Pharmacokinetic evaluation of gemcitabine hydrochloride for the treatment of cervical cancer

INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.     

Phase II study of cisplatin, 5-fluorouracil and interferon-α in recurrent carcinoma of the cervix

Standard cytotoxic regimens have failed to prolong survival in patients with recurrent cervical cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Cisplatin and 5-fluorouracil are one of the most active regimens currently available for recurrent cervical cancer. Interferon-α can potentiate thein vitro andin vivo activity of both agents. Therefore, we sought to define the feasibility and activity of adding interferon-α to the cisplatin-5-fluorouracil regimen. Patients with histologically proven recurrent cervical carcinoma received interferon-α (5×10⁶ units/m²/day for 5 days) combined with cisplatin (75 mg/m² on day 1) plus 5-fluorouracil (500 mg/m²/day for 5 days) in recurrent cervical cancer. Twenty-six patients were included in this study and received a total of 95 courses of therapy. All 26 had prior radiotherapy and five had prior chemotherapy. This regimen was relatively well tolerated as toxicity was comparable to that of cisplatin plus 5-fluorouracil alone. Major response occurred in 8 patients (31%) and 5 (19%) had complete responses. The median response duration was 6 months (range, 2–34 months) and the median survival duration was 9 months (range, 2–38 months). The addition of interferon-α to cisplatin plus 5-fluorouracil is feasible. Further studies will be necessary to determine if the addition of interferon-α to this regimen is superior to cisplatin plus 5-fluorouracil alone. Division of Surgery     

A review on the treatment of relapsed/metastatic head and neck cancer

The efficacy of traditional chemotherapy in inducing objective responses and prolonging survival in recurrent or metastatic head and neck cancer has been disappointing. More recent drugs have not proven superior to the classic regimen of cisplatin and 5-fluorouracil. Anti-EGFR monoclonal antibodies, either as single agents or associated to chemotherapy, have been shown to be active and little toxic. Among them, cetuximab has proven to be the most promising. Indeed the Extreme study, which compared the classic couple cisplatin (CDDP) + 5-fluorouracil with the same regimen plus cetuximab, has constituted a remarkable innovation. The results of that trial seem to indicate a third agent added to CDDP and 5-fluorouracil improved both progression-free survival and overall survival in the recurrent or metastatic setting. Unfortunately, the results obtained with the tyrosine kinase inhibitors are less impressive, and additional studies are needed to explore the potentiality of this class of drug. As far as antiangiogenetics are concerned, the research is insufficient for any conclusion to be drawn in terms of efficacy. It is hoped that, in the near future, the most active combination between biological agents and traditional chemotherapy will be found, so that the path successfully taken in other neoplastic diseases may be retraced.     

Pharmaceutical management of ovarian cancer : current status

Over recent decades, truly impressive progress has been made in the outcome associated with the pharmacological antineoplastic management of women with advanced ovarian cancer. Following initial surgery, the large majority of patients with this malignancy will receive a chemotherapy regimen that includes a platinum drug (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). Currently, objective responses are observed in approximately 60-80% of patients treated in the front-line setting, with documented improvements in overall survival compared with prior non-platinum and taxane programmes. Unfortunately, despite the high response rate to initial chemotherapy, the majority of women with advanced disease will experience recurrence of the malignant process and be candidates for a variety of possible second-line therapeutic options. It is well recognized that ovarian cancer patients who are documented to experience an initial response to platinum-based chemotherapy but where the disease recurs approximately 6 or more months following the completion of primary therapy, may have another clinically meaningful response (both objective and subjective) to a second platinum-based strategy. However, an optimal management approach in this setting remains to be defined. Furthermore, the malignant cell populations in all ovarian cancer patients who experience an initial relapse of the disease process will eventually be resistant to the platinum agents. In this setting, multiple drugs have been shown to be biologically active. Again, an optimal strategy to be employed in the platinum-resistant setting has yet to be demonstrated through the conduct of evidence-based trials. Reasonable goals of therapy in women with recurrent or resistant ovarian cancer are to improve overall survival, reduce the severity (and delay the occurrence) of symptoms and optimize overall quality of life.     

吉西他滨联合洛铂或顺铂治疗蒽环类和紫杉类药物耐药晚期乳腺癌的比较研究

目的:比较吉西他滨联合洛铂或顺铂治疗蒽环类和紫杉类药物耐药晚期乳腺癌的疗效和不良反应。方法:61例晚期乳腺癌患者随机分为吉西他滨加洛铂组(GL组)和吉西他滨加顺铂组(GP组)。至少治疗2个周期后分别评价疗效和不良反应发生情况。结果:GL组和GP组缓解率分别为43.33%和38.71%;GL、GP组中位肿瘤进展时间分别为6.29个月和5.59个月(P>0.05)。GL组的中性粒细胞减少、血小板减少发生率较GP组多见,而GP组的恶心呕吐发生率较GL组多见,两组间有统计学差异(P<0.05)。结论:GL和GP方案均为治疗蒽环类和紫杉类药物耐药晚期乳腺癌的有效方案,两组缓解率及中位肿瘤进展时间相近。但GL组的血液学毒性发生率较GP组多见,而GP组的胃肠道反应较GL组多见。这两种方案可能适合不同人群,值得临床进一步研究。     

某肿瘤专科医院白蛋白结合型紫杉醇超适应证用药分析

目的 调查分析某肿瘤专科医院白蛋白结合型紫杉醇超说明书使用情况,为规范临床用药提供循证依据.方法 抽取2018年1月～2019年12月使用白蛋白结合型紫杉醇的1631份用药医嘱进行分析,依据国家药品监督管理局(NMPA)颁布的说明书、美国食品和药物管理局(FDA)批准的药品说明书以及美国国立综合癌症网络(NCCN)临床...     

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol?, Bristol-Myers Squibb and docetaxel, Taxotere?, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Emerging drugs in endometrial cancers

Importance of the field: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving.

Areas covered in this review: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers.

What the reader will gain: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents.

Take home message: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas.     

治疗复发或转移性宫颈癌的抗体偶联药物：Tisotumab Vedotin-tftv

Tisotumab Vedotin-tftv是美国食品药品监督管理局（FDA）批准的首款治疗宫颈癌的抗体偶联药物,也是全球首个获批靶向组织因子的抗体偶联药物,为复发或转移性宫颈癌患者提供了新的治疗选择。临床研究表明,Tisotumab Vedotin-tftv在复发或转移性宫颈癌患者中具有较好的抗癌活性,且安全性良好。本文就Tisotumab Vedotin-tftv的作用机制、药动学、临床研究及安全性进行概述。     

Topotecan in the management of cervical cancer

Topotecan, a semisynthetic camptothecin, exerts its cytotoxic effect through inhibition of DNA topoisomerase I. Single-agent topotecan has demonstrated activity against persistent, metastatic and recurrent cancer of the uterine cervix. When combined with cisplatin in Phase II trials, further improved response rates have been reported. The cisplatin/topotecan doublet subsequently proved to be the first regimen in a series of multiple Phase III studies to demonstrate improved disease-free and overall survival in this setting compared with cisplatin alone, thus leading to its third indication by both the US FDA and the European Medicines Agency in 2006. This survival advantage was achieved at the expense of an increase in grade 3-4 hematologic toxicity; however, there was no difference in patient-reported quality of life between the cisplatin/topotecan doublet and single-agent cisplatin. This article reviews the pharmacology of topotecan and its evolution as an active agent in advanced and metastatic cervical cancer that is not amenable to cure with surgery or radiotherapy.     

Medical therapy of endometrial cancer: current status and promising novel treatments

While early-stage endometrial cancer is often successfully treated with surgical intervention, treatment of advanced endometrial carcinoma can be difficult and prognosis poor, particularly in the context of metastatic or recurrent disease. Standard chemotherapy agents for both adjuvant first-line treatment (for selected patients deemed at high risk of relapse) and recurrent endometrial cancer include doxorubicin, platinum agents and paclitaxel. Investigational options currently being studied in phase II trials include both combined regimens of standard chemotherapeutic agents versus radiation as well as targeted treatments such as epothilones, mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenic agents. Recent interest in the molecular pathways of carcinogenesis have lead to increased investigation of these novel agents and the hope that they will impact positively on the overall survival of women with endometrial cancer.     

乳腺癌术后疾病进展的治疗

目的探讨乳腺癌术后病情进展治疗的方法和预后,评价其安全性和疗效。方法回顾分析我科从1999年2月～2007年3月收治的乳腺癌术后发生局部复发和远处转移的37例患者,应用紫杉醇/多西紫杉醇和卡铂(TP)联合化疗方案辅助化疗。结果总体有效率(CR PR)59.5%,CR5例,PR17例,SD12例,疾病进展并死亡3例。结论TP联合化疗方案治疗转移性乳腺癌积极、有效、不良反应轻且容易控制。     

Aromatase inhibition: a potential target for the management of recurrent or metastatic endometrial cancer by letrozole: more questions than answers?

Introduction: Endometrial cancer generally presents as early and resectable disease, but about 20% of patients present with either incurable or recurrent/metastatic disease. Patients with good performance status will be treated with hormonal agents, including progestins and tamoxifen, followed by cytotoxic chemotherapy. The options are restricted to hormonal agents for those with multiple comorbidities and older age. Therefore, there is a need to identify novel hormonal agents and other targeted therapeutics with improved therapeutic window in this setting.

Area covered: Clinical trials of letrozole in localized and metastatic settings are reviewed. In the localized setting, limited by the small sample size, preliminary and conflicting clinical activities were observed. Despite the selection of Type I endometrial cancer, which is more estrogen-dependent for its growth, modest clinical activity was observed in the metastatic setting. Thus far, no biomarkers for efficacy have been identified.

Expert opinion: Further understanding of the relevance of aromatase and estrogen receptor and their interplay with other growth pathways will be necessary to guide further development of letrozole. It is premature to declare letrozole a therapeutic option in recurrent/metastatic endometrial cancer.     

紫杉醇联合吉西他滨治疗蒽环类耐药晚期乳腺癌临床观察

目的观察紫杉醇联合吉西他滨治疗蒽环类耐药晚期乳腺癌的临床疗效和毒副反应。方法30例含蒽环类方案治疗失败的晚期乳腺癌患者,采用GT方案（紫杉醇＋吉西他滨）治疗,紫杉醇135mg／m2静脉滴注,第1天;吉西他滨850mg／m。静脉滴注,第1天、第8天,每3周重复。每2周期评价疗效。结果30例患者均可评价疗效。完全缓解（CR）3例（10％）,部分缓解（PR）11例（36．7％）,稳定（SD）11例（36．7％）,进展（PO）5例（16．7％）,总有效率（CR＋PR）（46．7％）。全组中位疾病进展时间7．1个月,中位总生存时间15．6个月。Ⅲ、Ⅳ度毒副反应为白细胞减少10例（30．0％）,血小板减少4例（13．3％）。结论紫杉醇联合吉西他滨方案治疗蒽环类耐药晚期乳腺癌疗效满意,患者耐受性好。     

ABI 007

ABI 007 is an albumin-stabilised nanoparticle formulation of paclitaxel designed to overcome insolubility problems encountered with paclitaxel. This then eliminates the need for toxic solvents like cremophor, which limits the dose of paclitaxel that can be administered and hence effect overall drug efficacy. ABI 007 is being developed for the treatment of a variety of tumour types by American Pharmaceutical Partners. In addition to the standard infusion formulation of ABI 007, oral and pulmonary delivery formulations are also being investigated. American Pharmaceutical Partners, a subsidiary of American BioScience, secured exclusive North American marketing and manufacturing rights to ABI 007 from American BioScience in November 2001. American BioScience completed a phase III study in the US in metastatic breast cancer patients in early 2003. An indication for which ABI 007 was granted fast track status in January 2003. The phase III study directly compared the efficacy of ABI 007 260 mg/m(2) with paclitaxel 175 mg/m(2). Both agents were administered every 3 weeks. ABI 007 was administered as a 30-minute infusion without steroid pretreatment. Paclitaxel-treated patients received steroid pretreatment and the drug was administered over 3 hours. In October 2002, a Data Monitoring Committee concluded that a sample size adjustment of the phase III trial would not be required and that the study can be continued to completion. Enrolment was completed in December 2002 with 460 first- and second-line metastatic breast cancer patients enrolled. The results were expected to be unblinded in mid-2003. A phase II trial of ABI 007 is also underway in metastatic breast cancer patients who have failed taxane therapy. The trial is evaluating a weekly rather than 3-weekly regimen of ABI 007. Earlier, in May 2003, American Pharmaceutical Partners reported that ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. However, the phase of development for these indications remains unclear.     

Recent findings with docetaxel in postoperative treatment for breast cancer

Breast cancer is the most common cancer affecting women. A comparison of docetaxel and 5-fluorouracil in women with operable node-positive breast cancer, also taking doxorubicin and cyclophosphamide, was started in 1997. The primary end point was disease-free survival; the time from randomisation to clinical relapse, a second cancer, or death. In a median follow up of 55 months, fewer events had occurred in the docetaxel (172/745) than the 5-fluorouracil group (227/746). This suggests that docetaxel should replace 5-fluorouracil, and that docetaxel, doxorubicin and cyclophosphamide should become the standard treatment of operable node-positive breast cancer. Paclitaxel and docetaxel are approved for use in patients with metastatic breast cancer. In a head-to-head trial of paclitaxel with docetaxel in patients with metastatic breast cancer, despite previous chemotherapy including anthracycline, an overall response (complete and partial) was observed in more docetaxel than paclitaxel patients. This suggests that docetaxel should be preferred to paclitaxel in this group of patients.     

Phase II study of CT-2103 as first- or second-line chemotherapy in patients with metastatic breast cancer: unexpected incidence of hypersensitivity reactions

Summary This study evaluated the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-l-glutamate, in patients with HER2-negative, metastatic breast cancer who had received 0 or 1 prior lines of chemotherapy. Although CT-2103 had activity in this small study, neurotoxicity and hypersensitivity reactions were more frequent in this patient population than expected, and led to early termination of the trial. Purpose To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-l-glutamate, in patients with metastatic breast cancer who had received 0 or 1 prior lines of chemotherapy. Patients and Methods Eighteen women with HER2-negative breast cancer were enrolled. Patients received intravenous CT-2103 at a dose of 175 mg/m² of conjugated paclitaxel over 10 min every 3 weeks, without routine premedication. Eighty-three percent of women had received prior chemotherapy as part of adjuvant (39%), metastatic (17%), or both adjuvant and metastatic (28%) treatment. Three patients (17%) had previously received a taxane in the adjuvant setting. Results Objective responses were observed in 4 of 18 patients (overall response rate, 22%, 95% confidence interval, 6 to 48%). Grade 3 or 4 neuropathy was observed in four patients. Grade 3 or 4 hypersensitivity reactions (HSR) were observed in four patients; none occurred prior to cycle 4 of therapy. Because of the higher-than-expected rate of HSR, the study was terminated early. Conclusion Although CT-2103 had activity in this small study of women with HER2-negative metastatic breast cancer, neurotoxicity and hypersensitivity reactions were more frequent in this patient population than expected. Hypersensitivity reactions were most likely to occur in later cycles of treatment, suggesting a true drug allergy, distinct from the HSR typically seen with standard paclitaxel.     

Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2.

Trastuzumab is a humanised monoclonal antibody developed to target the HER2 receptor which is overexpressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumour cells that overexpress HER2. A large well designed multicentre study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical (IHC) assay or a positive HER2 result using fluorescence in situ hybridisation (FISH), benefit more from trastuzumab therapy than those with tumours overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. CONCLUSION: Intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.     

Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.     

Gemcitabine and Cisplatin for Patients with Metastatic or Recurrent Esophageal Carcinoma: A Southwest Oncology Group Study

PURPOSE: Experimental data, both in vivo and in vitro, suggest that the combination of gemcitabine and cisplatin acts synergistically. Within the Southwest Oncology Group, we designed a Phase II trial to test this chemotherapy combination for patients with esophageal cancer. EXPERIMENTAL DESIGN: Patients with metastatic or recurrent esophageal cancer were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15, and cisplatin 100 mg/m(2) on day 15. Cycles were repeated every 28 days. The statistical endpoint was overall survival. RESULTS: Sixty-four eligible patients were accrued from 37 institutions. Twenty-six percent of patients had prior chemotherapy. The treatment was generally well-tolerated, with the most common toxicity being neutropenia in 31% of patients. All 64 patients have died. Survival at 3 months was 81%, and at 1 year was 20%. Median survival was 7.3 months. CONCLUSIONS: This regimen is tolerable palliative option for patients with metastatic esophageal cancer.