Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods

Objective: To assess factors that affect cisplatin nephrotoxicity. Methods: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. Results: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2–5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. Conclusions: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes. (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney. Received: 28 February 1996 / Accepted: 17 December 1996     

A randomized phase II study of cisplatin alone versus cisplatin plus disulfiram

Preclinical evidence has suggested that disulfiram (DS) and related compounds can decrease the toxicity and enhance the therapeutic index of cisplatin (CP). To study this further, we have performed a prospective randomized study wherein 53 patients with CP-sensitive malignancies were assigned to therapy with CP 100 mg/m2 alone (group I) or CP 100 mg/m2 and oral DS 2,000 mg/m2 (group II). Both groups were comparable with regard to sex distribution, age, performance status, prior chemotherapy, and radiotherapy. Twenty-three patients were not evaluable for response (3 refused follow-up, 18 had less than two courses, one had an early death, and one had excessive toxicity during the first cycle of treatment). Of the 30 evaluable patients (16 in group I, 14 in group II), only one in group II achieved a complete response. There was no statistically significant difference in response rate, time to progression, or median survival between the two groups. Fifty-two patients (98.1%) were evaluable for toxicity. Significant differences in toxicities were observed between the two groups: patients in group I encountered lower [Eastern Cooperative Oncology Group (ECOG) 0-1)] grades of nausea, vomiting, and ototoxicity, and patients in group II experienced higher grades (ECOG 2-3) of toxicity in general. In addition, there was no difference in nephrotoxicity between the two groups, as measured by the change in serum creatine or 24-h urine creatinine clearance over the first course of treatment. We conclude that, contrary to previously published reports, DS does not afford significant nephroprotection against CP and, in fact, enhances gastrointestinal and ototoxicities.     

Second-generation cisplatin analogs

Since the introduction into clinical practice in 1972, cisplatin (CDDP) has assumed an important role in the treatment of various tumors such as testicular, ovarian or pulmonary cancer. Its toxicities include emesis, renal impairment, neuropathy, hearing loss and anemia. In clinical trials renal toxicity has been proved to be dose limiting factor. Thus the total number of courses which may be given is limited. For this reason second-generation CDDP analogues with reduced toxicity have been tried to develop and are reaching clinical testing. A number of studies have now been published relating the results of these trials. The best studied of these analogues is carboplatin (CBDCA, JM-8) which was noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical study. Phase I trials have shown that CBDCA is relatively free of renal toxicity and that its dose limiting factor is myelosuppression, especially thrombocytopenia. In phase II trials CBDCA has been shown to be an active agent in advanced carcinomas of the ovary, head and neck, lung and urogenital organs. Similar results have been obtained in clinical trials of iproplatin (CHIP, JM-9) which is synthesized as an analogue of CDDP. Two other analogues developed in Japan have been evaluated to be active for various mouse tumors in preclinical studies. Phase I trials of these agents is now ongoing.     

Pharmacokinetics of cisplatin in combined cisplatin and 5-fluorouracil therapy: a comparative study of three different schedules of cisplatin administration

BACKGROUND: Cisplatin is widely used in combination chemotherapy against a variety of tumors; however, the optimal administration schedule of cisplatin is still controversial. To clarify the pharmacokinetic differences according to the administration schedules of cisplatin, we compared three different administration schedules of cisplatin such as single short-term infusion, daily short-term infusion and daily continuous infusion in combination with 5-fluorouracil. Preliminary clinical responses and toxicities were also investigated. METHODS: A total of 12 courses in combination of cisplatin and 5-fluorouracil therapy was studied. The schedules of cisplatin tested were as follows: single short-term infusion (80 mg/m2, day 1,2 h div., n = 4), daily short-term infusion (20 mg/m2, days 1 to 5, 2 h div., n = 4), daily continuous infusion (100 mg/m2, 120 h, n = 4). In all schedules, 5-fluorouracil was continuously administered at a dose of 800 mg/m2/day on days 1 to 5. The area under the time-concentration curve (AUC) and the maximum concentration (Cmax) of total and free Pt were investigated. RESULTS: The highest AUC of total and free Pt and the lowest Cmax of free Pt were observed in the daily continuous infusion (total AUC; 162.53 +/- 18.39 micrograms h/ml, free AUC; 5.50 +/- 0.9 micrograms h/ml, free Cmax; 0.07 +/- 0.01 microgram/ml, mean +/- SEM). Two patients in the single short-term infusion and one patient in the daily continuous infusion indicated partial responses clinically. No nephrotoxicity or ototoxicity was observed. All toxicities were mild and tolerable in all regimens; however, the incidence of GI toxicity in daily continuous infusion seemed to be relatively higher. CONCLUSIONS: Daily continuous infusion of cisplatin gave the best pharmacokinetic results and to evaluate the clinical advantage of this schedule a prospective randomized trial should be conducted with sufficient numbers of patients.      

Estrophilic cisplatin derivatives

Our approach to develop platinum complexes with a selective effect on the hormone-dependent MC by exchanging the two NH₃ groups of cisplatin by an 1,2-bis(4-hydroxyphenyl)ethylenediamine derivative which possesses estrogenic activity, was successful. The most interesting compound of this new platinum complex series, meso-(1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine) dichloroplatinum (II) (meso- 1 -PtC1₂) and its water soluble sulfatoplatinum(II) derivative (meso-1-PtSO₄) were significantly more active on the DMBA-MC and the receptor positive MXT-MC than cisplatin and the related ligand 1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine (meso- 1).According to our proposed mechanism of action, meso-l-PtX (X = Cl₂ or SO₄) should be enriched in the nuclei of mammary tumor cells, which possess an intact ER system (i.e. an intact cytoplasma nucleus translocation process), thereby causing very strong tumor growth inhibition.Preliminary studies of meso-l-PtSO₄ on the DMBA-MC confirm this assumption. In the tumor tissue we found higher Pt-levels than in uterine tissue, which also contains ERs. The Pt-levels of the tumor tissue are much higher than those of skeletal muscle and of blood.In therapeutic dosages meso-1-PtSO₄ does not cause kidney damages in rats.     

Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer

Purpose  

Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin, particularly the nephrotoxicity, and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer (NSCLC). Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non-squamous NSCLC.     

Platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer

ObjectiveThe concept of platinum sensitivity and cross-resistance among platinum agents are widely known in the management of recurrent ovarian cancer. The aim of this study was to evaluate two hypotheses regarding the validity of the concept of platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.MethodsIn this retrospective study, the clinical data of patients with recurrent cervical cancer, who had a history of receiving cisplatin based chemotherapy (including concurrent chemoradiotherapy [CCRT] with cisplatin) and who received second-line chemotherapy at the time of recurrence between April 2004 and July 2012 were reviewed.ResultsIn total, 49 patients-34 squamous cell carcinomas (69.4%) and 15 non-squamous cell carcinomas (30.6%)-were enrolled. The median age was 53 years (range, 26 to 79 years). Univariate and multivariate analysis showed that a platinum free interval (PFI) of 12 months has a strong relationship with the response rate to second-line chemotherapy. Upon multivariate analysis of survival after second-line platinum-based chemotherapy, a PFI of 12 months significantly influenced both progression-free survival (hazard ratio [HR], 0.349; 95% confidence interval [CI], 0.140 to 0.871; p=0.024) and overall survival (HR, 0.322; 95% CI, 0.123 to 0.842; p=0.021). In patients with a PFI of less than 6 months, the difference of progression-free survival between patients with re-administration of cisplatin (3.0 months) and administration of cisplatin analogue (7.2 months) as second-line chemotherapy was statistically significant (p=0.049, log-rank test).ConclusionThe concept of platinum sensitivity could be applied to recurrent cervical cancer and there is a possibility of noncross-resistance of cisplatin analogue with cisplatin.     

顺铂水针剂与粉针剂体外细胞毒作用的差异性研究

目的:比较两种不同剂型顺铂针剂的细胞毒效应.方法:用含不同终浓度顺铂水针剂与粉针剂的培养液培养Hela细胞系,采用四甲基偶氮唑蓝比色法(MTT)检测细胞存活率并计算顺铂的50%抑制浓度(IC50),分析比较两种不同顺铂剂型针剂在体外的细胞毒效应.结果:相对于顺铂粉针剂,相同终浓度顺铂水针剂作用的Hela细胞存活率较低,其IC50值分别为(14.0±0.07)μg·ml-1及(15.03±0.26)μg·ml-1(P=0.003).其中在(0.1、1、10)μg·ml-1组中细胞存活率存在差异.结论:顺铂水针剂较粉针剂体外细胞毒效应强.     

Pharmacokinetics of consecutive low-dose cisplatin

The present study investigated the optimal mode of cisplatin (CDDP) dosing in terms of pharmacokinetics. Ten patients with stage Ic ovarian cancer were randomly assigned to receive either bolus-CDDP (70 mg/m(2), 2-h infusion on day 1) or consecutive low-dose (CLD)-CDDP (10 mg/m(2), 4-h infusion for 7 consecutive days) in the adjuvant setting. Maximum concentration (C-max) of total and filterable platinum for the bolus-CDDP group were significantly higher than those for the CLD-CDDP group. Whereas, filterable drug exposure defined by the area under the concentration-time curve (AUC) was approximately 2-fold higher for the CLD-CDDP group. Urine excretion rates, which were considered to be related with nephrotoxicities, were significantly lower for the CLD-CDDP. Anti-tumor effect of CDDP has been reported to be dependent on the AUC rather than C-max of filterable platinum. Thus, CLD-CDDP dosing may possibly deliver an improved therapeutic index as compared to the usual bolus dosing method, especially for patients with pelvic tumors which eventually involve the urinary tract leading to impaired renal function.     

顺铂肾毒性的早期诊断

目的：探讨顺铂（ＤＤＰ）化疗肾毒性的早期诊断方法。方法：动态检测４８例患者接受大剂量ＤＤＰ（１００￣１２０ｍｇ／ｍ＾２）化疗８７个周期的血清尿素氮（ＢＵＮ）,肌酐（Ｃｒ）、以及尿β２－微球蛋白（β２－ＭＧ）、α１－微球蛋白（α１－ＭＧ）、白蛋白（Ａｌｂ）、转铁蛋白（ＴＲＦ）、维生素Ａ１结合蛋白（ＲＢＰ）、Ｎ－乙酰－β－氨基葡萄糖苷酶（ＮＧＡ）和总氨基酸（ＴＡＡ）等项目,筛选出有价值的早期诊断顺铂肾     

Molecular mechanisms of cisplatin resistance

Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNA-cisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.     

Clinical pharmacology of high-dose cisplatin

Summary Although nephrotoxicity has frequently limited conventional treatment with cisplatin to doses of 100–120 mg/m² per cycle, vigorous chloruresis can permit the administration of high-dose cisplatin (200 mg/m² per cycle) with minimal nephrotoxicity. Systemic toxicities are worsened, but therapeutic response seems to be enhanced. The pharmacokinetics of cisplatin in plasma and urine were examined to assess the causes of these effects. Plasma disappearance of ultrafiltrable platinum was well-described by a single exponential for each patient. The mean t_1/2 was 50% longer for patients receiving high-dose cisplatin than for patients receiving conventional doses. The total systemic exposure was three times greater in the high-dose group, which tends to explain the systemic toxicity and improved tumor efficacy, but not the lack of nephrotoxicity. It is suggested that the kidneys of patients in the high-dose group were relatively protected by dilution of active Pt species in the urine in the tubule lumen as well as by high chloride ion concentrations in the urine.     

DNA-based drug interactions of cisplatin

The interactions of cisplatin with other anti-cancer agents on the DNA level have been studied extensively in pre-clinical experiments. In general, combination of cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result in a modulation of platinum pharmacology on the DNA, for example, enhanced retention of the platinum-DNA adducts. These interactions are mostly sequence and cell type dependent. In cell line models, antimetabolites can enhance the number of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However, in clinical trials, the opposite effect has been observed, with a reduction of these adducts upon combined treatment. For the taxanes it has been shown that they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I inhibitors increase the number of adducts, resulting in strong synergistic cytotoxicity. For this last interaction a mechanistic model has recently been proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which yields large stabilised lesions to the DNA that are probably difficult to repair. Ongoing studies will proceed to elucidate the exact mechanism underlying the interactions between cisplatin and other anti-neoplastic agents on the DNA level. Such increased understanding might help in designing new and more effective treatment regimens for cancer. In this paper, we review the pre-clinical and clinical studies investigating the observed interactions between cisplatin, the antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.     

NC与GC方案治疗耐药晚期乳腺癌近期疗效对照研究

 目的 研究吉西他滨与长春瑞滨（商品名：诺维本）分别联合顺铂治疗对蒽环类和紫杉类药物耐药的晚期乳腺癌患者的近期疗效及毒副反应。方法 经病理组织学或细胞学证实的46例晚期乳腺癌患者，随机分为两组，吉西他滨联合顺铂组（A组）23例，以吉西他滨1000 mg／m2静脉滴注，第1天、第8天；顺铂25 mg／m2静脉滴注，第1天至第3天。长春瑞滨联合顺铂组（B组）23例，以长春瑞滨25 mg／m2，第1天、第8天溶于生理盐水100 ml中快速静脉滴注。顺铂用法同A组。两方案均每3周重复，2个周期以上评价疗效。结果 两组的有效率分别为60.8 %（14／23）和56.5 %（13／23），两组比较差异无统计学意义（P＞0.05）。A组Ⅲ～Ⅳ度血小板减少高于B组，但B组Ⅲ～Ⅳ度白细胞减少及静脉炎相对较明显。结论 NC与GC方案治疗耐药晚期乳腺癌有较高的缓解率，不良反应较轻。