Envafolimab combined with chemotherapy in the treatment of combined small cell lung cancer: A case report

BACKGROUND Combined small cell lung cancer(C-SCLC) is a special subtype of small cell lung cancer that is relatively rare, aggressive, and prone to early metastasis and has a poor prognosis. Currently, there are limited studies on C-SCLC, and there is no uniform standard treatment, especially for extensive C-SCLC, which still faces great challenges. In recent years, the development and progress of immunotherapy have provided more possibilities for the treatment of C-SCLC. We used immunotherapy c...     

Phase II Study of Combination Chemotherapy with Etoposide and Ifosfamide in Patients with Heavily Pretreated Recurrent or Persistent Epithelial Ovarian Cancer

The aim of this trial was to investigate the efficacy and toxicity of combination chemotherapy with etoposide and ifosfamide (ETI) in the management of heavily pretreated recurrent or persistent epithelial ovarian cancer (EOC). Patients with recurrent or persistent EOC who had measurable disease and at least two prior chemotherapy participating in this phase II trial were to receive etoposide at a dose of 100 mg/m²/day intravenously (IV) on days 1 to 3 in combination with ifosfamide 1 g/m²/day IV on days 1 to 5, every 21 days. Thirty-seven patients were treated; about 78% had previously received more than two separate regimens. The response rate (RR) was 18.9% and median duration of response was 7 months (range, 1-15). Treatment free interval prior to ETI (TFI) has significant correlation with RR rate (P=0.034). Patients (n=6) with TFI ≥6 months had 50% of RR, while patients (n=31) with TFI <6 months had 12.9%. Median survival was 9 months at a median follow-up of 9.2 months. Grade 3 or 4 toxicities included neutropenia in 20.1% of the 139 cycles of ETI, anemia in 7.2% and thrombocytopenia in 8.6%. The ETI produces relatively low toxicity and modest activity in heavily pretreated recurrent or persistent EOC. This is significant in patients with TFI ≥6 months.     

In vivo inhibition of etoposide-mediated apoptosis,toxicity, and antitumor effect by the topoisomerase II-uncoupling anthracycline aclarubicin

A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracyclines daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80–90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.This work was supported by the Danish Cancer Society     

In vitro and in vivo Effects of Cisplatin and Etoposide in Combination on Small Cell Lung Cancer Cell Lines

The effects of cisplatin (CDDP) and etoposide (ETP) in combination were evaluated in vitro and in vivo using small cell lung cancer cell lines. The combination effects in vitro were investigated using isohologram analysis. Used together, CDDF and ETP showed a synergistic effect against cell growth on only 1 cell line (SBC-3), additive effects on 6 (SBC-2, SBC-5, Lul30, Lul34AH, Lul35T and H69) and an antagonistic effect on 1 (SBC-1). In the in vivo experiment, nude mice were inoculated with SBC-1, SBC-3 and SBC-5 cells. Two or 5 mgAg CDDP and 10 or 30 mgAg ETP were administered intraperitoneally alone and simultaneously in combination to nude mice. The in vivo effects of the combination were determined by comparing the observed growth ratio in mice treated with the combination with the expected value of this ratio calculated based on the assumption that the effects of the drugs were simply additive. According to this definition, synergistic effects were observed against all 3 tumors. Thus, the in vivo and in vitro effects differed. The toxicity of the combination therapy, which was analyzed by estimating the body weight change of mice, was no higher than that of CDDP or ETP alone. These results suggest that the excellent clinical effects of CDDP and ETP combination therapy may he attributable not to drug interaction at the cellular level hut to the feasibility of combined use of them at full doses without overlapping side effects.     

Etoposide protein binding in cancer patients

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r=–0.74), daily dose (r=–0.37) and age (r=–0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.     

Is there a circadian variation in plasma concentrations of etoposide given by prolonged continuous infusion?

 The prolonged continuous infusion of low-dose etoposide is a new approach to treating cancer. Whether or not a circadian variation in the plasma levels of etoposide existed was investigated in nine patients with non-small-cell lung cancer. Etoposide was infused for 14 days and blood samples were obtained every 4 h for 1 day. There was no significant circadian variation, and the observed small within-day variations seemed to lack clinical significance. Received: 24 March 1995 / Accepted: 2 August 1995     

Inhibition of etoposide elimination in the isolated perfused rat liver by Cremophor EL and Tween 80

 Cremophor EL, a surfactant used in the clinical formulation of cyclosporine and paclitaxel, will reverse the multidrug resistance (MDR) phenotype in vitro. As other MDR modulators can alter the pharmacokinetics of cytotoxic drugs, the aim of this study was to examine the effect of Cremophor and another MDR-reversing surfactant, Tween 80, on the hepatic elimination and biliary excretion of etoposide. Using the isolated perfused rat-liver model with 80 ml recirculating perfusate containing 20% red blood cells and 4% bovine serum albumin, etoposide (1.6 mg) with and without Cremophor (800 or 80 mg) or Tween 80 (80 mg) was given into the perfusate reservoir, and perfusate and bile samples were collected for 3 h. Etoposide was measured by high-performance liquid chromatography (HPLC) and Cremophor was measured using a bioassay. Both surfactants changed the etoposide elimination profile from biphasic to monophasic. High-dose Cremophor increased the AUC (from 334±23 to 1540±490 μg min ml^-1, P<0.05) and decreased the total clearance (from 4.8±0.3 to 1.1±0.3 ml/min, P<0.05) and biliary clearance (from 2.6±1.1 to 0.5±0.2 ml/min, P<0.05) but decreased the elimination half-life (from 62±17 to 40±5 min, P<0.05) and volume of distribution (from 424±85 to 65±19 ml, P<0.05). Low-dose Cremophor and Tween 80 caused intermediate effects on these parameters that were statistically significant for total clearance, half-life, and volume of distribution. Cremophor had no adverse effect on liver function, whereas Tween 80 caused haemolysis and cholestasis. The initial high-dose Cremophor perfusate concentration was 0.8 mg/ml, which previous studies have shown to be clinically relevant and close to the optimal level for MDR reversal in vitro (1.0 mg/ml). Cremophor may be a clinically useful MDR modulator, but it may alter the pharmacokinetics of the cytotoxic drug. Received: 5 January 1995/Accepted: 25 August 1995     

Treatment of advanced gastric cancer with etoposide,folinic acid,and fluorouracil in the clinical setting: efficacy of therapy and value of serum tumor markers

The combination of etoposide, folinic acid, and 5-fluorouracil (5-FU) (ELF regimen) has been proved to be an active chemotherapy in patients with advanced gastric cancer. The aim of this study was to confirm the efficacy in the clinical setting and to correlate response with different parameters like serum tumor markers. We treated 60 patients with advanced gastric cancer with 120 mg/m² etoposide, 300 mg/m² folinic acid, and 500 mg/m² 5-FU, on d 1–3. The cycle was repeated on d 21. Objective response was obtained in 23% of all patients with measurable disease. Stable disease was obtained in 37%. The tumor-growth-control rate in patients with proximal carcinoma was significantly higher than in those with distal carcinoma (85% vs 48%, p=0.04). Median survival for all patients was 8.0 mo (95% confidence interval [CI] 7.0–8.5). In responsive patients, survival was more than two-fold longer than in patients with progressive disease. The administration of ELF could be performed safely on an outpatient basis. Toxicity was rather mild. The most frequently elevated serum tumor marker was CA 72-4 (55% of the patients). An elevated level of carcinoembryonic antigen before treatment was significantly correlated with progressive disease. A more than two-fold elevation of at least one marker under treatment was significantly correlated to progressive disease (p<0.002). A reduction of at least one marker under treatment was significantly correlated to tumor growth control (p<0.00015). The results of the present trial confirm the efficacy and low toxicity of the ELF regimen in advanced gastric carcinoma. Serum tumor markers proved suitable parameters for assessing response to treatment.     

嗅神经母细胞瘤的化疗

分析影响嗅神经母细胞瘤化疗的因素并探讨嗅神经母细胞瘤的化疗方案。方法：回顾分析1993年3月至2004年6月收治的4例行化疗的嗅神经母细胞瘤患者的临床资料，包括就诊时年龄、性别、病程、Kadish分期、组织病理学分级、治疗方式、预后，并对文献进行复习。结果：4例均为男性，平均31.5岁，Kadish分期均为C期。组织病理学分级：2级1例，3级2例，4级1例。化疗药物4例含有足叶乙甙、3例含有铂类药物。化疗在首次治疗中应用1例（病理2级随访6个月，带瘤生存），挽救治疗中应用3例（2例病理3级分别随访48个月、6个月无瘤生存，1例病理4级随访12个月带瘤生存）。结论：嗅神经母细胞瘤治疗采用化疗有效，组织病理学分级影响肿瘤对化疗的敏感性，化疗宜采用含铂类及足叶乙甙的多种药物。     

伊立替康联合顺铂方案与足叶乙甙联合顺铂方案治疗小细胞肺癌的随机对照临床研究

背景与目的 足叶乙甙＋顺铂（EP）方案是治疗小细胞肺癌（SCLC）的标准方案，本试验拟比较伊立替康＋顺铂（IP）方案与EP方案治疗SCLC的近期疗效和毒副作用。方法 61例SCLC患者被随机分组，接受IP或EP方案化疗2个周期以上，评价疗效及毒副作用。结果 ①IP组有效率为66．7％，完全缓解率为23．3％；EP组有效率为61．3％，完全缓解率为16．1％。两组近期疗效比较无显著性差异（P〉0．05）。②IP组Ⅲ～Ⅳ度白细胞下降2例（6．7％），EP组11例（35．5％），两组比较有显著性差异（P〈0．01）；IP组Ⅲ～Ⅳ度中性粒细胞下降2例（6．7％），EP组16例（51．6％），两组比较有显著性差异（P〈0．001）；IP组血小板减少8例（26．7％），EP组25例（80．6％），两组比较有显著性差异（P〈0．001）；IP组腹泻11例（36．7％），EP组2例（6．5％），两组比较有显著性差异（P〈0．01）；两组Ⅲ～Ⅳ度恶心呕吐比较无显著性差异（P〉0．05）；胆碱能综合征、肝肾功能异常、周围神经炎、脱发、静脉炎等均少见。结论 IP和EP方案是治疗SCLC有效的方案。与EP方案相比，IP方案疗效相似，而血液学毒性较轻，IP方案的腹泻毒性较明显，可以通过对症治疗控制。