Gemcitabine and ifosfamide as a second-line treatment for cisplatin-refractory metastatic urothelial carcinoma: a phase II study

Few treatment options are available for cisplatin-refractory urothelial carcinoma. We evaluated the efficacy and safety of a new regimen composed of gemcitabine and ifosfamide as a second-line salvage chemotherapy for the disease. The gemcitabine and ifosfamide regimen consists of gemcitabine 800 mg/m/day intravenously for 30 min on days 1, 8, and 15; ifosfamide 1500 mg/m/day intravenously for 24 h on days 8-10; and mesna 800 mg intravenously bolus before ifosfamide and 1500 mg/m/day intravenously for 24 h on days 8-11. Cycles are repeated every 28 days. Between 1998 and 2005, 23 patients (median age 66) unresponsive to cisplatin-based chemotherapy (n=10) or who had tumor progression within 6 months of a previous response to cisplatin-based therapy (n=13) were enrolled. The median interval between the two chemotherapy regimens was 1.8 months (range 0.9-5.6). In total, 82 treatment cycles (median 3, range 1-8) were given. The overall response rate was 22% (95% confidence interval 5-39) with one complete response and four partial responses. Twenty-one patients succumbed to the disease. The median progression-free survival and overall survival were 3.5 and 4.8 months, respectively. Grade 3 or 4 leukopenia and thrombocytopenia occurred in 10 and eight patients, respectively. One, two and two patients complicated with grade 3 vomiting, diarrhea and stomatitis were present, respectively. No grade 3 or 4 neurotoxicity or nephrotoxicity was seen in these patients. The gemcitabine and ifosfamide regimen has an acceptable toxicity profile, but shows insufficient clinical activity in patients with cisplatin-refractory urothelial carcinoma to warrant further testing.     

Gemcitabine plus docetaxel as first-line biweekly therapy in locally advanced and/or metastatic urothelial carcinoma: a phase II study

The purpose of the study was to evaluate objective response rate, survival and toxicity of the combination of gemcitabine-docetaxel administered on a biweekly schedule as first-line treatment in advanced/relapsed or metastatic urothelial carcinoma. Treatment consisted of the sequenced administration of gemcitabine 1500 mg/m(2) and docetaxel 60 mg/m(2) (2 h intravenous infusion) on days 1, 14 of a 28-day cycle for 6 months. A total of 33 patients, 22 men and 11 women, were enrolled, aged 41-75 years (median 64 years). The majority of patients had a good performance status (94%; status<2). Thirteen patients had locally advanced disease (39%) and 20 metastasic disease (41%). A total of 178 treatment cycles were administered with a median number of 5.4 cycles for a patients (range 2-8). Toxicity was primarily hematologic with the most frequent grade >2 being neutropenia (11%), with three episodes of febrile neutropenia. Anemia and thrombocytopenia were milder and had a lower incidence. The most frequent nonhematological toxicities were alopecia, followed by asthenia. Cardiac and pulmonary toxicity was minimal. No toxic deaths were recorded during study and follow-up. Overall response rate was 53.1%, including four complete responses (12.5%) and 13 partial responses (40.6%), whereas six patients (18.8%) had disease stabilization. Median time to progression was 10.2 months (95% confidence interval: 5.1-13.7), with a median survival of 14.8 months (95% confidence interval: 9.4-20.2) after an observation of 30 months (range 4-30+). The results of this study suggested that combination therapy with gemcitabine and docetaxel administered twice a week is particularly active and well tolerated as first-line treatment in advanced and/or metastatic urothelial carcinoma. Once data are confirmed in a larger study and longer follow-up, the favorable toxicity profile of this regimen may offer an interesting alternative to the cisplatin-based regimen.     

二次电切联合吉西他滨即刻灌注治疗非肌层浸润性膀胱癌的临床效果

目的 研究二次电切联合吉西他滨即刻膀胱灌注治疗非肌层浸润性膀胱癌的临床效果。方法 选择2011年10月至2014年10月在中国人民解放军联勤保障部队第901医院行经尿道膀胱肿瘤切除术（TURB-t）治疗的52例非肌层浸润性膀胱癌患者,将仅行TURB-t的24例患者为对照组,TURB-t术后且行二次电切的28例患者为观察组,两组患者均使用吉西他滨即刻灌注治疗。分析两组患者肿瘤病灶残留、肿瘤的复发率及进展率情况。结果 对照组患者首次TURB-t术后残留率为8.33%,观察组为14.29%,两组差异无统计学意义（χ²=0.055,P=0.815）。对照组患者12个月内肿瘤复发率为33.33%,观察组为7.14%,两组差异有统计学意义（χ²=4.145,P=0.042）;对照组患者24个月内复发率为50.00%,观察组为17.86%,两组差异有统计学意义（χ²=6.068,P=0.014）。对照组患者24个月内肿瘤进展率为33.33%,观察组为7.14%,两组差异有统计学意义（χ²=4.145,P=0.042）。结论 二次电切能减少肿瘤病灶残留,二次电切联合吉西他滨即刻膀胱灌注治疗能够降低非肌层浸润性膀胱癌的复发率。     

Gemcitabine in bladder cancer

Gemcitabine, a deoxycytidine analogue, is an inhibitor of DNA synthesis. With myelosupression being its most serious toxicity, gemcitabine has, however, a favourable toxicity profile. It was tested in urothelial bladder cancer at different stages of the disease. In superficial Bacillus Calmette-GuErin (BCG)-resistant bladder cancer as well as in BCG-intolerant patients, intravesical gemcitabine instillation has demonstrated a significant activity. In the adjuvant setting, the combination of gemcitabine and cisplatin (GC) has proved to be a feasible protocol. In locally advanced and metastatic disease, GC is admitted as a standard alternative first-line regimen. Gemcitabine is also an interesting choice for unfit patients when used as a single treatment or in combination with other chemotherapeutic agents as carboplatin or taxanes. This article reviews most of the studies performed in order to promote the usefulness of gemcitabine in bladder cancer.     

盐酸吉西他滨的合成

2-脱氧-2，2-二氟-D-赤型-呋喃戊糖-1-酮-3，5-二苯甲酸酯经四氢锂铝还原、甲磺酰化得2-脱氧-2，2-二氟-D-呋喃核糖-3，5-二苯甲酸酯-1-甲磺酸酯，与胞嘧啶缩合后在含氨甲醇中脱保护基，成盐后于含水丙酮中结晶分离得盐酸吉西他滨，总收率14％。     

Gemcitabine: vascular toxicity and prothrombotic potential

Background: Gemcitabine has been associated with important thrombotic and vascular side effects. As indications for its use in oncology and hematology are expanding, comprehensive characterization of these complications becomes imperative. Objective: This article reviews the prothrombotic potential and other vascular effects of gemcitabine and experience accrued through its use in research laboratories, clinical trials and clinical practice. Methods: The most relevant publications were identified through the PubMed database and by reviewing the drug information released by the FDA. Results/conclusions: In the author's opinion, the incidence of thrombotic and vascular toxicity with gemcitabine is higher than previously estimated. Venous thromboembolism (VTE) and acute arterial events, digital ischemia and necrosis, vasculitis and thrombotic microangiopathy, potentially fatal systemic capillary leak and reversible posterior leukoencephalopathy syndromes are only a few items on the long list of vascular–toxic effects of gemcitabine. These toxicities seem to be more frequent with the use of gemcitabine–platinum doublets than with gemcitabine alone. Careful consideration of gemcitabine use should be given in the setting of pre-existing arterial vascular disease, venous thromboembolism, collagenoses, heart failure, liver damage and advanced hepatic metastases. Specific treatment requirements of individual patients, their comorbidities and the gemcitabine risk:benefit ratio should be always sought before using this agent in antineoplastic therapy.     

Gemcitabine and Vinorelbine (GemVin) Regimen

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110–545, Arlington, VA 22203, e-mail: ten.tsacmoc@cvSxRcnO; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: ten.retrahc@ruofddaw.Regimen Name: Gemcitabine and vinorelbine (GemVin)Origin of Name: The regimen is named for the 2 drugs it contains: gemcitabine and vinorelbine.     

Gemcitabine and radiosensitization in human tumor cells

Summary Gemcitabine is a nucleoside analogue with excellent clinical activity against solid tumors. Within the cell, gemcitabine is rapidly phosphorylated to its active di-and triphosphate metabolites. Cytotoxicity with gemcitabine appears to be related to multiple effects on DNA replication, where gemcitabine triphosphate can serve as both an inhibitor and substrate for DNA synthesis. Gemcitabine diphosphate inhibits ribonucleotide reductase, producing decreases in cellular dNTP pool levels in a cell-specific manner. These two major characteristics of gemcitabine, reduction in cellular dNTP pools and incorporation into DNA, are features of other antimetabolites antitumor agents which also exhibit radiosensitizing properties. Based on these favorable metabolic characteristics and the clinical activity of gemcitabine in tumor types which are commonly treated with radiation, the ability of gemcitabine to enhance X-radiation induced cytotoxicity was evaluated. Gemcitabine has been shown to be a potent radiosensitizer in a variety of tumor cell lines, including HT-29 colorectal carcinoma, pancreatic cancer, breast, non-small cell lung and head and neck cancer cell lines. Gemcitabine was most effective as a radiosensitizer when administered at least 2 hours prior to irradiation. For most cell lines, radiosensitization was evident at non-cytotoxic concentrations. The extent of radiosensitization increased with both increasing gemcitabine concentration and duration of exposure. Radiosensitization did not require redistribution of cells into a more radiosensitive phase of the cell cycle. The major metabolic effects observed under radiosensitizing conditions were the accumulation of high levels of gemcitabine triphosphate, and a selective decrease in the cellular dATP pool. The pattern of dATP decrease paralleled the increase in radiosensitization, whereas the level of gemcitabine triphosphate was not associated with the enhanced sensitivity to radiation. Compared to other radiosensitizers, the advantage of gemcitabine is that is can induce radiosensitization at concentrations that are 1000 times lower than typical plasma levels obtained with this drug. These studies will be used as guidelines for developing clinical trials of gemcitabine with radiation.     

吉西他滨联合顺铂与联合卡培他滨治疗晚期胰腺癌的疗效比较

目的观察吉西他滨联合顺铂（GEMDDP方案）与吉西他滨联合卡培他滨（GEMCAP方案）治疗晚期胰腺癌的疗效及不良反应。方法60例晚期胰腺癌患者,随机分为两组,分别予GEMDDP方案与GEMCAP方案治疗。结果可评估病例54例,GEMCAP组在疾病控制率、临床受益反应方面均高于GEMD—DP组（73．1％与50．O％）、（53．6％与37．9％）,但无统计学意义。两组6个月生存率、12个月生存率及中位总生存期,差异无统计学意义。GEMCAP组手足综合征常见,其余不良反应相似。结论两组治疗方案的疗效及主要不良反应相似。     

培美曲塞联合吉西他滨与吉西他滨单药治疗胰腺癌患者的临床对照研究

目的 对比观察培美曲塞联合吉西他滨化疗与吉西他滨单药治疗胰腺癌的临床疗效,进一步优化胰腺癌化疗方案.方法 将72例非手术治疗的胰腺癌患者随机分为两组:联合化疗组35例,静脉滴注培美曲塞600 mg/m²与吉西他滨1 000 mg/m²联合化疗.单药治疗组37例,吉西他滨单药600 mg/m²化疗,疗程均为4个周期(每个周期间隔21 d).26周进行近期疗效及安全性分析,随访2年观察患者生存期.结果 (1)疾病控制率(DCR):联合治疗组为62.86%,单药治疗组为51.35%,两组比较差异无统计学意义(χ²=0.97,P=0.32);但早期患者联合治疗组DCR(85.71%)优于单药治疗组(56.52%),两组比较差异有统计学意义(χ²=4.49,P=0.034);(2)生存时间:联合治疗组中位生存时间为8.9个月,单药治疗组为8.1个月,两组比较无统计学差异.(3)不良反应:联合治疗组粒细胞、血小板减少和肝功能异常的发生率(60.2%、53.9%、54.2%)均高于单药组(32.1%、24.3%、27.0%),差异有统计学意义(P <0.05).结论 培美曲塞与吉西他滨联合化疗可以提高早期胰腺癌患者的疗效,同时也相应地增加对骨髓造血功能的抑制和肝损伤的风险.     

Interstitial Pneumonitis from Treatment with Gemcitabine

Introduction:

The use of gemcitabine may lead to numerous adverse effects ranging from mild to very severe, such as interstitial pneumonitis. The diagnosis of this complication is based on multiple laboratory findings, radiographic evidence, and high clinical suspicion. Presented is a case report of a patient who met these criteria and had onset consistent with drug-induced interstitial pneumonitis.

Case Presentation:

A 76-year-old White female was treated with gemcitabine for pancreatic cancer. Two months after the initiation of therapy, she was admitted to the hospital for worsening dyspnea and cough. High clinical suspicion, bilateral interstitial opacities on chest x-ray, worsening pulmonary status, and onset 2 months after initiation of therapy led to the diagnosis of gemcitabine-induced interstitial pneumonitis. Steroid therapy with prednisone was initiated, and the patient’s clinical symptoms and radiographic findings improved.

Discussion:

Gemcitabine-induced interstitial pneumonitis is well described in the literature. It is a rare but serious complication associated with gemcitabine therapy in which patients present with worsening dyspnea. Most patients only require supportive care and discontinuation of the drug for treatment, but in severe cases supplemental oxygen and steroid therapy must be used before resolution of symptoms. It is important to obtain an accurate medication history to evaluate for other potentially pulmonary toxic medications. Radiographic findings such as bilateral infiltrates should be completely resolved after therapy.

Conclusion:

Radiographic findings, clinical symptoms, and clinical suspicion can lead to early recognition of interstitial pneumonitis from gemcitabine. Physician awareness of this adverse effect and early recognition are keys to providing prompt treatment in resolving symptoms and decreasing mortality.Key Words: gemcitabine, pneumonitis, pulmonary toxicityGemcitabine is an antineoplastic agent used for the treatment of cancers such as non-small-cell lung and pancreatic cancer. Antineoplastic agents are vital to patient outcomes due to the high mortality rate of untreated forms of cancer. Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis thus affecting many organ systems. Common adverse events include myelosuppression, dyspnea, nausea, and vomiting. The severity and duration of dyspnea vary based on individual factors. A severe form of lung toxicity associated with gemcitabine is known as interstitial pneumonitis, which involves acute or chronic interstitial fibrosis of the lung with the tissues becoming stiff and scarred. The fibrosis of the lung interferes with the patient’s ability to breathe. The incidence of interstitial pneumonitis from gemcitabine is estimated at 1% to 2% when the drug is used as a single agent in treatment.¹ The incidence may increase when combined with other agents potentially associated with pulmonary toxicity and should be treated early to improve chances of recovery. Underlying pulmonary dysfunction increases the risk of gemcitabine-induced pulmonary toxicity. ²The exact mechanism of lung toxicity remains unknown; however, proposed mechanisms have been documented in the literature. One proposed mechanism of toxicity is the release of cytokines in the body, which could result in damage to areas throughout the body. This process could lead to capillary leak syndrome or pulmonary edema. ³The diagnosis of interstitial pneumonitis is difficult due to the multiple etiologies of lung dysfunction and should include other likely diagnoses consistent with bilateral interstitial opacities on chest x-ray and worsening respiratory status. Myelosuppression, a common and well-documented adverse event with gemcitabine use, increases the likelihood of acquiring an infection that could decrease lung function. ⁴This article follows a patient who presented with increased cough and dyspnea that progressed to respiratory failure. The patient was diagnosed with interstitial pneumonitis likely secondary to gemcitabine. This case report follows the progression of the illness, the treatment, and her response to treatment.     

替吉奥联合吉西他滨与单药吉西他滨治疗进展期胰腺癌的疗效比较

目的 评价吉西他滨单药以及与替吉奥联合治疗局部晚期或转移性胰腺癌的有效率、临床受益反应（评价指标包括患者的疼痛强度、止痛药物消耗量、体力状况评分和体重变化）、生存时间和不良反应。方法 回顾性分析2009年1月至2011年10月收治的62例晚期胰腺癌患者,分为吉西他滨单药组（30例）和吉西他滨＋替吉奥联合组（32例）。单药组：吉西他滨1 000 mg·m-2、第1,8天,静脉滴注30 min,每3周重复。联合组：吉西他滨用法同单药组,替吉奥口服2次·d-1,第1~14天,每3周重复。结果 62例患者均可评价客观疗效,可评价临床受益反应者56例（单药组27例,联合组29例）。单药组和联合组有效率分别为23.3％和31.3％（P〈0.05）,临床受益率分别为59.2%和72.4%（P〉0.05）。2组6个月生存率分别为60.0%和68.7%（P〉0.05）,1年生存率分别为26.6%和31.2%（P〉0.05）。中位无疾病进展时间（PFS）分别为3.9个月和5.4个月（P〈0.05）,中位总生存时间分别为7.8个月和9.1个月（P〉0.05）。2组不良反应比较差异无统计学意义（P〉0.05）。结论 吉西他滨联合替吉奥与单药吉西他滨治疗晚期胰腺癌安全有效,前者有效率优于后者。在延长生存期方面也显示出一定的优势,但该差异无统计学意义。     

Gemcitabine in non-small cell lung cancer

Gemcitabine is considered to be one of the most active drugs in the treatment of non-small cell lung cancer (NSCLC). When used as a single agent, gemcitabine yielded response rates consistently > 20%, with a uniformly good tolerance profile. Preclinical data indicated synergism between gemcitabine and platinum compounds, such as cisplatin or carboplatin. The gemcitabine-cisplatin combination is considered one of the reference regimens for advanced NSCLC and the recommended schedule is gemcitabine 1000 - 1250 mg/m(2) on days 1 - 8 and cisplatin 70 - 80 mg/m(2) on days 1 or 2. In order to avoid many of the non-haematological toxicities associated with cisplatin, several trials evaluated the gemcitabine-carboplatin combination. Previous trials using the 28-day schedule showed unacceptable haematological toxicity. Recent studies demonstrated the activity and feasibility of gemcitabine-carboplatin combination using a 21-day schedule, with carboplatin administered on day 1 and gemcitabine on days 1 and 8. Gemcitabine can be combined with one of the other new agents, such as the taxanes or vinorelbine, to create novel non-platinum-doublets. Although encouraging, the available data are still conflicting and non-platinum-based combinations are not indicated outside clinical trials. Three-drug combinations increased toxicity and failed to demonstrate any advantage over standard doublets in advanced NSCLC. Gemcitabine is active and well tolerated in elderly patients and represents a reasonable therapeutic option. Although no Phase III trials have been conducted to compare gemcitabine to the best supportive care or docetaxel in pretreated NSCLC, gemcitabine alone or in combination with vinorelbine or one of the taxanes can be considered a valid option for second-line treatment in patients who had a previous response or who achieved stable disease with a platinum-containing regimen. Gemcitabine is considered the most radiopotentiating agent available amongst the newer agents we have in terms of activity and toxicity, but the routine use of gemcitabine in combination with radical thoracic radiotherapy, although promising, is not yet recommended. Further testing of gemcitabine-based combinations with concurrent radiation is underway.     

盐酸吉西他滨脂质体注射液制备

用胆固醇、氢化磷脂酰胆碱、聚氧乙烯化磷脂酰乙醇胺制备盐酸吉西他滨脂质体,以减少吉西他滨的毒副作用。以α-生育酚作为抗氧剂、通氮排氧、控制制备温度不高于50℃,可以减少具有副作用的溶血性磷脂的形成。     

Gemcitabine in non-small cell lung cancer

Incidence of small bowel adenocarcinoma is slowly but steadily increasing. As we gain more knowledge of the molecular basis of this disease, we may be able to approach it via using novel biologic or targeted therapies with or without traditional chemotherapy agents. In the meantime, early diagnosis is still best as it prompts early surgical resection and offers potential cure. The role of adjuvant and neoadjuvant therapy is currently being explored in clinical trials. Several clinical trials have suggested that first-line chemotherapy for patients with metastatic disease should consist of either 5-fluorouracil-leucovorin-oxalipatin or capecitabine-oxaliplatin, while 5-fluorouracil-leucovorin-irinotecan can be reserved for second-line treatment. However, we realize the limitations of these studies, given their small sample size and/or retrospective nature. Single-agent 5-fluorouracil/capecitabine should be considered in patients who are either intolerant to or experience significant side effects with oxaliplatin or irinotecan. We believe that cancers originating in the ampulla of Vater probably deserve a prospective randomized trial of cisplatin-gemcitabine, the current standard of therapy for advanced biliary malignancies.     

吉西他滨温敏凝胶注射剂的制备及其含量测定

目的 制备吉西他滨温敏凝胶注射剂,并建立其含量测定方法。 方法 以聚乙二醇/聚酯嵌段共聚物(PLGA-PEG-PLGA)为载体,制备吉西他滨温敏凝胶注射剂,采用¹H NMR、FT-IR对其结构进行表征, HPLC法测定其中药物的含量。 结果 吉西他滨温敏凝胶注射剂中,PLGA-PEG-PLGA的质量分数为20%,吉西他滨含量为40 mg/ml,胶凝温度为(37±0.15) ℃,在接近人体温度时黏度最大;吉西他滨在5~500 μg/ml范围内线性关系良好(r=0.999 8),精密度和重复性良好,溶液24 h内稳定性良好,低、中、高浓度的吉西他滨的回收率分别为(99.5±3.2)%、(100.4±2.4)%、(102.1±2.4)%,n=3。3批样品中吉西他滨的平均含量分别为标示量的(101.87±2.95)%、 (99.4±2.73)%、(98.98±0.71)%,n=3。 结论 采用PLGA-PEG-PLGA聚合物为载体制备的吉西他滨温敏凝胶注射剂质量可控,是一种很有开发前景的抗胰腺癌制剂。