Management of small cell lung cancer: recent developments for optimal care

Small cell lung cancer (SCLC) represents approximately 13% of all lung cancer diagnoses and the incidence has reduced over the last 20 years. Treatment of SCLC remains challenging because of its rapid growth, early dissemination and development of drug resistance during the course of the disease. Chemotherapy remains the cornerstone of treatment for limited (LD) and extensive disease (ED), with concurrent chemotherapy and radical thoracic radiotherapy representing the best treatment option for fit patients with LD. Platinum-based chemotherapy is the treatment of choice in fit patients with good organ function, and the radiosensitizing effect of cisplatin is critically important for concurrent chemoradiotherapy in LD. Anthracycline-containing regimens represent a viable alternative for patients where platinum-based chemotherapy is contraindicated. Patients who relapse or progress after first-line chemotherapy have a very poor prognosis. Second-line therapy may produce a modest clinical benefit. Maintenance chemotherapy has not been shown to convincingly improve outcomes for SCLC. A number of targeted agents have been investigated in LD and ED, mostly in unselected populations, with disappointing results. Prophylactic cranial irradiation has been shown to reduce the incidence of brain metastases and prolong survival for both LD and ED without negative impact on quality of life (QOL) and cognitive function. Ongoing trials will shed some light on the impact of thoracic radiotherapy on QOL, symptom control and survival in ED SCLC patients who benefitted from first-line chemotherapy.     

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit.

Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy.

Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.     

Chemotherapy strategies in the treatment of small cell lung cancer

Lung cancer is the most prevalent, yet most preventable malignancy worldwide. Given the tendency of small cell lung cancer (SCLC) to early relapse and its subsequent resistance to treatment, there is an urgent need to optimize standard treatment strategies and develop new treatments. Over the last decade, several strategies have been adopted and advances in the molecular biology of lung cancer have identified a number of targets for future therapy. In this article, we review chemotherapy strategies that have been evaluated in the management of patients with SCLC.     

增强紫杉醇对结直肠癌化疗疗效的研究进展

结直肠癌作为我国发病率逐年增高的一种恶性肿瘤,由于其隐匿的临床表现及有限的筛查手段,许多患者确诊时已发生较深的肿瘤浸润或出现了远处转移,此时则需要做术后化疗或新辅助化疗。而现有的结直肠癌化疗方案由于其不良反应多且易产生耐药性,故许多学者均在积极探索新的其他可用于结直肠癌的化疗药物。紫杉醇是治疗乳腺癌、卵巢癌、胰腺癌等恶性肿瘤的一线化疗药物,但结直肠癌细胞却易对其产生耐药性,治疗效果不理想,但可以通过开发新的给药系统、与其他药物联合用药等方式增强对结直肠癌的疗效。针对紫杉醇治疗结直肠癌的有效治疗策略进行综述,以期为结直肠癌更有效的化疗方案提供新的思路。     

伊立替康联合铂类治疗广泛期小细胞肺癌的循证评价

目的 循证评价伊立替康联合铂类治疗广泛期小细胞肺癌超说明书用药的合理性。方法 查询国内外伊立替康的最新版药品说明书,收集伊立替康的全部适应证。计算机检索PubMed、Cochrane Library、Epistemonikos、EMbase、CBM、CNKI和万方数据库,检索时限为从建库至2018年11月,收集伊立替康治疗广泛期小细胞肺癌的相关指南与系统评价,对该方案治疗广泛期小细胞肺癌的有效性和安全性进行分析评价。结果 FDA说明书提及伊立替康用于广泛期小细胞肺癌,但NMPA说明书未提及;国内外共有4篇指南推荐伊立替康联合铂类治疗广泛期小细胞肺癌,5篇系统评价对铂类联合伊立替康与依托泊苷进行分析,认为铂类联合伊立替康可作为广泛期小细胞肺癌的一线治疗方案,但要警惕不良反应的发生。结论 目前有关铂类联合伊立替康治疗广泛期小细胞肺癌的证据较充分,可作为广泛期小细胞肺癌的治疗用药。     

Bevacizumab: a review of its use in combination with paclitaxel or capecitabine as first-line therapy for HER2-negative metastatic breast cancer

Bevacizumab (Avastin?) is a humanized monoclonal antibody directed against vascular endothelial growth factor. In patients with human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer, bevacizumab is indicated as first-line therapy in combination with paclitaxel, or in combination with capecitabine when treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. This article reviews the efficacy and tolerability of these combination therapies in the first-line treatment of patients with metastatic breast cancer, and summarizes the pharmacological properties of bevacizumab. In randomized, controlled, phase III trials in patients with predominantly HER2-negative metastatic or locally recurrent breast cancer, the addition of bevacizumab to paclitaxel or capecitabine significantly prolonged progression-free survival (PFS; investigator assessment) by a median of 5.9 and 2.9 months, respectively, relative to paclitaxel or capecitabine alone. It also significantly increased the objective response rate, but not overall survival. Independent reviews of data supported the results of the primary analyses of investigator-assessed PFS. However, as the efficacy of bevacizumab in combination with capecitabine appears to be less than that of other available options, it should be used only if treatment with other chemotherapy options are not considered appropriate. The addition of bevacizumab to paclitaxel had no significant adverse effects on health-related quality of life. Efficacy data from two routine clinical practice studies were generally consistent with those from the phase III trials. Bevacizumab had generally acceptable tolerability when administered in combination with paclitaxel or capecitabine as first-line therapy in these studies, and adverse events were consistent with the known tolerability profiles of the individual agents. The most common adverse events associated with bevacizumab combination therapy in phase III trials were sensory neuropathy and grade ≥3 hypertension, occurring more frequently with combination therapy than with chemotherapy alone. Potentially life-threatening events, such as venous thromboembolism, gastrointestinal perforation, arterial thromboembolism, haemorrhage and left ventricular dysfunction, occurred in ≤5% of patients receiving combination therapy in these trials. In conclusion, bevacizumab administered in combination with paclitaxel, or in combination with capecitabine if other chemotherapy regimens are not appropriate, may be considered as an option for the first-line treatment of patients with HER2-negative metastatic breast cancer.     

Advances in pharmacotherapy of small cell lung cancer

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastatic dissemination and responsiveness to initial therapy. The incidence of SCLC has been declining over the past two decades. Limited-stage SCLC is a potentially curable disease with long-term survival of ～ 20% when treated with platinum-based chemotherapy plus concurrent thoracic radiation and prophylactic cranial irradiation. For patients with extensive-stage SCLC, survival can be increased with combination platinum-based chemotherapy, but the disease remains incurable.

Areas covered: This review looks at the current advances in pharmacotherapy for SCLC.

Expert opinion: Many chemotherapeutic strategies and newer cytotoxic agents have been evaluated in SCLC, and some had promising activity in early clinical trials. However, none have demonstrated consistent improvements in outcome over standard platinum-based treatment. Similarly, although many potential molecular targets have been identified in preclinical studies of SCLC, molecularly targeted therapy has yet to demonstrate any substantial activity in clinical trials. Nonetheless, future advances in this disease will undoubtedly depend on improvements in our understanding of the molecular mechanisms that drive the proliferation and survival of SCLC cells.     

Emerging drugs for small-cell lung cancer

Small-cell lung cancer (SCLC) is a rapidly progressing tumor in which chemotherapy has a limited impact on survival. Unfortunately, little progress has been made in the medical management of SCLC during the last 30 years, which is best exemplified by the fact that standard first-line chemotherapy has remained platinum-based over time. On the other hand, improvements in survival have been obtained only with the introduction of innovative radiation strategies such as accelerated hyperfractionation to the thorax for limited-stage disease and prophylactic cranial irradiation for both limited- and extensive-stage disease. However, recent advances in the understanding of SCLC biology have renewed the interest in the clinical development of active drugs for SCLC. In this review, we address the most promising agents under clinical evaluation, discussing both novel chemotherapeutic agents and targeted agents. Particularly, amrubicin, a fully synthetic anthracycline, is a very active agent for SCLC, and ongoing Phase III trials are evaluating this agent either in the first-line setting of extensive-stage or relapsed disease. Among targeted agents, anti-angiogenic strategies and Bcl-2 inhibitors represent the most promising approaches, and they are being specifically tested in combination with and/or as maintenance therapy after first-line platinum-based chemotherapy.     

Current role of oral etoposide in the management of small cell lung cancer

Etoposide is part of first-line chemotherapy for patients with small cell lung cancer (SCLC) and is one of the few cytotoxic drugs available in an oral formulation. There have been 3 major avenues of investigation of the role of oral etoposide in SCLC: the optimal schedule of administration, its potential as single agent therapy, and its incorporation into combination chemotherapy. Current evidence suggests that, in SCLC, the optimal schedule of administration is over 3 to 5 days. Its use as a single agent for palliation cannot be supported, but it has a continued use within combination chemotherapy for most patients. In addition, it is likely to be incorporated into regimens with new agents that may offer significant advantages over current combinations.     

老年非小细胞肺癌患者化疗药物治疗进展

结合国内外相关文献资料分析老年非小细胞肺癌(NSCLC)患者化疗的必要性,第三代抗肿瘤药物和不同化疗方案的疗效,以及分子靶向药物在老年患者中的治疗进展情况.单药化疗仍然是老年晚期NSCLC 一线治疗方案;部分PS 评分佳的老年患者可采用含卡铂、低剂量顺铂联合方案化疗;分子靶向药物治疗因其口服方便及不良反应小,适用于高龄、PS 评分差或有明显合并症的老年晚期NSCLC 患者的一线治疗.化疗对老年晚期NSCLC 患者疗效好,单药化疗、含铂或不含铂联合化疗及靶向治疗疗效相似.     

非小细胞肺癌EGFR-TKI耐药后转化为小细胞肺癌2例

摘 要 表皮生长因子受体-酪氨酸激酶抑制药 (EGFR-TKI) 治疗晚期非小细胞肺癌 （NSCLC）的耐药机制逐渐明了,其中小细胞肺癌（SCLC）转化引发了学者极大关注。本文详细报道2例女性EGFR基因19外显子缺失突变肺腺癌患者,在EGFR-TKI靶向治疗耐药后伴随血清神经元特异性烯醇化酶（NSE）水平的显著升高;同时,二次活检发现小细胞肺癌（SCLC）的转化,予以标准SCLC化疗方案治疗有效。提示医生应考虑NSCLC EGFR-TKI 治疗失败后 SCLC 转化的可能,并重视NSE动态监测及二次活检病理分析的重要性。     

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan

Tolerability and response rate to weekly combination chemotherapy with trastuzumab and vinorelbine in Japanese women with HER2-overexpressing breast cancer not previously receiving either therapy were assessed. Tumor response was evaluated every 4 weeks and adverse events were graded. A total of 23 patients from six participating centers in Japan were enrolled. Median dose intensity of vinorelbine was 16.9 mg/m2/week and response rate was 73% (complete response+partial response); complete response=9%, partial response=64%, and progressive disease=5%. Time to progression was 361 days, with 75.0% of liver metastases and 60% of lung metastases responding to this treatment. The most common adverse events were leukocytopenia and neutropenia (96%); however, hematologic toxicity associated with vinorelbine was manageable by adjusting the dose. No pharmacokinetic differences for vinorelbine were found between single administration and combination with trastuzumab. This combination therapy produced high response rates and good tolerability, indicating a promising role in first-line chemotherapy for HER2-overexpressing metastatic breast cancer in Japan.     

拓扑替康在临床应用的研究进展

拓扑替康 (topotecan ,TPT)是新的喜树碱衍生物。TPT是DNA拓扑异构酶Ⅰ抑制剂。 1996年FDA批准治疗小细胞肺癌 (SCLC)和卵巢癌(OVC)。临床试验表明 ,TPT与顺铂和紫杉醇无交叉耐药性。TPT单药治疗SCLC的效果与目前的一线治疗方案相当。TPT单药治疗OVC的效果相同或好于紫杉醇 ,TPT单药或结合治疗作为一线药物 ,治疗SCLC和OVC进行了很多研究并得到肯定的结果。TPT是少有的能进入血脑屏障的药物之一 ,口服TPT与静脉注射效果相同 ,但有低的骨髓抑制毒性。TPT单药或结合治疗也对白血病、非何杰金病、骨髓异常增生症、选择性胰腺癌有效     

非小细胞肺癌EGFR-TKI治疗失败后小细胞肺癌转化

表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)的耐药分子机制逐渐明了,其中小细胞肺癌(SCLC)转化引发了学者极大关注。这种表型转化和伴发EGFR突变是肿瘤细胞异质性,或是肿瘤干细胞,或是某些分子事件使然,但无论那种机制均是推测且无直接证据。目前临床实践中对这种EGFR-TKI耐药转化为SCLC患者的治疗仅是经验分享,亦无更高级别的证据推荐。     

Optimal drugs for second-line treatment of patients with small-cell lung cancer

Introduction: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed.

Areas covered: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials.

Expert opinion: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.     

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.     

Adverse drug reaction prevalence and mechanisms of action of first-line anti-tubercular drugs

PurposeUnderstanding the appearance of anti-tubercular drug-related adverse drug reactions (ADRs) in patients receiving tuberculosis (TB) treatment is important, and may be related to morbidity and mortality if not recognized early. Here, we aimed to characterize the mechanisms underlying adverse drug reactions due to combination anti-tuberculosis therapy of the Revised National Tuberculosis Control Program (RNTCP).MethodsThis was a prospective observational study conducted in 9 DOTS centers of New Delhi, India. All enrolled TB patients receiving first-line tuberculosis treatment as per RNTCP guidelines were monitored for ADRs. All ADRs that appeared during the treatment were recorded and analyzed.ResultsThe study included 1011 TB patients on anti-TB treatment under DOTS. According to Naranjo’s probability scale, of a total 351 (34.72%) reported adverse events, 102 (10.09%) were definite, 59 (5.83%) probable, 123 (12.17%) possible, and 67 (6.63%) doubtful. On the Hartwig severity scale, of the 351 adverse drug events, 225 (22.26%) were mild, 105 (10.38%) were moderate, and 21 (2.08%) were severe. Out of 102 reported adverse drug reactions, 81 (79.41%) were moderate and 21 (20.59%), while 65.28% did not experience any ADRs.ConclusionsDirectly Observed Treatment (DOT) is effective and safe compared to daily treatment regimens. Patients receiving DOTS therapy needed close monitoring for adverse events. Therefore, a pharmacovigilance program should be added at the National level to accesses the adverse event incidence.     

MicroRNA-targeted therapeutics for lung cancer treatment

Introduction: Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists.

Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease.

Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.     

Oral etoposide

Etoposide, a semisynthetic derivative of podophyllotoxin, has been commercially available for intravenous use for a number of years, and has been used as part of first-line combination chemotherapy programs for small cell lung cancer (SCLC). It has also been used to treat testicular cancer, non-small cell lung cancer, and a variety of other malignancies. Etoposide for oral use has become commercially available and is approved for use in the treatment of SCLC. Although no clinical trials comparing intravenous and oral etoposide in SCLC have been reported, several pharmacokinetic studies have been described. These studies have demonstrated a mean bioavailability of 50 percent, with a wide range among patients. Other pharmacokinetic parameters are similar for both the intravenous and oral methods of administration. Based on these results, the recommended dose of oral etoposide is twice the intravenous dose. Oral etoposide has been demonstrated to be effective in the treatment of SCLC. It offers a reasonable and cost-effective outpatient alternative for this group of patients.     

中药有效成分逆转肝癌顺铂耐药机制的研究进展

肝癌是最常见的恶性肿瘤之一，也是全球癌症相关死亡的主要原因。顺铂是临床上治疗肝癌的一线化疗药物，然而不良反应和耐药性是顺铂治疗肝癌的两大挑战，因此一些天然产物作为潜在的抗癌药物和增敏剂引起了广大学者的密切关注。中药有效成分联合顺铂可发挥协同增效、降低化疗不良反应等作用来更好地抗肝癌。从逆转细胞凋亡受阻、调控细胞自噬、降低化疗药物浓度、诱导DNA损伤和抑制上皮–间充质转化5个方面综述中药有效成分逆转肝癌顺铂耐药的机制，以期为未来减轻临床肝癌顺铂耐药、提高肝癌患者的生存质量和治疗效果提供参考。