Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide versus temozolomide

Purpose: Despite the progress made in neurosurgery and radiotherapy, the prognosis of glioblastoma multiforme (GB) is poor, due to the lack of an effective salvage therapy. In vitro analysis revealed activity for ifosfamide and temozolomide. The usefulness of these agents in recurrent disease was investigated. Methods: Six adult patients with recurrent GB received one to four courses of 1,500 mg/m² ifosfamide given over 5 days intravenously. Furthermore, temozolomide (100–200 mg/m²) was given orally over 5 days to 14 patients. Results: After ifosfamide treatment, one partial response and two cases of stable disease were observed. The median survival time was 24 weeks (range of 9–52 weeks). Toxicity analysis revealed one paranoid reaction, three grade III leukocytopenia, and one grade I–II nausea, anemia, and hematuria. Temozolomide therapy resulted in three partial responses and four cases of stable disease. The median survival time (Kaplan-Meier) was 21 weeks (range 4–64 weeks). The major toxicities were grade I–II nausea and hematological side effects (one case of grade IV leuko- and thrombocytopenia). Conclusions: Ifosfamide treatment might be a feasible approach, but it necessitates hospitalization. Temozolomide showed promising results. Due to its oral application, the patient's quality of life (time out of hospital) is favorable. Subgroups with improved survival were observed. Received: 7 December 1998 / Accepted: 21 January 1999     

VIP方案治疗晚期非小细胞肺癌

采用VIP联合化疗方案治疗晚期复治的非小细胞肺癌24例。结果：CR1例,PR9例,NC9例,PD5例。有效率41．67％（10／24）。毒性反应主要是骨髓抑制及消化道反应。加用Mesna后,全组未出现肉眼血尿。提示VIP方案治疗晚期复治的非小细胞肺癌有较好疗效,值得推广使用。     

Response to chemotherapy of solitary fibrous tumour: A retrospective study

BackgroundTo report on anthracycline-based chemotherapy in a retrospective case-series analysis of solitary fibrous tumour (SFT) patients treated within the Italian Rare Cancer Network.Patients and methodsWe reviewed a set of SFT treated with chemotherapy since 2002, focusing on anthracycline, administered alone or in combination with ifosfamide. Responses to ifosfamide as a single agent were also evaluated. Pathologic diagnosis was centrally reviewed, distinguishing typical, malignant (MSFT) and dedifferentiated (DSFT) subtypes.ResultsAmong 42 SFT patients treated with chemotherapy, we selected 31 cases (mean age: 62 years; locally advanced/metastatic: 13/18; front-line/further line: 25/6; typical/MSFT/DSFT/not assessable: 1/17/12/1) who received anthracycline-based chemotherapy (anthracycline monotherapy: eight; anthracycline + ifosfamide: 23). 30 patients are evaluable for response. Best response by Response Evaluation Criteria in Solid Tumours (RECIST) was: partial response (PR): 6 (20%), stable disease (SD): eight (27%), progressive disease (PD): 16 (53%) cases. Responses were confirmed after 3 months. Median progression-free survival (PFS) was 4 (range 2–15) months, with 20% of patients being progression-free at 6 months. PR was found in 2/18 (11%) MSFT and 4/12 (30%) DSFT, with a median PFS of 3.5 and 5 months in MSFT and DSFT, respectively. 19 patients received high-dose prolonged-infusion ifosfamide (front-line/further line: 11/8; typical/MSFT/DSFT: 0/15/4) with two (10%) PR, five (26%) SD, 12 (63%) PD.ConclusionsThis retrospective series suggests that in SFT anthracyclines have a degree of antitumour activity in the range of soft tissue sarcoma chemotherapy. Ifosfamide monotherapy seemed to have lower activity. A higher response rate was observed in DSFT in comparison to MSFT. Studies on targeted therapies are ongoing.     

Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats

Purpose Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC. Methods Male Wistar rats (150–200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-α inhibitor), pentoxifyllin (non-selective TNF-α inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin. Results COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically. Conclusions COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-α inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.     

吉西他滨联合异环磷酰胺二线治疗晚期非小细胞肺癌的疗效观察

目的探讨吉西他滨＋异环磷酰胺二线用于进展非小细胞肺癌的疗效和不良反应。方法观察吉西他滨联合异环磷酰胺化疗方案治疗非小细胞肺癌铂类基础一线方案进展患者46例,21天为1个周期,每2个周期影像学评价化疗效果,每周期观察化疗反应情况。结果总有效率为39．1％,主要不良反应是骨髓抑制、胃肠道反应,多为Ⅰ～Ⅱ度。结论吉西他滨联合异环磷酰胺方案为二、三线治疗进展非小细胞肺癌的有效方案。     

Phase II study with gemcitabine, ifosfamide and cisplatin in advanced non-small cell lung cancer

The aim of the present study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine, ifosfamide and cisplatin (GIP), administered every 3 weeks, in patients with inoperable non-small cell lung cancer (NSCLC). From October 1998 to July 1999, 18 previously untreated stages IIIb (4) and IV (14) patients were enrolled into the study. Gemcitabine and ifosfamide (with mesna as uroprotection) was administered on days 1 and 6, at a dose of 1000 and 1500 mg/m², respectively; and cisplatin was given on day 1 at a dose of 60 mg/m², every 3 weeks. All 18 patients were evaluable for response and toxicity profiles. One patient achieved a complete response, and 11 patients achieved a partial response, with an overall response rate of 66.7% (95% CI, 45–89%). The main toxicity was hematological, a NCI grade 3–4 neutropenia in 16 patients (88.9%) during the treatment course. Febrile neutropenia occurred in three patients (16.6%). Grade 3 anemia occurred in eight patients (44.4%) and grade 3–4 thrombocytopenia occurred in 11 patients (61.1%). Non-hematological toxicity was mild and tolerable. No toxic death occurred. The median survival was 12.7 months and 1 year survival was 58.4%. The GIP combination chemotherapy produced a high response rate in advanced NSCLC; however, there was a relatively high percentage of hematological toxicity that still could be tolerated. A randomized trial comparing GIP to a two-drug combination of gemcitabine and cisplatin is planned.     

Ifosfamide/mesna as salvage therapy in platinum pretreated ovarian cancer patients--long-term results of a phase II study

Purpose: Salvage chemotherapy in advanced ovarian cancer is not yet standardized. Patients: Twenty-one consecutive patients progressing on or relapsing after previous platinum-containing treatment were eligible for treatment with ifosfamide 5 g/m² infused over a 24-hour period every 3 weeks in a Phase II trial. After an initial bolus of 1 g/m² of mesna, mesna was applied at a dosage of 5 g/m² concomitantly with ifosfamide followed by additional dosages of 200 mg 3 times at 4-hour intervals after termination of the ifosfamide infusion. Results: The rate of objective responses was 19 percent, with a 95%CI [5.45-41.91 percent]. One patient achieved a pathologic complete remission (pCR) and 3 patients a clinical partial remission (PR). Median time-to-progression was 3 months. One patient was a long-term survivor. Main toxicities according to NCI-CTC included Grade 4 neurotoxicity in one patient, Grade 3 gastrointestinal toxicity in 5 patients, Grade 3 infection in one patient, and Grade 3 and 4 leucopenia in 6 and 2 patients, respectively. Conclusions: Monotherapy with ifosfamide represents an active regimen for salvage chemotherapy in advanced ovarian cancer patients progressing on or relapsing after previous platinum-pretreatment, even yielding a long-term surivor.     

复发宫颈癌的药物治疗

目的 研究异环磷酰胺（Ifosfamide,IFO）、卡铂（Carboplatin，CBP）和博莱霉素（Bleomycin,BLM）联合治疗复发性宫颈癌的疗效和毒性反应。方法 采用IFO2．0g加NS500ml第1-5d静脉滴注，CBP 200mg加NS500ml第1-3d静脉滴注，BLM30mg加NS20ml第1d静脉注射。结果 总有效率52．0％，毒副反应以骨髓抑制最明显．白细胞降低62．5％，胃肠反应轻微。结论 IFO、CBP、BLM联合应用治疗复发性宫颈癌疗效肯定，副反应轻．值得临床推广使用。     

长春地辛,异环磷酰胺和顺铂联合治疗晚期肺癌20例近期疗效观察

目的观察长春地辛、异环磷酰胺和顺铂联合治疗晚期肺癌患者疗效和毒性。方法符合化疗条件的２０例晚期肺癌患者,均完成２周期以上的化疗。方案组成：ＶＤＳ３ｍｇ／ｍ２静注第１、８天,ＩＦＯ２ｇ／日静滴,第１－５天,ｍｅｓｎａ４００ｍｇ静滴,每８小时１次,ＤＤＰ３０ｍｇ／ｍ２第２－４天或８０ｍｇ／ｍ２,第１天,２１－２８天为一周期,完成二周期后评价疗效。结果有效率７５％（１５／２０）,完全缓解率１５％（３／２０）,部分缓解率６０％（１２／２０）,其中小细胞肺癌有效率８３．３％（５／６）非小细胞肺癌７１．４％（１０／１４）。常见毒副反应是白细胞减少Ⅲ度－Ⅳ度,占８５％,其次恶心、呕吐Ⅲ度占２５％。结论该方案对晚期肺癌是疗效较高方案,有条件者可作为一线方案应用。     

Combined intravenous and oral mesna in outpatients treated with ifosfamide

Purpose: To prevent hemorrhagic cystitis, mesna is typically injected intravenously (IV) at the time of an ifosfamide dose and 4 and 8 h later. To simplify outpatient ifosfamide therapy, we gave the second and third mesna doses orally. Methods: The mesna doses (400 or 600 mg/m²) were 40% (w/w) of each ifosfamide dose (1.0 or 1.5 g/m²), which was given daily for 5 days. We evaluated urinary mesna excretion and plasma concentrations in ten patients from the beginning of mesna infusion until the time of the second oral dose. The first oral dose was administered at hour 2 in the last six patients to allow time for absorption of mesna. Results: The rate and amount of mesna excretion was less variable over time and among patients after oral than after IV administration. No macrohematuria was observed in these ten patients nor in an additional 50 patients given oral mesna at hours 2 and 8 during at least two cycles of ifosfamide therapy. Conclusion: These pharmacokinetic and clinical efficacy data support the use of a combined regimen of IV and oral mesna to simplify outpatient ifosfamide administration. Received: 16 July 1996 / Accepted: 17 December 1996