Economic evaluation of lenograstim for prophylaxis of chemotherapy-induced neutropenia in patients with small cell lung cancer

The impact of lenograstim, recombinant human granulocyte colony-stimulating factor, on healthcare costs was evaluated on the basis of the results of a clinical trial of the drug in patients receiving VICE (vincristine, ifosfamide, carboplatin and etoposide) chemotherapy for small cell lung cancer (SCLC). The use of lenograstim resulted in a significant (p < 0.03) increase in the cumulative chemotherapy dose intensity (125% with lenograstim vs 118% without). Lenograstim was found to have no significant impact on the use of healthcare resources for administration of chemotherapy, chemotherapy-induced neutropenia, and associated infections. The cost of healthcare for the lenograstim group (excluding lenograstim acquisition costs) was 700 pounds higher per patient than that for the group not treated with lenograstim (95% CI -930 pounds to 2300 pounds). The use of lenograstim to intensify the chemotherapy dose is likely to increase the costs of treatment for SCLC. However, any increased costs need to be balanced against the potential cost savings associated with the possible long term benefits resulting from chemotherapy dose intensification.     

Therapeutic strategies for chemotherapy-induced neutropenia in patients with solid tumors

Introduction: Chemotherapy-induced neutropenia (CIN) is a common adverse event during treatment of cancer patients, associated with increased morbidity, mortality, health care costs and impairment of patients’ quality of life which necessitate dose reductions.

Areas covered: A computerized systematic literature search was performed through Medline, PubMed, Google Scholar and the Cochrane Library to identify peer reviewed publications relevant to CIN, pathophysiology and epidemiology, patient risk-assessment and existing treatment approaches. Additionally, emerging issues such as alternative therapeutic options and implications in elderly care were addressed.

Expert opinion: Although CIN represents a common adverse event in the management of patients with solid tumors, the heterogeneity in clinical practice across different settings underlines the need to improve existing tools for accurate patient classification. Moreover, the definition of the optimal implementation of out-patient treatment and the use of colony-stimulating factor as add-on treatment together with antibiotics should be further investigated in order to accumulate more solid data. Finally, physician education is required to ensure that scientific knowledge is implemented in the daily clinical practice.     

Prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia with lipegfilgrastim in 2489 cancer patients: final results from the non-interventional study NADIR

Objectives: The non-interventional study (NIS) NADIR (DRKS00005711) evaluated the effectiveness and safety of prophylaxis with lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, in 2500 patients undergoing chemotherapy in routine clinical practice. Primary objective was the incidence of chemotherapy-induced severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications.

Methods: NADIR was a prospective NIS conducted in 201 study centers in Germany.

Results: The analysis included 2489 patients. Main tumor types were breast cancer (n?=?1198, 48.1%), lung cancer (n?=?303, 12.2%), non-Hodgkin lymphoma (NHL; n?=?337, 13.5%), and prostate cancer (n?=?111, 4.5%). Nine hundred and ten (36.6%) patients were aged ≥65?years (regarded as “elderly” patients). Severe neutropenia (CTCAE grade 3/4) was reported in 26.8% (n?=?666) and 25.2% (n?=?229) of the total population and elderly patients, respectively. FN was documented in 2.7% (n?=?68) of the total population vs 3.0% (n?=?27) of elderly patients. Primary prophylaxis with lipegfilgrastim among patients with high risk of FN (>20%) was documented in 83.5% of the total population and 75.1% of elderly patients. Infections (CTCAE grade 3/4) were documented in 99 patients (4.0%) in the total population vs 47 (5.1%) elderly patients. Fatal infections were reported in 14 (0.6%) patients in the total population vs 11 (1.2%) elderly patients. Overall, most frequent lipegfilgrastim-related adverse events (AEs) included bone pain (8.0%), anemia (3.2%), leucocytosis (2.7%), and thrombocytopenia (2.5%). Of the patients, 18.0% had ≥1 documented serious AE; none of the fatal events (2.7%) was lipegfilgrastim-related.

Conclusions: Lipegfilgrastim administered to patients with solid tumor/NHL undergoing chemotherapy in routine clinical practice showed similar effectiveness and safety compared to the pivotal trials.     

非小细胞肺癌患者化疗后骨髓抑制的影响因素分析

目的:探讨非小细胞肺癌化疗后骨髓抑制影响因素,为化疗前对患者进行评估提供参考依据。方法:回顾性分析2149例化疗后非小细胞肺癌患者信息,对骨髓抑制可能有关的因素进行单因素分析及多因素Logistic回归分析。结果:合并放疗、多周期化疗(化疗周期>4周期)为血红蛋白(合并化疗:OR=1.452;多周期化疗:OR=1.884)、白细胞计数(合并化疗:OR=2.242;多周期化疗:OR=2.126)、粒细胞计数(合并化疗:OR=1.348;多周期化疗:OR=1.905)降低的危险因素;Karnofsky功能状态(KPS)评分≤80为血红蛋白(OR=1.770)、血小板计数(OR=1.407)降低发生的危险因素;应用长春瑞滨联合铂类为血红蛋白(OR=2.468)、白细胞计数(OR=4.827)降低的危险因素;应用依托泊苷联合铂类为白细胞计数(OR=2.455)、粒细胞计数(OR=2.855)降低的危险因素;年龄≥65岁,身体质量指数(BMI)<18.5,肿瘤分期(TNM分期)在Ⅲ～Ⅳ期,有骨转移为血红蛋白(OR依次为:1.619,2.021,1.388,1.447)降低的危险因素;应用培美曲塞联合铂类治疗可降低患者白细胞计数(OR=0.561)、血小板计数(OR=0.319)降低发生风险。结论:年龄、KPS评分、TNM分期、化疗方案,骨转移情况,放疗情况均为影响骨髓抑制发生的关键因素,密切关注这些相关因素可为降低非小细胞肺癌患者化疗相关性骨髓抑制风险提供参考。     

Treatment and outcomes for elderly patients with small cell lung cancer

It is estimated that approximately half of the 500 000 people diagnosed with lung cancer worldwide every year are aged >70 years. Thus, this disease represents a major problem in the elderly and one that will indeed increase as the median age of the population increases. For small cell lung cancer (SCLC), which accounts for approximately 20% of cases of lung cancer, the primary treatment is chemotherapy and in the majority of cases the primary aim is to control the disease which generally would have spread beyond the lungs at the time of presentation. A small number of 'standard' chemotherapy regimens (combined with radiotherapy for patients with limited disease) have been shown to improve survival and quality of life and are widely used. Much of the work investigating the relationship between age and treatment outcomes has been based on clinical trial data and may itself be inherently biased due to trial eligibility criteria excluding elderly patients. However, there is no good evidence that elderly patients fare worse with treatment than their younger counterparts in terms of response rates and survival. Nevertheless with increasing age comes increasing concomitant illnesses which may account for the widely observed increases in drug toxicity, and this may be the primary consideration in selecting the treatment option. Thus for many elderly patients, carboplatin/ etoposide may be the treatment of choice because it is perhaps the least toxic of the standard regimens. Whatever regimen is chosen, the key to treatment effectiveness seems to be to deliver the first 3 or 4 cycles without delay or dosage reduction. Although palliation of symptoms remains a major goal in the treatment of all patients with SCLC there is a dearth of data on whether elderly patients are equally well palliated as their younger counterparts. There is no good evidence that age per se should be a factor in deciding whether patients should receive standard treatment rather than a more gentle approach, and more elderly patients should be included in clinical trials. The key areas where more information is required regarding the treatment and outcomes of elderly patients with SCLC are the assessment of palliation, and comprehensive reviews of all patients diagnosed with the disease, not just those included in trials.     

埃克替尼治疗表皮生长因子受体突变型非小细胞肺癌患者49例

目的评价埃克替尼治疗表皮生长因子受体(EGFR)突变型非小细胞肺癌(NSCLC)患者的临床有效性及安全性。方法回顾性分析本院2011年12月—2013年12月年内住院的服用埃克替尼治疗的49例EGFR突变型NSCLC患者,以同期服用吉非替尼治疗的21例患者作为对照,比较两组的体能状态、生活质量评价及疗效和安全性评价。结果埃克替尼和吉非替尼组客观有效率分别为59%和57%,疾病控制率分别为84%和81%,两组相比无显著差异(P>0.05)。埃克替尼组在不良反应发生的类别、发生率及不良反应的分级等方面与吉非替尼组无显著差异(P>0.05)。结论埃克替尼治疗EGFR突变型NSCLC患者疗效确切、不良反应发生率较低,与吉非替尼相似。     

Ganetespib for small cell lung cancer

Introduction: Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC).

Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed.

Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future.     

The association between chemotherapy-induced febrile neutropenia and breast cancer subtype in Japanese patients

Background Chemotherapy-induced febrile neutropenia is a common and potentially lethal side effect; therefore, predicting febrile neutropenia development is important. Objective This study examined the risk factors for febrile neutropenia development according to breast cancer subtype among Japanese patients receiving chemotherapy. Methods This single-center retrospective study evaluated 60 outpatients who received chemotherapy for breast cancer (epirubicin plus cyclophosphamide or docetaxel plus cyclophosphamide). Their characteristics were evaluated to identify factors associated with febrile neutropenia development. Results Thirty-three patients developed febrile neutropenia and 27 patients did not. The risk of developing febrile neutropenia was significantly associated with estrogen receptor negativity (p?<?0.05). Logistic regression analysis further confirmed that estrogen receptor negativity was an independent risk factor for febrile neutropenia development (odds ratio: 4.35, 95% confidence interval: 1.05–18.0). Moreover, the highest rate of febrile neutropenia was observed in patients with hormone receptor (estrogen and/or progesterone receptor)-negative/human epidermal growth factor receptor 2-positive breast cancer. Conclusion In addition to the known risk factors for febrile neutropenia, our findings revealed that the risk of developing chemotherapy-induced febrile neutropenia is associated with the hormone receptor-negative/human epidermal growth factor receptor 2-positive subtype in Japanese patients with breast cancer.

     

小细胞肺癌与非小细胞肺癌宝石CT能谱研究

目的通过对小细胞肺癌与非小细胞肺癌能谱CT增强扫描,探讨CT能谱成像定量分析在鉴别小细胞肺癌与非小细胞肺癌影的像学价值。方法回顾性选取病理已确诊的小细胞肺癌与非小细胞肺癌各20例,均用宝石能谱CT进行GSI扫描,在宝石能谱成像浏览器（GSIviewer）的软件上进行,得到能谱曲线含碘量图40-140keV能量水平的CT值及斜率值对比,最后进行数据分析。结果增强扫描中40-140keV能量水平的CT值中,40-70keV能量水平的CT值小细胞肺癌组低于非小细胞肺癌组。小细胞肺癌组与非小细胞肺癌组能谱曲线肿瘤内40-70keV兴趣区（ROI）碘含量斜率各为（2．07＋0．76）、（3．08＋1．16）,两组组间斜率差异有统计学意义（t=3．23,P〈0．05）。结论小细胞肺癌与非小细胞肺癌能谱成像上碘含量不同的特征,可以初步区分小细胞肺癌与非小细胞肺癌,为影像学鉴别诊断提供一定的参考价值。     

Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemotherapy-induced neutropenia

Recombinant granulocyte colony-stimulating factor (rG-CSF) therapy is associated with a dose-proportional reduction in the frequency, duration and severity of neutropenia associated with cytotoxic chemotherapy. This is associated with a decrease in the incidence of infection, with subsequent reductions in the number of hospitalisations, days of hospitalisation and antibiotic requirements. These effects produce marked reductions in costs, and could contribute substantially towards offsetting the costs of rG-CSF, although the magnitude of the savings will vary between institutions and with the chemotherapy regimen used. Other benefits include a reduction in the frequency and severity of mucositis, and an improved patient quality of life. However, further research is required to evaluate other potentially important considerations including the targeting of specific patient populations (e.g. those receiving regimens with a curative intent), and additional improvements in patient quality of life and, perhaps, mortality. Thus, although specific pharmacoeconomic analyses are limited, preliminary evidence indicates that rG-CSF, administered prior to the onset of neutropenia in patients receiving cytotoxic chemotherapy, can provide cost reductions both from an institutional and a payor perspective, with even greater potential savings from a societal viewpoint.     

Transient neutropenia after intravenous injection of vindesine in patients with lung cancer

We have found transient circulating neutropenia and pulmonary sequestration of neutrophils after the intravenous injection of vindesine, a microtubule disruptor.Experiment 1 Ten patients with lung cancer were given a bolus intravenous injection of 3 mg·m^-2 vindesine (Fildesine(r)). In all patients, total leukocyte and neutrophil counts in the venous blood fell to 65 % and 47 % of baseline values respectively within 30 min, and returned to baseline values within 6 h. In contrast, the lymphocyte count was stable.Experiment 2 Male Wistar rats were given saline or 0.08 mg·kg^-1 vindesine intravenously and were sacrificed after 30 min. Vindesine produced a 58 % reduction in the neutrophil count in the systemic circulation and a threefold increase in the neutrophil/erythrocyte ratio in the pulmonary microvasculature.Experiment 3 We studied the effects of vindesine in vitro on neutrophils and lymphocytes isolated from the venous blood of healthy volunteers. Vindesine (10^-5–10^-8 mol·1^-1) reduced neutrophil deformability (filterability) and induced neutrophil polarization, with reversibility of both effects after washout. These effects of vindesine were completely inhibited by cytochalasin B, an actin filament disrupter. Vindesine did not stimulate the neutrophil functions of adherence to polystyrene tubes, chemotaxis, or superoxide anion generation. The filterability and morphology of lymphocytes were not altered by vindesine.Thus, we conclude that a bolus injection of vindesine produces pulmonary sequestration of neutrophils, which produces circulatory neutropenia, and that it is primarily mediated by a decrease in neutrophil deformability that occurs without activation of the cells.     

Economic evaluations of granulocyte colony-stimulating factor: in the prevention and treatment of chemotherapy-induced neutropenia

The prevailing uncertainty about the pharmacoeconomic positioning of granulocyte colony-stimulating factor (G-CSF) in the prevention and treatment of chemotherapy-induced febrile neutropenia has resulted in a number of pharmacoeconomic evaluations published in the past 10 years. These studies vary considerably regarding the approaches used and the results presented. In order to contribute to a clearer pharmacoeconomic positioning of G-CSF, a systematic review of economic evaluations was carried out.The focus of the review was prophylaxis and therapy of chemotherapy-induced neutropenia in patients with cancer. A computerised bibliography search of several databases was conducted yielding 33 studies.The findings demonstrated the cost-saving potential of G-CSF in standard-dose chemotherapy to be limited, with lower costs often seen in the control group. The results of these studies were too heterogeneous to extract a clear recommendation from a cost-saving point of view. The administration of G-CSF after high-dose chemotherapy with stem cell support resulted more often in cost savings in the G-CSF group as compared with standard-dose chemotherapy, illustrating a possible cost-saving potential of G-CSF. In the treatment of established chemotherapy-induced febrile neutropenia, cost savings were found in all studies. This result is surprising but hampered by the small number of studies (n = 5) and remains to be confirmed by more rigourously designed prospective economic analyses.Despite the substantial research on this topic, the economic evaluation of G-CSF is far from being settled and needs further investigation.     

氨柔比星及氨柔比星醇在小细胞肺癌患者的药代动力学

目的：评价中国小细胞肺癌患者中单次给药和多次给药后氨柔比星及其活性代谢产物氨柔比星醇的药代动力学特征。方法用多中心、开放、单次和多次给药的试验设计。12例广泛期小细胞肺癌患者,每日静脉推注盐酸氨柔比星40 mg· m-2,连续3 d,并在第1 d静脉输注顺铂60 mg· m-2。用LC-MS/MS法测定原型药物和活性代谢产物在血浆、全血和血细胞中的浓度,用WinNonlin非房室模型计算药代动力学参数。结果单次和多次给药后,氨柔比星的主要药代动力学参数,乙二胺四乙酸三钾（EDTAK3）抗凝血浆：cmax分别为（3460±1273）,（4080±1895）ng· mL-1,AUC0-t分别为（2050±408）,（2190±411）h· ng· mL-1;肝素抗凝血浆：cmax分别为（3660±1382）,（4360±2065）ng· mL-1, AUC0-t分别为（2100±363）,（2220±404） h· ng· mL-1;全血：cmax分别为（3240±1133）,（3920±1582）ng· mL-1,AUC0-t分别为（2150±465）,（2560± 853）h· ng· mL-1;血细胞：cmax分别为（2100±544）,（2500±796）ng· mL-1, AUC0-t分别为（2030±465）,（2340±653）h· ng· mL-1。氨柔比星醇的主要药代动力学参数,EDTAK3抗凝血浆：cmax分别为（18.2±3.3）,（30.1±3.8）ng· mL-1,AUC0-t分别为（258±43）,（992±182）h· ng· mL-1;肝素抗凝血浆：cmax分别为（17.9±3.8）,（30.9±5.7）ng· mL-1,AUC0-t分别为（259±51）,（978± 190）ng· h· mL-1;全血：cmax分别为（50.3±12.8）,（81.9±19.3）ng· mL-1, AUC0-t为分别（723±198）,（2610±656） h· ng· mL-1;血细胞：cmax分别为（83.6±19.9）,（153.0±25.2）ng· mL-1,AUC0-t分别为（1290±319）,（4400± 831） h· ng· mL-1。结论氨柔比星醇在多次给药后发生蓄积,蓄积程度与文献报道的日本人相同,单次和多次给药后的血浆AUC0-24与日本人近似,血细胞cmax与日本人相似,但血浆cmax呈低于日本人的趋势。     

小细胞肺癌预防性脑放射治疗

小细胞肺癌经过前期治疗有效者需要进行预防性脑放射治疗,然而临床应用时临床医生仍存在一定顾虑。本文就近年来临床研究数据阐明了预防性脑放射治疗(PCI)临床价值,回答了一些临床应用的疑问并给出了PCI应用的推荐。     

拓扑替康单药治疗难治性小细胞肺癌的临床评价

目的 :观察拓扑替康单药治疗难治性小细胞肺癌 (SCLC)的疗效及其毒副反应。方法 :难治性SCLC患者 3 8例 ,采用拓扑替康 (topotecan,T ,金喜素 ) 1 .2mg·m- 2 ·d- 1 ,静脉滴注 ,d1～ 5,2 1d为 1个周期 ,共 2～ 3个周期。结果 :拓扑替康单药的有效率为 2 3 .68% (9 3 8) ,其中局限型病例的有效率为3 6.3 6% (4 1 1 ) ,广泛型为 1 8.5 2 % (5 2 7) ,组间比较无统计学差异 (χ2 =0 .5 67,P >0 .0 5 )。毒副反应以血液毒性为主 ,白细胞和血小板Ⅲ +Ⅳ度下降病例为 2 3 .68% ,2 6.3 2 % ,血红蛋白未见明显的毒副反应 ,其他反应轻微。结论 :拓扑替康单药治疗难治性SCLC具有较好的疗效并可以作为SCLC的二线治疗药物应用。     

小细胞肺癌患者预后的影响因素分析

目的分析小细胞肺癌(SCLC)患者预后的影响因素。方法回顾性分析97例SCLC患者的临床资料,采用单因素和多因素Cox回归模型分析患者预后的影响因素。结果患者的中位总生存期为21.4个月,1年、2年和5年生存率分别为47.4%、15.4%和1.0%。局限期和广泛期患者2年累积复发率分别为75.3%和98.9%。血清神经元特异性烯醇化酶(NSE)水平升高(HR=4.02,P<0.05)、未化疗(HR=3.07,P<0.01)是SCLC总生存期的独立危险因素,而化疗周期大于2个(HR=0.29,P<0.01)是SCLC总生存期的独立保护因素。2个周期治疗后进展(HR=4.04,P<0.01)、广泛期(HR=4.10,P<0.05)及骨转移(HR=2.01,P<0.05)是无进展生存期的独立危险因素。结论积极规范化疗、化疗超过2个周期以及血清NSE水平正常的SCLC患者的预后更好。     

非小细胞肺癌患者贫血的临床相关因素分析

目的 探讨非小细胞肺癌患者临床、病理特点等因素与贫血的关系.方法 回顾性分析了均有病理证实的非小细胞肺癌住院患者90例.结果 贫血发生率为35.6％;非小细胞肺癌患者是否贫血在患者的性别、年龄、肿瘤发生部位等方面均无统计学差异.化疗患者贫血发生率高于未化疗者,且有统计学意义(P＜0.05).中晚期肺癌患者贫血的发生率比早期患者高,也有统计学意义(P＜0.05).结论 非小细胞肺癌患者贫血的发生与其分期、化疗与否有一定关系.     

Therapeutic advances in small cell lung cancer

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.