Phase II study of fotemustine in recurrent supratentorial malignant gliomas

doi:10.1016/0277-5379(91)90133-X

European Journal of Cancer and Clinical Oncology

Volume 27, Issue 7, July 1991, Pages 852-856

European Journal of ...

https://doi.org/10.1016/0277-5379(91)90133-X Get rights and content

Abstract

38 adults with recurrent supratentorial malignant gliomas, including glioblastoma multiforme (21), anaplastic astrocytomas (9), probably transformed low-grade astrocytomas (6), pinealoblastoma (1) and non-metastatic tumour of unknown histology (1), were treated with fotemustine 100 mg/m² intravenously every week for 3 consecutive weeks followed by a 5-week rest period. Maintenance treatment consisted of one infusion every 3 weeks. Patients were divided into three groups according to treatment effect. 10 objective responses (26%) with a median time without progression of 32.7 weeks, 18 stabilisations (47%) and 10 failures (26%) were observed. Pathological findings of the initial primary tumour and neurological functional status were unequally distributed in these groups. Haematological and liver toxicities were mild, delayed, transient and reversible. Thrombocytopenia and leukopenia were more frequent (30%) in patients treated with prior chemotherapy. Fotemustine is a well tolerated active drug in recurrent malignant gliomas with an original and short treatment schedule.

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Citation Excerpt :
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The persisting reservation against the use of chemotherapy in patients with malignant glioma was finally overcome by the breakthrough achieved with the use of the oral alkylating agent temozolomide (TMZ) as concomitant and adjuvant chemotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). The basic condition for an effective systemic drug therapy against malignant glioma is that the drug be able to cross the blood–brain barrier (BBB) and the brain–tumor barrier. Drugs crossing the BBB have to be nonpolar, small molecules with a molecular weight of less than 500 Da, to bear no electrical charge, or to be able to use active transport mechanisms, as the BBB is functional in the peripheral growing areas of GBM. The prerequisite of liposolubility is best achieved by a group of drugs termed alkylating agents; nitrosoureas were the agents used most historically, until the now most widely used drug, TMZ, became available.
All alkylating agents share a common molecular mechanism of action, which is by nature cytotoxic, mutagenic, and carcinogenic. They differ greatly in their pharmacokinetic features and liposolubility, and thus also in the pattern of toxicities observed, such as myelosuppression, induction of secondary tumors, impact on fertility in both sexes, and induction of nausea and vomiting. The effectiveness of alkylating chemotherapy in tumors of glial origin depends on the DNA repair capacity of the individual tumor – most precisely on the intracellular presence of the DNA repair enzyme MGMT (O⁶-methylguanine-DNA methyltransferase). The promoter of the gene encoding for MGMT may be silenced by epigenetic methylation; in this case, the tumor responds to alkylating therapy. At the time of writing, it is not clear whether prolonged exposure to alkylating chemotherapy succeeds in depleting MGMT in tumor cells and might thus produce a response in patients whose tumor cells have an unmethylated MGMT promoter sequence.
The most prominent clinically relevant side-effect is myelosuppression, most pronounced for white blood cells and platelets, less for red blood cells. ACNU (nimustine), BCNU (carmustine), and CCNU (lomustine) are nitrosourea drugs that have been used for the treatment of brain tumors for more than 40 years. Their most prominent side-effect is delayed myelosuppression, with the nadir occurring 5–6 weeks after drug administration. This long delay to the occurrence of the dose-limiting side-effects of leukocytopenia and thrombocytopenia demands special attention for controls and complicates the use of drug combinations. For TMZ, the risk of severe myelosuppression in the standard dosage is around 7% for thrombocytopenia and for leukocytopenia. With increasing duration of TMZ use, the rate of lymphopenia, selective for CD4 lymphocytes, increases, with up to 47% encountered in the 21/28 schedule. When the CD4 count drops below 200/mm³ or the total lymphocytes decrease to less than 400/mm³, there is a significant risk of opportunistic infection, such as Pneumocystis carinii pneumonia, herpes zoster, Kaposi sarcoma, or reactivation of herpes or hepatitis B infection. In analogy to patients with HIV/AIDS, P. carinii prophylaxis with trimethoprim or monthly pentamidine inhalations is strongly recommended during concomitant chemotherapy and/or for patients with lymphocyte counts below 400/mm³.
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Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group
2011, Annals of Oncology
Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood–brain barrier has demonstrated preclinical activity in glioma models.
Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m² over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.
Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3–18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3–12.3), with a 1-year survival rate of 31.6% (95% CI 17.7–46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.
No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.
Turcot's syndrome confirmed by molecular biological tests
2006, Revue Neurologique
Le syndrome de Turcot est un syndrome clinique, présumant d’une susceptibilité génétique aux cancers, qui associe des tumeurs cérébrales primitives et une polypose colique familiale ou des cancers colo-rectaux.
Nous rapportons le cas d’une patiente âgée de 45 ans qui fut prise en charge en 1995 pour un astrocytome anaplasique selon la classification de l’OMS. Elle eut une séquence thérapeutique complète dès la présentation : chirurgie d’exérèse complète, radiothérapie, chimiothérapie de première (nitroso-urées) et seconde lignes (sels de platine). La reprise de l’anamnèse mit en évidence l’existence d’un cancer du côlon chez son frère âgé de 41 ans. Une analyse génétique de la patiente, réalisée à la recherche d’un syndrome de Turcot, montra une mutation du gène hMSH2, spécifique du syndrome HNPCC (Human Non Polyposis Colorectal Cancer). La colonoscopie était normale. La patiente décéda plus de 7 ans après le diagnostic, d’une gliomatose cérébrale diffuse.
Le syndrome de Turcot doit être recherché devant une histoire personnelle ou familiale évocatrice. II modifie la prise en charge du patient et de sa famille et est probablement sous-estimé.
Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer.
We report a case of a 45-year-old woman who underwent in 1995 neuro-oncological treatment for an anaplastic astrocytoma (grade III according to the World Health Organization classification). Treatment included complete surgery, radiotherapy, a first-line nitrosourea-based chemotherapy regimen and a second-line platinium salt-based regimen. It was then noted that the patient's brother had colorectal cancer. A genetic study detected a germ-line mutation on the hMSH2 gene specific of HNPCC syndrome (Human Non Polyposis Colorectal Cancer). Colonoscopy was normal. Eight years after the diagnosis, the patient developed a gliomatosis cerebri and died.
Relevant personal and familial history can provide the clue to the diagnosis of Turcot's syndrome. Molecular diagnosis may contribute to appropriate care of affected patients.
High grade gliomas: Anaplastic astrocytomas and glioblastomas
2005, EMC - Neurologie
Les gliomes malins demeurent le problème majeur de la neuro-oncologie, par leur fréquence, leur gravité et les difficultés de traitement qu’ils posent. Les étapes de diagnostic clinique et neuroradiologique sont bien établies et performantes ; la stabilité de ces acquis contraste avec le paradoxe des avancées de la recherche biologique qui demeurent sans conséquence pratique, sinon de susciter une multitude de protocoles de recherche clinique. En neuropathologie des gliomes malins, les nouvelles méthodes d’immunohistochimie et de génétique moléculaire font entrevoir les insuffisances des seuls aspects morphologiques au profit de critères d’ontogenèse cellulaire auquel le neuropathologue n’avait pas accès antérieurement. Ces données de biologie moléculaire et de génétique tumorale sont attendues en routine pour établir des diagnostics précis guidant les stratégies de traitement spécifique de chaque type tumoral. En neurochirurgie, le lien entre l’étendue des exérèses et la durée de survie a été établi et la chirurgie « optimale » aidée par les nouvelles technologies peropératoires est devenu le temps essentiel du traitement initial et parfois de la récidive des gliomes. Surtout, le développement des méthodes de nanoneurochirurgie, d’implantation in situ d’agents cytotoxiques ou immunomodulateurs et les réponses obtenues par ces dépôts ouvrent un champ d’actions thérapeutiques imaginées de longue date, mais demeurées virtuelles faute de disposer des technologies adéquates de mise en œuvre. En radiothérapie, les méthodes d’imagerie, les algorithmes de recalage conformationnel et de dosimétrie ont permis la réduction considérable des effets iatrogènes mais les résultats obtenus sont encore modestes et surtout transitoires. En chimiothérapie, les obstacles pharmacocinétiques, le faible nombre de molécules disponibles et les capacités innées ou acquises des systèmes de chimiorésistance et de réparation des lésions alkylantes sont retenus pour rendre compte de la médiocrité de l’apport objectif pour les patients, mais il y a espoir : des sous-groupes chimiosensibles peuvent être identifiés, de nouvelles molécules (fotémustine, témozolomide) et surtout les antagonistes des boucles de prolifération cellulaire, autocrines et paracrines, font envisager la mise à disposition des cliniciens de nouvelles associations et espérer des complémentarités d’action. Enfin, les multiples possibilités de l’immunothérapie et des thérapies géniques sont en exploration dans des études de phase I et II ; elles tentent de combler cette distance entre les connaissances acquises par la recherche fondamentale et les résultats obtenus en clinique. Au total, les gliomes malins demeurent d’un pronostic très défavorable, mais les avancées des méthodes diagnostiques et thérapeutiques sont certaines ; dès à présent, quelques types tumoraux relèvent de traitements spécifiques qui montrent que ces nouvelles approches dérivées des recherches en oncogenèse sont possibles et valident les théories biologiques qui les sous-tendent.
Malignant gliomas remain a major issue in neuro-oncology, due to their high incidence, their poor prognosis and the challenge of their treatment. Whereas clinical and radiological diagnosis may be easily established on a routine basis via CT or MRI imaging, the gap between the growing understanding of their biology and the lack of any cure benefit for the patients remains a major issue. Neuropathological classification of malignant gliomas is not yet settled, and recent methods based on immuno-histology and molecular genetics provide new data that question the accuracy of pure morphological diagnosis, and modify previous understanding of the morphologically suggested oncogenetic lineage of gliomas. Neurosurgical procedures change: “ total resection” is the aim, and optimal resection of the tumour tissue may be obtained using new per-operative technologies. The development of nano-neurosurgery is already part of many protocols lying upon local depots of cytotoxic or immunomodulatory agents. Radiotherapy has also been improved through three-dimensional dosimetry and conformational irradiation. Chemotherapies have been disappointing, but new drugs and new targets to the autocrine and paracrine loops have initiated an era of combined drug protocols, some to be used via nano-neurosurgical methods and tools. Immunotherapies are currently evaluated either as specific targeting tools or as a true immunological modulation against tumour cells. Gene therapies, after disappointing results of the gancyclovir suicide gene strategy, are now attempting to act upon biological characteristics of tumour cells. In summary, malignant glioma treatments remain unsatisfactory, despite considerable amount of clinical research. This review emphasizes the progress made especially in clinical diagnosis, in understanding the oncogenesis and the biological basis of new ongoing protocols.
Phase II study of fotemustine in patients with advanced ovarian carcinoma. A trial of the EORTC Gynecological Cancer Group
2003, European Journal of Cancer
Citation Excerpt :
The median platelet nadir was 46×109/l (range 16–222×109), including 5 patients with WHO grade 4 toxicity. In spite of promising activity in other chemotherapy-refractory diseases [7–11], fotemustine has shown no activity in advanced ovarian cancer patients in our cohort. It has previously been postulated that resistance to nitrosurea chemotherapy in ovarian carcinoma may be related to high cellular expression of the ATase protein in these tumours [12], which may be of relevance in this respect.
30 patients with advanced ovarian cancer, all platinum pretreated, were treated with an induction cycle of fotemustine. Maintenance therapy was given to 6 patients. No objective response was observed among the 21 evaluable patients. The main toxicities were gastrointestinal, with grade 3 nausea and vomiting reported in 40% of the patients, and haematological, with grade 4 leucopenia reported in 2 patients and grade 4 thrombocytopenia in 5 patients. Therefore, no role has been demonstrated in our cohort for the use of fotemustine, a nitrosourea, in pretreated ovarian cancer.
Clinical and pharmacokinetic phase II study of fotemustine in refractory and relapsing multiple myeloma patients
2003, Annals of Oncology
Citation Excerpt :
The most widely used drug today is melphalan, either by repeated oral administration or as high-dose therapy. Fotemustine is a chloroethylnitrosourea that has demonstrated significant antitumour activity in patients with melanoma and glioma [12, 13], but which has not been tested in patients with multiple myeloma. The toxicity spectrum of this alkylating agent is characteristic, with delayed thrombocytopenia and little or no mucositis.
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.
Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m² on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m² 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.
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.
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.

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Specialist interest articlePhase II study of fotemustine in recurrent supratentorial malignant gliomas

Abstract

Neurol Clin

Chemotherapy for malignant gliomas

J Neurosurg

Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery

N Engl J Med

BCNU—5-fluorouracil combination therapy for recurrent malignant brain tumors

Cancer Treat Rep

Brain tumor chemotherapy: an evaluation of agents in current use for phase II and III trials

Cancer Treat Rep

Chemistry and structure activity studies of the nitrosoureas

Cancer Treat Rep

Antitumor activity of the novel nitrosourea S 10036 in rodent tumors

Anticancer Res

Activity of the nitrosourea fotemustine against a human glioma xenograft in the nude mouse

Phase I clinical study of the new amino acid linked nitrosourea, S 10036, administered on a weekly schedule

Cancer Res

Specialist interest article
Phase II study of fotemustine in recurrent supratentorial malignant gliomas