Chemotherapy in the management of brain metastases: the emerging role of fotemustine for patients with melanoma and NSCLC.

INTRODUCTION: An estimated 20 - 40% of cancer patients will develop brain metastases that are the most common intracranial tumors in adults. Patients with cerebral metastases represent a variegate group where selection of the most appropriate treatment depends on many patient- and disease-related factors. The impact of therapeutic option on overall survival is lacking and it is important to consider quality of life (QOL) when treating patients with brain metastases. AREAS COVERED: A considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. The role of chemotherapy was limited in the past. Recently, several chemotherapeutic agents have been identified as potentially useful. This article examines the pharmacokinetics, efficacy and safety and tolerability of fotemustine (FTM) for the management of patients with cerebral metastasis from melanoma and non-small cell lung cancer (NSCLC). EXPERT OPINION: FTM is a third-generation nitrosourea that has proved its efficacy on brain metastases of melanoma and showed promising results for the treatment of brain metastasis of NSCLC because of its ability to pass the blood-brain barrier.

Fotemustine for the treatment of melanoma.

INTRODUCTION: Melanoma is a rare but very aggressive form of cancer. Survival in melanoma varies widely depending on the stage of the tumor. In metastatic melanoma, prognosis is usually poor and the treatment is based on chemotherapy. So far, dacarbazine has been the drug of reference, with an average response rate of 15 - 20% when used as a monotherapy. As single drugs go, fotemustine is considered the second-best treatment, after dacarbazine. AREAS COVERED: This review of the scientific literature focuses on the use of fotemustine in patients with cutaneous melanoma and discusses its clinical efficacy and safety. EXPERT OPINION: Fotemustine is a nitrosurea that has proved its efficacy in metastatic melanoma and particularly on cerebral metastases, given its high lipophilicity, facilitating its active penetration in all tissues including the central nervous system. However, overall response rates are low, with only few complete remissions and short response durations.

Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways.

Metabolomics of tumors may allow discovery of tumor biomarkers and metabolic therapeutic targets. Metabolomics by two-dimensional proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy was applied to investigate metabolite disorders following treatment by chloroethylnitrosourea of murine B16 melanoma (n = 33) and 3LL pulmonary carcinoma (n = 31) in vivo. Treated tumors of both types resumed growth after a delay. Nitrosoureas provoke DNA damage but the metabolic consequences of genotoxic stress are little known yet. Although some differences were observed in the metabolite profile of untreated tumor types, the prominent metabolic features of the response to nitrosourea were common to both. During the growth inhibition phase, there was an accumulation of glucose (more than x10; P < 0.05), glutamine (x3 to 4; P < 0.01), and aspartate (x2 to 5; P < 0.01). This response testified to nucleoside de novo synthesis down-regulation and drug efficacy. However, this phase also involved the increase in alanine (P < 0.001 in B16 melanoma), the decrease in succinate (P < 0.001), and the accumulation of serine-derived metabolites (glycine, phosphoethanolamine, and formate; P < 0.01). This response witnessed the activation of pathways implicated in energy production and resumption of nucleotide de novo synthesis, thus metabolic pathways of DNA repair and adaptation to treatment. During the growth recovery phase, it remained polyunsaturated fatty acid accumulation (x1.5 to 2; P < 0.05) and reduced utilization of glucose compared with glutamine (P < 0.05), a metabolic fingerprint of adaptation. Thus, this study provides the proof of principle that metabolomics of tumor response to an anticancer agent may help discover metabolic pathways of drug efficacy and adaptation to treatment.

Focus on Fotemustine.

Fotemustine is a cytotoxic alkylating agent, belonging to the group of nitrosourea family. Its mechanism of action is similar to that of other nitrosoureas, characterized by a mono-functional/bi-functional alkylating activity. Worth of consideration is the finding that the presence of high levels of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) in cancer cells confers drug resistance. In different clinical trials Fotemustine showed a remarkable antitumor activity as single agent, and in association with other antineoplastic compounds or treatment modalities. Moreover, its toxicity is generally considered acceptable. The drug has been employed in the treatment of metastatic melanoma, and, on the basis of its pharmacokinetic properties, in brain tumors, either primitive or metastatic. Moreover, Fotemustine shows pharmacodynamic properties similar to those of mono-functional alkylating compounds (e.g. DNA methylating drugs, such as Temozolomide), that have been recently considered for the management of acute refractory leukaemia. Therefore, it is reasonable to assume that this agent could be a good candidate to play a potential role in haematological malignancies.

Preliminary study on pharmacokinetics of dacarbazine and fotemustine in glioblastoma multiforme patients does not indicate gender-specific differences.

Twelve patients (six female and six male) with histologically proven glioblastoma multiforme were investigated during the administration of the first cycle of dacarbazine (D; 200 mg/m) and fotemustine (F; 100 mg/m). In total, 18 blood samples were collected for pharmacokinetic analysis (maximum plasma concentration, area under the concentration-time curve and total clearance) of D and F at 14 time points during therapy. D, its metabolite 5-aminoimidazole-4-carboxamide and F were evaluated by reversed-phase HPLC. For statistical calculations, groups were compared by the non-parametric Wilcoxon test. p<0.05 was considered statistically significant. No significant gender-dependent differences were observed in the pharmacokinetics of D and F. An additional response re-evaluation of 100 patients (50 female and 50 male) with glioblastoma multiforme, treated at our institution with D and F, gave no hint of any gender-dependent different response rates. We conclude that there is no evidence, neither from pharmacokinetic nor from our clinical data, to consider different dosages of D and F in female and male patients with glioblastoma multiforme.

Clinical and pharmacokinetic phase II study of fotemustine in refractory and relapsing multiple myeloma patients.

BACKGROUND: Patients with relapsing or refractory multiple myeloma have poor prognosis. Few compounds are active in these patients and response duration remains short. We report the results of an open phase II trial evaluating the efficacy and safety of fotemustine monotherapy. PATIENTS AND METHODS: Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m(2) on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m(2) every 3 weeks until progression or unacceptable toxicity. Fotemustine pharmacokinetics during the first day of induction was compared between patients with normal or abnormal renal function. RESULTS: Five of 20 eligible patients had an objective response giving an intention-to-treat response rate of 25% [95% confidence interval (CI) 6% to 44%] and a 35.7% response rate (95% CI 11% to 61%) in the 14 patients having received at least four injections of fotemustine. The median time to objective response was 8.9 months. The median times to progression and survival were 13.8 and 23.1 months, respectively, with a 2-year survival rate of 49%. The main toxicity was myelosuppression with grade 3-4 neutropenia and thrombocytopenia in 66% and 71% of patients, respectively. There was one toxic death by sepsis after induction. The pharmacokinetic parameters in renal-impaired patients were not significantly different from those in patients with normal renal function with a similar incidence of grade 3-4 toxicity in both groups. CONCLUSIONS: Fotemustine as a single agent has definite activity in patients with relapsing or refractory multiple myeloma, with acceptable toxicity and can be administered at conventional doses in patients with mild or moderate renal impairment.

Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients.

BACKGROUND: Cystemustine is a chloroethylnitrosourea mostly active in humans against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule. The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated. PATIENTS AND METHODS: Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m2. The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period. RESULTS: Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible, but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min. CONCLUSIONS: There was a clear linear relationship between the area under the blood drug concentration-time curve (AUC) and the dose of cystemustine (P < 0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P < 0.001). A reasonable starting dose for phase II studies is 40 mg/m2, with dose escalation based on blood cell counts.

Drug delivery to tumors of the central nervous system.

Contemporary treatment of malignant brain tumors has been hampered by problems with drug delivery to the tumor bed. Inherent boundaries of the central nervous system, such as the blood-brain barrier or the blood-cerebrospinal fluid barrier, and a general lack of response to many chemotherapeutic agents have led to alternative treatment modalities. In general, all these modalities have sought to either disrupt or bypass the physiologic brain barriers and deliver the drug directly to the tumor. This article reviews past, as well as current, methods of drug delivery to tumors of the central nervous system. Special emphasis is placed on biodegradable polymers that can release chemotherapeutic agents against malignant gliomas. A variety of other nonchemotherapeutic drugs, including antiangiogenesis and immunotherapeutic agents, are presented in the context of new polymer technology. Finally, future directions in drug delivery are discussed with an overview on new advances in emerging biotechnology.

Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Phase I pharmacological study of intra-arterially infused fotemustine for colorectal liver metastases.

Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 +/- 11.5 min) and a high body clearance (CL = 2193 +/- 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1-3.

Clinical experience of fotemustine, cisplatin and high dose tamoxifen in patients with metastatic malignant melanoma.

Inspired by the high response rates achieved with the DBCT regimen (dacarbazine [DTIC], carmustine [BCNU], cisplatin and tamoxifen [TAM]), we administered the nitrosourea compound fotemustine, cisplatin and TAM (FCT regimen) to 69 patients with metastatic melanoma. Fotemustine (100 mg/m2) and cisplatin (100 mg/m2) were administered every 4 weeks, preceded by TAM 160 mg daily for 7 days from the second course onwards. Pharmacokinetic blood sampling was performed in 14 patients during the initial two cycles to compare the pharmacokinetic behaviour of fotemustine with or without TAM. Previous chemo- or radiotherapy was allowed, and patients with brain metastases or concomitant other malignancies were included. Four complete and 11 partial responders were observed among 66 evaluable patients, yielding a response rate of 22.7% (95% confidence interval 12.9 32.5%). The median survival time was 6.4 months (range 0.1-52+ months). The main toxicities were thrombocytopenia, protracted nausea/vomiting and ototoxicity. Renal toxicity was generally mild, but possibly contributed to two deaths. Seven patients experienced deep venous thrombosis during the study. TAM had no influence on the pharmacokinetics of fotemustine. The activity of the FCT regimen was clearly inferior to that initially reported with DBCT treatment. However, a recent publication concludes that the latter achieves a considerably lower response rate when administered to a larger patient group. We believe our results reflect the true activity of FCT and similar regimens when administered routinely to unselected patients. Considering the number of potentially serious side effects, we cannot recommend the moderately active FCT regimen as a palliative treatment option for melanoma patients.

[The biochemical mechanisms of the action of N-alkyl-N-nitrosoureas. The possible reasons for drug resistance to these compounds]. / Biokhimicheskie mekhanizmy deistviia N-alkil-N-nitrozomochevin. Vozmozhnye prichiny lekarstvennoi ustoichivosti k étim soedineniiam.

N-alkyl-N-nitrosoureas exhibit a wide spectrum of antitumor activity. They react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and 06 of guanine. The formation and persistence of 0(6)-alkylguanine (0(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas. 0(6)-AG adducts of DNA of the tumor cells are repaired by protein 0(6)-alkylguanine-DNA transferase (0(6)-AGT) which transfers the alkyl group to internal cysteine residue being the acceptor protein for the alkyl group in an irreversible transfer reaction. 0(6)-AGT can protect the tumor cells against 0(6)-AG adducts by the way of inhibiting the formation of the DNA interstrand cross-links 0(6)-AGT plays an important role in the drug resistance because it repairs the DNA alkyl adducts at the 0(6) position of guanine. The 0(6)-AGT activity inversely correlates with the cytotoxic effect of the nitrosoureas. The agents like 0(6)-methylguanosine, 0(6)-methyl-2'-deoxyguanosine, and some 0(6)-benzylated guanine derivatives are effective inactivators of 0(6)-AGT, and thus can be used to enhance the cytotoxicity of N-nitrosoureas. The activation of 0(6)-AGT and other repairing enzymes such as alpha and beta DNA-polymerases as well as an increase in the level of reduced glutathione may be used in developing the resistance to the nitrosoureas.

Pharmacokinetics and pharmacodynamics of nitrosourea fotemustine: a French cancer centre multicentric study.

The nitrosourea, fotemustine, was given intravenously in 1 h constant-rate infusion to 66 patients in a multicentric study to assess both fotemustine pharmacokinetic behaviour and the pharmacokinetic-pharmacodynamic relationships. Depending on the tumour type treated, two administration and sampling protocols were used: 100 mg/m2/week as a conventional dose (six samples, 44 patients) and 300-500 mg/m2/day as a high dose (10 samples, 22 patients). The 91 time-concentration curves were best described by either a one-(55) or a two-compartment (36) model, and their mean clearance values did not differ significantly (85.3 +/- 6.5 and 101.3 +/- 9.5 l/h, respectively, P = 0.1727). Fotemustine pharmacokinetics were not influenced by repeated treatment (time-independence) nor by dose level (dose-independence). The pharmacodynamic effect observed on white blood cell count was expressed by a logit regression model involving the area under the curve mainly and the total administered dose. White blood cell toxicity could be predicted as a function of the dose for a given patient with a known fotemustine clearance value.

Chromosome aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose.

Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130 mg/m2 or 40 mg/m2 on 3 consecutive days. Peak plasma concentrations (mean +/- SD) were obtained at a similar time after both treatments, i.e., at 38 +/- 25, 32 +/- 24, 28 +/- 14, and 40 +/- 26 min after administration of 130 mg/m2 on day 1 and after that of 40 mg/m2 on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40 mg/m2 x 3 was similar to that noted after treatment with a single dose of 130 mg/m2, i.e., 180 and 179 micrograms min ml-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40 mg/m2 producing 5.5% CAs and 130 mg/m2 yielding 20.9% CAs at 24 h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180 +/- 62.8 and 179 +/- 115 micrograms min ml-1, respectively.

[Intratumoral pharmacokinetics following intraarterial administration of MCNU in patients with malignant gliomas].

This clinical study was undertaken to examine intratumoral (i.t.) pharmacokinetics after intraarterial (i.a.) administration of MCNU (80mg/m2) in 5 patients with glioblastoma (GB) and 2 with anaplastic astrocytoma (AA). After resection or stereotactic biopsy of the cystic lesion, an Ommaya reservoir was placed into the tumor cavity in all patients. The distribution of MCNU in blood was compatible with a two-compartment model, and the half life of the alpha-phase and beta-phase was 4.1 minutes and 160.4 minutes, respectively. MCNU was detected in the i.t. fluid in 5 cases, 4 of GB and 1 of AA. The concentration of i.t. MCNU gradually increased during the 5 to 30 minutes after i.a. injection to a level about 20.0% of its blood concentration. However, no MCNU was detected in patients showing partial response (3 of GB and 1 of AA) or no change (1 of GB) after the i.a. infusion of MCNU during maintenance chemotherapy. These results suggests that MCNU may transfer into the tumor tissues. Further investigation is warranted.