泰索帝每周给药联合顺铂一线治疗晚期非小细胞肺癌的临床研究

目的确定泰索帝每周给药联合顺铂治疗晚期非小细胞肺癌的最大耐受剂量（MTD）和剂量限制毒性（DLT）,观察其疗效（RR）和安全性,并进行药代动力学研究。方法泰索帝每周给药,连用3周,休息1周,顺铂每周期的第1天给药;每28d为1个治疗周期。顺铂的剂量为75mg／m^2。泰索帝在Ⅰ期临床阶段共有4个剂量组：25mg／m^2、30mg／m^2、35mg／m^2和40mg／m^2,每个剂量组至少人选3例患者。在Ⅱ期临床阶段,根据Ⅰ期临床推荐剂量,泰索帝35mg／m^2每周给药。药代动力学为第一周期第1天和第15天抽取血样待分析。根据Ⅰ期临床研究推荐剂量,进行Ⅱ期临床研究。结果Ⅰ期临床的15例患者中,有14例可评价疗效,其中5例部分缓解,有效率为35．7％,其中位生存时间16个月（范围5-40个月）。1、2、3年生存率分别为73．3％、26．6％和20．0％。中位疾病进展时间9个月（6～14个月）。Ⅱ期临床研究的83例初治的晚期非小细胞肺癌患者共接受了216个周期的化疗,可评价者75例。有1例患者完全缓解,22例患者部分缓解,占全部人组病例的27．7％（23／83）,占可评价病例的30．7％（23／75）;其中位生存时间为10．7个月（范围3—34个月）,1年生存率为48．6％。主要不良反应为Ⅲ-Ⅳ度的粒细胞减少以及乏力、指甲毒性及液体潴留。结论泰索帝（35mg／m^2）每周给药联合顺铂（75mg／m^2）作为一线方案治疗晚期非小细胞肺癌,疗效较好,骨髓毒性较小。     

多西他赛每周给药联合顺铂治疗晚期非小细胞肺癌

目的：研究多西他赛(泰索帝)每周给药联合顺铂治疗晚期非小细胞肺癌的疗效和不良反应。方法：多西他赛35mg／m^2，每周给药，连用3周休息一周，顺铂75mg／m^2，每周期的第一天给药。每28天为一个治疗周期。至少2周期评价疗效。结果：有12例患者部分缓解，占全部入组病例(36例)的33％，占可评价病例(33例)的36％；中位生存时间11．5月(范围4～27月)；一年生存率50％。Ⅲ～Ⅳ度的粒细胞减少为22％，非血液系统毒副反应为乏力、指甲毒性及液体潴留。结论：多西他赛每周给药联合顺铂治疗初治的晚期非小细胞肺癌疗效较好，骨髓毒性较轻。     

泰索帝每周方案治疗晚期乳腺癌及非小细胞肺癌临床疗效观察

目的：观察泰索帝(Taxotere)每周用药方案治疗晚期乳腺癌及非小细胞肺癌的临床疗效和毒性反应。方法：泰索帝25mg／m^2，d1、d8、d15，静脉滴入1h，每次给药前30min予地塞米松10mg静脉推注。乳腺癌联合吡喃阿霉素40mg／m^2，d2，静脉推注；非小细胞肺癌联合卡铂300mg／m^2，d2，静脉滴入。28d为1个周期。治疗2个周期。结果：乳腺癌5例，PR2例，NC3例，有效率40．0％；非小细胞肺癌11例，CRl例，PR3例，NC5例，PD2例，有效率36．4％。全组16例，有效6例，总有效率37．5％。毒性反应主要为白细胞减少，但无IV度者。非血液毒性为乏力、恶心及脱发。结论：泰索帝每周给药方案与每3周给药方案相比疗效基本相同且具有良好的耐受性，骨髓抑制轻微。     

多西紫杉醇联合顺铂或卡铂治疗晚期非小细胞肺癌

目的：观察多西紫杉醇(泰索帝)联合顺铂或卡铂治疗晚期非小细胞肺癌的疗效及毒副反应。方法：对病理学或细胞学证实的32例晚期非小细胞肺癌患给予泰索帝联合顺铂或卡铂治疗。采用每周疗法，泰索帝25mg／m^2／次，静滴，第1、8、15天三次给药；顺铂75～80mg／m^2静滴，第1～5天或第2、9天分次给予；或卡铂AUC6．0-7．0，静点，第1天或第2、9天分次给予。每28天为一周期，每例患均接受2周期治疗或以上。结果：全组32例中获得完全缓解1例，部分缓解13例，稳定16例，进展2例，总有效率43．7％。临床最常见的毒副反应为骨髓抑制，Ⅲ、Ⅳ度白细胞和血小板下降率分别为15．6％和9．4％，其余无严重毒副反应。结论：泰索帝联合顺铂或卡铂治疗晚期非小细胞肺癌疗效较好，毒副反应较轻，采用每周疗法，病人耐受性较好，针对老年晚期患更加适宜。     

单药泰索帝治疗晚期乳腺癌每周方案与每3周方案疗效及毒性比较

目的：分析单药泰索帝治疗晚期乳腺癌每3周方案与每周方案疗效与毒性的关系。方法：33例晚期乳腺癌患者。其中12例患者接受每3周方案，剂量范围为70．7mg/m^2-86.1mg/m^2，中位剂量为75mg/m^2；20例患者接受每周方案，剂量范围为20．4mg/m^2-28．7mg/m^2，中位剂量为25mg/m^2。结果：本组患者的总有效率为25．0％，其中软组织、肺、骨及肝脏有效率分别为60％、23．1％、21．4％和27．8％；既往应用过蒽环类的患者有效率为25．0％，既往应用过紫杉醇的患者有效率27．3％；每3周方案与每周方案疗效均为25．0％，两者之间无统计学差异；每3周方案的Ⅲ度～Ⅳ度白细胞毒性大．而每周方案白细胞毒性轻，耐受性良好。结论：单药泰索帝治疗晚期乳腺癌疗效肯定。对老年、一般状况差及部分难治性乳腺癌患者仍有疗效，每周方案更易被耐受。     

局部晚期鼻咽癌同期放化疗顺铂单药每周方案剂量递增临床研究

目的:本研究旨在确定每周1次顺铂化疗与常规放疗加后程三维适形放疗同期治疗局部晚期鼻咽癌患者,其顺铂用药的最大耐受剂量(maximum tolerated dose, MTD).方法:选择Ⅲ/ⅣA期局部晚期鼻咽癌初治患者,进行同期放化疗顺铂单药每周方案剂量递增试验,评价治疗不良反应,以出现剂量限制毒性(dose-limiting toxicity, DLT)作为观察终点.顺铂剂量递增范围为15～45 mg·m-2·d-1,每一级剂量水平递增5 mg·m-2·d-1.放疗采用常规放疗加后程三维适形放疗.同期放化疗结束后,评价不良反应和治疗效果.结果: 共入组24例患者,完成每周1次顺铂15～45 mg·m-2·d-1共7个剂量水平的163个用药周期.15～35 mg·m-2·d-1这5个剂量水平的15例患者均未出现DLT, 40 mg·m-2·d-1剂量水平的3例患者中有1例出现Ⅲ度骨髓抑制,45 mg·m-2·d-1剂量水平的3例患者中有3例出现Ⅲ度骨髓抑制,因此确定本研究治疗方案中顺铂的MTD为每周1次40 mg·m-2·d-1.研究中未观察到Ⅳ度不良反应.全组患者治疗结束时,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%.结论:局部晚期鼻咽癌同期放化疗顺铂单药每周方案的MTD为40 mg·m-2·d-1,DLT为骨髓抑制.     

多西他赛联合顺铂每周给药方案治疗30例老年非小细胞肺癌的近期疗效

目的 探讨多西他赛联合顺铂每周给药方案治疗老年非小细胞肺癌的疗效及毒副反应。方法 对30例老年NSCLC患者用多西他赛30mg／m^2联合顺铂25mg／m^2，第1，8，15天给药方案治疗。每4周重复，至少完成2周期。结果 30例患者：CR1例；PR10例；SD15例；PD4例。总有效率（RR）：36.6％（11／30）。Ⅲ～Ⅳ度的中性粒细胞减少发生率为30.0％（9例），非血液学毒性主要为疲劳乏力等（40．0％）。结论 多西他赛联合顺铂每周给药治疗老年非小细胞肺癌是安全有效的。     

大剂量法乐通加EP方案与多西他赛单药二线治疗晚期NSCLC的对照研究

目的：论证大剂量法乐通＋EP方案二线治疗对铂类耐药的晚期非小细胞肺癌（NSCLC）的疗效和毒性，并与泰索帝单药进行比较。方法：共98例对铂类耐药的晚期NSCLC非随机化进入A组（法乐通480mg，连服7．5d；依托泊苷100mg／m^2，静脉滴入，d4～d6，顺铂80mg／m^2静脉滴入，d4）和B组（秦索帝单药75mg／m^2，静脉滴入，d1）。两组的主要临床特性相平衡，但顺铂的累计量≥320mg／m^2只能入B组。结果：可评价的86例患者除B组的白细胞下降和神经毒性显著高于A组外（P〈0．005，P=0．040），其他毒性相仿，差异无统计学意义。A组与B组的中住生存期，中住缓解期，化疗的有效率和1年生存率均差异无统计学意义。结论：大剂量法乐通加EP方案治疗对铂类为主的化疗方案耐药的晚期NSCLC效果好，不良反应轻，耐受性好，达到了单药泰索帝二线治疗的效果。     

奥沙利铂联合氟尿嘧啶和亚叶酸钙治疗晚期大肠癌

目的：研究奥沙利铂、氟尿嘧啶、亚叶酸钙联合治疗晚期大肠癌的疗效和毒性反应，并将该方案和氟尿嘧啶与亚叶酸钙联合治疗方案相比较。方法：经病理确诊的晚期大肠癌83例分为以下两组：治疗组行奥沙利铂(oxalipatin)130mg／m^2静脉滴注，第1天给药：氟尿嘧啶(5-FU)425mg／m^2静脉滴注，第1-5天给药；亚叶酸钙(CF)100mg／m^2静脉滴注，第1～5天给药；每3周重复。对照组行氟尿嘧啶(5-FU)42h5mg／m^2静脉滴注,第1～5天给药；亚叶酸钙(CF)100mg／m^2。静脉滴注，第1-5天给药；每3周重复。每例患者至少完成两个周期。结果：治疗组有效率为46．5％，常见的毒性反应为神经毒性；对照组有效率为17．5％，与治疗组差别有统计学意义，未见神经毒性，其他毒性与治疗组无统计学差异。结论：奥沙利铂联合氟尿嘧啶和亚叶酸钙治疗晚期大肠癌,患者对其耐受良好，毒副反应较轻，疗效高于氟尿嘧啶加亚叶酸钙方案。     

健择联合顺铂治疗晚期非小细胞肺癌疗效分析

目的：观察健择(gemcitabine，GEM)／顺铂(DDP)每周给药方案治疗晚期非小细胞肺癌(non-small cell lung cancel，NSCLC)的近期疗效和毒性反应。方法：37例晚期NSCLC，分别于d1、d8和d15联合应用GEM(1000mg／m^2)和DDP(25mg／m^2)．28d为1个周期。治疗至少2个周期评价疗效。结果：36例可评价疗效，所有患者无CR，PR12例，NC15例，PD9例，总有效率为33．3％(12／36)。37例可评价毒性，3、4度粒细胞减少、血小板减少分别为13．5％(5／37)和16．2％(6／37)。结论：GEM／DDP每周给药方案疗效与其他GEM／DDP联合方案疗效相仿，但毒性反应明显低于其他方案，可用于老年患者或一般状况较差患者的治疗。     

Toxicology and pharmacokinetics of (1,1-bis(aminomethyl)cyclohexane)oxalatoplatinum(II) (TNO-38)

Preclinical studies on toxicology and pharmacokinetics were performed for (1,1-bis(aminomethyl)cyclohexane)oxalatoplatinum(II) (TNO-38) in rats and a dog after ld₁₀ and ld₅₀ assessment in mice. In drug-treated rats, ura and creatinine concentrations were 1,4-1.9 times those in control rats. Histopathology showed necrosis of tubular epithelium of the kidneys, which was comparable to damage observed after treatment with cisplatin (CDDP), and extensive necrosis of crypt epithelium, especially in the ileum.Similar to CDDP, TNO-38 was emetic in the dog. Non-specific subacute inflammatory changes were observed in the ileum. Renal damage was much less pronounced.Half-lives of distribution and elimination were 6.2 min and 5.2 days, respectively. The cumulative excretion of Pt in urine over 1 and 7 days after drug treatment was 38.3 and 49.3% of the dose, respectively. Twelve weeks after drug administration, Pt concentrations were highest in kidneys and liver.TNO-38 is adequately water soluble. Its reported antitumour activity is consistently lower than that of CDDP. The drug's toxicity was, in general, comparable to that of CDDP. Its pharmacokinetic profile was very similar to that of CDDP. It is concluded that TNO-38 should probably not be further evaluated in clinical studies.     

Clinical trials of Herceptin(R) (trastuzumab)

This report summarises the clinical efficacy and safety findings from clinical trials of the new anti-HER2 monoclonal antibody Herceptin(R) (trastuzumab). Data from pivotal trials indicate that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination significantly prolonged the median time to disease progression, increased the overall response rate, increased the duration of response, and improved median survival time by approximately 25% compared with chemotherapy alone. Furthermore, trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer, inducing durable objective tumour responses. In total, 15% of patients who had received extensive prior treatment for metastatic disease had an objective response. The median duration of response was 9.1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable.     

Antitumor effects of three platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate (DWA2114R), cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP), in mice.

(-)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP) were compared for their antitumor effects and nephrotoxicity-inducing activities at the same dosage (1/8, 1/4, 1/3, 1/2, 2/3 or 3/4 of the LD10 or LD10) on the basis of their intravenous lethal doses in mice. DWA2114R was effective against murine tumor lines, Colon 26 and Colon 38 carcinomas, M5076 ovarian sarcoma and P388 L1210 leukemias, implanted subcutaneously (s.c.). Triple injection every other day of DWA2114R was more effective than a single injection at each sublethal dose. The antitumor effects of DWA2114R against these tumors were more effective than or were similar to those of CBDCA and CDDP. The antitumor effect against CDDP-resistant L1210 leukemia implanted s.c. was only observed in the treatment of DWA2114R, but not in CBDCA and CDDP. No excellent antitumor effects of three platinum complexes were observed against Lewis lung carcinoma and B16 melanoma implanted s.c. even at triple injection every other day, and no effect was obtained against Meth-A fibrosarcoma under similar conditions. While the treatment of CDDP showed marked increases in levels of blood urea nitrogen and of urinary protein and sugar at effective doses in the antitumor evaluations, the treatment of DWA2114R as well as CBDCA showed no increase in these parameters. These results indicate that DWA2114R represents a desirable second generation antitumor platinum complex.     

Synergism of cytotoxicity between cis-diaminedichloro-platinum-(ii) and cis-diamine(1,1-cyclobutanedicarboxylate)-platinum-(ii)

In an attempts to increase the antitumor effect and to reduce normal tissue toxicity, the combined cytotoxic effect of cis-Diamminedichloroplatinum (II) (CDDP) and cis-diammine(1,1-cyclobutane dicarboxylate) platinum (II) (CBDCA) was investigated using HeLa and colon 26 cell lines and the combination index (CI). Cytotoxicity of the combination of CDDP and CBDCA on 27 surgically resected specimens of human gastric and colorectal adenocarcinomas was also evaluated using the in vitro succinate dehydrogenase inhibition (SDI) test. The CI values varied with the dose ratio examined (1:1-1:6) of CDDP and CBDCA, with findings that CI<1, synergy, was obtained at fraction affected (Fa)>0.75 for HeLa cells and at Fa<0.9 for colon 26 cells in cases of a dose ratio of 1:1 to 1:2. Of all 27 clinical human adenocarcinomas, the succinate dehydrogenase (SD) activity was significantly lower in cancer cells concomitantly exposed to both CDDP and CBDCA than in those exposed to either drug alone. These positive effects of a combination of two platinum analogues on human malignant tissues have heretofore not been reported, which would warrant the clinical application of this combination for human malignant tumors.     

In vitro evaluation of dichloro-bis(pyrazole)palladium(II) and dichloro-bis(pyrazole)platinum(II) complexes as anticancer agents

Introduction  Cisplatin (cis-diamminedichloroplatinum) was first identified for its anti-bacterial activity, and was later also shown to be an efficient anticancer agent. However, the therapeutic use of this anticancer drug is somewhat limited by its toxic side effects, which include nephrotoxicity, nausea, and vomiting. Furthermore the development of drug-resistant tumours is commonly observed following therapy with cisplatin. Hence there is a need for improved platinum derived drugs to overcome these limitations. Aims  Apoptosis contributes significantly to the cytotoxic effects of anticancer agents such as cisplatin; therefore in this study the potential anticancer properties of a series of pyrazole palladium(II) and platinum(II) complexes, [(3,5-R₂pz)₂PdCl₂] {R = H (1), R = Me (2)} and [(3,5-R₂pz)₂PtCl₂] {R = H (3), R = Me (4)}, were evaluated by assessment of their pro-apoptotic activity. Methods  The induction of apoptosis was measured in CHO cells by the detection of phosphatidylserine (PS) exposure using the annexin V and APOPercentage™ assays; DNA fragmentation using the Terminal deoxynucleotide transferase dUTP Nick End Labelling (TUNEL) assay; and the detection of activated caspase-3. Results  The platinum complexes were shown to be considerably more active than the palladium complexes, with complex 3 demonstrating the highest level of cytotoxic and pro-apoptotic activity. The LD₅₀ values for complex 3 and cisplatin were 20 and 70 μM, respectively, demonstrating that the cytotoxic activity for complex 3 was three times higher than for cisplatin. Various human cancer cell lines, including CaSki, HeLa, as well as the p53 mutant Jurkat T cell line were also shown to be susceptible to complex 3. Conclusions  Collectively, this in vitro study provides insights into action of palladium and platinum complexes and demonstrates the potential use of these compounds, and in particular complex 3, in the development of new anticancer agents.     

Non-surgical (medical) treatment of hepatocellular carcinoma (HCC)

Choice of treatment for HCC depends mainly on the size of tumor and patient's liver function because more than 80% of HCC patients are associated with liver cirrhosis. Percutaneous ethanol injection therapy (PEIT), transcatheter arterial embolization (TAE) and intraarterial infusion chemotherapy are, at present, commonly used treatments for HCC in Japan. PEIT is a safe and reliable treatment, in which absolute ethanol is injected to the tumor through a fine needle under US guide. PEIT is indicated for tumors of small size, which can not be removed surgically. The survival rate of PEIT for small liver cancer, less than 2 cm in diameter, is similar with the one of surgically removed cases. TAE is indicated for advanced HCC. Chemoembolization with Lipiodol is commonly used with good result. After TAE has been often performed, the survival rate of HCC patients was dramatically increased. In future, TAE combined with percutaneous transhepatic portal embolization or PEIT would be applied more often to obtain complete destruction of the lesion for advanced HCC. Intraarterial infusion chemotherapy is indicated for advanced HCC, in which TAE can not be performed. MMC, ADM and CDDP are commonly used anti-cancer drugs. Recently frequent infusion of these drugs has become possible by using implantable reservoir with good result. We have performed chemosensitivity test by SRCA for HCC specimens obtained by biopsy using a fine needle.     

Central nervous system (CNS) penetration of homoharringtonine (HHT)

Generally tritiated homoharringtonine ([³H]HHT, 150 Ci, 430 g) was administered intravenously to seven patients at varying times before surgical resection of malignant brain tumor. Plasma, urine, cerebrospinal fluid (CSF), and tumor specimens were obtained during surgery, and the concentrations of HHT, its major metabolite, and [³H]HHT equivalent were determined chromatographically and radiochemically. For [³H]HHT equivalent, the concentration in tumor ranged from 0.6 to 4.3 ng/g and the ratio of tumor to plasma concentration from 0.5 to 1.8. In one patient who had CSF available for drug determination, the CSF to plasma ratio of total [³H]HHT was 0.3 at 45 minutes after drug administration and less than 0.2 ng/ml was unchanged HHT. For unchanged HHT, drug concentration in tumor ranged from undetectable (4 patients) to 1.8 ng/g. A major metabolite of HHT was detectable in the tumor specimens of all the patients. These results indicate that homoharringtonine can penetrate into brain tumors; in 3 patients with brain tumors, the ratios of HHT concentration in the tumor to that in the concurrent plasma were greater than one. address for offprints