Chemotherapy in elderly patients with advanced non-small cell lung cancer

Because of increasing life expectancy and of higher risk of cancer with ageing, lung cancer in elderly is a frequent disease. For a long time nihilism influenced treatment decisions in elderly patients with advanced non-small cell lung cancer. Since the beginning of the last decade single agent chemotherapy has been accepted as standard of care, vinorelbine and gemcitabine being the most frequently used drugs in Europe and US, docetaxel in Japan.Platinum-based doublets have been shown to be superior to monotherapy in young and fit patients with advanced non-small cell lung cancer. Although there were some indications from subgroup analyses of clinical trials not specifically dedicated to elderly patients that a platinum-based doublet might also benefit to older patients, there was no definitive proof of concept until ASCO meeting 2010. At this meeting results of a phase 3 trial showed that PS 0-2 patients, aged 70-89 years drove a significant benefit from a treatment with carboplatin associated to weekly paclitaxel compared to a monotherapy. Thus, the paradigm of treatment in elderly patients should perhaps be modified from a single agent to doublet chemotherapy. Whether other platinum-based doublets would provide the same benefit as the specific one studied remains to be evaluated.     

Chemotherapy in elderly patients with advanced lung cancer. Part I: General aspects and treatment of small cell lung cancer (SCLC)

There is much uncertainty whether chemotherapy is beneficial for elderly patients with advanced lung cancer. Whereas age alone is not an adverse prognostic factor, decline of physiological function and comorbidity can result in higher rates of treatment-related toxicity, in particular myelosuppression. The higher incidence of comorbid conditions, frequently sharing the risk profile of the malignancy, can translate into worse survival. Therefore, a geriatric assessment of the patient's overall situation should guide decision-making. Mainstay of treatment of small cell lung cancer (SCLC), also in the elderly, is combination therapy. Several retrospective analyses reveal that in elderly patients often lower drug doses are delivered. However, the treatment outcome of these patients does not appear to be worse compared to younger patients. For functionally independent elderly patients, combination chemotherapy with carboplatin and etoposide, supported by optimized supportive care, possibly including hematopoietic growth factors (G-CSF) to minimize toxicity, should be considered. Special attention to renal function should be given and individualized drug dosing, adapted to the glomerular filtration rate, is mandatory. For patients with some functional dependence or showing a certain degree of comorbidity, preliminary data indicate that single-agent therapy with carboplatin can confer the same benefit as combination chemotherapy, but with reduced toxicity. Single agent oral etoposide, however, seems to be inferior to combination treatment and should not be given routinely in the treatment of this cohort. Further evaluation of these topics is needed, and can be achieved by trials specifically designed for elderly patients or patients with reduced performance status.     

胸腺肽在晚期非小细胞肺癌化疗中的作用

背景与目的：肺癌的发生、发展与机体的免疫功能状况密切相关,恶性肿瘤患者存在明显的免疫功能紊乱,主要表现为细胞免疫功能下降.本研究评价胸腺肽联合化疗对晚期非小细胞肺癌的疗效、毒副反应、生活质量及免疫功能的影响.方法：42例非小细胞肺癌随机分为2组,治疗组：NP方案＋胸腺肽.长春瑞滨（NVB）25 mg/m^2,静脉滴注,第1、8天,顺铂（DDP）70～80 mg/m^2,静脉滴注,第1天.化疗后第3天每日静脉滴注胸腺肽200 mg,连续7～10 d.对照组：单化疗,用NP方案,剂量、用法同上.结果：治疗组化疗后CD4和NK细胞活性显著高于化疗前和对照组化疗后水平（P＜0.01）,对照组NK细胞活性化疗后显著低于化疗前水平（P＜0.05）.治疗组KPS提高率为61.9%（13/21）,而对照组为28.6%（6/21）,两组差异有显著性（P＜0.05）.治疗组有效率52.4%（11/21）,1年生存率为52.6%.对照组有效率42.9%（9/21）,1年生存率38.8%.两组间疗效、毒副反应及1年生存率比较差异无显著性（P＞0.05）.结论：胸腺肽联合化疗能提高肺癌化疗患者机体的免疫功能,改善患者生存质量.     

Treatment of lung cancer in the elderly. Part I: non-small cell lung cancer

There is a general trend worldwide of an increasing incidence of elderly population. Age is the greatest risk factor for cancer; therefore, this demographic shift is the main reason for an increase of cancer incidence. Lung cancer is a typical disease of the elderly patients. This review summarizes the issues of treatment of non-small cell lung cancer (NSCLC) in the elderly. Early stage NSCLC is usually treated with radical surgery, locally advanced NSCLC with radiotherapy (RT) and/or chemotherapy (CHT) and metastatic disease with CHT, but the evidence for these approaches is based on studies which are usually performed with highly selected patients while elderly patients are under-represented. We used the data from studies addressing particularly elderly or providing subgroup information on age to analyse the feasibility of current standard approaches for elderly and discuss alternative approaches. Surgery is an effective method in elderly patients with early stage NSCLC although some approaches bear a somewhat higher risk of operative morbidity and mortality. RT for early stage may be an alternative with curative potential. For locally advanced stage RT alone, or combined radiochemotherapy in selected cases, is feasible for elderly patients with locally advanced NSCLC when a careful assessment of pre-therapeutic status is made and appropriate drugs are selected. Advanced age alone also should not preclude CHT, although the risk of adverse effect may be higher in certain cases. New generation drugs seem to be particularly feasible and efficient in elderly patients. In general, age itself does not seem to preclude patients from standard treatments although in some cases co-morbidity forces to alternative approaches. Currently, single-agent CHT should be considered as the standard treatment of advanced NSCLC elderly patients.     

Chemotherapy options for the elderly patient with advanced non-small cell lung cancer

Combination chemotherapy has been shown to improve overall survival compared with best supportive care in patients with advanced non-small cell lung cancer (NSCLC). The survival advantage is modest and was initially demonstrated with cisplatin-containing regimens in a large meta-analysis of randomized trials reported in 1995. Newer chemotherapy combinations have been shown to be better tolerated than older cisplatin-based combinations, and some trials have also shown greater efficacy and survival benefits with these newer combinations. Combination chemotherapy is, therefore, the currently accepted standard of care for patients with good performance statuses aged less than 70 years with advanced NSCLC. However, there are limited data from clinical trials to support the use of combination chemotherapy in elderly patients over 70 years of age with advanced NSCLC. Subgroup analyses of large randomized phase III trials suggest that elderly patients with good performance statuses do as well as younger patients treated with combination chemotherapy. There are few randomized trials reported that evaluate chemotherapy in patients aged greater than 70 years only. Based on data from trials performed by an Italian group, single-agent vinorelbine has been shown to have significant activity in elderly patients with advanced NSCLC and to be well tolerated by those patients with Eastern Cooperative Oncology Group performance statuses of two or less, with associated improvements in measures of global health.     

A phase II study of carboplatin and paclitaxel as first line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC)

INTRODUCTION: Lung cancer is the leading cause of tumour-related deaths in the elderly population but the optimal management of advanced NSCLC in older patients has not been defined to date. The present phase II study was planned to evaluate the efficacy and toxicity of the combination of carboplatin and paclitaxel in elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients (>70 years old) who had pathologically been proven to have a NSCLC and measurable lesions were treated with paclitaxel (175 mg/m2 for 3h) and carboplatin [area under the concentration-time curve (AUC=5)] on day 1 every 3 weeks. RESULTS: Forty patients were enrolled into the study. The median age was 74 years (range, 70-78 years). Approximately 85% of the patients had stage IV and 80% had a performance status (PS) of 0-1. Nine of the 40 (22.5%; 90% CI 17.6-28.1) included patients had a partial response; one patient (2.5%; 90% CI 1.7-3.2) achieved a complete response. The overall response rate was 25% (90% CI 15.3-38.6). In addition stable disease was observed in 13 patients (32.5%; 90% CI 24.3-40.7). The median survival was 7.8 months (95% confidence interval, 5.1-11.8 months). The actual 1-year survival was 18% (95% confidence interval, 12-29%). The median time to disease progression was 4.1 months (95% CI 2.8-8.5). Overall, 37.5% of patients experienced grade 3-4 neutropenia of any duration with only two patients (5%) developing neutropenic fever. Grade 3 or 4 non-haematological toxicity was uncommon apart alopecia. CONCLUSIONS: In the present phase II study the combination of paclitaxel and carboplatin has demonstrated to be active and safe in an age-selected population.     

Treatment of patients with advanced non-small cell lung cancer

In advanced non-small cell lung cancer (NSCLC), an objective response to chemotherapy is of limited value and the impact of chemotherapy on survival is modest. Therefore, endpoints evaluating the patients’ subjective benefit such as symptom control (SC), quality of life (QOL) or clinical benefit (CB) have recently been implemented into clinical trials, mostly as secondary endpoints. Chemotherapy offers SC, not only in patients with an objective response, but also in a proportion of patients with disease stabilization. For this purpose, three to four cycles of platinum-based chemotherapy are recommended. Interpretation of QOL objectives is limited by several methodologic problems. Studies comparing best supportive care alone with either older platinum-based combinations or single-agent chemotherapy with a new cytotoxic drug usually indicate improved survival and improvement of some component(s) of QOL in the active treatment arm. However, results from studies comparing different chemotherapies are less definitive. Trials comparing single-agent therapy with a new drug with new combinations mostly report no difference in QOL. In addition, most trials comparing new platinum-based combinations with older ones, and trials comparing new platinum-based regimens fail to show any differences in QOL. As a whole, it is far from clear whether combination therapy is superior to modern single-agent therapy, when the patient’s benefit is the primary endpoint. Non-platinum-based doublets, compared with platinum-based doublets, may lead to slightly inferior survival, are not always less toxic, and have not been proven to provide better QOL outcomes. The CB response, originally reported in pancreatic cancer, measures more than SC, but not full QOL. Encouraging experience with this tool was reported in advanced NSCLC. Randomized studies designed to look at some form of patient benefit as a primary endpoint should be a priority in advanced NSCLC.     

多西他赛每周给药联合奈达铂治疗晚期高龄非小细胞肺癌的临床研究

目的:探讨多西他赛每周给药联合奈达铂治疗晚期高龄非小细胞肺癌(NSCLC)的疗效及不良反应.方法:对33例晚期高龄NSCLC患者用多西他赛30mg/m2,每周给药,连用3周休息1周;奈达铂80mg/m2,每周期的第1d给药,每28d为1个治疗周期.3周期评价疗效,以上化疗方案每4周重复,每例进行2-4周期化疗.结果:全组33例,有效率36.36%(12/33),其中CR 1例,PR 11例,SD 16例,PD 5例,Ⅲ-Ⅳ度的中性粒细胞减少发生率为15.15%(5/33),非血液学毒性主要为消化系统不良反应,其他不良反应轻微.结论:多西他赛每周给药联合奈达铂治疗晚期高龄NSCLC疗效较好,骨髓毒性较轻.     

Serum levels of Magic Roundabout protein in patients with advanced non-small cell lung cancer (NSCLC)

BACKGROUND: Magic Roundabout (MR; ROBO 4) is a recently discovered gene which encodes a protein that derived its name form the structural homology with the roundabout family of genes. Genes of the roundabout family comprise neuronal-specific cell surface receptors that are involved in axon guidance. MR in contrast showed endothelial specificity in vitro and in vivo using immunohistochemistry and in situ hybridisation. The putative role of MR as an endothelial analogue of Roundabout in angiogenesis makes it an attractive target for anti-angiogenic cancer therapy. PATIENTS AND METHODS: Using specific antibodies against MR peptide, we screened pretreatment sera from 193 patients with advanced non-small cell lung cancer (NSCLC) for MR-protein levels. RESULTS: Patients with serum levels of MR-protein lower than median (E(450 nm) = 0.652) had a median survival of 41.0 weeks whereas those with a higher serum level had a considerably shorter median survival of 32.4 weeks (P = 0.05). The pretreatment serum level of MR-protein achieved no significance in a univariate Cox regression analysis. CONCLUSIONS: This is the first study to present clinical data that link MR expression with outcome in patients with NSCLC, whether the correlation of pretreatment serum levels of MR and survival can be attributed to MR dependent angiogenesis remains to be investigated.     

Chemotherapy for advanced non-small cell lung cancer

Lung cancer is an aggressive disease with poor prognosis after it has advanced. Over the past several years, there has been slow but steady progress in treatment options. Chemotherapy results in a modest improvement in survival, improved quality of life, and decreased pulmonary symptoms. For first-line therapy, platinum-based regimens have generally been the standard of care, with no one regimen clearly superior to the others in terms of overall survival, although there may be differences in response rates, time to progression, toxicities, cost, and schedule. There does not appear to be such a uniform consensus for nonplatinum agents. Triplet regimens are not more effective than doublet regimens and are more toxic and expensive. Chemotherapy should be given for four cycles unless there is unaccepted toxicity or disease progression. Patients with poor PS generally experience increased toxicities and fewer benefits, although this finding needs further investigation to ascertain the appropriate treatment. In second-line setting, docetaxel is the agent that has been extensively studied and approved. Furthermore, molecularly targeted therapy holds a promising future and is discussed in articles elsewhere in this issue. Lung cancer is an aggressive disease with poor prognosis after it has advanced. Over the past several years, there has been slow but steady progress in treatment options. Chemotherapy results in a modest improvement in survival, improved quality of life, and decreased pulmonary symptoms. For first-line therapy, platinum-based regimens have generally been the standard of care, with no one regimen clearly superior to the others in terms of overall survival, although there may be differences in response rates, time to progression, toxicities, cost, and schedule. There does not appear to be such a uniform consensus for nonplatinum agents. Triplet regimens are not more effective than doublet regimens and are more toxic and expensive. Chemotherapy should be given for four cycles unless there is unaccepted toxicity or disease progression. Patients with poor PS generally experience increased toxicities and fewer benefits, although this finding needs further investigation to ascertain the appropriate treatment. In second-line setting, docetaxel is the agent that has been extensively studied and approved. Furthermore, molecularly targeted therapy holds a promising future and is discussed in articles elsewhere in this issue.     

拉司太特单药治疗老年晚期非小细胞肺癌疗效观察

目的评价拉司太特单药治疗晚期老年非小细胞肺癌(NSCLC)的疗效和安全性。方法30例晚期非小细胞肺癌患者采用拉司太特口服25mg,每日2次,服药21d,间隔1周后重复,共3周期,并进行评价。治疗前、治疗后2个月及3个月分别用肺癌患者生存质量测定量表FACT-L中文版进行生活质量(QOL)测评。结果30例患者均完成3个周期化疗,部分缓解7例,总有效率23.3%。Ⅲ/Ⅳ度白细胞减少发生率16.7%,其他副反应轻微。结论拉司太特治疗晚期非小细胞肺癌有一定疗效,但要注意白细胞下降。     

Treatment for elderly patients with non-small cell lung cancer

Recently, with the increasing population of elderly people, the number of patients who suffer from lung cancer has been increasing, necessitating the establishment of treatment for elderly lung cancer patients. However, a standard therapy, for elderly lung cancer patients, including surgical treatment, radiotherapy, and chemotherapy, has not been established for the following reasons: (1) there is a difference between calendar age and actual age; and (2) most elderly lung cancer patients are excluded from general clinical study. As a matter of fact, even in elderly patients with good performance status, routine treatments could sometimes cause unpredicted complications. Therefore, some guidelines for treatment of elderly lung cancer patients are necessary. Here, the author reviews the recent common views for treatment of elderly lung cancer patients.     

Chemotherapy for advanced non-small cell lung cancer

It is well-known that cisplatin-based chemotherapy can prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). This report reviews the recently published clinical trials of chemotherapy for advanced NSCLC. New agents developed in the 1990s such as paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan prolonged the survival of patients with advanced NSCLC by single-agent chemotherapy, and combinations of platinum and one of the new agents were superior to existing platinum-based combinations. Accordingly, the current standard chemotherapy for previously untreated patients with advanced NSCLC is considered to be a two-drug combination consisting of cisplatin and one of the new agents. For elderly patients, single-agent chemotherapy using vinorelbine or gemcitabine is recommended. However, the usefulness of platinum-containing chemotherapy for elderly patients has not yet been throughly evaluated. As salvage chemotherapy for patients previously treated with chemotherapy, the effectiveness of docetaxel is confirmed by two randomized trials. However, since many promising agents including pemetrexed and molecular targeting agents such as gefitinib, erlotinib and bevacizumab have been currently developed, we have to evaluate the usefulness of these agents by well-designed clinical trials.     

308例非小细胞肺癌放疗效果的临床因素分析

目的：探讨非小细胞肺癌单纯放疗的生存情况及影响预后的临床因素。方法：回顾性分析1985年1月－1991年12月收治的308例非小细胞肺癌,Ⅰ期11例,Ⅱ期68例,ⅢA期155例,ⅢB期74例。均经病理或细胞学证实,采用10MV－X线或CO－60机照射,常规分割,周剂量7－11,50Gy。有47例放疗开始或半量时按治疗计划布野,全程包括纵隔及原发灶,纵隔剂量大于56Gy其它病例纵隔剂量40Gy,生存率计算采用Kaplan-Meier法及Log-rank检验。结果：全组中位生期期10个月,1、3、5年生存率分别为43％、15％和9％,影响生存的临床因素分析结果表明,临床分期、近期疗效和周剂量和与预后有密切关系（P＜0．05）,而放疗总剂量和纵隔剂量与预后未见明显关系（P＜0．05）。结论：影响肺癌患者放疗预后的临床因素主要是临床分期,近期疗效和周剂量的大小,而放疗总剂量和纵隔剂量高低与生存率无明显关系     

多西紫杉醇单药治疗老年非小细胞肺癌的临床观察

目的　观察多西紫杉醇单药每周疗法治疗老年非小细胞肺癌（ＮＳＣＬＣ）的疗效及安全性。方法　我院收治年龄＞７０岁ＮＳＣＬＣ患者３２例,给予多西紫杉醇２５～３０ｍｇ／ｍ^２,每周１次,连用３周,２８天为１周期,治疗不超过６个周期,观察疗效及不良反应。结果　３２例患者均可评价疗效,获ＣＲ１例,ＰＲ９例,有效率（ＲＲ）３１.３％,中位疾病进展时间为４.５个月,１年生存率为４３.８％（１４／３２）。ＦＡＣＴ-Ｌ生存质量和ＫＰＳ行为状态评分治疗后分别提高２２分和１１分,与治疗前比较差异显著（Ｐ＜０.０５）。主要不良反应包括１～２级粒细胞减少、血红蛋白减少和乏力,未发生３～４级的毒性反应。结论　低剂量多西紫杉醇每周给药治疗老年ＮＳＣＬＣ疗效确切,毒副反应轻微,耐受性良好,值得在临床推广。     

A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer.

PURPOSE: Our aim was to evaluate the efficacy, toxicity, and pharmacokinetic behavior of single-agent paclitaxel given weekly to elderly patients with lung cancer. EXPERIMENTAL DESIGN: Previously untreated patients with stage IIIB/IV non-small cell lung cancer were eligible for the study if they were at least 70 years of age and had preserved organ function. Paclitaxel was administered over 1 h at a dose of 90 mg/m(2) for 6 consecutive weeks on an 8-week cycle. The pharmacokinetics of paclitaxel were assessed during the first and sixth week of therapy in a subgroup of eight patients. RESULTS: A total of 35 patients (median age, 76 years; range, 70-85) were enrolled. The overall response rate was 23%. Median time to failure was 5.2 months, whereas the median survival time was 10.3 months. Survival rates after 1 and 2 years were 45 and 22%, respectively. Grade 3/4 toxicities included neutropenia (5.8%), hyperglycemia (17.6%), neuropathy (5.8%), and infection (8.8%). Two patients died from treatment-related toxicity. There was no significant difference (P = 0.18) between the total body clearance of paclitaxel on the first (17.4 +/- 2.9 liters/h/m(2), mean +/- SD) and sixth (15.8 +/- 4.1 liters/h/m(2)) week of therapy. CONCLUSION: Paclitaxel administered as a weekly 1-h infusion at a dose of 90 mg/m(2) is a safe and effective therapy for elderly patients with advanced non-small cell lung cancer. Its pharmacokinetics in elderly patients do not appear to differ from historical data for younger patients, and there was no suggestion of a change in drug clearance after repeated weekly dosing.