抗肿瘤新药FOTEMUSTINE的药理和临床

Fotemustine是一种新的亚硝脲类抗肿瘤药物。于1989年11月在法国上市。经动物实验和临床研究证实,本品对多种肿瘤有效,尤其是对恶性黑色素瘤疗效显著。本文就近年来的研究情况对其药效学、药代动力学及临床研究进行了综述。

恶性胶质瘤术后Fotemustine化疗的疗效和毒性评估

４０例手术后确认为恶性胶质瘤患者进行了Ｆｏｔｅｍｕｓｔｉｎｅ化疗，方案为每周一次静脉给药，剂量１００ｍｇ／ｍ＾２，共３周，休息５周后，进行维持期治疗，每３周一次剂量仍为１００ｍｇ／ｍ＾２。定期随访并复查脑ＣＴ／ＭＲＩ，１２周结果，２人完全缓解，９人部分缓解，２２人病情稳定，７人病情恶化；３０月随访，其中死亡１０人，有３０例仍生存。毒性反应有骨髓抑制和胃肠反应，轻度肝功损害，均可停药后自行恢复。

Fotemustine-based therapy in combination with rituximab as a first-line induction chemotherapy followed by WBRT for newly diagnosed primary central nervous system lymphoma: a prospective phase II trial

Objective:This study aimed to evaluate the safety,efficacy,and feasibility of the rituximab,fotemustine,pemetrexed,and dexamethasone(R-FPD)regimen followed by whole-brain radiotherapy(WBRT)for patients with primary central nervous system lymphoma(PCNSL).Methods:A prospective,single-center phase II clinical trial was conducted.Patients with PCNSL newly diagnosed at the First Affiliated Hospital of Zhengzhou University between July 2018 and July 2020 were studied.The R-FPD regimen consisted of rituximab(375 mg/m2 i.v.on D0),fotemustine(100 mg/m2 i.v.on D1),pemetrexed(600 mg/m2 i.v.on D1),and dexamethasone(40 mg i.v.on D1-5).Patients 60 years or younger who showed a complete response(CR)were treated with 23.4 Gy of WBRT after the end of chemotherapy;those older than 60 years with CR were treated with a wait-and-see approach;and those who did not show CR after the 4th cycle of chemotherapy were given salvage WBRT 30 Gy+local tumor field irradiation up to 45 Gy,regardless of age.Results:A total of 30 patients were included.After 2 cycles,the objective response rate(ORR)was 96.5%(28/29,1 CR,27 PR,0 SD,and 1 PD).After 4 cycles,the ORR was 73.1%(19/26,11 CR,8 PR,4 SD,and 3 PD).After WBRT,the ORR was 90.9%(10/11,7 CR,3 PR,and 1 SD).The grade III and IV toxicity responses were mainly leukopenia(20.0%),thrombocytopenia(23.3%),and anemia(10.0%).Conclusions:Fotemustine-based therapy in combination with rituximab chemotherapy followed by WBRT can improve outcomes,providing ORR benefits and favorable tolerability in patients newly diagnosed with PCNSL.

A Phase Ⅱ Study of Fotemustine Plus Dacarbazine with Dendritic Cell Vaccines as First-Line Therapy for Chinese Patients with Advanced Acral Lentiginous Melanoma

Objective： To investigate fotemustine plus dacarbazine （DTIC） with dendritic cell （DC） vaccines on patients with advanced acral lentiginous melanoma （ALM）. Fotemustine is a cytotoxic alkylating agent with a remarkable antitumor activity as single agent but also in association with （DTIC）. DC is the strongest antigen presenting cell which could induce durable clinical responses. Methods： This was a single-center study. Between July 2003 and June 2006, twenty-eight chemotherapy-naive patients of advanced ALM received fotemustine 100 mg/m^2, dr, 12, DTIC 400 mg/d d2-6, DC vaccines subcutaneously dT, 9, 13 repeated every 28 days. Ten HLA-A02＋24＋ patients received vaccines pulsed with melanoma antigen derived peptides, melanoma antigen recognized by T-cells 1 （Mart-i） and S-100. Eighteen patients received DC loaded with allogeneic melanoma lysate. The primary end-point was progression free survival （PFS）. Secondary end-points were overall survival （OS）, overall response rate （ORR） and toxicity. Tumor assessment was performed every 8 weeks and evaluated according to response evaluation criteria in solid tumors （RECIST）. Results： The 15 men and 13 women had a median age of 51 years. 16 patients had stage Mlc disease and 11/16 had liver metastasis. Patients received an average of 3.82±1.25 cycles. Follow-up for the 18 surviving patients ranged from 7-41 months with a median of 12 months. Median PFS was 8.5 months （95% CI： 7.86-15.21） with 12 patients remaining progression free. Only 10 patients died. Median OS was 12 months （95% CI： 10.33-18.24）. ORR （CR＋PR） was 35.7% including 3 complete response （CR） and 7 partial response （PR）. Six patients had disease stable. A total of 19 Grade Ⅲ/Ⅳ toxicities were observed including thrombocytopenia （n=8）, neutropenia （n=5）, fatigue （n=6） and hypersensitivity reaction （n=1）. One patient died of Grade IV thrombocytopenia. Conclusion： Fotemustine and dacarbazine plus DC vaccines are safe and tolerable to Chinese ALM patients. The regimen brings clinical benefit with a higher ORR and may provide a survival advantage. Updated survival data will be presented.

Complete response with fotemustine and bevacizumab after early progression following radiotherapy and temozolomide treatment in patient with glioblastoma multiforme

Glioblastoma multiforme is the most common type of primary central nervous system tumor and is noted for its short survival and poor response to chemotherapeutic agents.Unfortunately,the relapse rate is very high,and there is no reference drug for second-line treatment.In this study,a patient was treated with the Soffi etti regimen.The induction phase was fotemustine 75 mg/m^(2) at day 1 and day 8 and bevacizumab 10 mg/kg at day 1 and day 15.The maintenance phase was fotemustine 75 mg/m^(2) and bevacizumab 10 mg/kg every 3 weeks for two cycles.Follow-up magnetic resonance imaging showed post-surgical changes at the left occipital level,without contrast enhancement,and toxic left leuko-encephalopathy post-treatment without mass effect and with no evidence of tumor residue.The patient then was maintained with bevacizumab monotherapy until it was withdrawn when pulmonary thromboembolism occurred.Following tumor regrowth,fotemustine was started again as maintenance therapy.The patient achieved stabilization of his disease until his death due to thromboembolic and infectious complications.