长春瑞滨加异环磷酰胺加顺铂治疗晚期非小细胞肺癌98例临床疗效观察

目的观察长春瑞滨(NVB)、异环磷酰胺(IFO)、顺铂(PDD)三药联合(NIP)治疗晚期非小细胞肺癌的疗效和毒性.方法共收治ⅢB～Ⅳ期非小细胞肺癌98例,其中鳞癌51例,腺癌42例,大细胞癌5例.ⅢB期59例,Ⅳ期39例.初治71例,复治27例.方案:NVB 25 mg/m2静滴,第1,8天;IFO 1.5 g/m2,静滴,第1～3天;PDD 30 mg/m2,静滴,第1～3天.4周为一周期.结果 CR 1例,PR 44例,NC 45例,PD 8例,总有效率(CR PR)为45.9%.中位缓解期8个月,中位生存期11个月,1年生存率为48.0%.骨髓抑制为剂量限制性毒性,其中Ⅲ～Ⅳ度占40.8%.结论 NIP方案是治疗晚期非小细胞肺癌有效且安全的方案.     

Technetium-99m dimercaptosuccinic acid and ifosfamide tubular dysfunction in children with cancer

Quantitative ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA) renal scintigraphy was used to asses ifosfamide-induced changes in renal function in 11 children who received chemotherapy for various malignancies. Serial measurements of absolute ^99mTc-DMSA renal uptake, calculated on conjugated views, were performed during and after chemotherapy. Data of 37 studies obtained before and at different cumulative dose levels of ifosfamide were analysed in relation to clinical and biochemical parameters. A highly significant relationship between ^99mTc-DMSA uptake and cumulative ifosfamide dose was found (P<0.001). The most frequently observed abnormal pattern on scintigraphic images was decreased kidney uptake together with increased accumulation in bladder. ^99mTc-DMSA uptake was more consistent than ₂-microglobulin values in urine and more sensitive than quantitative hyperaminoaciduria and tubular resorption of phosphate for the detection of ifosfamide-induced tubular dysfunction. ^99mTc-DMSA uptake was decreased in both patients with and patients without clinical toxicity. Persistently reduced ^99mTc-DMSA uptake was observed in four patients during follow-up; in one of them, who was asymptomatic after ifosfamide therapy, sudden onset of Fanconi syndrome was observed when he was retreated with carboplatin 1 year later. It is concluded that ^99mTc-DMSA renal scintigraphy is a suitable method to assess progressive ifosfamide-induced tubular injury whereas scintigraphic imaging is helpful for interpreting renal uptake changes. The test is able to detect subclinical injury and may potentially predict high risk at retreatment.     

Occupational exposure to antineoplastic agents at several departments in a hospital

Summary The occupational exposure to cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5FU), and methotrexate (MTX) of 25 pharmacy technicians and nurses from four departments of a hospital was investigated. Previously developed methods for the detection of exposure to some antineoplastic agents were validated. Exposure to CP, IF, 5FU, and MTX was measured by the analysis of these compounds in the environment (air samples and wipe samples from possible contaminated surfaces and objects). Contamination of the work environment was found not only on the working trays of the hoods and on the floors of the different rooms but also on other objects like tables, the sink unit, cleaned urinals and chamber pots, and drug vials and ampules used for preparation and packing of drugs. The gloves used during preparation of the drugs and during cleaning of the hoods were always contaminated. The uptake of CP or IF was determined by the analysis of both compounds in urine. CP or IF was detected in the urine of eight pharmacy technicians and nurses. The amounts ranged from < 0.01 to 0.5 g (median: 0.1 g). CP and IF were found not only in the urine of pharmacy technicians and nurses actively handling these compounds (n = 2) but also in the urine of pharmacy technicians and nurses not directly involved in the preparation and administration of these two drugs (n = 6). CP and IF were excreted during different periods ranging from 1.40 to 24.15 h after the beginning of the working day, suggesting different times of exposure, different exposure routes, and/or interindividual differences in biotransformation and excretion rate for these compounds. The urinary CP and IF determination method seems to be sensitive and suitable for monitoring the exposure to and measuring the uptake of these toxic compounds by pharmacy technicians and nurses during occupational activities.     

持续滴注异长春花碱联合异环磷酰胺治疗难治性非霍奇金淋巴瘤

目的：临床研究持续性静脉滴注诺维本(Navelbine，NVB)联合异环磷酰胺(Ifosfamide，IFO)治疗难治性非霍奇金淋巴瘤(NHL)的近期疗效与毒副反应。方法：入组22例经CHOP治疗失败的NHL患，给予持续性静脉滴注NVB联合IFO化疗，至少2个周期，疗效及毒性判定按照WHO标准。结果：完全缓解(CR)6例，部分缓解(PR)13例，稳定(NC)1例，进展(PD)2例，总有效率86．4％。主要毒副作用为骨髓抑制。结论：持续静脉滴注NVB联合IFO治疗难治性NHL有较高的疗效，并较为安全，患可耐受。     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

Feasibility trial of high-dose 7-day continuous-infusion ifosfamide given on an outpatient basis

 High-dose ifosfamide (HD-IFX) has shown significant antitumor activity in advanced sarcoma and breast carcinoma. The use of uroprotective agents and the availability of ambulatory continuous-infusion pumps has allowed dose escalation in the administration of ifosfamide (IFX) on an outpatient schedule. We report the results of a phase II trial of IFX given at high doses to heavily pretreated patients. IFX was infused at 2 g/m² per day for a total of 7 days through a central venous access, with cycles being repeated every 21 days. Mesna was given concomitantly at equimolar doses. No hematopoietic support was used. A total of 27 heavily pretreated patients whose disease had progressed during conventional-dose chemotherapy were included (14 sarcomas, 10 breast carcinomas, and 3 bladder carcinomas). Reversible neutropenia and gastrointestinal toxicity were the most frequently encountered toxicities. Only two patients developed transient renal failure, and two others developed central nervous system toxicity. No treatment-related death was observed. Of 22 patients who were evaluable for response, 6 (27%) showed an objective response (OR), all ORs being partial responses (PRs) with a median duration of 6 months, and 12 patients had stable disease (SD; 55%) with a median duration of 3.5 months. The median overall survival (OS) was 6 months. Three patients underwent high-dose chemotherapy after showing a response to our IFX schedule. We conclude that continuous-infusion IFX given in an outpatient setting is a feasible and active regimen that produces, a manageable toxicity profile in heavily pretreated breast cancer and sarcoma patients. Early institution of this schedule in less advanced stages could improve the results obtained. Received: 30 June 1996 / Accepted: 20 January 1997     

In vitro studies of the hyperthermic enhancement of activated ifosfamide (4-hydroperoxy-ifosfamide) and glucose isophosphoramide mustard

Purpose: To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide.Methods: In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 °C (control), 40.5 °C, 41.8 °C, 42.5 °C, and 43 °C) for 65 min.Results: The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 °C, respectively; for D-18851 in L929 1.7 at 41.8 °C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 °C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 °C. Conclusion: The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia. Received: 9 May 1996 / Accepted: 2 October 1996     

Acute changes in urine protein excretion may predict chronic ifosfamide nephrotoxicity: a preliminary observation

Purpose: To evaluate proteinuria occurring early after ifosfamide therapy and to assess the use of changes in proteinuria in the prediction of severe chronic nephrotoxicity. Methods: One-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis was used to characterize urine protein excretion in 12 children with solid tumours before and after the first course of ifosfamide treatment, and in 24 healthy children. Chronic nephrotoxicity was evaluated at 6 months after ifosfamide treatment and graded as none, mild, moderate or severe. Results: Urine from healthy children and from 10 of 12 patients before ifosfamide therapy showed a protein band with a molecular weight (95.4 kDa) corresponding to that of Tamm-Horsfall protein but no lower molecular weight proteins. After the first course of ifosfamide this 95.4-kDa protein was lost in six of ten patients with a concomitant appearance of a low molecular weight proteinuria (<70 kDa) in eight. Tamm-Horsfall protein was lost in two of five patients who subsequently developed no or mild nephrotoxicity and in four of five patients who subsequently developed moderate or severe nephrotoxicity. Conclusions: Early subclinical changes in urine protein excretion after ifosfamide, manifested by a loss of Tamm-Horsfall protein excretion, may be predictive of subsequent chronic nephrotoxicity. Received: 27 August 1996 / Accepted: 25 July 1997     

异环磷酰胺治疗晚期恶性肿瘤病人42例的护理体会

目的　总结采用联合异环磷酰胺化疗的晚期恶性肿瘤人护理对策。方法　对 4 2例晚期恶性肿瘤病人采用联合异环磷酰胺方案化疗 ,全程观察治疗过程所出现的护理问题 ,记录并总结其要点。结果　4 2例病人顺利度过化疗期 ,心理表现也正常。结论　护士熟悉药物的特性和毒性反应 ,及早预防、及时处理和加强毒性反应护理 ,才能保证化疗的顺利进行。     

Toxicité rénale des anticancéreux

The renal toxicity of anticancer drugs is a clinical challenge because of the intrinsic toxicity of some anticancer drugs and because the cancer itself. Indeed, cancer patients are exposed to all types of renal disorders (obstructive, functional, organic because of radiotherapy, paraneoplastic glomerulopathy, thrombotic microangiopathy…). The therapeutic index of anticancer drugs is often narrow and the doses used for optimal efficacy are high. Improving safety requires a better dose adjustment, which depends on the correct evaluation of the renal function. Prevention remains important as the mortality associated with acute renal failure is very high.