Cisplatin clinical administration

Intraperitoneal administration of chemotherapeutic agents has been used for many years as a way of increasing the delivery of drugs to tumors (e.g., ovarian carcinoma) located in the peritoneal cavity (Markman, 1986 Howell and Zimra, 1988). Cisplatin (Casper et al., 1983 Markman et al., 1985), cytosine arabinoside (Ara-C) (King et al., 1984 Markman et al., 1985, 1986), and bleomycin (Markman et al., 1986) are examples of intraperitoneally administered drugs which were already successfully applied in clinical settings. 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

The fourth criteria, that of oral administration, is being developed and evaluated for ZD0473 as just mentioned. Another candidate in this field, JM216, cis, trans, cw-[dichlorodiacetatoammine(cyclohexylamine)platinum(IV)] (see Figure 7.6D), is an orally active platinum(IV) drug being evaluated in clinical trials. This platinum (IV) complex has demonstrated activity in cisplatin-resistant tumors and exhibits less nephrotoxicity and neurotoxicity than does cisDDP. 

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin. 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

Since the late seventies, the clinical application of cisplatin has increased enormously16-18), mainly as a result of improved administration procedures and its use in combination therapy, i.e. the simultaneous application of a variety of synergistic antitumor drugs. Nowadays, usually a dosage per patient of about 100 mg of cisplatin per m2 body surface area, dissolved in saline, is given intravenously every month by standard administration protocols. 

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, several studies have shown that carboplatin and paclitaxel yields clinical results similar to what is achieved with the cisplatin plus paclitaxel combination however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy. 

One of the adverse effects of clinically used venlafaxine 10 is nausea that may be connected with its mixed serotonin/noradrenaline profile. The selective noradrenaline-reuptake inhibitor sila-velafaxime (R)-ll at oral administration effectively inhibited emetic episodes caused by emetogen (morphine) in the ferret emesis model (06BMCL2555). Intraperitoneally administered sila-venlafaxine (R)-ll was able to reduce cisplatin-induced acute and delayed emesis (08TAP369). 

Co-administration of cisplatin before topotecan has a sequence-dependent effect on the disposition of topotecan. Cisplatin-related acute changes in glomerular filtration rate can temporarily alter topotecan clearance, causing more severe myelosuppression. Nevertheless, this sequence has been recommended in clinical trials, based on its high antineoplastic efficacy. Patients therefore have to be monitored closely when the two agents are given together (154). 

Early in the development of cisplatin, more than 70% of patients developed acute renal failure that appeared to be cisplatin dose-related [34, 35]. Despite aggressive hydration, especially with NaCl solutions, which are routinely apphed in the clinical setting to prevent nephrotoxicity [36], renal failure still occurs [37,38,39]. Therefore several attempts have been made to reduce nephrotoxicity by either co administration of other compounds, alternate method of administration, or by developing analogues with an improved therapeutic index. 

Experience with ifosfamide-contain-ing regimens has revealed a consistent clinical pattern of nephrotoxicity. Fanco-ni syndrome, which is characterized by acid, sodium, potassium, magnesium, and small molecular weight proteins, occurs in 1-5% of the children who have received repeated treatments of ifosfamide [94] [95]. In fact the development of rickets secondary to Fanconi syndrome has been reported following treatment with ifosfamide [96]. Patients who have received therapy with cisplatin or carboplatin in addition to ifosfamide may be at greater risk for development of Fanconi syndrome [97]. Hemorrhagic cystitis is a significant toxicity that occurs with ifosfamide administration [98,... 

The duration of consolidative chemotherapy has been evaluated in several studies. In advanced ovarian cancer, the administration of five cycles of cyclophosphamide, cisplatin, and doxorubicin was equally effective and less toxic as compared to 10 cycles of chemotherapy. Six to nine cycles of chemotherapy has become the standard approach and results in clinical response rates of approximately 60% to 70%, with 5-year survival rates of 10% to 20%. Because approximately 50% of patients with a confirmed pathologic response will ultimately relapse, chemotherapy may be extended for two or three cycles beyond best response. ... 

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