Fotemustine in the Treatment of Brain Primary Tumors and Metastases

Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma.

In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intra-arterially, with 10 objective responses observed among 26 evaluable patients.

In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising.

In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%.

Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.     

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.     

A phase II study of the sequential administration of dacarbazine and fotemustine in the treatment of cerebral metastases from malignant melanoma

34 patients with cerebral metastases from malignant melanoma received sequential dacarbazine at 250 mg/m² followed 2 h later by foteraustine at 100 mg/m²; this was repeated on day 8. Maintenance therapy was given every 4 weeks to patients with radiological evidence of response or stable disease until a maximum response was achieved plus two more cycles. A 12% response rate was obtained for cerebral metastases, with 2 complete responses lasting 12 and 36+ months, and 2 partial responses lasting 2.5 and 3.75 months. Toxicity was mainly haematological with grade 3–4 leucopenia and thrombocytopenia in 23.5% of patients. No pulmonary toxicity was seen. This schedule of sequential dacarbazine and fotemustine has low activity against metastatic melanoma, and the response rate for cerebral metastases is not superior to that shown in other studies with single agent fotemustine, but the treatment was well tolerated and can be delivered on an outpatient basis.     

Chemotherapy by fotemustine in cerebral metastases of disseminated malignant melanoma

Summary A total of 42 patients with cerebral metastases of malignant melanoma were included in this study of the nitrosourea fotemustine. The treatment plan consisted of a 1-h i. v. infusion of 100 mg/m² fotemustine every week for 3–4 weeks, followed by a 4- to 5-week rest period. Responding or stabilised patients then received 100 mg/m² fotemustine every 3 weeks. Among the 39 evaluable patients, 2 complete responses and 9 partial responses were documented, leading to an overall response rate of 28.2%. Most of the responses were obtained in previously untreated patients and/or those presenting with a single cerebral metastasis. Toxicity was mild and mainly hematological, especially in patients previously treated by polychemotherapeutic regimen. Our study confirms the activity of fotemustine in cerebral metastases of disseminated malignant melanoma.Others institutions involved in this trial: A. Bernadou, Hôtel Dieu, Paris; J. Clavier, CHR de Brest; M. Delaunay, Hôpital Pellegrin Tripode, Bordeaux; J. P. Escande, Hôpital Tarnier, Paris; P. Fargeot, Centre George François Leclerc, Dijon; P. Lauret, Hôpital Charles Nicolle, Rouen; R. Leblay, Hôpital Sud, Rennes; P. Litoux, CHR de Nantes; G. Lorette, Hôpital Trousseau, Tours; R. Metz, Centre Alexis Vautrin, Nancy; A. Monnier, CHR Boulloche, Montbelliard; M. Mousseau, CHR de la Tronche, Grenoble; J. P. Olivier, Hôpital Dupuytren, Limoges; R. Touraine, Hôpital Henri Mondor, Créteil; F. Truchetet, Hôpital de Thionville, France     

Fotemustine (S 10036) in the intra-arterial treatment of liver metastasis from malignant melanoma. A phase II Study

Fotemustine is a new nitrosourea which has shown some efficacy on disseminated malignant melanoma (DMM) (24.2% response rate (RR) among 153 patients in a Phase II trial) but little activity on hepatic metastasis (8.8% RR). In order to improve those poor results, hepatic intra-arterial infusion (HIAI) of fotemustine was performed. After two years, thirteen patients, all in good general condition, were evaluable. Seven were pretreated and six had extrahepatic metastasis on entry into the study. All patients had a surgically implanted intra-arterial catheter. The induction cycle consisted of 100 mg/m2/week for 3-4 weeks, followed by 5 weeks rest and maintenance therapy of 100 mg/m2 every 3 weeks for stabilized or responding patients. Two complete responses (CR) (72+ and 145+ weeks) and six partial responses (PR) (7-18.5 weeks) were observed. The hepatic RR reached 61.5%. A RR of 42.8% was registered on preexisting EHM (one CR and one PR on cerebral lesions). Nevertheless, this treatment is limited by the high progression rate of 46.1% in extrahepatic disease. Toxicity was mainly hematologic (grade III-IV), comprising 36% neutropenia and 15% thrombopenia. Hepatic intra-arterial infusion of fotemustine is efficient therapy for liver metastases of DMM, but combination schedules (IV + HIA) are warranted.     

A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma

The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.     

Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma]

PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.     

Treatment of metastatic malignant melanoma with dacarbazine plus fotemustine

Despite the poor prognosis of metastatic malignant melanoma, polychemotherapy with dacarbazine and fotemustine has shown promising results in several studies. We report on the clinical efficacy of a new sequential administration regimen with dacarbazine at a dose of 200 mg/m2 followed 24 h later by fotemustine 100 mg/m2 every 4 weeks in 63 patients with metastatic melanoma. A complete response was noted in 3 patients (5%), a partial response in 4 patients (6%), stable disease in 33 patients (5%) and progressive disease in 23 patients (37%). The duration of the 3 complete responses was 5, 14+ and 60+ months, for the 4 partial responses, 3, 4, 6 and 13 months. The median duration for stable disease was 4 months. The best response rates were obtained for lung and lymph node metastases. Toxicity was mild and mainly limited to haematological without pulmonary side-effects. Although there was a relatively low objective response rate, this chemotherapy regimen as a palliative treatment, is potentially valuable for patients with progressive stage IV melanoma.     

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.     

Phase II trial of recombinant tumor necrosis factor in disseminated malignant melanoma.

Twenty-one patients with disseminated malignant melanoma received recombinant tumor necrosis factor (TNF), 150 micrograms/m2 intravenously on days 1-5 every 2 weeks for four cycles and then every 3 weeks. Recombinant TNF produced no meaningful palliation. One patient (5%) attained an objective response of nodal, but not visceral, disease, which lasted 3 weeks. The median time to progression was 4 weeks. The median survival was 7.7 months. Ninety percent of patients developed mild to severe cytokine "flu." Ten percent developed significant hepatic toxicity (AST greater than 3 times normal). As a single agent, recombinant TNF is not likely to palliate disseminated malignant melanoma. However, combinations of recombinant TNF and cytotoxic or immune modulatory agents, particularly gamma interferon, may merit further investigation.     

High-dose Roncoleukin in patients with disseminated cutaneous melanoma: a phase 1 study

High doses of recombinant interleukin-2 (rlL-2) have been shown to provide clinical effect and long-term survival in patients with malignant melanoma. We have performed a phase 1 study of rIL-2 "Roncoleukin", produced in Saccharomyces cerevisiae. Twenty six patients with disseminated malignant melanoma received from 12 up to 108 millions international units (MIU) of IL-2 as 3-hour i.v. infusions days 1-5 of the 21-day cycle. From 2 to 6 patients were included on each dose level. Response was assessed according to RECIST criteria. Twenty two patients were available for response and 26 for toxicity; 68 cycles of therapy performed. No grade 4 toxicity or toxic death occurred. Main dose limiting toxicity was cardiologic, skin and constitutional (fever) symptoms. One hundred and eight MIU of "Roncoleukin" was considered the highest tolerable dose because of grade 3 toxicity in 2/2 patients, receiving this dose. One complete response (CR) and 2 partial responses (PR) were observed at dose levels of 72 MIU (1 CR and 1 PR) and 84 MIU (1 PR). 3/4 objective responses were in patients with metastases in soft tissues and lymph nodes. Overall response rate was 13.7%. "Roncoleukin" provide certain efficiency in patients with malignant melanoma. This drug has acceptable toxicity; the maximum tolerable dose is 108 MIU. Recommended dose for phase 2 clinical trails is 72 MIU.     

Pilot study of hepatic intraarterial fotemustine chemotherapy for liver metastases from uveal melanoma: a single-center experience with seven patients

Background. Uveal melanoma is characterized by a high frequency of hepatic metastases. For patients with liver metastases, who have a median survival of 5 to 7 months, surgery and systemic conventional chemotherapy have little to offer. Methods. Between February 1995 and July 1999, seven patients with isolated hepatic metastases from uveal melanoma were enrolled into a pilot trial of intraarterial fotemustine therapy. An implantable Port-A-Cath catheter was inserted into the hepatic artery for regional chemotherapy via the gastroduodenal artery. Fotemustine 100 mg/m² was administered intraarterially over a 4-h period. The induction phase consisted of one administration per week for 4 weeks, followed by a 5-week rest period. Maintenance therapy with administration of fotemustine every 3 weeks continued until progression or toxicity. Results. Ten patients were evaluated for the trial. One patient was not eligible because of impaired liver function, and in two patients implantation of the port system was not possible for anatomic reasons. Seven patients received a median of 16 treatment cycles (range, 4–28) and all were evaluable for response. Two patients achieved a partial response (PR), three had stable disease (SD), and tumor progressed in two patients (PD). The median survival time from diagnosis of liver metastasis was 24 months (range, 4 to 50+ months). Two patients survived for more than 2 years and two patients are still alive. The toxicity was low and the treatment could be administered on an outpatient basis. Conclusion. Intraarterial fotemustine treatment of uveal melanoma metastatic to the liver is well tolerated, and in some patients is associated with prolonged survival. Received: May 22, 2000 / Accpted: October 13, 2000     

Dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A phase I-II trial

Dacarbazine-vindesine-cisplatin treatment was evaluated in a phase II study of patients with disseminated malignant melanoma after the dose of cisplatin had been determined in a phase I study. Dose of dacarbazine was 250 mg/m2 X V every 4 weeks, vindesine 3 mg/m2 once every week, and cisplatin 100 mg/m2 every 4 weeks. Forty patients with advanced disseminated malignant melanoma are available for response. Complete remissions were obtained in three patients (8%) and partial remissions in 12 patients (30%). The total response rate was 38%. Median response duration was 4 months. Toxicity was unacceptable in five cases (nephrotoxicity, one patient; ototoxicity, two patients; hypotonia, one patient; gastrointestinal toxicity, one patient). The conclusion is that the combination dacarbazine-vindesine-cisplatin gives rise to a high response rate in patients with advanced disseminated malignant melanoma. Despite its considerable toxicity, the regimen should be tested on patients with a limited tumor burden.     

Temozolomide in combination with fotemustine in patients with metastatic melanoma

Purpose  Temozolomide and fotemustine are both active drugs for treating metastatic melanoma. The present study was designed to assess the efficacy and safety of combination therapy with temozolomide + fotemustine in patients with metastatic melanoma. Methods  Forty patients (median age 50.5 and 22 males) with pathologically confirmed, unresectable, AJCO stage IV melanoma were enrolled into the study. The primary endpoints were tumor response and safety. Patients received oral temozolomide 125 mg/m² on days 1–7 and intravenous fotemustine 80 mg/m² on day 3 every 3 weeks. Results  Fourteen (35%) patients achieved an objective response, including 3 (7.5%) complete and 11 (27.5%) partial responses. Median overall survival time was 6.7 months and 6-month survival rate was 57.4%. Myelosupression, particularly thrombocytopenia, was the primary toxicity. Conclusion  The regimen, temozolomide combined with fotemustine, is an active and moderately safe first-line chemotherapy regimen with acceptable and easily manageable toxicities in patients with metastatic melanoma.     

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

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). Treatment consisted of fotemustine 100 mg m-2 administered on days 1 and 8 followed by a 5 week rest period. Afterwards, responding or stabilised patients received fotemustine 100 mg m-2 every 3 weeks as a maintenance therapy. Toxicity and quality of life were recorded during therapy. Thirteen patients (17%; 95% CI 9-25%) had an objective response (11% for pretreated, 26% for non-pretreated) with a median duration of 22 weeks (range 7-41 weeks). Two objective responses were observed among the 12 patients with evaluable brain metastases. No response was observed among the 14 patients with adenocarcinoma. Haematological, gastrointestinal, hepatic and renal toxicities were mild to moderate and manageable. The most frequent biological adverse reactions were delayed thrombocytopenia and neutropenia. Quality of life did not significantly decrease during the first 6 treatment weeks. Moreover, it remained stable during the study period in patients with response or stabilisation, whereas it significantly decreased in patients who experienced progression of the disease. Fotemustine is feasible for single-drug chemotherapy in non-small-cell lung cancer even though poor prognostic variables such as brain metastases are present. It can be administered on an outpatient basis and toxicity is moderate and manageable. Thus, fotemustine can be considered as a putative drug in further combinations.     

A clinical trial of intravenous vinorelbine tartrate plus tamoxifen in the treatment of patients with advanced malignant melanoma

BACKGROUND: The aim of the current trial was to assess the efficacy and toxicity of weekly intravenous vinorelbine tartrate with daily oral tamoxifen in the treatment of patients with advanced or metastatic malignant melanoma. METHODS: Thirty-one patients were treated with vinorelbine tartrate, 30 mg/m(2) intravenously, weekly every 13 weeks and then every 2 weeks thereafter until progression of disease or severity of toxicity warranted discontinuation. Tamoxifen, 10 mg orally, twice a day was administered daily starting on Day 1 of chemotherapy with vinorelbine tartrate. Thirty patients had cutaneous melanoma with metastases and 1 patient had ocular melanoma with metastases. Eight patients had received prior chemotherapy. RESULTS: Of the 30 evaluable patients with cutaneous melanoma, 6 achieved a partial response, for an overall response rate of 20% (95% confidence interval, 7-38%). There was no response in the patient with ocular melanoma. Major sites of response include the adrenal gland, lung, tonsil, and cutaneous/subcutaneous tissues. Three patients had a prolonged duration of response lasting > or = 12 months. Side effects generally were mild and tolerable. Grade 3 or 4 hematologic toxicity occurred in 26% and 13% of patients, respectively. Nonhematologic toxicity included mild fatigue, paresthesia, and local arm discomfort from infusion. CONCLUSIONS: Weekly intravenous vinorelbine tartrate plus daily oral tamoxifen appears to be active in the treatment of patients with malignant melanoma. Further clinical trials in malignant melanoma patients treated with vinorelbine tartrate and tamoxifen appear warranted.     

Combination of cisplatin, vindesine, and dacarbazine in advanced malignant melanoma. A Phase II Study of the EORTC Malignant Melanoma Cooperative Group

A Phase II study combining cisplatin, vindesine, and dacarbazine was performed on patients with disseminated malignant melanoma by the European Organization for Research and Treatment of Cancer (EORTC) Malignant Melanoma Cooperative Group (MMCG). The treatment consisted of intravenous administrations of dacarbazine 450 mg/m2, vindesine 3 mg/m2, and cisplatin 50 mg/m2 on day 1 and 8 of each course. Courses were repeated every 4 weeks. Treatment was discontinued in case of progression after two courses, otherwise continued until progression or for a minimum of six courses. One hundred five patients entered the trial with 92 patients being evaluable. The response rate calculated after clearance by the Extramural Review Committee shows four complete and 18 partial responses, i.e., 24%, with a median remission duration of 23 weeks. Toxicity and subjective tolerance to this regimen were moderate, requiring 140 modifications of 642 administrations (22%). Main toxicities were nausea and vomiting (95%), leucopenia (70%), alopecia (56%), peripheral neuropathy (32%), and nephrotoxicity (17%). The discussion emphasizes some particular points of interest in the management of advanced malignant melanoma.     

替莫唑胺与福莫司汀治疗恶性脑胶质瘤的临床观察

目的:比较替莫唑胺(TMZ)与福莫司汀(Fotemustine)治疗恶性脑胶质瘤的疗效、生存期及不良反应。方法:56例首次术后脑胶质瘤患者随机分为TMZ组和福莫司汀组各28例,两组患者均给予常规放疗,2Gy/d,5d/w,共持续6-7w,射线总剂量60-66Gy。放疗结束后1周开始化疗。TMZ组在放疗期间每日口服替莫唑胺75mg/m2,放疗结束后4周,继续口服TMZ(150-200)mg/(m2.d),5d/w,每5天为1个疗程,每疗程间隔23天,28天为1个治疗周期,根据患者耐受情况给药4-6个周期。福莫司汀组给予100mg/m2静脉滴注,每周1次连续3周,停药5周,维持期治疗每3周静脉注射1次,共4-6次。结果:TMZ组近期疗效(CR+PR)明显优于福莫司汀组(78.6%vs 50%,P<0.05);TMZ组1、2、3年生存率分别是71.4%(20/28)、39.3%(11/28)、28.6%(8/28),中位生存期22个月。Fotemustine组1、2、3年生存率分别是57.1%(16/28)、32.1%(9/28)、17.9%(5/28),中位生存期12个月。两组比较无显著差异(P>0.05),但有提高生存率的趋势。TMZ组恶心、呕吐及骨髓抑制程度明显低于福莫司汀组(P<0.001),而急慢性脑损伤无显著性差异(P>0.05)。结论:TMZ比福莫司汀可更明显地缩小肿瘤体积,提高近期疗效,有延长患者生存期的趋势,不良作用少,值得临床推广应用。     

Combination chemotherapy of dacarbazine and fotemustine in disseminated malignant melanoma

Summary A total of 70 patients presenting with a disseminated malignant melanoma were entered into a multicentric study of combination chemotherapy using dacarbazine and fotemustine. In all, 63 patients were evaluable, 31.8% of whom had previously received cytotoxic chemotherapy. The protocol consisted of induction treatment with a weekly infusion of 100 mg/m² fotemustine on days 1 and 8 and a daily infusion of 250 mg/m² dacarbazine on days 15/18 followed by a 4- to 5-week rest period. Responding and stabilized patients were given maintenance treatment comprising fotemustine (100 mg/m², day 1) and dacarbazine (250 mg/m², days 2/5) every 3 weeks. The response rate was 33.3% (9 complete responses (CRs) and 12 partial responses (PRs)) and was outstanding among pretreated patients (34.9%). Responses were also documented in cerebral (28.6%), visceral (23.1%) and nonvisceral (43.3%) metastatic sites. Toxicity was mainly hematologic (22.2%, grade III/IV leukopenia; 20.3%, grade III/IV thrombocytopenia) and was acceptable. These results are encouraging in terms of the antitumor activity against nonvisceral metastases (43.3%) and the percentage of CRs obtained (23.3%), and they confirm the activity of fotemustine in cerebral metastatic sites.Other investigators involved in this trial included B. AUDHUY, CHR Louis Pasteur, Colmar; A. BERNADOU, Hôtel Dieu, Paris; J. J. BONERANDI, Hôpital Ste Marguerite; F. DANIEL, Hôpital St Joseph. Paris; P. FARGEOT, Centre Georges François Leelerc. Dijon; Pr KALIS, Hôpital Sébastopol, Reims; B. LABEILLE, Hôpital Sud, Amiens; P. LAURET, Centre Henri Becquerel, Rouen; P. LTTOUX, Hôtel Dieu, Nantes; G. LORETTE, Hôpital Trousseau, Chambray les Tours: R. METZ, Centre Alexis Vautrin, Vandoeuvre les Nancy; M. MOUSSEAU, CHR de la Tronche, Grenoble; J. L. VERRET, CHR, Angers, France     

Results of a phase II trial with cystemustine at 90 mg/m(2) as a first- or second-line treatment in advanced malignant melanoma: a trial of the EORTC Clinical Studies Group

From May 1991 to January 1996, 54 patients with advanced malignant melanoma were enrolled into a phase II trial testing the new nitrosourea cystemustine, administrated intravenously as a 15 min infusion every 2 weeks at 90 mg/m2 for three cycles followed by 60 mg/m2. Out of the 54 enrolled patients, 10 were Ineligible, leaving 44 fully evaluable patients (World Health Organization criteria). Twenty one patients had already received first-line palliative chemotherapy and/or immunotherapy. The median age was 62 years (range 30-74 years) and the median performance status was 0 (grade 0, 19 patients; grade 1, 21 patients; grade 2, 4 patients). Five patients with partial responses (lasting 16-29 weeks, mean duration 24 weeks), nine with stable disease and 28 showing progression were observed, giving an overall response rate of 11% (confidence interval 3.8-24.6%). Toxicity was mild and consisted mainly of neutropenia (39% grade III-IV), thrombocytopenia (42% grade III-IV); febrile aplasia was rare. Cystemustine administered to this schedule appears to have limited clinical activity and acceptable toxicity in untreated or second-line advanced malignant melanoma.