glioblastoma multiforme ( gbm ) is the most common type of adult primary central nervous system tumour , accounting for 50  % of gliomas . while elderly patients constitute a large component of the gbm population , the optimal management of elderly patients still remains controversial . in fact , no evidence - based standard of care exists for this unique subpopulation that is often excluded from clinical trials . survival of elderly gbm patients is poor , probably due to the reduced use of standard management approaches , increased toxicity of available therapies , and increased presence of comorbidities in this older patient population . elderly patients commonly receive temozolomide ( tmz ) or radiotherapy ( rt ) , even if most of them are candidate for palliative approaches following surgical diagnosis [ 25 ] . concurrent tmz chemotherapy during rt improves the survival of younger patients with gbm , but the benefit in elderly patients is unclear , although a growing body of evidence suggests that fit elderly patients benefit from the addition of tmz to standard surgery and radiation [ 712 ] . fotemustine ( ftm ) , a third generation chloroethylnitrosourea , has been investigated in malignant glioma patients recurring after tmz standard treatment [ 1317 ] . however , in these trials data on the efficacy and feasibility in elderly patients are not available . we retrospectively evaluated the efficacy and toxicity of second - line ftm in elderly patients with recurrent gbm treated with prior radiotherapy and tmz , as well as specific independent predictors of survival . patients older than 65  years with recurrent or progressive , histologically - confirmed gbm , previously treated with surgery and rt plus concomitant and adjuvant tmz , were included in the analysis . they received 1  h intravenous infusion of ftm according to the following schedule : induction phase dose of 70100  mg / m on days 1 , 8 , 15 , followed by a 4/5-week rest period , and a maintenance phase dose of 70100  mg / m every 21  days . toxicity was graded according to the national cancer institute ( nci ) common toxicity criteria ( ctc , version 3.0 ) . baseline mri or ct neuro - imaging was performed before administration of ftm , and subsequent evaluations were carried out after completion of the induction phase , every two cycles during the maintenance phase , according to macdonald s criteria . steroid dosing was considered during radiographic disease assessment . in the presence of complete or partial responses ( cr and pr ) or stable disease ( sd ) , the time to progression ( ttp ) was evaluated until progressive disease ( pd ) , even if the treatment was discontinued . disease control ( dc ) was defined as cr  +  pr  +  sd . overall survival ( os ) was measured from the start of ftm to death for any reason , or last follow - up assessment . neurological status was assessed by considering signs and symptoms possibly correlated with progression , as compared with the previous examination . the endpoints of this analysis were : toxicity profile , dc , progression - free survival rate at 6  months ( pfs-6 ) and at 1  year ( pfs-1y ) , os from the diagnosis and from the beginning of ftms , overall survival rate at 1  year ( os-1y ) and ttp . cox proportional hazards models were applied to explore patients characteristics predictors of survival in univariate- and multivariable - adjusted analysis using a stepwise selection approach with type i error of 0.05 for model entry and 0.10 for elimination . additional elimination was applied to identify significant variables at the level of p  <  0.05 . we used pasw ( predictive analytics software ) ( v 18 ; ibm spss ) . between january 2004 and december 2011 , among the 206 gbm patients receiving ftm as second - line treatment after surgery and concomitant radio - chemotherapy plus adjuvant tmz failure , 65 patients ( 35 males and 30 females ) older than 65  years , were included in this analysis . the demographic and clinical characteristics of patients are outlined in table  1.table  1patients characteristicspatients65gender  female30  male35age ( years )  median70  657030  707531  > 754karnofsky performance status  9010024  708038  < 703extent of resection  gross total resection53  partial resection or biopsy12cycles of adjuvant temozolomide  median6  range224cycles of fotemustine  median4  range220 patients characteristics all patients received at least one dose of ftm . forty - one patients ( 63.1  % ) started maintenance chemotherapy , with a median of 4 cycles received after the induction phase ( range 117 ) . eight patients ( 12.3  % ) did not start maintenance therapy because of a disease progression . one complete response ( 1.5  % ) , 12 partial responses ( 18.5 , 95  % ci : 9.127.9  % ) , 18 stable disease ( 27.7 , 95  % ci : 16.838.6  % ) , and 34 patients progressions ( 52.3 , 95  % ci : 35.659.8  % ) were obtained after ftm induction . median duration of disease stabilization was 7.3  months ( 95  % ci : 4.510.1 ) . the median os from the start of ftm treatment was 7.1  months ( 95  % ci , 1.635.9 ) and the 1y - os rate was 20.0  % ( 95  % ci 10.329.7  % ) . the median ttp for ftm was 4.2  months ( 95  % ci 1.224.1  months ) ( fig .  1 ) , with a pfs-6 rate of 35.4  % ( 95  % ci 23.847.0  % ) and pfs-1y of 13.8  % ( 95  % ci 5.422.8  % ) . 1overall survival ( os ) , survival after fotemustine and progression - free survival ( pfs ) in elderly glioblastoma patients treated with fotemustine as second - line therapytable  2results obtained by using fotemustine as second - line therapy in elderly patients with recurrent glioblastomaobjective responsescomplete responses ( cr)1 ( 1.5  % ) partial responses ( pr)12 ( 18.5  % ) stable diseases ( sd)18 ( 27.7  % ) progressive diseases ( pd)34 ( 52.3  % ) disease control ( dc)43.1  % median overall survival ( months)20.6median overall survival from ii line fotemustine ( months)7.1progression free survival ( months)4.2six months - progression free survival ( % ) 35.4  % one year - progression free survival ( % ) 13.8  % overall survival ( os ) , survival after fotemustine and progression - free survival ( pfs ) in elderly glioblastoma patients treated with fotemustine as second - line therapy results obtained by using fotemustine as second - line therapy in elderly patients with recurrent glioblastoma fourteen patients ( 21.5  % ) with progressive disease after ftm and acceptable general conditions underwent a third line chemotherapy . ftm administration was well tolerated and the most relevant grade 34 toxicity events were thrombocytopenia ( 15.3  % ) and neutropenia ( 9.2  % ) ( table  3 ) . only one patient , with prolonged grade 2 thrombocytopenia , discontinued therapy due to toxicity during the induction phase . no significant differences in terms of incidence of hematologic toxicities were found in patients stratified by age ( > 65/>70/>75).table  3incidence of drug - related adverse events during ii line treatment with fotemustine in elderly patients with recurrent glioblastomathrombocytopenian ( % )  grade 129 ( 13.8 )  grade 3410 ( 15.3)leukopenia  grade 1211 ( 16.9 )  grade 346 ( 9.2)neutropenia  grade 127 ( 10.8 )  grade 346 ( 9.2)lymphopenia  grade 126 ( 10.0 )  grade 345 ( 7.7)anemia  grade 124 ( 6.2 )  grade 342 ( 3.1)transaminase elevation  grade 125 ( 7.7 )  grade 343 ( 4.6 ) incidence of drug - related adverse events during ii line treatment with fotemustine in elderly patients with recurrent glioblastoma furthermore , we performed an univariate and multivariate analysis to evaluate the impact of gender , time from rt to ftm , number of tmz and ftm cycles and dc on os and pfs of elderly patients . in univariate analysis , time from rt to ftm ( p  <  0.001 ) , number of tmz ( p  =  0.001 ) and ftm cycles ( p  <  0.001 ) and dc ( p  < 0.001 ) had a significant impact on os , whereas only time from rt to ftm and number of tmz cycles significantly affected pfs . multivariate analysis showed time from rt to ftm ( p  <  0.001 ) , number of tmz ( p  <  0.001 ) and ftm cycles ( p  <  0.001 ) and dc ( p  =  0.021 ) for os and time from rt to ftm ( p  =  0.03 ) and number of tmz cycles ( p  <  0.001 ) for pfs as independent prognostic factors ( tables  4 , 5).table  4univariate and multivariate analysis of os in elderly patients treated with fotemustine for recurrent glioblastomaosunivariate cox regressionmultivariable cox regressionhr ( 95  % ci)p valuehr ( 95  % ci)p valuesex ( m / f)1.07 ( 0.631.80)0.809n cycles of tmz ( cont)0.89 ( 0.840.95)0.0010.77 ( 0.680.88)<0.001time from rt to ftm0.89 ( 0.840.93)<0.0010.90 ( 0.850.95)<0.001n cycles of ftms ( cont)0.35 ( 0.200.61)<0.0010.84 ( 0.780.91)<0.001disease control ( n / y)2.72 ( 1.564.75)<0.0012.03 ( 1.113.69)0.021os overall survival , hr hazard ratio , ci confidence interval , tmz temozolomide , ftm fotemustine , n number , cont continuous variable , rt radiotherapytable  5univariate and multivariate analysis of pfs in elderly patients treated with fotemustine for recurrent glioblastomapfsunivariate cox regressionmultivariable cox regressionhr ( 95  % ci)p valuehr ( 95  % ci)p valuesex ( m / f)1.29 ( 0.792.11)0.311time from rt to ftm0.95 ( 0.920.99)0.0080.95 ( 0.910.99)0.03n cycles of tmz ( cont)0.87 ( 0.810.93)<0.0010.87 ( 0.810.93)<0.001os overall survival , hr hazard ratio , ci confidence interval , tmz temozolomide , ftm fotemustine , n number , cont continuous variable , rt radiotherapy univariate and multivariate analysis of os in elderly patients treated with fotemustine for recurrent glioblastoma os overall survival , hr hazard ratio , ci confidence interval , tmz temozolomide , ftm fotemustine , n number , cont continuous variable , rt radiotherapy univariate and multivariate analysis of pfs in elderly patients treated with fotemustine for recurrent glioblastoma os overall survival , hr hazard ratio , ci confidence interval , tmz temozolomide , ftm fotemustine , n number , cont continuous variable , rt radiotherapy recurrent gbm is resistant to most therapeutic approaches and elderly patients ( > 65  years old ) have a significantly worse life expectancy compared with younger patients . in addition , no evidence - based standard of care exists for this unique subpopulation ( table  6).table  6results with the use of second - line fotemustine in glioblastoma patientsauthorsyearspatients enrolledmedian pfspfs-6 ( % ) malhaire et al . 2012163nr25.043.8os overall survival , pfs progression - free survival , pfs-6 progression - free survival at 6  months , nr not reported results with the use of second - line fotemustine in glioblastoma patients os overall survival , pfs progression - free survival , pfs-6 progression - free survival at 6  months , nr not reported elderly patients with gbm represent a major focus in neuro - oncology . recently , malmstrm et al . have led a phase iii study of gbm patients older then 60y , randomized to receive tmz vs. standard 6-week radiotherapy versus hypofractionated radiotherapy . the results showed that standard radiotherapy was associated with poor outcomes , suggesting to consider both tmz and hypofractionated radiotherapy as standard treatment options in elderly patients with gbm . additionally , wick et al . has recently reported that tmz alone is non - inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma . ftm has been demonstrated to represent a valid option for patients with recurrent or progressive gbm . several trials [ 1317 ] have investigated the use of ftm in recurrent gbm patients , with the pfs-6 ranging from the 20  % reported by gicno   to the 48 and 51.5  % reported , respectively by scoccianti et al .   and fabrini et al .   ( table 6 ) . in these studies , myelosuppression was the most common adverse event that occurred , mainly during the induction phase of treatment and more frequently in tmz pretreated patients . the comparison between the results reported by paccapelo   and perry   could suggest a potentially different response pattern between recurrent gbm patients treated with ftm and those with rechallenge tmz . indeed , tmz seemed to be active in early and late progression patients , while ftm was always active in recurrent patients . the major difference was registered in gbm patients who failed after more than 6 months of tmz . as regard to the use of bevacizumab alone or in combination with irinotecan in gbm patients in first or second relapse , friedman et al showed an estimated pfs-6 of 42.6% and 50.3% , respectively . however , in this study median age was < 60 in the two groups , and data on the elderly patients were not reported in the results . our retrospective study represents the first report on efficacy and safety of ftm in elderly patients with recurrent gbm . in our analysis , ftm was a valuable therapeutic option for elderly patients with recurrent gbm , obtaining a median os of 7.1  months , a pfs-6 of 35.4  % and a median pfs of 4.2  months . in addition , ftm administration was feasible with an acceptable toxicity , even in this group of patients . when stratified by age category ( > 65/>70/>75 ) , no significant differences were registered in the incidence of hematologic adverse events , although this analysis is limited by the small number of patients > 75y in our study . furthermore , in our study population , time from rt to ftm , number of tmz and ftm cycles and dc resulted independent treatment - related prognostic factors . it is also of interest the high percentage ( 21.5  % ) of patients still fit for third line chemotherapy after ftm failure . however , elderly gbm patients fit for second - line therapies are good prognosis patients , and our data in terms of tolerance and efficacy of ftm may not be extended to the overall elderly gbm population . in conclusion , ftm may be considered as a treatment option , even for elderly gbm patients , especially for those receiving a significant benefit from prior tmz therapy and with good kps . based on these data these patients should definitely be included in adult patients clinical trials .
fotemustine ( ftm ) is a common treatment option for glioblastoma patients refractory to temozolomide ( tmz ) . 
 although elderly patients represent a large component of glioblastoma population , the feasibility and the efficacy of second - line ftm are not available in those patients.we retrospectively analyzed the records of glioblastoma patients older than 65  years , receiving ftm at a dose of 70100  mg / m2 of ftm every week for 3 consecutive weeks ( induction phase ) and then every 3  weeks ( 70100  mg / m2 ) , as second - line treatment.between january 2004 and december 2011 , 65 glioblastoma patients ( median age , 70  years ; range , 6579  years ) were eligible for this analysis . 
 sixty - five patients received a total of 364 ftm cycles , with a median of 4 cycles for each patient . 
 after induction , we observed 1 complete response ( 1.5  % ) , 12 partial responses ( 18.5  % ) , 18 stable diseases ( 27.7  % ) , and 34 patients progressions ( 47.7  % ) . 
 disease control rate was 43.1  % . 
 median survival from the beginning of ftm therapy was 7.1  months , while the median progression - free survival was 4.2  months , and the 6-months progression free survival rate was 35.4  % . 
 the most relevant grade 34 toxicity events were thrombocytopenia ( 15.3  % ) and neutropenia ( 9.2  % ) . in the univariate and multivariate analysis , time from radiotherapy to ftm , number of tmz and ftm cycles and disease control resulted independent prognostic factors.this study showed that ftm is a valuable therapeutic option for elderly glioblastoma patients , with a safe toxicity profile .