Discussion
tumor, neutropenic, cancer, nephrotic syndrome, infections, medulloblastoma
TUMOR, RECURRENCE, PROLIFERATION, CANCER, DISEASE, NEPHROTIC SYNDROME, INFECTIONS, ADVERSE EFFECTS, MEDULLOBLASTOMA, LUPUS NEPHRITIS
Effective treatment for recurrent medulloblastoma remains a significant unmet need, with no approved therapies and only rare long-term survivors. The metronomic antiangiogenic drug combination with intraventricular therapy used in MEMMAT significantly prolonged survival and was able to produce durable responses in patients without a ventriculoperitoneal shunt who had previously received irradiation. The treatment is predominantly oral, well tolerated, outpatient, and easily adapted in these heavily pretreated patients.In the past, numerous attempts have been made to treat relapsed medulloblastoma. In some of these studies, significant responses have been observed, but these responses lasted only a short period in patients who had previously received irradiation.In accordance with a previous study,MEMMAT differs from conventional treatment regimens because it applies a metronomic antiangiogenic combinatorial approach to target the tumor microenvironment. Metronomic chemotherapy is defined as the long-term administration of chemotherapy at low, minimally toxic doses, without prolonged drug-free breaks designed to treat vascular cells needed to maintain tumor cell proliferation, migration, and metastatic spread. Beyond its antiangiogenic effect, metronomic chemotherapy appears to also affect other cells within the tumor microenvironment that may play important roles by inducing immunogenic pathways that can activate both innate and adaptive immune responses. Metronomic cyclophosphamide, for example, was shown to deplete regulatory T cells in various tumor types and is a common treatment for nephrotic syndrome and lupus nephritis.Given the redundancy of mechanisms involved in new blood vessel formation by cancer, growth interference via multiple pathways is required for induction and maintenance of tumor response. Therefore, MEMMAT combined metronomic chemotherapy with the repurposing of nonchemotherapeutic drugs, as was previously done in the COMBAT (combined oral metronomic biodifferentiating antiangiogenic treatment) regimen.Metronomic chemotherapy has been reported to be better tolerated and to induce less severe adverse effects than conventional chemotherapy. This was also confirmed by MEMMAT, in which this therapy was generally well tolerated in a heavily pretreated cohort in an outpatient setting. The MEMMAT combination was feasible because the patients were adherent even with the frequent necessary visits to the outpatient clinic for intraventricular therapy, and only 1 of all patients dropped out of the study. Most toxic effects were hematologic and consistent with low-dose chemotherapy. Frequent clinical and laboratory checks were used to closely monitor the treatment, and dose modification was added to reduce neutropenic episodes and infections while minimizing prolonged drug-free breaks.Quality of life during metronomic therapy has rarely been reported but is even more important for patients with an overall poor prognosis.All but 2 patients in our study had disease recurrence at distant central nervous system sites with or without disease in the original tumor bed, a pattern that is consistent with previous observations.Although it was not an original objective of the trial, with the recent subclassification of medulloblastoma,