Phase II study of fotemustine in recurrent supratentorial malignant gliomas

Frénay, Marc; Giroux, B.; Khoury, Simon; Derlon, Jean-Michel; Namer, M.

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

Cited by 54 publications

(29 citation statements)

References 7 publications

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“…However, the two cases of interstitial pneumonitis in our study received a cumulative dosage of < 400 mg m-2 of fotemustine suggesting that the synergy between DTIC and fotemustine (as used in the schedule here) may be responsible for the acute pulmonary event, possibly related to greater cytotoxicity in normal lung cells following depletion of the endogenous ATase. A recent phase II study of fotemustine alone in 153 patients with disseminated melanoma was not associated with any pulmonary toxicity and similar finding was reported in another 38 patients with gliomas treated with fotemustine alone (Jacquillat et al, 1990;Frenay et al, 1991). Lung tissue has a relatively low ATase activity in comparison with other tissues (Grafstrom et al, 1984;Gerson et al, 1986) and as a result they may be more sensitive to the cytotoxic effects of DNA alkylation.…”

Section: Discussionmentioning

confidence: 57%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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Summary There is increasing experimental evidence to suggest that expression of 06-alkylguanine-DNAalkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the 06-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m') at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800mg m2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.

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Section: Discussionmentioning

confidence: 57%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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“…Because of the potential lung toxicity of carmustine, lomustine has been used in combination regimens (e.g., PCV). Fotemustine (Muphoran ® ; Servier SA, France), a chloroethylnitrosourea with high lipophylicity, is administered intravenously and is more frequently used in France [61,62]. For nimustine, data as first-line therapy in conjunction with RT are available only from Japan and Germany [21,[63][64][65].…”

Section: Approved or Older Agentsmentioning

confidence: 99%

Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma

Stupp

Hegi

Bent³

et al. 2006

The Oncologist

371

241

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Learning ObjectivesAfter completing this course, the reader will be able to:1. List the different major subtypes of glioma and identify the appropriate treatment strategies for patients with high-grade and low-grade gliomas.2. Discuss the available evidence for the treatment of newly diagnosed glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma.3. Identify approved agents and other active or investigational agents used to treat patients with newly diagnosed and recurrent glioma. shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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“…This cytotoxic drug induced a 24% objective response (OR) rate in a phase II study of fotemustine as a single-drug therapy in disseminated malignant melanoma (Jacquillat et al, 1990a), including patients with brain metastases (Jacquillat et al, 1990b). This drug has also been reported to be active in primary brain tumours (Frenay et al, 1991). In a previous phase II study, we tested fotemustine in the treatment of squamous cell carcinoma using the 100 mg m-2 dosage on a day 1, 8 and 15 regimen followed by a 5 week rest period, with maintenance therapy thereafter consisting of a course of 100 mg m-2 every 3 weeks (Le Chevalier et al, 1989).…”

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confidence: 99%

Phase II study of nitrosourea fotemustine as single-drug chemotherapy in poor-prognosis non-small-cell lung cancer

Pujol

Monnier²,

Bérille³

et al. 1994

Br J Cancer

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A phase II study was designed to evaluate objective response rate and toxicity of fotemustine as single-drug chemotherapy in non-small-cell lung cancer. Eighty-seven patients with unresectable non-small-cell lung cancer took part in the study. Seventy-seven were evaluable for response. Of these, 60% had received prior chemotherapy and 74% had metastatic disease. Moreover, 22 patients had central nervous system metastases (of whom 12 were evaluable for this site). Chemotherapy is still an experimental treatment in a majority of patients with non-small-cell lung cancer (NSCLC) (Hansen, 1988). Combinations of cisplatin and vinca alkaloids induce a survival improvement in unresectable NSCLC when compared with best supportive care. However, the ratio of the benefit in duration of survival to the benefit in quality of life (QL) might be suboptimal owing to the high frequency of toxic events induced by cisplatinbased regimens. Among NSCLC patients, those who relapse after first-line chemotherapy or those presenting central nervous system metastases are considered to have poor prognosis and are usually ineligible for cisplatin-based therapy. Thus, a search for new drugs is required in an attempt to obtain a survival advantage without inacceptable toxicity, particularly in patients with poor-prognosis NSCLC.Fotemustine, a new amino acid phosphonate derivative of the nitrosourea group, has been recently introduced in the treatment of human solid malignancies (Avril et al., 1990;Jacquillat et al., 1990a). This cytotoxic drug induced a 24% objective response (OR) rate in a phase II study of fotemustine as a single-drug therapy in disseminated malignant melanoma (Jacquillat et al., 1990a), including patients with brain metastases (Jacquillat et al., 1990b). This drug has also been reported to be active in primary brain tumours (Frenay et al., 1991). In a previous phase II study, we tested fotemustine in the treatment of squamous cell carcinoma using the 100 mg m-2 dosage on a day 1, 8 and 15 regimen followed by a 5 week rest period, with maintenance therapy thereafter consisting of a course of 100 mg m-2 every 3 weeks (Le Chevalier et al., 1989). An OR rate of 12% was observed but the treatment was associated with a 30% grade IV thrombopenia toxicity. It has been observed, in a more recent study of fotemustine 100 mg m-2 in melanoma, that the day 1, day 8 schedule is well tolerated with a similar efficacy (Avril et al., 1990 We report herein a French multicentre phase II study on fotemustine on day 1 and day 8 in patients with poorprognosis advanced NSCLC. Patients and methods Eligibility criteriaPatients of both sexes with histologically proven and unresectable NSCLC were entered. Inclusion criteria were: age below 75 years; Karnofsky index > 60%; baseline leucocytes 4,000 ttl' or more, neutrophils 2,000 pl`' or more and platelets 150,000 l-1 or more; bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) lower than twice the normal upper limits; meas...

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Phase II study of fotemustine in recurrent supratentorial malignant gliomas

Cited by 54 publications

References 7 publications

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma

Phase II study of nitrosourea fotemustine as single-drug chemotherapy in poor-prognosis non-small-cell lung cancer

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