Abstract
Background/Aim: Anaplastic ependymoma is a rare cancer of the central nervous system. The treatment includes optimal resection with focal radiotherapy. Some case reports or retrospective studies have suggested efficacy of regimens containing platinum or bevacizumab. We describe the feasibility and clinical benefit of the cisplatin-bevacizumab-cyclophosphamide treatment of anaplastic ependymoma. Patients and Methods: Patients were identified through the Adolescent and Young Adults (AYAS) brain tumor national Web conference. We estimated the median progression-free (PFS) and overall survival (OS). Results: There were eight patients with anaplastic ependymoma, with a median age of 36 years. The median OS was 19.9 months and median PFS was 12.3 months. Three patients obtained partial response, four stable disease, and one patient had disease progression during induction. Six patients received maintenance with a median duration of 224 days. Conclusion: This study confirms the tolerance of bevacizumab-cyclophosphamide-cisplatin treatment of anaplastic ependymoma. The clinical benefit seems even superior to that described in the literature.
Anaplastic ependymoma is an extremely rare cancer of the central nervous system (CNS) in adults. Ependymomas are CNS neuroepithelial tumours, comprising about 1.6% of all CNS tumours (in the USA) (1). Ependymoma can be anaplastic from scratch or arise from a WHO grade II ependymoma. It may be located in the spinal region, cerebral or both. Optimal resection with focal radiation therapy is the main treatment, but natural history is marked by local relapses or cerebral or/and spinal distant metastasis. These relapses are treated by maximal resection or/and re-irradiation; however, they are usually fatal. Furthermore, chemotherapy has a poor effect on overall survival. Some case reports or retrospective studies have shown efficacy of platinum-containing regimens or bevacizumab for the treatment of relapsing anaplastic ependymoma (2, 3).
A report on clinical and radiological response to cisplatin-bevacizumab-cyclophosphamide regimen was published in 2012 for two patients (4). Moreover, one year later, the patients were still alive without recurrence and under maintenance. With these encouraging results, French neurooncologists have proposed this regimen for eligible patients after discussion in the Adolescent and Young Adults (AYAS) brain tumor national Web conference (5). We aimed to evaluate the efficacy of this combination, ten years later, in this retrospective study.
Patients and Methods
We used the national register of the neurooncology adolescent-young-adults (AYA) to retrospectively identify patients with a recurrent anaplastic ependymoma treated by cisplatin-bevacizumab-cyclophosphamide regimen since 2011. This chemotherapy regimen is composed of an induction and a maintenance part. The induction is composed of cisplatin 100 mg/m2, I.V., every 4 weeks, bevacizumab 10 mg/kg, I.V., every 2 weeks, and cyclophosphamide 50 mg, per os, daily. The cycle duration is 28 days. The maintenance is bevacizumab 10 mg/kg every 2 weeks and cyclophosphamide 50 mg daily. We estimated the median progression free-survival (PFS) and overall survival (OS) by the Kaplan–Meier method from the beginning of treatment. Data were updated as of February 22th, 2022. Data were collected according to the European law of the General Data Protection Regulation (GDPR). This study was approved by the institutional review board of the Eugène Marquis Centre according to the French Reference Methodology MR-004 (Commission Nationale Informatique et Libertés CNIL reference number 2211136).
Results
There were 8 patients, 4 of whom were men, with a median age of 36 years [range=17-57 years], (Table I). Seven had an anaplastic ependymoma at diagnosis, one grade II ependymoma had an anaplastic relapse 20 years after initial surgery. Four patients had cerebral location (one infratentorial, two supratentorial, and one not specified), two spinal, and two metastatic (one cerebral and spinal disease, and the other with spinal disease). Prior treatment was surgery: complete 37.5% (3/8), subtotal 12.5% (1/8), partial 50% (4/8), focal or cranio-spinal radiotherapy 62.5% (5/8) or 25% (2/8), respectively, and not known for 12.5% (1/8). The median delay from diagnosis to first relapse was 15 months (range=0.7-69.4 months). The relapse treatment was mainly surgery with a median of two (range=0-6), and radiotherapy with a median of one (range=0-3). Five patients had received chemotherapy with temozolomide (one was rechallenged by temozolomide). One of these patients had further line with carboplatin-etoposide. Three were naïve of chemotherapy. The median delay between the last treatment and the induction was 12.8 months (range=0.9-61.2 months).
Patient characteristics prior to study treatment.
Three patients obtained a partial response (PR) and four a stable disease (SD). One patient had disease progression during induction and died quickly after it. He did not receive a maintenance. Another patient with a PR did not receive maintenance, without explanations. The median maintenance duration of treatment was 224 days (range=36-481 days). The best response during maintenance was 3 SD and 4 progressions (Table II and Figure 1).
Details of patient’s characteristics during the chemotherapy regimen.
Swimmer plot showing the treatment and follow-up history of patients from the first line of chemotherapy to death.
The median OS was 19.96 months (range=5.49-51.55 months) and the median PFS was 12.36 months (range=2.43-35.57 months) (Figure 2).
Progression free-survival (PFS) and overall survival (OS) of patients with a relapse of an anaplastic ependymoma treated with cisplatin-bevacizumab-cyclophosphamide regimen.
Concerning side effects, data were available for only six patients. Hematotoxicity was reported for four: one developed anaemia and neutropenia, one thrombocytopenia, two not specified. One patient presented bleeding (localization not specified), another digestive toxicity cumulated with hematotoxicity responsible for termination of cisplatin treatment, one nephrotoxicity and two peripheral neurological toxicity. For one patient, this peripheral neurological toxicity was so severe that cisplatin was stopped. One patient had an anaphylactic reaction to cisplatin requiring premedication prior to injections.
Delay between each induction cycle was available for only four patients, and the median was 28 days (range=28-72 days). One patient had severe neutropenia and anaemia in each cycle, with a median between cycles of 36 days (range=32-72 days). In this case, cyclophosphamide was omitted for seven weeks.
Discussion
There is no standard chemotherapy for anaplastic ependymoma in adults, and because of its rarity, clinical trials are difficult. Nevertheless, there are few publications whose primary endpoint was efficacy. Green et al. published a retrospective study which examined the efficacy of Bevacizumab used with chemotherapy (Irinotecan, Carboplatin or Temozolomide) or alone (2). It included a small cohort of 8 adults with recurrent intracranial ependymomas (five grade II and three grade III). The median PFS and median OS were 6.4 months and 9.4 months, respectively. It should be noted that the average age of the population was 40-year-old, roughly equivalent to ours. Another retrospective study which tested temozolomide on 18 patients (8 grade II and 10 WHO grade III) reported PFS and OS medians of 9.69 months and 30.55 months, respectively (6). Similar results were obtained in a study on intracranial ependymoma using different regimens (7). In the present study, the median PFS [12.36 months (range=2.4-35.5 months)] was better than that reported in the literature, even though we were only interested in anaplastic and refractory ependymoma. It is possible that the association of an antiangiogenic drug (bevacizumab, anti-VEGF monoclonal antibody) and cisplatin has a synergistic beneficial effect, resulting in improved tumoral response (3). Therefore, bevacizumab should play a role in stabilization of the disease because VEGF is over expressed in anaplastic ependymomas (8, 9). However, only three of the eight patients had partial response. Moreover, this conclusion was based on medical reports and on radiologic evaluation of the response by the investigator, without a centralized review.
The European Association of Neuro-Oncology proposes chemotherapy for the treatment of recurrent ependymomas when local therapy is not possible (10). Based on good practice recommendations, temozolomide is proposed before the administration of cisplatin because of its more favourable toxicity profile. In this study, patients developed classical toxicities to the drugs and only two patients stopped induction therapy because of cisplatin toxicities. Thus, this study confirms the toxicity problem when cisplatin is used, but the management of this drug is well known. Five patients had chemotherapy before the study regimen and most of them were treated with temozolomide. Cisplatin-bevacizumab-cyclophosphamide regimen could be a therapeutic option with clinical benefit and manageable toxicity for refractory anaplastic ependymoma treated in the first line with temozolomide.
Footnotes
Authors’ Contributions
All Authors collated data, X. Choderlos de Laclos has interpreted the data, performed the analyses, and edited the manuscript, figures and tables. E. Vauleon edited the manuscript. All Authors approved the final manuscript.
Conflicts of Interest
The Authors declare no conflict of interest in relation to this study.
- Received March 18, 2022.
- Revision received June 21, 2022.
- Accepted June 24, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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