Docetaxel in non-small cell lung cancer: a review

Docetaxel (Taxotere, Aventis Pharma), a semisynthetic taxane targeting the beta-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel-platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.     

Vinorelbine: a review of its use in elderly patients with advanced non-small cell lung cancer

Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelosuppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC.     

Docetaxel: a review of its use in metastatic breast cancer

Docetaxel (Taxotere), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.     

Erlotinib in non-small cell lung cancer: a review

Erlotinib (Tarceva?, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.     

Erlotinib in non-small cell lung cancer: a review

Erlotinib (Tarceva, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.     

多西紫杉醇对非小细胞肺癌细胞株A-549放疗增敏作用及机制

目的：研究多西紫杉醇对体外培养非小细胞肺癌细胞的细胞周期改变和凋亡影响,及其放疗增敏的作用及机制。方法：以非小细胞肺癌细胞株A-549为实验对象,MTT法观察多西紫杉醇对A-549细胞增殖抑制;克隆形成实验分析细胞放射敏感性;流式细胞技术检测细胞周期及凋亡率。结果：多西紫杉醇对A-549细胞有生长抑制作用,且呈剂量依赖性,在较低浓度（1μg/ml）时即可降低A-549细胞的克隆形成率。各处理组细胞的细胞周期和凋亡率结果表明,多西紫杉醇＋放疗组G2/M期细胞比例较其他组明显升高,差异有统计学意义（P〈0.05）;细胞凋亡率差异亦有统计学意义（P〈0.05）。结论：多西紫杉醇在低细胞毒性浓度下对非小细胞肺癌细胞株A-549有放射增敏作用;多西紫杉醇对A-549细胞增敏其机制可能与其能改变细胞生长周期并诱导其凋亡有关。     

多西他赛联合顺铂治疗非小细胞肺癌的临床疗效分析

目的以多西他赛（TXT）联合顺铂（DDP）治疗非小细胞肺癌的临床疗效来进行分析。方法我院肿瘤科2007年12月至2008年12月住院治疗的NSCLC患者,共选取30例。30例患者完成3个周期的TXT加DDP化疗。结果完全缓解（CR）0例,部分缓解（PR）8例（26.67%）,稳定（SD）7例（23.33%）,进展（PD）15例（50%）,疾病控制率（CR＋PR＋SD）15例（50%）。差异有统计学意义。结论采用多西他赛（TXT）联合顺铂（DDP）治疗非小细胞肺癌疗效确切。     

Docetaxel (taxotere) in the treatment of non-small cell lung cancer

Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.     

Docetaxel in non-small cell lung cancer: impact on quality of life and pharmacoeconomics

Lung cancer is one of the leading causes of cancer-related deaths in industrialised countries, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. A large proportion of patients present with advanced disease and are >65 years of age at the time of diagnosis. Systemic chemotherapy may be offered in an effort to improve survival and quality of life (QOL). Chemotherapy with platinum-based compounds has been shown to modestly improve survival and QOL, and is considered the standard of care as first-line treatment in patients with a good performance status. The last decade has seen the emergence of newer generation chemotherapy agents for the treatment of all cancer types. We review the evidence for the use of docetaxel, an antimicrotubular agent, in patients with advanced NSCLC. In this review, we evaluate not only the effects of docetaxel on survival, but also its impact on QOL and economic issues. Docetaxel is a potent anticancer agent with activity both as a single agent or in combination, and is used both as a first- and second-line treatment in advanced NSCLC. The improvements observed in patients' QOL and the cost effectiveness of docetaxel make it a very reasonable choice in older patients with good performance status and advanced disease who are candidates for chemotherapy.     

吉西他滨联合多西紫杉醇新辅助化疗方案在晚期非小细胞肺癌中的应用观察

目的探讨吉西他滨联合多西紫杉醇新辅助化疗方案在晚期非小细胞肺癌中的应用观察。方法 2008年2月至2010年10月符合入选标准晚期非小细胞肺癌患者134例分为GT组64例,NP组70例,观察两组病例临床疗效、分期下调率及毒性反应。结果 GT组总有效率46.87%,NP组总有效率51.42%,两组比较,差异无统计学意义(P>0.05)。两组不良反应中白细胞减少、血小板减少、发生率进行比较,差异无统计学意义(P>0.05)。两组病例消化系统不良反应恶心呕吐症状进行比较,差异有统计学意义(P<0.05)。结论吉西他滨联合多西紫杉醇新辅助化疗方案与含铂方案相比近期疗效,总有效率相似,胃肠道反应轻微易于被患者所接受。     

紫杉醇治疗中国人群非小细胞肺癌的系统评价

目的：系统评价紫杉醇在非小细胞肺癌治疗中的临床疗效和安全性。方法：检索万方数据库。纳入含紫杉醇治疗非小细胞肺癌的随机对照研究。结果：共纳入25个随机对照研究,2160例非小细胞肺癌患者。Meta分析结果表明,含紫杉醇治疗方案的治疗反应率较对照组高[OR=1.12,95%CI（1.03,1.23）];致Ⅲ度及以上白细胞减少高于对照组[OR=1.35,95%CI（1.05,1.74）];致Ⅲ度及以上血小板减少低于对照组[OR=0.37,95%CI（0.24,0.58）];致Ⅲ度及以上消化道反应与对照组相近似[OR=1.24,95%CI（0.85,1.80）];治疗组与对照组化疗后的1年生存人数差异无明显区别[OR=1.15,95%CI（0.94,1.40）]。结论：紫杉醇治疗非小细胞肺癌有一定的疗效。由于本系统评价纳入的研究存在偏倚的可能,对结果的论证强度会有影响,期待有更多高质量的随机双盲对照试验加以证明。     

Docetaxel: a review of its use for the first-line treatment of advanced castration-resistant prostate cancer

Docetaxel (Taxotere?) is a well established anti-mitotic chemotherapy agent. Among other therapeutic indications, docetaxel plus prednisone is indicated for first-line chemotherapy in patients with castration-resistant prostate cancer (CRPC). Docetaxel every 3 weeks plus continuous prednisone has been standard first-line chemotherapy in CRPC since demonstrating improved survival compared with the previous standard regimen, mitoxantrone plus prednisone, in the phase III TAX 327 trial in 2004. Since that time, docetaxel has been combined with various agents that demonstrated additive or synergistic activity in preclinical studies in an effort to further improve outcomes, but to date, overall survival has not been extended compared with docetaxel plus prednisone. However, several promising agents are emerging with a potential role in docetaxel-based combinations based on efficacy and manageable toxicity, including bevacizumab, dasatinib and atrasentan. In the TAX 327 trial, neutropenia was relatively common in the group receiving 3-weekly docetaxel plus prednisone, but infection was rare. The tolerability of a weekly docetaxel regimen also administered in this trial was not significantly different to that of the 3-weekly regimen, except for a lower incidence of grade 3 or 4 neutropenia. However, weekly or 2-weekly docetaxel administration schedules may have a place in very elderly or frail patients in order to improve tolerability compared with the 3-weekly regimen. In conclusion, docetaxel every 3 weeks plus prednisone remains the optimum first-line chemotherapy for most patients with advanced CRPC until such time that ongoing research with docetaxel and emerging therapeutic agents can demonstrate improved survival.     

多西他赛联合顺铂同步放化疗治疗局部晚期非小细胞肺癌

目的探讨多西他赛联合顺铂化疗同步三维适形放射治疗(3-DCRT)局部晚期非小细胞肺癌的近期疗效及近远期不良反应。方法 68例局部晚期非小细胞肺癌患者随机分为同期放化疗(同步组)与新辅助化疗加放疗(诱导组)两组。两组病例均采用3-DCRT计划。诱导组:多西他赛60mg/m2,静脉滴入,d1,顺铂30 mg/m2,静脉滴入,d1～d3,每3周1次,2个周期后行3-DCRT。同步组:多西他赛20mg/m2,静脉滴入,dl,顺铂30mg/m2,静脉滴入,dl,在放射治疗开始时同步进行,1次/周,用7～8次。结果同步组和诱导组的总有效率分别为70.6%和41.2%,差异有统计学意义(P<0.05);中位生存时间分别为22.6和18.9个月;1年总生存率分别为66.35%和51.99%。结论 3-DCRT联合周剂量多西他赛加顺铂同步治疗局部晚期非小细胞肺癌近期疗效较好,能明显提高患者的生活质量,不良反应均能耐受。     

Sorafenib in non-small cell lung cancer

Introduction: Conventional chemotherapy has reached a plateau of effectiveness for the treatment of non-small cell lung cancer (NSCLC). Patients with EGFR mutation or ALK translocations will benefit significantly from agents targeting these pathways, however, only 20% of western NSCLC patients have these mutations. Anti-VEGF antibody bevacizumab was approved for advanced NSCLC, but the clinical benefits are modest and all patients eventually develop resistance. Multi-targeted tyrosine kinase inhibitors (TKI) may offer more efficient inhibition of angiogenesis by blocking overlapping pathways and they may also have direct anti-tumor effects. Sorafenib is approved in the treatment of renal cell carcinoma and hepatocellular carcinoma and is now under investigation in the treatment of NSCLC. Areas covered: This review summarizes recent studies evaluating sorafenib in the treatment of NSCLC. Expert opinion: Sorafenib has shown anti-tumor activity in NSCLC. However, because NSCLC is complex and molecularly heterogeneous, it is very likely that only a subset of NSCLC patients will benefit from sorafenib, and so it is imperative to discover biomarkers to select patients who will probably benefit from sorafenib. Combination with other agents targeting parallel and compensatory pathways, such as EGFR inhibitors, may offer broader coverage and better disease control.     

Sorafenib in non-small cell lung cancer

ISIS 2302 is a 20 base phosphorothioate oligodeoxynucleotide (ODN) that inhibits intercellular adhesion molecule 1 (ICAM-1) expression through an antisense mechanism. Murine and rat analogues have been effective at doses of 0.06 - 10 mg/kg in a spectrum of models of human inflammatory diseases and allograft transplantation, and ISIS 2302 inhibits the upregulation of ICAM-1 expression in a variety of human cells in vitro. In animals, including primates, plasma distribution half-life ranges from 30 - 60 min, but tissue elimination half-lives range from 1 - 5 days, and the compound is metabolised as other nucleic acids. In a Phase I iv. study, the pharmacokinetic behaviour of ISIS 2302 was similar to that in other primates, and single and multiple every other day doses from 0.06 - 2 mg/kg infused over 2 h were well-tolerated. Phase IIa studies have been completed in Crohn’s disease, rheumatoid arthritis, and psoriasis, and a combined Phase I/II renal allograft acute rejection prophylaxis study has just completed enrolment. In these studies, ISIS 2302, 0.5 - 2 mg/kg, or placebo was administered iv. every 2 - 3 days over 14 - 26 days (7 - 13 infusions) to 17 - 52 patients, with follow up for 6 months. In the Crohn’s study, evidence of highly durable (5+ month) remission-inducing and steroid-sparing properties were demonstrated, without clinically important adverse events. A 300-patient, pivotal quality trial investigating the steroid-sparing and remission-inducing qualities of ISIS 2302 in patients with steroid-dependent Crohn’s disease is completely enrolled, with results expected in the first half of 2000. Modest efficacy and excellent tolerability were demonstrated in the psoriasis and rheumatoid arthritis trials. A Phase IIa trial of a topical formulation in patients with psoriasis is expected to commence in late 1999, as is a trial of an enema formulation in distal ulcerative colitis. Administration by nebulisation for asthma is undergoing preclinical evaluation. Execution of future plans in organ transplantation will await the results of the ongoing Phase I/II trial.     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa^TM), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received ≤ 2 (IDEAL1) or ≥ 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were ~ 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

Topotecan: a review of its efficacy in small cell lung cancer.

Topotecan, a water soluble semisynthetic derivative of camptothecin, has demonstrated antineoplastic activity in a wide range of cell culture and xenograft systems and is currently approved for second-line therapy in ovarian and small cell lung cancer (SCLC). The drug inhibits replication of rapidly dividing cells by disrupting the normal function of the nuclear enzyme topoisomerase I. The efficacy of topotecan is related to exposure time and the recommended regimen is 1.5 mg/m2 as a 30-minute intravenous infusion, daily for 5 days, repeated every 21 days. In phase II trials of topotecan in SCLC (usually with the 1.5mg/m2, 5 day regimen) the overall response rate in refractory patients (those who had relapsed < or =90 days after first-line therapy) was low at 2 to 11%, whereas in sensitive patients (those relapsing > or =90 days after first-line therapy) the overall response rate was 14 to 37%. Topotecan was compared with combined cyclophosphamide/doxorubicin(adriamycin)/vincristine (CAV) therapy in patients with relapsed, sensitive (relapsed > or =60 days after first-line therapy) SCLC. The response rates were 24.3% and 18.3% and, respectively, for the topotecan- and CAV-treated groups, and no significant differences were detected when primary efficacy endpoints (response rates and duration) were compared. However, the results of a symptom-specific questionnaire for SCLC did suggest that topotecan offered superior control of some symptoms. SCLC is usually treated with combinations of cytotoxic drugs, and topotecan is showing promise when partnered with paclitaxel and platinum compounds. The efficacy of an oral formulation of topotecan is also being investigated; preliminary results are encouraging and suggest similar efficacy to intravenous formulations, but with less frequent neutropenia. The tolerability and compliance advantages of oral topotecan may make this the route of choice in the future. Noncumulative anaemia, neutropenia and thrombocytopenia are the dose-limiting adverse effects associated with topotecan. CAV and topotecan therapy had similar suppressive effects on neutrophils in patients with SCLC, but the incidences of grade 3 or 4 anaemia and grade 4 thrombocytopenia were significantly higher in topotecan-treated patients. Non-haematological adverse events in SCLC patients treated with topotecan or CAV were similar and most were grade 1 or 2. Gastrointestinal disturbances were common in both groups, as were alopecia and fatigue. CONCLUSIONS: In a large randomised comparative study, topotecan was as effective as CAV in treating relapsed SCLC. The response rate was modest and further comparative and drug-combination studies are required to accurately position topotecan within the schedule of available drugs used to treat SCLC, particularly in relation to first-line therapy. However, recurrent SCLC is extremely intractable to therapy and topotecan is a valuable extension to the limited range of treatment options for SCLC.     

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.     

参芪扶正注射液辅助化疗治疗晚期非小细胞肺癌的系统评价

目的根据现有临床研究,系统评价参芪扶正注射液(SFI)辅助化疗治疗晚期非小细胞肺癌(NSCLC)的疗效及安全性。方法检索1989年至2011年Cochrane图书馆临床对照试验库、Pubmed、EMbase、CBM、CNKI、VIP等数据库,纳入SFI辅助化疗治疗晚期NSCLC的随机对照研究(RCTs),采用Cochrane系统评价方法进行评价。由两位评价者独立评价并交叉核对纳入研究的质量,对同质研究采用RevMan 5.1软件进行Meta分析。结果经筛选,最后纳入38篇RCTs,2 598例受试者,文献质量评价均为C级。Meta分析结果显示SFI可显著改善或稳定化疗患者的生活质量[RR=1.40,95%CI(1.30,1.52)],改善乏力、纳差症状[RR=0.45,95%CI(0.30,0.68)];明显减少化疗引起的Ⅲ～Ⅳ度骨髓抑制[白细胞计数RR=0.41,95%CI(0.30,0.56);血小板计数RR=0.44,95%CI(0.32,0.60);血红蛋白RR=0.43,95%CI(0.28,0.66)]和胃肠道反应[RR=0.30,95%CI(0.21,0.42)]的发生率;SFI辅助长春瑞滨+顺铂(NP)方案的有效率高于NP方案[RR=1.19,95%CI(1.01,1.40)];SFI辅助紫杉醇+顺铂(TP)方案的有效率高于TP方案[RR=1.30,95%CI(1.10,1.53)];SFI辅助吉西他滨+顺铂(GP)方案的有效率高于GP方案[RR=1.24,95%CI(1.01,1.52)];SFI辅助多西他赛+顺铂(DP)方案与DP方案的有效率相当[RR=1.04,95%CI(0.65,1.68)];经敏感性分析后发现,SFI辅助TP方案治疗晚期NSCLC有效率的Meta分析结果稳定,但SFI辅助NP或GP方案有效率的Meta分析结果不稳定。结论 SFI辅助TP治疗晚期NSCLC,可以明显改善乏力、纳差症状,减少化疗导致Ⅲ～Ⅳ度骨髓抑制和胃肠道反应,显著提高或稳定肿瘤患者生活质量。但SFI辅助NP、GP或DP方案治疗晚期NSCLC的疗效和安全性尚需进一步高质量RCTs验证。