Pharmacokinetic analysis of a combined chemoendocrine treatment with paclitaxel and toremifene for metastatic breast cancer

Background  Multidrug resistance protein could be a target for improving the efficacy of paclitaxel (PXL). Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. Some P-gp moderators may change the pharmacokinetic parameters of PXL in vivo. A pharmacokinetic (PK) study in metastatic breast cancer patients (MBC) was conducted to determine the safety and efficacy of PXL and TOR. Method and patients  Fifteen patients received 80 mg/m² PXL (i.v.) weekly and 120 mg/body TOR (p.o.) daily. For the pharmacokinetic study, PXL was administered on days 1, 8, 15, 32, and 39; TOR was given from day 18 to the end of study. On days 1, 8, 15, 18, 32, and 39, blood samples were collected from the patients who received either PXL alone or PXL + TOR, and these were analyzed by high-performance liquid chromatography. Results  Among the 15 patients enrolled in the study, one showed a partial response, and eight had a stable disease. TOR caused no specific adverse events that were greater than grade 3, and its toxicity profile in combination with PXL was similar to that of PXL monotherapy. The PK profile of PXL was similar with or without TOR. The PK parameters of PXL indicated no inter- or intra-patient variability in previously treated patients with MBC. No increased PXL toxicity was observed. Conclusion  The PK profile of combined PXL and TOR was similar to that of PXL monotherapy. The addition of TOR to PXL in previously treated patients with MBC appears safe.     

toremifene增敏含铂方案治疗ⅢB、Ⅳ期NSCLC的临床Ⅱ期随机对照研究的初步结果

目的 在ⅢB、Ⅳ期非小细胞肺癌(NSCLC)患者中，观察大剂量toremifene是否能够增加含铂联合化疗方案的疗效。方法ⅢB、Ⅳ期初治NSCLC患者随机分成A、B两组，A组接受大剂量toremifene加铂类为基础的联合化疗方案，B组仅行以铂类为基础的联合化疗。结果 第1次中期分析有30例符合入选标准的患者入组，两组之间的血液毒性和非血液毒性均没有统计学差异。A组中位生存期为8个月，95％置信区间(CI)为6．63～9．37，B组中位生存期为7．5个月，95％CI为4．75～10．25，差异无统计学意义(P=0．9)。A组1年生存率为31%，对照组28%，差异无统计学意义(P=0．87)。A组化疗有效率为25％(4／16)，对照组21％(3/14)，差异无统计学意义(P=0．99)。结论 大剂量toremifene加含铂联合化疗方案治疗ⅢB、Ⅳ期NSCLC，与单用含铂联合化疗方案比较，未能显示增加化疗疗效作用，但毒性可耐受。     

A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors

Background Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR. GF120918 is a third-generation MDR converter with high affinity for P-glycoprotein and can be given orally. We performed a phase 1 study with escalating doses of GF120918 in combination with doxorubicin.Patients and methods The study group comprised 46 patients with advanced solid tumors. Doxorubicin was administered on day 1 (cycle 1), GF120918 on days 22–24 (cycle 2), and on days 29–33 with doxorubicin administered on day 31 (cycle 3). Pharmacokinetics of both GF120918 and doxorubicin were studied. The starting daily dose of GF120918 was 50 mg and was to be increased in subsequent cohorts until a steady state plasma level of 100 ng/ml was reached. The starting dose of doxorubicin was 50 mg/m² and was to be increased after reaching the target dose level of GF120918.Results In 37 of the 46 patients, full pharmacokinetic data from the three scheduled cycles were obtained. Pharmacokinetics of GF120918 showed a less than linear increase in C _max with increasing doses, with considerable interpatient variation. The target steady-state plasma level for GF120918 was exceeded in 12 out of 19 patients who received 400 mg GF120918 alone twice daily and in 12 of 17 patients who received 400 mg GF120918 twice daily in combination with doxorubicin. GF120918 pharmacokinetics were not influenced by coadministration of doxorubicin. The doxorubicin AUC was only marginally influenced by GF120918 and only at the highest dose levels. In these patients there was a significant increase in the AUC of doxorubicinol in cycle 3 as compared to cycle 1. Hematologic toxicity mainly consisted of neutropenia and was more severe in cycle 3 than in cycle 1 (13 vs 5 patients with grade 4 neutropenia, P=0.003). Neutropenic fever was the dose-limiting toxicity at a doxorubicin dose of 75 mg/m² with 400 mg GF120918 twice daily. The toxicity of GF120918 was limited to somnolence in eight patients and occasional gastrointestinal complaints.Conclusion GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro. A doxorubicin dose of 60 mg/m² on day 3 in combination with 400 mg GF120918 twice daily on days 1–5 is an acceptable regimen for further clinical trials.     

大剂量托瑞米芬逆转肺癌多药耐药及化疗增敏的临床研究

目的探讨大剂量托瑞米芬增敏长春瑞滨和顺铂（NP方案）对非小细胞肺癌（NSCLC）的化疗及逆转肺癌多药耐药的效果。方法入组患者随机分为两组。治疗组采用大剂量托瑞米芬＋NP方案治疗。对照组仅用NP方案治疗。治疗组患者在口服托瑞米芬后第2天和第8天抽血测定托瑞米芬血清浓度。结果治疗组PR 8例,SD 14例,PD 2例,有效率为33.3%。对照组PR 2例,SD19例,PD 3例,有效率为8.3%。治疗组与对照组相比,有效率差异有显著性（P〈0.05）。治疗组中位生存期9.4个月,对照组为6.3个月,两组中位生存期差异有显著性（P〈0.05）。治疗组1年生存率41.7%,对照组为20.8%,两组差异无显著性（P〉0.05）。两组不良反应差异无显著性。托瑞米芬血清浓度在第2天和第8天均超过5μmol/L。结论通过随机对照研究证实,大剂量托瑞米芬能增敏长春瑞滨和顺铂对NSCLC的化疗及逆转肺癌多药耐药,联合NP方案治疗NSCLC安全有效。     

多柔比星的耐药机制

多柔比星广泛应用于乳腺癌等肿瘤的化疗中,但因耐药使其应用受到一定限制。多柔比星耐药的产生机制可能涉及转运蛋白、凋亡蛋白、DNA修复功能、酶等因素。逆转多柔比星耐药的研究也在持续进行,为临床上克服多柔比星耐药提供了有效方案。但具体机制仍有待进一步阐释,并期待提出更合理的策略以提高疗效。     

Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis

IntroductionMany patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and β-catenin pathways.Material and methodsWe retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed.ResultsForty-four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G≥2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients.DiscussionPresent series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999     

Capecitabine and doxorubicin combination chemotherapy as salvage therapy in pretreated advanced gastric cancer

Purpose The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Methods Patients received capecitabine, 2,500 mg/m²/day PO for 14 days (D1–14) and doxorubicin, 30 mg/m² IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Results Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1–12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m²/week, respectively. The overall response rate was 6.7% (95% CI, 4.1–12.5%) and the disease control rate was 46.7% (95% CI, 28.6–87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6–16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3–39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). Conclusions The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer.     

Evaluation of combination therapy of high-dose toremifene and oral chemotherapy

High-dose toremifene therapy (120 mg/day) is useful for the recurrence of receptor-positive breast cancer. However, some reports show that combination therapy of high-dose toremifene and chemotherapy exhibits additive effects. Twelve patients were given oral chemotherapy (capecitabine, 5'-DFUR+CPA, S-1) with high-dose toremifene. The overall response rate was 41.7%, in addition to 58.3% with no change beyond three months. Adverse events were restricted to headache, stomatitis and nausea. Average time to progressive (TTP) was 5.8 months. It was shown that high-dose toremifene and oral chemotherapy were useful for breast cancer recurrence without severe side effects.     

法乐通治疗晚期乳腺癌临床总结

目的 考察法乐通治疗晚期绝经后乳腺癌的放疗及其不良反应。方法：法乐通一线治疗每日一次６０ｍｇ口服,二线治疗每日一次１２０ｍｇ口服。结果：共６０例,有效率１８．３％,一线治疗１８例,有效率３３．３％,二线治疗４２例,有效率１１．９％,淋巴结和骨转移疗效较好,肝转移,肺转移及胸壁转移也有一定疗效。一线治疗较二线治疗,未用内分泌治疗较曾用内分泌治疗,绝经时间长（≥１０年）较经时间短（〈１０年）以及疗后无     

A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer

Purpose  This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. Patients and methods  Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m² of bortezomib with 15 mg/m² of doxorubicin to 1.5 mg/m² of bortezomib with 20 mg/m² of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. Results  The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m² bortezomib, 20 mg/m² doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m² bortezomib, 15 mg/m² doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. Conclusions  Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m² intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease. Supported by grant: U01 CA062491 “Early Clinical Trials of Anti-Cancer Agents With Phase I Emphasis, NCI” and M01 RR03186 “General Clinical Research Center Program of The National Center for Research Resources, NIH”.     

Influence of age on toremifene pharmacokinetics

Toremifene pharmacokinetics were compared in ten healthy young men (< 33 years) and elderly women (< 65 years). A single oral 120-mg dose of toremifene was given after an overnight fast and blood samples were collected over 28 days. Serum levels of the parent drug and the metabolites were determined; appropriate pharmacokinetic parameters were calculated and statistically evaluated. Toremifene peak concentrations (average 640 ng/ml) were achieved at 3.5 h. The area under the curve (AUC) and the apparent oral clearance were comparable in the young and elderly subjects. The half-life was prolonged (4.2 versus 7.2 days) and the apparent volume of distribution was increased (457 versus 627 l) in the elderly. The peak concentration of the main metabolite N-demethyltoremifene was lower (159 versus 233 ng/ml) and the half-life was prolonged (8.3 versus 19.1 days) in the elderly subjects, but the AUC values were comparable. The results suggest that toremifene is distributed more widely in the elderly but that its clearance is unaffected by age. It is concluded that the dosage requirement of the drug is unlikely to differ between young and elderly subjects. Received: 16 June 1996 / Accepted: 15 December 1996     

A new procedure for the preparation of liposomal doxorubicin: biological activity in multidrug-resistant tumor cells

We describe a new procedure for the preparation of liposomal doxorubicin. Doxorubicin can be efficiently complexed to preformed or lyophilized cardiolipin-containing liposomes. Complex formation was performed by vigorous vortexing. As much as 96.8% of the initial drug quanitty may be bound to those liposomes under optimal incubation conditions (4 h at 37°C). The binding study showed the presence of two levels of specific binding (dissociation constants, 28±8 M and 1.0±0.3 mM). The drug is firmly integrated in the liposome-membrane lipid bilayer rather than binding at the surface. Cytotoxicity studies using tumor cells revealed efficient drug delivery using liposome-complexed doxorubicin. This new liposomal doxorubicin preparation reverses multidrug resistance in MCF-7/ADR and CH LZ cells at levels equivalent to that obtained with a previously described liposome-encapsulated doxorubicin preparation, showing that the drug is integrated as well in the liposome carrier and is transported as well into cells. Increased concentration of liposomes at the subcytotoxic level in liposome-complexed doxorubicin enhances drug cytotoxicity in multidrug-resistant CH LZ cells as compared with liposome-encapsulated drug. This new preparation for liposomal doxorubicin may be carried out immediately prior to clinical administration, offering advantages in terms of cost and stability.Abbreviations Dox Doxorubicin - Lip liposomes - Dox-Lip liposomally encapsulated doxorubicin - Dox+Lip liposomally associated doxorubicin - MDR multidrug resistance     

阿霉素耐药性研究与流式细胞分析

目的 探讨流式细胞术在阿霉素多药耐药研究中的特殊意义。方法 对两组不同耐药倍数的阿霉素耐药细胞系（S－180R和BGC－823／DOX）进行动态、对比性流式细胞分析。结果 流式细胞术在高倍数耐药细胞系S－180R中表现出与亲代细胞耐药性的直观的整体差异，在低倍数耐药细胞系BGC－823／DOX中则可以定量地分辨与亲代细胞耐药性的细微差异。在动态分析中，检测到耐药细胞群中个体细胞耐药性的变化，即个体细胞内荧光含量的接近，细胞荧光峰的集中。结论 流式细胞术在阿霉素耐药性研究中具有灵敏、准确、定量的作用。     

艾迪与多柔比星联合对骨肉瘤细胞杀伤协同作用的观察

目的:探讨中药制剂艾迪对骨肉瘤化疗的增效作用及其相关机制。方法:将艾迪与多柔比星单独及联合应用于骨肉瘤OS732细胞,MTT法检测细胞生长抑制率,流式细胞仪定量分析凋亡细胞所占比例,倒置相差显微镜及荧光显微镜下观察凋亡细胞形态改变,免疫细胞化学技术分析凋亡相关蛋白Fas表达。结果:艾迪与多柔比星对骨肉瘤细胞都有剂量依赖性杀伤作用,艾迪浓度达到25μL/mL时,细胞生长受到抑制,再增加艾迪浓度抑制率不再明显改变,但如与1μg/mL多柔比星合用将使细胞生长抑制率进一步提升,P=0.003。细胞超微结构观察及凋亡率测定结果也显示,艾迪与多柔比星联用可诱导更多骨肉瘤细胞凋亡,且联用时骨肉瘤Fas表达明显提升,P=0.005。结论:艾迪与小剂量多柔比星合用与单用多柔比星相比可更高效杀伤骨肉瘤细胞,此作用与上调Fas表达诱导骨肉瘤细胞凋亡有关。     

Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients

Purpose: The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer. Methods: The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety. Results: A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity. Conclusions: Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses. Received: 5 August 1999 / Accepted: 28 October 1999     

托瑞米芬逆转乳腺癌耐药蛋白介导的多药耐药机制

目的 探讨托瑞米芬逆转乳腺癌耐药蛋白(BCRP)介导的多药耐药机制。方法 通过基因扩增,构建分别由BCRP启动子和巨细胞病毒(CMV)启动子启动表达BCRP的重组质粒pcDNA3-Promoter-BCRP和作为对照的质粒pcDNA3-CMV-BCRP,将其分别转染雌激素受体α（ERα）阳性的MCF-7和ERα阴性的MDA-MB-231乳腺癌细胞系,建立由BCRP启动子和CMV启动子启动表达BCRP的4种耐药细胞系MCF-7/Promoter-BCRP、MCF-7/CMV-BCRP、MDA-MB-231/PromoterBCRP和MDA-MB-231/CMV-BCRP。在耐药细胞培养基中加入托瑞米芬,通过逆转录聚合酶链反应(RT-PCR)、Western blot、外排实验以及细胞毒性实验观察托瑞米芬对不同细胞系的耐药逆转效果。结果与空白对照组（未加药物）相比,托瑞米芬以剂量依赖方式抑制BCRP mRNA的表达,0.1、1和10 μmol/L托瑞米芬处理组MCF-7/Promoter-BCRP细胞中BCRP mRNA的表达水平分别下调29.5％(P＜0.05)、68.1％ (P＜0.01)和97.4％(P＜0.01);MCF-7/Promoter-BCRP细胞经托瑞米芬和17β-雌二醇联合处理后,细胞中BCRP mRNA的相对表达水平为64.2％±1.3％,明显高于托瑞米芬单独处理组(3.8％±0.2％,P＜0.01)。托瑞米芬对各组细胞系中BCRP蛋白表达的调控作用与mRNA相似。经托瑞米芬处理后,MCF-7/Promoter-BCRP细胞内米托蒽醌的荧光强度显著增强,外排米托蒽醌的能力降低了 47.3％ (P ＜0.05);经托瑞米芬和17β-雌二醇联合处理后,MCF-7/Promoter-BCRP细胞内米托蒽醌的荧光强度明显低于托瑞米芬单独处理组,外排米托蒽醌的能力升高了61.5％。托瑞米芬可有效逆转MCF-7/Promoter-BCRP细胞对米托蒽醌的耐药性。上述作用在MCF-7/CMV-BCRP、MDA-MB-231/Promoter-BCRP和MDA-MB-231/CMV-BCRP细胞中未能体现。结论 托瑞米芬可能通过ERot的介导与BCRP启动子上游调控序列中的ERE结合,负性调节BCRP的表达,抑制BCRP蛋白的功能,在体外有效逆转BCRP介导的多药耐药。     

大剂量法乐通加EP方案治疗耐药晚期非小细胞肺癌临床分析

目的评价大剂量法乐通加EP方案治疗难治性晚期非小细胞肺癌的疗效和毒副反应.方法既往对含顺铂为主的化疗方案耐药的晚期非小细胞肺癌采用大剂量的法乐通加EP方案治疗,法乐通480 mg,口服,连用7.5 d;鬼臼乙叉甙100 mg/m2,静滴,第4～6天;顺铂80 mg/m2,静滴,第4天,每4周重复.结果共50例进入临床研究,可评价疗效43例,1例完全缓解,8例部分缓解,总有效率为20.9%(按ITT计算为18.0%);中位生存期和无疾病进展生存期分别为8.1和3.2个月;1年生存率为37.2%.主要的不良反应为轻至中度的骨髓抑制、恶心和呕吐.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非小细胞肺癌效果较好,不良反应轻,耐受性好.     

The effects of atamestane and toremifene alone and in combination compared with letrozole on bone,serum lipids and the uterus in an ovariectomized rat model

Summary We compared the effects of atamestane (ATA) and toremifene (TOR) alone and in combination, with letrozole (LET) on bone, serum lipids and the uterus in ovariectomized (OVX) rats after 16 weeks of treatment. Compared to OVX controls lumbar vertebral and femoral BMD as well as mechanical strength and trabecular bone volume were significantly greater in animals given ATA, TOR or ATA + TOR. The effects of ATA were not reversed by the androgen receptor blocker, flutamide (FLT). Serum cholesterol, low-density lipoprotein cholesterol and triglycerides were reduced by TOR and ATA + TOR whereas they remained unchanged in animals receiving ATA, ATA + FLT, and LET. The uterine epithelium in OVX animals was equally stimulated by TOR and ATA + TOR and unaffected by ATA or LET. Intact animals had significant atrophy of the uterine epithelium when receiving ATA. In summary, TOR alone or in combination with ATA had a predictable stimulatory effect on bone and the uterine epithelium while reducing key parameters of lipid metabolism. In contrast, ATA but not LET had an unexpected stimulatory effect on the OVX rat’s bone and this was not reversed by the anti-androgen FLT leaving this finding unexplained for now. ATA is distinct from LET on end-organ function and this favorable profile makes clinical testing of this steroidal aromatase inhibitor of interest in the clinical setting.     

A phase II study of oxaliplatin in combination with doxorubicin as first-line systemic chemotherapy in patients with inoperable hepatocellular carcinoma

Purpose  We designed a phase II trial of the combination with oxaliplatin and doxorubicin for patients with unresectable HCC to evaluate the overall response rate (ORR) and the toxicity. Methods  Forty patients with inoperable, systemic chemotherapy naive HCC were enrolled. Finally, 32 patients received oxaliplatin (130 mg/m²) and doxorubicin (60 mg/m²) every 3 weeks. Results  Eighty-two treatment cycles were administered (median 2 cycles, range 1–6). There was no treatment-related mortality. The ORR was 15.6% (95% CI, 3.3–28.7) with five partial responses. The median overall survival and median overall progression free survival were 31 weeks (95% CI, 22–40 weeks) and 12 weeks (95% CI, 5-19 weeks). Nausea and peripheral neuropathy were most frequent non-hematologic toxicities (nausea, n = 15; peripheral neuropathy, n = 10). The most frequent grade 3–4 hematologic adverse event was neutropenia (14 of 82 cycles) including three cases of febrile neutropenia. Conclusions  The combination of oxaliplatin and doxorubicin showed modest activity and a tolerable toxicity profile in advanced HCC patients.