Fotemustine Treatment Research Articles

Clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent glioblastoma: a mono-institutional retrospective study.

The optimal treatment of recurrent glioblastoma (GBM) in elderly patients is unclear. Fotemustine (FTM) is a third-generation nitrosourea showing efficacy in gliomas and it has been used with different schedules in adult patients. We performed, for the first time anywhere, a mono-institutional retrospective study to analyze the clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent GBM. Retrospectively, we analyzed all GBM patients 65years or older previously treated with the combination of radiation therapy and temozolomide (TMZ), receiving an alternative FTM schedule as second-line treatment at our Oncological Center from October 2011 to October 2014 with an ECOG PS≤2. FTM was administrated at 80mg/m(2) every 2weeks for five consecutive administrations (induction phase), and then every 4weeks at 80mg/m(2) as maintenance. We enrolled 44 patients, 33 males and 11 females; average age was 70years. ECOG PS was 0-1 in 80% of the patients. 38 patients relapsed during temozolomide (TMZ) therapy. MGMT methylation status was analyzed in 34 patients and MGMT was methylated in 53% of the patients. The median progression free survival (PFS) and overall survival (OS) from FTM treatment was 4.1months (95% CI 3.1-5.2) and 7months (95% CI 5.2-8.4), respectively. Patients with MGMT methylated status and patients who relapsed after completing TMZ therapy had a longer PFS and OS from the beginning of FTM. Thrombocytopenia was the most frequent grade 3-4 haematological toxicity (9%). The alternative schedule of FTM may be an active and safe treatment for elderly patients with recurrent glioblastoma, especially patients with methylated MGMT and who relapsed after completing temozolomide therapy.

GEINOFOTE: efficacy and safety of fotemustine in patients with high-grade recurrent gliomas and poor performance status.

The treatment of recurrent high-grade gliomas (HGG) is controversial. There are different therapeutic schedules but without a clear orientation about which of them should be used in each clinical situation. In addition, when patients suffer a second recurrence or they have poor performance status, they are excluded from clinical trials, although second recurrences and poor performance status are indeed more and more real and common situations in the clinical setting. In this study, we assessed the efficacy and safety of fotemustine (FTM) in HGG [fundamentally, glioblastomas (GB)], independent of time of recurrence or performance status. Retrospective study in HGG patients treated with FTM in second or further line according to standard, the Addeo or any other scheme, starting treatment prior to 30 November 2012. Included patients reflect the regular situation in which the drug is used in terms of comorbidities and analytic situation (hematologic, renal and hepatic functions). Response assessment was performed by MRI and according to the clinical protocols of each center (every 8-12weeks). Clinical situation and supportive care drugs were evaluated in each medical consultation. Clinical end-points analyzed, among others, were: PFS-6, PFS, OS, response rates, toxicity, quality of life and neurocognitive impact. In terms of activity, an overall response rate of 8% was observed: partial response 6% (7 patients) and complete response 2% (2 patients). The median time to achieve the greater response with FTM was 73days (4-841days). Patients treated according to the Addeo schedule had a shorter time to greater response in comparison with other schedules (85.9 vs 114days), although without statistical significance. There were no significant differences in progression-free survival (PFS) when comparing different FTM schedules or using FTM in first or second recurrence. Median PFS: 3months. PFS-6: 30.3%. Overall survival (OS): although without significant differences, a tendency to better survival when using the Addeo schedule versus other schedules was observed (at 6months, 44.6 vs 34.5%; at 12months, 25 vs 23.6%; at 18months, 11.5 vs 7.9%), as well as if earlier use (second vs third line) concerning OS-12 (33.7 vs 18.2%). Median OS: 5.2months. Grades 3-4 toxicity was 28% (31 patients), being neutropenia (4%) and thrombocytopenia (17%) the most frequent adverse reactions. From quality of life and neuro-cognitive function perspectives, 11 patients (10%) and 16 (14%) improved the Karnofsky Index and neurological impairment, respectively, after FTM treatment. This study has shown that FTM is safe and has a comparable activity with other available therapeutic options of use in the treatment of recurrent HGG.

An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab.

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

Complete Remission and Long Term Survival in Recurrent Malignant Glioblastoma Treated with Fotemustine Monotherapy: A Case Report

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Conventional therapies are considered palliative and long-term progression-free survival remains low for most GBM patients even after surgical excision, concomitant radiotherapy and/or chemotherapy with nitrosoureas or Temozolomide. We report the case of a 47-year-old man who presented worsening headache over a month, accompanied by episodes of morning vomiting and hyposthenia of the left hemisoma. Cerebral tomographic scan revealed an expansive process on the right frontal site. Following surgical resection, the patient was diagnosed with diffusely infiltrating GBM. After surgery, the patient underwent radiotherapy and chemotherapy with Temozolomide for 6 months. Eleven months later, the patient underwent a second-look surgery with excision of a new right superior frontal nodule. This time the patient refused both radio and chemotherapy and underwent follow-up only. After 12 months he underwent a new craniotomy for the excision of a third GBM relapse. Following resection, the patient agreed to be treated for 6 months with fotemustine (FTM) 100 mg/m2 intravenously every 4 weeks as chemotherapy. After 3 months of treatment the patient underwent a full physical examination and diagnostic monitoring of the tumor using Magnetic Resonance Imaging (MRI) of the brain and whole body Computerised Tomography (CT). During FTM treatment, the most frequent, but reversible toxic effect was hematological grade 2 anemia and thrombocytopenia but no other grade >2 toxicity was recorded, so there was no reduction or delay in treatment. Presently, after 8 years of follow-up, the patient is in excellent health and has no evidence of intracranial disease recurrence. In light of this case, post-surgical FTM treatment seems to represent an interesting well-tolerated treatment possibility in patients with recurrent malignant GBM of the brain, given that there are very few reports of such a remission in the literature.

Fotemustine-related leukoencephalopathy

A 66-year-old woman with an 11-year history of melanoma initially treated by surgery, reaching stage IV at age 60 (with cervical and later also pancreatic lymph node metastases), received 9 cycles of 800 mg/m dacarbazine (given every 3 weeks, started at age 63) and 4 cycles of 3 mg/kg ipilimumab (a monoclonal antibody treatment, given every 3 weeks, started at age 64). Three months after the end of ipilimumab treatment, brain CT was normal (Fig. 1). Five months after the end of ipilimumab treatment, fotemustine (an alkylating antineoplastic agent) induction phase treatment was started, followed by 100 mg/m fotemustine every 3 weeks). Ten months after the start of fotemustine treatment, the patient developed mental slowing, cognitive deficit, and tetrapyramidal syndrome. CT and MRI showed dramatic, strictly supratentorial, symmetrical, leukoencephalopathy on FLAIR sequences in absence of gadolinium-enhancement on T1-weighted imaging, together with severe generalised subcortical brain atrophy (Fig. 1). At that time, fotemustine treatment was stopped. Lumbar puncture was performed, and repeated twice during the following 3 months. CSF analysis was strictly normal including PCR for JC virus. The patient refused brain biopsy. The patient worsened progressively, became bedridden, and died 6 months after onset of neurological deficit. The patient’s family refused autopsy. Differential diagnoses in our patient included brain lymphoma, progressive multifocal leukoencephalopathy, and toxic leukoencephalopathy. Symmetrical MRI abnormalities, the respect of deep grey nuclei, the absence of gadolinium-enhancement, and normal CSF analysis made lymphoma diagnosis in our patient unlikely. Absence of repeated PCR for JC virus and the very symmetrical MRI changes were against a diagnosis of progressive multifocal leukoencephalopathy. Toxic leukoencephalopathy has been reported in a large group of drugs including alkylating antineoplastic agents such as cyclophosphamide, carmustine, and busulfan, but not in fotemustine [1, 2]. Strictly toxic leukoencencephalopathy (i.e. non-JC-virus-related) has never been reported in dacarbazine, ipilimumab or other monoclonal antibody drugs. Although delayed toxic leukoencephalopathy due to dacarbazine or ipilimumab, lymphoma, and progressive multifocal leukoencephalopathy could not be ruled out completely (especially in the absence of histological examination), fotemustine-related toxic leukoencephalopathy seemed to be most probably the cause of leukoencephalopathy in our case, since fotemustine was the most recently administered drug preceding onset of neurological deficit and MRI abnormalities. D. Renard (&) C. Campello Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, Nimes Cedex 4 30029, France e-mail: dimitrirenard@hotmail.com

Predictable clinical responses to sorafenib in stage IV uveal melanoma.

e19032 Background: Uveal melanoma is an orphan disease with poor prognosis, once metastasized. There is currently no approved systemic treatment and all clinical trials so far failed to significantly improve OS in stage IV uveal melanoma patients (see results of the EORTC 18021 trial, abstract 95725). Sorafenib is a pleiotropic kinase inhibitor targeting tumor metabolism and related neoangiogenesis. Although sorafenib failed as monotherapy in metastasized melanoma, results from small phase II trials have indicated synergism with chemotherapy in some patients. We therefore offered compassionate use treatment with sorafenib to patients with documented progressive stage IV uveal melanoma after fotemustine iv or HIA treatment (EORTC 18021 trial). Methods: Sorafenib 400 mg orally bid was combined with fotemustine 100 mg/m² at 3 week intervals to treat a total of 7 patients with metastatic uveal melanoma. Patients were closely followed by repeated analyses of serum tumor markers and ultrasound scans of liver metastases. Complete staging by CT/MR scans was done every 3 months. Results: 3 of 7 patients with initially elevated tumormarkers showed an early rapid drop in serum MIA and/or S100 within two weeks of sorafenib treatment followed by partial responses and long term stabilization of the disease up to 20 months. Responder patients could also be identified by a rapid drop in tumorperfusion as shown by contrast enhanced ultrasound of liver metastases. Due to hematologic toxicity treatment had to be modified in all responder patients. Neither reduction of sorafenib dosage to 200 mg orally bid nor omittance of fotemustine treatment resulted in early disease progression, pinpointing potential high sorafenib responsiveness in uveal melanoma patients. Conclusions: Patients with stage IV uveal melanoma may benefit from treatment with the kinase inhibitor sorafenib. Our observations suggest selection of responder patients by early drop of elevated tumor markers S100 / MIA and early drop in tumor perfusion. Stimulated by these data a first phase II trial investigating sorafenib in uveal melanoma patients has been initiated in Germany (ClinicalTrials.gov NCT0137702: A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma (STREAM).

A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy

BackgroundAt recurrence the use of nitrosoureas is widely-used as a therapeutic option for glioblastoma (GBM) patients. The efficacy of fotemustine (FTM) has been demonstrated in phase II clinical trials; however, these papers report a wide range of progression-free-survival (PFS-6 m) rates, ranging from 21% to 52%. We investigated whether FTM could have a different response pattern in respect to time to adjuvant temozolomide failure, or whether specific independent risk factors could be responsible for the wide range of response rates observed.MethodsRecurrent GBM patients have been treated with fotemustine 75-100 mg/sqm at day 1, 8, 15 and after 4/5 weeks of rest with 100 mg/sqm every 21 days. Patients were stratified in 4 groups according to time to temozolomide failure: before starting (B0), during the first 6 months (B1), after more than 6 months of therapy (B2), and after a treatment-free interval (B3). Primary endpoint was PFS-6 m. A multivariable analysis was performed to identify whether gender, time after radiotherapy, second surgery and number of TMZ cycles could be independent predictors of the clinical benefit to FTM treatment.Results163 recurrent GBM patients were included in the analysis. PFS-6 m rates for the B0, B1, B2 and B3 groups were 25%, 28%, 31.1% and 43.8%, respectively. The probability of disease control was higher in patients with a longer time after radiotherapy (p = 0.0161) and in those who had undergone a second surgery (p = 0.0306).ConclusionsFTM is confirmed as a valuable therapeutic option for patients with recurrent GBM and was active in all study patient groups. Time after the completion of radiotherapy and second surgery are independent treatment-related risk factors that were predictive of clinical benefit.

Nouvelle toxicité de la fotémustine : une pneumopathie interstitielle diffuse

Fotemustine is an alkylating cytostatic drug belonging to the nitrosourea family and is used in particular in the treatment of disseminated malignant melanoma. Herein, we report a case of interstitial lung disease associated with fotemustine. An 81-year-old man treated with fotemustine for metastatic melanoma presented acute interstitial lung disease 20 days after a fourth course of fotemustine monotherapy. The condition regressed spontaneously, with the patient returning to the clinical, radiological and blood gas status that had preceded fotemustine treatment. After other potential aetiologies had been ruled out, acute fotemustine-induced lung toxicity was considered and this treatment was definitively withdrawn. Other cytostatic agents belonging to the nitrosourea family can cause similar pictures, with a number of cases of interstitial lung disease thus being ascribed to fotemustine and dacarbazine. To our knowledge, this is the first case of interstitial lung disease induced by fotemustine monotherapy. This diagnosis should be considered where respiratory signs appear in melanoma patients undergoing fotemustine treatment.

Efficacy of nitrosourea-based chemotherapy in recurrent malignant glioma according to time to adjuvant temozolomide failure: A pooled analysis.

2060 Background: Concomitant and adjuvant temozolomide (TMZ) is the standard of care of the first-line treatment in glioblastoma (GBM) patients. At recurrence patients have few therapeutic options and the use of nitrosoureas, alternative schedule of TMZ and new target therapy have been widely studied. Recently Perry and colleagues (JCO 2010;28:2051-2057) have demonstrated that time to adjuvant temozolomide failure seems to be predictable to dose-intense TMZ treatment. The aim of our pooled analysis was to assess the efficacy of nitrosourea in recurrent GBM patients according to time to adjuvant TMZ progression. Methods: Patients with GBM who failed the standard Stupp regimen have been treated with a nitrosoureas based regimen of fotemustine (FTM) 75-100mg/sqm at day 1, 8, 15 (induction phase) and after 4/5 weeks of rest 100 mg/sqm every 21 days. The primary endpoint of the study was 6-months progression free survival (PFS-6m), Overall survival at 1 year (OS1y), response rate (RR) and toxicity were secondary endpoints. Patients were stratified in 3 groups according to time to TMZ failure: GBM patients failing during the first 6 months of adjuvant TMZ (B1), those who failed after more than 6 months of therapy (B2) and GBM patients who recurred after a treatment-free interval (B3). Results: Six Italian centers participated in this study. At that time preliminary results are available: 119 patients with recurrent GBM have been evaluated. Results have been summarized in the table. Conclusions: Nitrosourea is a valuable therapeutic option for patients with recurrent GBM, not depending on time to adjuvant temozolomide failure and also patients recurred after 6 cycles of adjuvant TMZ (B2) seem to get a benefit from FTM treatment. A prospective randomized trial is warranted to define if TMZ and FTM have a different pattern of response in recurrent GBM. B1 (%) B2 (%) B3 (%) PSF-6m OS1y RR PSF-6m OS1y RR PSF-6m OS1y RR FTM 24.5 24.5 12.2 31.3 31.3 18.8 34.2 28.9 7.9 TMZ* 27.3 27.3 3 7.4 14.8 0 35.7 28.6 11.1

The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs

Temozolomide and fotemustine, representing methylating and chloroethylating agents, respectively, are used in the treatment of glioma and malignant melanoma. Because chemoresistance of these tumors is a common phenomenon, identification of the underlying mechanisms is needed. Here we show that Rev3L, the catalytic subunit of the translesion DNA polymerase zeta, mediates resistance to both temozolomide and fotemustine. Rev3L knockout cells are hypersensitive to both agents. It is remarkable that cells heterozygous for Rev3L showed an intermediate sensitivity. Rev3L is not involved in the tolerance of the toxic O6-methylguanine lesion. However, a possible role of Rev3L in the tolerance of O6-chloroethylguanine or the subsequently formed N1-guanine-N3-cytosine interstrand cross-link is shown. Rev3L had no influence on base excision repair (BER) of the N-alkylation lesions but is very likely to be involved in the tolerance of N-alkylations or apurinic/apyrimidinic sites originating from them. We also show that Rev3L exerts its protective effect in replicating cells and that loss of Rev3L leads to a significant increase in DNA double-strand breaks after temozolomide and fotemustine treatment. These data show that Rev3L contributes to temozolomide and fotemustine resistance, thus acting in concert with O6-methylguanine-DNA methyltransferase, BER, mismatch repair, and double-strand break repair in defense against simple alkylating anticancer drugs.

Genotoxic Effects Induced by Fotemustine and Vinorelbine in Human Lymphocytes

The aim of this study was to investigate the in vitro genotoxic effects of the anticancer drugs fotemustine and vinorelbine on human lymphocytes and to determine individual and sex-related responses to these drugs. Fotemustine is a DNA-alkylating drug while vinorelbine is a semi-synthetic Vinca alkaloid. The study was carried out with twenty independent healthy donors for each drug. We have tested the ability of these drugs to induce chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) as well as effect on the mitotic index (MI) in cultured human lymphocytes. Fotemustine was shown to induce CAs and SCEs at all concentrations tested (2, 4 and 8 microg/ml) in a dose-dependent manner. Additionally it also decreased the mitotic index in a similar dose-dependent manner. Vinorelbine had no effect on structural CAs, but it significantly increased the numerical CAs at all doses tested (0.5, 1 and 2 microg/ml). Vinorelbine also induced SCE events and increased the MI values. Two-way analyses of variance were used to compare the individual and gender-related susceptibilities to fotemustine and vinorelbine with respect to the CA, SCE and MI values. The results indicated that individuals in fotemustine treatment groups showed different genotoxic responses with respect to CA and SCE induction and additional findings indicated a gender-specific response in this group. Individuals in the vinorelbine test group also exhibited statistically significant numerical CA, SCE and MI responses to vinorelbine. A statistically significant gender-related SCE response to this drug was also evident. This study indicates that these drugs have potentially harmful effects on human health.