FDA批准docetaxel(多西他赛)的新适应症-前列腺癌

FDA批准Taxotere(商品名：泰索帝；通用名：docetaxel[多西他赛])注射液与泼尼松(prednisone)（一种类固醇）联合使用，用于治疗晚期转移性前列腺癌（advanced metastatic prostate cancer）患者。
这是被批准用于治疗激素抵抗性前列腺癌（hormone refractory prostate cancer）的首个药物。该药已显示出有促进患者生存的作用。
“我们认为这项批准意味着前列腺癌治疗手段上的重大进展，因为该药能够帮助延长患者的生存期。患者需要尽可能多的有效治疗方案以供选择。Taxontere与泼尼松联合使用，给予那些对其它治疗方案不起反应的患者新希望，”FDA代理专员Lester M. Crawford博士说。
前列腺癌占男性癌症死亡之因的第二位。Taxontere与泼尼松联合使用，对那些激素治疗不见效的患者来说，是一个新的治疗选择，并且已显示其促进生存的作用。
Taxotere通过抑制微管蛋白(tubulin)而发挥作用。微管蛋白是细胞分裂所必需的蛋白。Taxotere通过这一机制抑制癌细胞的分裂和数量上的增长。
Taxotere的安全性和有效性已经通过由1000多名患者参加的一个国际多中心随机临床试验进行评价。在此试验中，Taxotere与泼尼松的联合对照米托蒽醌(mitoxantrone)与泼尼松的联合，对转移性、激素抵抗的前列腺癌患者进行化疗。Taxotere与泼尼松的联合，每三周给药一次，显示比对照组延长约2.5个月的生存期的优势。
所报告的最常见不良反应为：恶心、脱发、骨髓抑制。此外，还观察到包括体液渚留（fluid retention）和外周神经病（peripheral neuropathy）(四肢麻刺感)在内的Taxotere的一些已知不良反应。

美国癌症学会（American Cancer Society）估计，2004年美国将新增23.09万个前列腺癌病例。今年就将有大约2.99万位男性死于该疾病。

Taxotere由Aventis Pharmaceuticals Inc.（安万特制药公司）销售。

【药物名称】泰索帝 Docetaxel
【药物类别】其他抗肿瘤药
【药物别名】多西他赛 Taxotere
【分子式】分子量807.9。
【制剂规格】注射剂：20、80mg

【药理毒理】属于紫杉类化合物抗肿瘤药。 本品的作用机制是加强微管蛋白聚合作用和抑制微管解聚作用，导致形成稳定的非功能性微管束，因而破坏肿瘤细胞的有丝分裂。本品在细胞内浓度比紫杉醇高3倍，并在细胞内滞留时间长,这是本品在体外试验中比紫杉醇抗肿瘤活性大的重要原因。在体内试验中，对小鼠的结肠癌、乳腺癌、肺癌、卵巢肿瘤移植物等有效。对顺铂、足叶乙苷、5Fu、或紫杉醇耐药的细胞株，本品不产生交叉耐药。

【药动学】按剂量100mg/m2静滴本品约1～2h，体内平均分布容积为113L，t1/2α为4min，t1/2β为36min，t1/2γ约为11.2h。体内清除率约为20L/h.m2，具有高蛋白结合率和低肾排泄率。在肝中代谢，主要经胆道从粪便排出，而经尿排泄仅占所给剂量5%～7%；肝功能异常者使本品在体内清除率减少，但年龄差异对本品在体内的药动学无明显改变。

【适应证】乳腺癌和非小细胞癌。肺癌、卵巢癌有效，对胰腺癌、胃癌、头颈癌等也有效

【不良反应】骨髓抑制。过敏反应。体液潴留。可能发生胃肠道反应如恶心、呕吐或腹泻。脱发。乏力。粘膜炎。关节痛和肌肉痛。低血压。神经毒性和心血管副反应极少发生。

【相互作用】本品和顺铂或长春瑞宾或阿霉素合用，提示有益的结果。与酮康唑合用，可能发生不良相互作用，使用时要格外小心。

【用法用量】推荐剂量为每3周用75 mg/m2，静脉滴注1 hr。

【注意事项】白细胞数目小于1500/m3的病人禁用。孕期、哺乳期妇女及儿童禁用。治疗前需预服糖皮质激素，如地塞米松，以减轻体液潴留的发生。治疗期间应经常监测血细胞数目。

Taxanes（DOCETAXEL/TAXETERE）
Docetaxel is a semisynthetic derivative of the readily available taxane precursor 10-deacetyl baccatin III, which is extracted from the needles of the european yew tree, taxus baccata, and other taxus species. Like paclitaxel,this agent alters microtubule dynamics by decreasing microtubule disassembly,stabilizing polymerized tubulin,and promoting microtubule assembly.Docetaxel differs from paclitaxel on the c10 taxane ring position, and on the ester side chain attached at C13. Clinical antitumor activities of the two taxane are similar, although doxetaxel appears to be more potent than paclitaxel with reguard to its antimicrotubule effects and cytotoxicity in vitro. However, this does not necessarily translate into enhanced therapeutic efficacy because it may also portend more severe toxicity at identical drug concentrations in vivo.Unlike paclitaxel,docetaxel has linear pharmacokinetics,a longer serum half-life, and longer intracellular retention

INDICATIONS
Impressive antitumor activity in patient with metastatic breast cancer as first-line or salvage treatment, non-small cell lung cancer as first-line or in platinum-refractory ovarian cancer. Currently approved by the US food and drug administration as second-line treatment following treatment with anthracyclines in patients with metastatic breast cancer. Its role as a component of adjuvant and neoadjuvant chemotherapy following the local treatment of early-stage breast cancer, and of first-line chemotherapy for locally advanced and metastatic non-small cell lung cancer, are being evaluated.Regulatory approval has been granted in many countries for the treatment of patient with locally advanced or metastatics non-small cell lung cancer,because agent has shown a survival advantage when used in the second-line setting following platinum-based therapy.In addition impressive activity in previously treated patients with carcinomas of the ovary,endometrium,head and neck,esophagus,stomach,urinary bladder,prostate, and small cell lung,as well as lymphomas and other neoplasms.Clinical antitumor spectra for paclitaxel and docetaxel are similar

DOSAGE AND ADMINISTRATION
Recommended dosage ranges from 60-100 mg/m2 given IV only 1 h every 3 wks.However,75-100 mg/m2 is commonest dose range in clinical practice.Similar to paclitaxel,weekly treatment has been associated with lower hematologic toxicity than 3 weekly schedules and appears to be well torerated at 36 mg/m2 /wk. In patient without hyperbilirubinemia,dose reduction of 25% are recommended with elavated hepatic transaminase (>1.5-fold) and alkaline phosphatase (>2.5-fold) regardless of whether the elevation are due to hepatic metastases.However, more substantial reduction (50 % or greater) may be required for patients who have moderate or severe hepatic excretory dysfunction.Dose modification are not required for impaired renal function or third space fluid collections.Premadication is required, with dexamethasone 8 mg PO twice daily,usually given for 3-5 days starting 1-2 days before treatment to minimize risk of fluid retention and hypersensitivity reactions. H1 - and H2 -histamine antagonists can also be given IV 30 minutes before docetaxel

PHARMACOKINETICS
Linear and are well fit by a three-compartment model. The agent binds avidly to plasma proteins(>80%-90%) and is widely distributed with a steady-state volume of distribution of 74 L/m2 . Does not cross the blood-brain barrier. Terminal half-life (T1/2g) ranges ranges from 10-15 h. It is cleared primarily by hepatic metabolism,with fecal excretion accounting for 70%-80% of drug. Urinary excretion accounts for less than 10%. CytochromeP450 mixed function oxidases, in particular isoforms CYP3A4 and CYP3A5, are mainly responsible for hepatic metabolism. Principal pharmacokinetic determinants of toxicity are drug exposure to biologically relevant plasma concentrations. Docetaxel exhibits a wide interpatient variation in clearance that results in varying degrees of toxicity, perhaps due to variability in CYP3A activity. The measurement of metabolites of substrates of CYP-3A, such as erythromycin in the erythromycin breast test, may predict CYP3-A activity, docetaxel clearance and toxicity

SPECIAL PRECAUTIONS
Severe hypersensitivity reactions are uncommon,with dyspnea,hypotension,and flushing occuring is less than 1% of patients. In patients with impaired liver function,dose reductions recommended. Dose modification are not required for renal impairment or third-space fluid collections

DRUG INTERACTIONS
Interactions with other classes of drugs that can effect the cytochrome P450 system are predicted based on interactions demonstrated for paclitaxel (See drug interactions in paclitaxel section).However,neither significant pharmacokinetic or toxicologic drug-drug interactions between docetaxel and the anthracyclines have been documented,which may reflect differences in taxane formulation and/or potencies that may lead to differences in the number of molecules available for competition for clearance mechanisms with the anthracyclines

TOXICITIES
Hematologic: neutropenia toxicity limits dosage of doxytaxel. It is not cumulative and treatment delays due to incomplete recovery of neutrophil counts are unusual.At 100 mg/m2 ,using the 1-h schedule,nadir counts are frequently less than 500/mL, which usually occur on day 9 with recovery by days 15-21. The most important predictor of neutropenia is the extent of previous therapy. Severe thrombocytopenia and anemia are infrequent;
Hypersensitivity: despite not being formulated in polyoxyethylated castor oil,docetaxel caused hypersensitivity reactions in approximately 31% of patients treated without premedication on early trials,which occurred within first few minutes of the initial two courses. Symtoms resolved rapidly with cessation of therapy.Treatment was usually recommended without adverse effect. Most reactions were minor with flushing,wheezing,chest tightness,anxiety,and low back pain.Dyspnea,hypotension,and bronchospasm leading to cyanosis were less common.Premedication reduces the risk hypersensitivity reactions;
Fluid retention: causes a unique fluid retention syndrome resulting in weight gain,edema,pleural effusions,and ascites,possibly resulting from increased capillary permeability resulting in fluid leakage from vascular compartment. It is not usually a significant problem until a cumulative dose of more than 400-mg/m2 docetaxel has been administered in the absence of corticosteroid premedication.Premeddication with corticosteroids and H1 - and H2 -histamine antagonists decreased incidence of fluid retention as a function of cumulative dose;
Dermatologic: alopecia;between 50% and 75% of patients develop an erythematous pruritic maculopapular rash affecting forearms and hands.Premedication decreases rash incidence.Superficial desquamation of the hands and feet and palmar-plantar erythrodysesthesia occur that may respond to oral pyridoxine 50 mg three times daily.Onychodystrophy with brown brittle nails,ridging,onycholysis,and soreness is common. Phlebitis along infusion course and at injection site is occasionally noted,but severe tissue necrosis following extravasation rare;
Neuromuscular : similar but less marked than with paclitaxel. Mild to moderate peripheral sensory neuropathy predominates,in approximately 40% of chemotherapy-native patients.Motor effects are less common. Severy toxicity is unusual in the absence of an underlying comorbid neurologic disorder (eg, diabetes, alcoholism).Arthralgia and myalgia following treatment are not uncommon but usually short-lived.
Other : severy lethargy and malaise occur infrequently,particularly in patients who have have received large cumulative doses o0n a weekly basis. Stomatitis more frequent than with -paclitaxel. Nausea,vomiting,and diarrhea are uncommon.Little evidence suggests cardiotoxicity

PATIENT MONITORING
Monitor for fluid retention,neurotoxicity,and myelosuppression and hepatic dysfunction, the later of which may require reduced dosage.Treatment is usually withheld until neutrophil count exceeds 1500 cells/mm3

NURSING INTERVENTIONS
Observe patient for hypersensitivity reactions, which usually occur in the first two courses within minutes of therapy.Care against extravasation is important,although extravasation reactions do not usually cause necrosis.Avoid infusion sets containing PCV

PATIENT INFORMATION
Advise patient of risk of hypersensitivity reactions,neutropenic sepsis,and fluid retention.Female patients should be advised to avoid pregnancy during treatment

FORMULATION

Proprietary name is Taxotere (aventis Pharmaceuticals, Bridgewater, NJ). Formulated with polysorbate 80 in sterile vials containing 40 mg/mL.Unopened vials should be strored between 2-8癱 and protected from light.It is diluted with the supplied sterile diluent containing 13% alcohol to a final premix solution of 10 mg/ml, which is stable for up to 8 h at room temperature and must be diluted in either 0.9% NaCl solution or 5% dextrose solution to achieve a final concentration of 0.3 to 0.9 mg/mL.After preparation,use solution as soon as possible.