Non‑conventional fotemustine schedule as second‑line treatment in recurrent malignant gliomas: Survival across disease and treatment subgroup analysis and review of the literature

Prelaj,Arsela; Rebuzzi,Sara  Elena; Grassi,Massimiliano; Salvati,Maurizio; D'Elia,Alessandro; Buttarelli,Francesca; Ferrara,Carla; Tomao,Silverio; Bianco,Vincenzo

doi:10.3892/mco.2018.1746

Non‑conventional fotemustine schedule as second‑line treatment in recurrent malignant gliomas: Survival across disease and treatment subgroup analysis and review of the literature

Authors:
- Arsela Prelaj
- Sara Elena Rebuzzi
- Massimiliano Grassi
- Maurizio Salvati
- Alessandro D'Elia
- Francesca Buttarelli
- Carla Ferrara
- Silverio Tomao
- Vincenzo Bianco
View Affiliations

Affiliations: Department of Radiological, Oncological and Anatomo‑Pathological Sciences, ‘Sapienza’ University of Rome, Policlinico Umberto I, I‑00161 Rome, Italy, Department of Medical Oncology, Ospedale Policlinico San Martino IST, University of Genoa, I‑16132 Genoa, Italy, Neurosurgery Department, IRCCS NEUROMED INM, Neurochirurgia, I‑86077 Pozzilli, Italy, Department of Neurology and Psychiatry ‘Sapienza’ University of Rome, Policlinico Umberto I, I‑00161 Rome, Italy, Department of Public Health and Infectious Diseases, ‘Sapienza’ University of Rome, I‑00185 Rome, Italy
Published online on: October 16, 2018 https://doi.org/10.3892/mco.2018.1746
Pages: 58-66
Copyright: © Prelaj et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Fotemustine (FTM) is a treatment option in recurrent malignant gliomas (MGs) after first‑line Stupp treatment. The efficacy and the safety of fractionated FTM schedule proposed by Addeo et al was analysed in the present study in recurrent MGs patients. A retrospective analysis on 40 recurrent MGs patients and second‑line fractionated FTM chemotherapy was performed. Response evaluation was assessed using RANO criteria and safety was assessed using CTCAE v.4.03. Subgroup analyses based on MGMT methylation, resurgery and reirradiation were performed. A review of the literature was also performed. The results revealed 5 partial responses (13%) and 19 stable diseases (47%) with a disease‑control rate of 60%. Median progression‑free survival (PFS) was 4 months, with a PFS of 33% at 6 months and 13% at 1 year. The median overall survival (OS) was 9 months and OS at 6 months was of 55% and at 1 year of 30%. Methylated patients experienced longer mPFS (6 vs. 3 months; p=0.004) and mOS (10 vs. 4 months; p<0.0001) compared with unmethylated patients. Patients treated with reirradiation experienced longer mPFS (5 vs. 3.5 months; p=0.48) and mOS (10 vs. 5 months; p=0.11). No survival benefit with resurgery was observed. Furthermore, the fractioned schedule was well tolerated, only 15% of patients developed severe myelotoxicities. Considering the present findings, fractionated FTM schedule is an efficient second‑line option for MGs associated with an acceptable myelotoxicity profile. Additionally, MGMT methylation is associated with improved survival outcomes. However, this study highlights the requirement for further prospective randomized studies on resurgery and reirradiation.

View Figures

View References

1	Ostrom Q, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-Οncol. 15:ii1–ii56. 2013.
2	Stupp R, Brada M, van den Bent MJ, Tonn JC and Pentheroudakis G: ESMO Guidelines Working Group: High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 25 Suppl 3:iii93–iii101. 2014. View Article : Google Scholar : PubMed/NCBI
3	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
4	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
5	Weller M, Cloughesy T, Perry JR and Wick W: Standards of care for treatment of recurrent glioblastoma-are we there yet? Neuro-oncol. 15:4–27. 2013. View Article : Google Scholar : PubMed/NCBI
6	Fabi A, Metro G, Vidiri A, Lanzetta G, Carosi M, Telera S, Maschio M, Russillo M, Sperduti I, Carapella CM, et al: Low-dose fotemustine for recurrent malignant glioma: A multicenter phase II study. J Neurooncol. 100:209–215. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tosoni A, Franceschi E, Poggi R and Brandes AA: Relapsed Glioblastoma: Treatment Strategies for Initial and Subsequent Recurrences. Curr Treat Options Oncol. 17:492016. View Article : Google Scholar : PubMed/NCBI
8	Beauchesne P: Fotemustine: A third-generation nitrosourea for the treatment of recurrent malignant gliomas. Cancers (Basel). 4:77–87. 2012. View Article : Google Scholar : PubMed/NCBI
9	Silvani A, Gaviani P, Lamperti E, Botturi A, Ferrari D, Simonetti G and Salmaggi A: Lecture: Fotemustine in brain tumors. Neurol Sci. 32 Suppl 2:S255–S257. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lombardi G, Farina P, Della Puppa A, Cecchin D, Pambuku A, Bellu L and Zagonel V: An overview of fotemustine in high-grade gliomas: From single agent to association with bevacizumab. BioMed Res Int. 2014:6985422014. View Article : Google Scholar : PubMed/NCBI
11	Kyritsis AP and Levin VA: An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting. Cancer Chemother Pharmacol. 67:971–983. 2011. View Article : Google Scholar : PubMed/NCBI
12	Frenay M, Giroux B, Khoury S, Derlon JM and Namer M: Phase II study of fotemustine in recurrent supratentorial malignant gliomas. Eur J Cancer. 27:852–856. 1991. View Article : Google Scholar : PubMed/NCBI
13	Scoccianti S, Detti B, Sardaro A, Iannalfi A, Meattini I, Leonulli BG, Borghesi S, Martinelli F, Bordi L, Ammannati F, et al: Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: A single institution experience. Anticancer Drugs. 19:613–620. 2008. View Article : Google Scholar : PubMed/NCBI
14	Fabrini MG, Silvano G, Lolli I, Perrone F, Marsella A, Scotti V and Cionini L: A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. J Neurooncol. 92:79–86. 2009. View Article : Google Scholar : PubMed/NCBI
15	Brandes AA, Tosoni A, Franceschi E, Blatt V, Santoro A, Faedi M, Amistà P, Gardiman M, Labianca R, Bianchini C, et al: Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: A phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol. 64:769–775. 2009. View Article : Google Scholar : PubMed/NCBI
16	Addeo R, Caraglia M, De Santi MS, Montella L, Abbruzzese A, Parlato C, Vincenzi B, Carraturo M, Faiola V, Genovese M, et al: A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. J Neurooncol. 102:417–424. 2011. View Article : Google Scholar : PubMed/NCBI
17	Montemurro N, Perrini P, Blanco MO and Vannozzi R: Second surgery for recurrent glioblastoma: A concise overview of the current literature. Clin Neurol Neurosurg. 142:60–64. 2016. View Article : Google Scholar : PubMed/NCBI
18	Sulman EP, Ismaila N, Armstrong TS, Tsien C, Batchelor TT, Cloughesy T, Galanis E, Gilbert M, Gondi V, Lovely M, et al: Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline. J Clin Oncol. 35:361–369. 2017. View Article : Google Scholar : PubMed/NCBI
19	Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, et al: Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol. 28:1963–1972. 2010. View Article : Google Scholar : PubMed/NCBI
20	Common Terminology Criteria for Adverse Events v4.03 (CTCAE). http://ctep.cancer.govAugust 10–2017
21	Kaplan E and Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53:457–481. 1958. View Article : Google Scholar
22	Fabi A, Metro G, Russillo M, Vidiri A, Carapella CM, Maschio M, Cognetti F, Jandolo B, Mirri MA, Sperduti I, et al: Treatment of recurrent malignant gliomas with fotemustine monotherapy: Impact of dose and correlation with MGMT promoter methylation. BMC Cancer. 9:1012009. View Article : Google Scholar : PubMed/NCBI
23	Paccapelo A, Lolli I, Fabrini MG, Silvano G, Detti B, Perrone F, Savio G, Santoni M, Bonizzoni E, Perrone T, et al: A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy. J Transl Med. 10:902012. View Article : Google Scholar : PubMed/NCBI
24	Gaviani P, Simonetti G, Salmaggi A, Lamperti E and Silvani A: Safety of second-line chemotherapy with non-conventional fotemustine schedule in recurrent high grade gliomas: A single institution experience. J Neurooncol. 113:527–529. 2013. View Article : Google Scholar : PubMed/NCBI
25	Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, et al: MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 26:2192–2197. 2008. View Article : Google Scholar : PubMed/NCBI
26	Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA, van Es CA and van den Bent MJ: Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 113:405–410. 2008. View Article : Google Scholar : PubMed/NCBI
27	Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI
28	Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, et al: DIRECTOR Study Group: MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 21:2057–2064. 2015. View Article : Google Scholar : PubMed/NCBI
29	Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, et al: Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol. 15:943–953. 2014. View Article : Google Scholar : PubMed/NCBI
30	Brandes AA, Finocchiaro G, Zagonel V, Reni M, Caserta C, Fabi A, Clavarezza M, Maiello E, Eoli M, Lombardi G, et al: AVAREG: A phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma. Neuro-oncol. 18:1304–1312. 2016. View Article : Google Scholar : PubMed/NCBI
31	Azoulay M, Santos F, Shenouda G, Petrecca K, Oweida A, Guiot MC, Owen S, Panet-Raymond V, Souhami L and Abdulkarim BS: Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: Results from a single institution. J Neurooncol. 132:419–426. 2017. View Article : Google Scholar : PubMed/NCBI
32	Seystahl K, Wick W and Weller M: Therapeutic options in recurrent glioblastoma-An update. Crit Rev Oncol Hematol. 99:389–408. 2016. View Article : Google Scholar : PubMed/NCBI