four induction cycle with another chemotherapy drug, and then we test the CSF again. And if the CSF is negative or if it is positive in a clinically stable patient, then the patient would go to maintenance therapy again. Otherwise, we would change the treatment or provide supportive care when adequate. So we compared the overall survival between patients with multi-agent IT chemotherapy and patients who received single-agent IT chemotherapy from patient-level data that we obtained from six out of the seven randomized controlled trials done for this disease. And we calculated the survival using the Kaplan-Meier technique and we compared the survival using the log-rank test. So results, we isolated 290 patients from the randomized controlled trials. 230 patients had solid tumors and 60 patients had lymphoma. From our cohort, we isolated 203 patients, 139 with solid tumors, 44 with lymphoma, and 20 with leukemia. And this is a survival distribution function for solid tumors. Now, the red curve, the survival curve for multi-agent cohort, and the blue curve is the single-agent cohort that we got from the randomized controlled trial. And as you can see, there's significant survival benefits in patients receiving multi-agent chemotherapy versus single-agent chemotherapy with median survival of 211 days versus 97 days. Both confidence intervals do not overlap, and the p-value is significant with a hazard ratio of 2.1 and a relatively narrow confidence interval. We did the same thing for patients with lymphoma, and again, the red curve is the multi-agent cohort and the blue curve is the single-agent cohort. And again, we found statistically significant benefit for multi-agent versus single-agent with 304 days versus 81 days and a hazard ratio of 6.3. Now for leukemia, we didn't find any patient with leukemia in the randomized controlled trial, so we did the statistics on our cohort, and we graphed the survival with a 95 percent confidence interval line, and the median survival was 205 days with a confidence interval of 125 to 310 days. Now, we looked at our solid tumor cohort, and we stratified the tumors per histology, and we graphed the survival curves for each histology consisting of breast cancer, lung cancer, melanoma, and primary brain tumors. And as you can tell from the graph that the curves intersect each other multiple times, so you can tell that there's no significance in difference in the survival if we stratify the solid tumors based on histology. And this is a very important slide because it flies in face of the orthodox teaching that tells us that tumor histology or the primary disease is an important prognostic factor for the patient and for the survival. And this slide shows the death from neoplastic meningitis, and the solid tumor multi-agent cohort has significantly less death from neoplastic meningitis as compared to the single-agent cohort. And our lymphoma cohort showed 29 percent death from neoplastic meningitis, still less than the rate that's reported in the literature, and the leukemia cohort showed 23 percent death from neoplastic meningitis. And this is the toxicity slide. Relatively, we had low level of toxicities in both groups, like multi-agent chemotherapy patients and the single-agent chemotherapy patients. It was 8 percent in our cohort and 23 percent in our randomized controlled trials, and significantly less in patients with multi-agent chemotherapy and in most types of toxicity except bacterial meningitis. So, in conclusion, multi-agent intrathecal chemotherapy is associated with dramatically increased survival in patients with solid tumors and lymphoma, and we think that these findings merit additional study in a randomized controlled trial. Thank you. Thank you.

video

Samer Zamar

multi-agent versus single-agent interventricular chemotherapy

neoplastic meningitis

overall survival