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P05.32 Update on a metronomic antiangiogenic combination therapy for recurrent atypical teratoid rhabdoid tumor

ABSTRACT: Abstract Background Prognosis of patients with recurrent atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 12 patients with recurrent ATRT treated with an antiangiogenic combination therapy. Patients and Methods: From 03/2008 to 02/2018, 12 patients were diagnosed with recurrent ATRT (6 first, 6 multiple recurrences), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine) with or without focal radiotherapy. Median age at start of antiangiogenic therapy was 3 (1–12) years. Results As of 05/2018, 6/12 patients are alive and in CR for 123, 90, 45, 9, 6 and 3 months after start of antiangiogenic therapy, the first three off therapy. One patient died of another cause 50 months after her recurrence in CR and without evidence of tumor at autopsy. OS for the whole cohort was 47.7 ± 16.6% at 3 years and 31.8 ± 17.1% at 5-years with a median OS of 22.8 months (KI 0.0–66.8). Therapy was generally well tolerated and toxicities were manageable. Conclusion The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

SUBMITTER: Slavc I

PROVIDER: S-EPMC6144353 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND: Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. We report on 28 patients with recurrent medulloblastoma and ATRT treated with an alternative approach to conventional chemotherapy that targets neovascularisation by interfering with tumor angiogenesis at various levels. Patients and METHODS: From 11/2006 to 06/2016, 28 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (13 first, 7 multiple recurrences) and eight with recurrent ATRT (5 first, 3 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 1.5 (1–13) years for ATRT. Results: As of 11/2016, 12/20 patients with medulloblastoma are alive at a median of 25 (12–97) months after their last recurrence. 8/12 surviving patients are currently in CR for 97, 94, 93, 29, 27, 23, 19 and 18 months, five off therapy for 79, 62, 60, 22 and 18 months, three are in PR 23, 12 and 2 months after their last recurrence and one patient has stable disease 12 months after her last recurrence. 5-year-OS is 57.6?±?13.2%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy and one patient with a very good PR died of a septicemia seven months after his last recurrence. Two patients had prior been treated with the same antiangiogenic approach and had recurred 67 and 40 months after their last recurrence while off therapy for 36 and 21 months and both patients are in remission again, one off therapy for 18 months. 3/8 patients with ATRT are alive. Follow-up since last recurrence is 72, 27 and 24 months and all patients are off therapy for 52, 14 and 13 months. One patient died of another cause without evidence of tumor at autopsy 54 months after recurrence and while off therapy for 46 months. One surviving patient with a germ line mutation and a fourth recurrence was prior treated with the same approach albeit without intrathecal therapy. He recurred 78 months after his last recurrence while off therapy for 36 months. He is again in CR and off therapy for 13 months. Therapy is primarily outpatient, was generally well tolerated, and toxicities were manageable. CONCLUSION: The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Project description:Abstract BACKGROUND Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 32 patients with recurrent medulloblastoma and ATRT treated with an antiangiogenic combination therapy. PATIENTS AND METHODS From 11/2006 to 02/2018, 32 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (14 first, 6 multiple recurrences) and 12 with recurrent ATRT (6 first, 6 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and aqueous or liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 3 (1–12) years for ATRT. RESULTS As of 05/2018, 10/20 patients with medulloblastoma are alive, eight in CR, six off therapy for 96, 79, 77, 34, 12, and 4 months. 5-year-OS is 54.5 ± 11.2% and 5-year-EFS is 25.0 ± 9.7%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy. 6/12 patients with ATRT are alive and in CR for 123, 90, 45, 9, 6 and 3 months after start of antiangiogenic therapy, the first three off therapy. OS for the whole cohort was 47.7 ± 16.6% at 3 years and 31.8 ± 17.1% at 5-years with a median OS of 22.8 months (KI 0.0–66.8). Therapy was generally well tolerated and toxicities were manageable. CONCLUSION The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133(+)), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133(+) were significantly augmented when compared to CD133(-). The clinical data showed that the amount of CD133(+) in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic-response profiles of CD133(+) and CD133(-) irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133(+) compared to CD133(-). Furthermore, we found that CD133(+) can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133(+) xenotransgrafts in SCID mice but not in IR-treated CD133(-). Importantly, the effect of IR in CD133(+) transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133(+) AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133(+) may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133(+) could be possible targets to improve future treatment of deadly diseases like AT/RT.

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P05.32 Update on a metronomic antiangiogenic combination therapy for recurrent atypical teratoid rhabdoid tumor

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