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Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma. Currently, high-dose methotrexate (HD-MTX)-based chemotherapy remains the standard first-line treatment. Previous clinical trials have reported that fotemustine-containing regimens offer promising efficacy and tolerability as an alternative option. To compare the efficacy, safety, and feasibility of fotemustine-containing regimens with HD-MTX-containing regimens for newly diagnosed PCNSL. A single-center, retrospective cohort study. We retrospectively analyzed 114 newly diagnosed PCNSL patients treated between April 2011 and December 2021. Patients were classified into two cohorts: those receiving fotemustine-containing regimens (  = 72) and those receiving HD-MTX-containing regimens (  = 42). The primary efficacy endpoint was the objective response rate (ORR). Secondary endpoints included complete response rate, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. No significant difference in ORR was observed between the fotemustine-containing group and HD-MTX-containing group (68% vs 67%,  = 0.879). At a median follow-up of 28.5 months, the survival outcomes were comparable, with no statistically significant differences in either PFS (hazard ratio (HR) = 0.887, 95% confidence interval (CI): 0.522-1.508;  = 0.654) or OS (HR = 0.966, 95% CI: 0.494-1.888;  = 0.918). Notably, fotemustine-based therapy was associated with significantly fewer AEs, including leukopenia, thrombocytopenia, digestive tract toxicity, and mucositis (all  < 0.05). Fotemustine-containing chemotherapeutics appear to confer a safer profile with comparable efficacy relative to HD-MTX-based regimens in newly-diagnosed PCNSL patients.

Target population These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). Question (Q1) In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy? Recommendation Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5 months of TMZ-treatment free interval. Level III: Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. Question (Q2) In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy? Recommendation Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. Question (Q3) In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy? Recommendation Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM. Level III: Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. Question (Q4) In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy? Recommendation Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. Question (Q5) In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy? Recommendation Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

Background/Aim: Bevacizumab and chemotherapy are used in glioblastoma multiforme (GBM) relapse. However, the choice of chemotherapeutic agent remains an open question and this study aimed to evaluate the efficacy and safety of different combinations. Patients and Methods: Between June 2005 and August 2020, all patients treated with chemotherapy plus bevacizumab (BVZ) for recurrent glioblastoma in the Georges-François Leclerc Cancer Center, Dijon, France were included in this retrospective comparative study. The primary objective was progression-free survival (PFS) and as secondary objectives, overall survival (OS), disease control rate (DCR), and safety were investigated. Factors associated with response were also analyzed. Results: A total of 160 patients were screened: 100 received fotemustine plus BVZ (62%) and 62 (38%) received another cytotoxic agent plus BVZ: 35 (22%) irinotecan (IRI), 18 (11%) temozolomide (TEM), and 7 (4%) lomustine (LOM). In the whole population, median PFS was 4.47 months, median OS was 9 months, and 3-month DCR was 51%. Regarding survival according to treatment, median OS was significantly lower in the fotemustine group compared to that in other cytotoxic agents: 7.3 vs. 19.9 months. In the fotemustine group, steroids use at baseline and low Karnofsky performance status were associated with poor median OS. Grade 3-4 adverse events were found in 21.9%, with no difference between groups, but 7 patients had grade 5 adverse events in the fotemustine group. Conclusion: Using real-life data, this study showed lower efficacy of fotemustine and bevacizumab, as compared to IRI or TEM or LOM-BVZ combinations.

The use of fotemustine (FTM) has been authorized in certain countries for the treatment of recurrent high-grade gliomas (HGG) after Stupp therapy. However, to the best of our knowledge, no studies have assessed changes in magnetic resonance imaging (MRI) during treatment with FTM monotherapy. The aim of the present study was to assess the neuroradiological findings in a cohort of patients with recurrent HGG treated with FTM monotherapy. Patients with HGG already undergoing the Stupp protocol were retrospectively included. MRIs (pre- and post-FTM treatment) were analyzed by two neuroradiologists in consensus: Volume and diffusion values of the contrast-enhanced component were measured on T1-weighted volumetric sequences after gadolinium injection and on apparent diffusion coefficient (ADC) maps, respectively. A total of 19 patients [median age, 49 years; interquartile range (IQR), 43-57 years] were included, 17 of whom had glioblastoma and 2 had astrocytoma isocitrate dehydrogenase-mutated grade 4. The median duration of FTM therapy was 4 months (IQR, 2-6 months). The median tumor volume measured on the contrast-enhanced component was 2,216 mm3 (IQR, 768-13,169 mm3) at baseline and 9,217 mm3 (IQR, 3,455-16,697 mm3) at the end of treatment, with a median change of +38% (IQR, −45-+574%). A total of seven patients showed a volume decrease. ADC value analysis of the enhancement area demonstrated no significant difference between the pre- and the post-FTM treatment periods (P=0.36); however, in three patients, the decreases in ADC levels were particularly marked. In conclusion, the present study described a series of patients with recurrent HGG treated with FTM in monotherapy, demonstrating a prevalent increase in lesion enhancement and three cases of marked restrictions on diffusion-weighted imaging. Further prospective studies are required to corroborate such preliminary results.

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6 % (95 % CI 29.3–55.2) and a median PFS of 5.2 months (95 % CI 3.8–6.6). The median OS was 9.1 months (95 % CI 7.3–10.3). Twenty-eight patients (52 %) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60 %). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76 %), while the diffuse non-enhancing progression accounted for 9.5 %. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22 %) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4 %) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant’Andrea Hospital. All patients had Karnofsky performance score (KPS) ≥ 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine ( p  = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively ( p  = 0.01). KPS > 70 ( p  = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies.

Background It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6–11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. Methods A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21–81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m 2 on days 1 and 2 and FM iv 100 mg/m 2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients. Results We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status. Conclusion This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed. Trial registration EUDRACT 2009–016487-36l ; date of registration 23 June 2010.

Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O 6 -methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg −1 protein, and there was a correlation between MGMT activity and the level of resistance to TMZ and fotemustine. MGMT inactivation by O 6 -benzylguanine sensitized all melanoma cell lines expressing MGMT to TMZ and fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O 6 -alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to TMZ without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and TMZ sensitivity was not found. Apoptosis in melanoma cells induced by TMZ and fotemustine was accompanied by double-strand break (DSB) formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For TMZ, DSBs correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to TMZ and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with TMZ. Overall, the findings are in line with the model that in melanoma cells TMZ-induced O 6 -methylguanine triggers the apoptotic (and necrotic) pathway through DSBs, whereas for chloroethylating agents apoptosis is triggered in a more complex manner.

Several anthropogenic products in wastewater are considered a threat to the aquatic environment. In addition to common industrial pollutants, levels of pharmaceuticals have been increasingly found in the environment in recent years, which may present a strong risk to the aquatic species that live there. The constant consumption of biologically active chemicals for human health has been matched by an increase in the leaking of these compounds in natural habitats over the last two decades. This study is aimed at evaluating the developmental toxicity of fotemustine in the ecological environment. Zebrafish embryos were exposed to doses of 25, 50 and 100 µg/mL from 4 h post-fertilization to 120 h. This study confirms that fotemustine exposure at 50 and 100 µg/mL affects the survival and hatching rate, morphology score and body length. Additionally, it significantly disturbs the antioxidant defense system and increases ROS in zebrafish larvae. From the molecular point of view, fotemustine exposure strongly induces apoptosis, endoplasmic reticulum stress (ERS) and the Wnt signaling pathway.

Background Standardized salvage treatment has not yet proved effective in glioblastoma multiforme (GBM) patients who receive prior standard radiotherapy plus concomitant and adjuvant temozolomide. Methods Patients with progressive GBM after radiotherapy plus concomitant and/or adjuvant temozolomide received three-weekly doses (100-75 mg m²) of fotemustine followed, after a 5-week rest, by fotemustine (100 mg m²) every 3 weeks for <=1 year. Results Forty-three patients (29 M, 14 F; median age 51 years, range 34-68; median KPS 90) were enrolled. Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: 9-33%); three patients (7.1%) had partial response (PR); 15 (34.9%), disease stabilization (SD). The median survival was 6 months (95% CI: 5-7). MGMT promoter status was methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease control was 75% versus 34.6% in methylated and unmethylated MGMT patients (P = 0.044); no significant difference was found between groups for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 20.9 and 16.3% of patients, during the induction phase, and in 0 and 9.5% patients during the maintenance phase, respectively. Conclusions The findings of the present trial, that evaluate fotemustine in a homogeneous population, may represent a new benchmark for nitrosourea activity. Moreover, this is the first study to evaluate correlation between MGMT promoter status and outcome of fotemustine for relapsing GBM previously treated with radiotherapy and temozolomide.