Chemotherapy for elderly patients with non-small cell lung cancer: a review of the evidence

Chemotherapy for elderly patients with non-small cell lung cancer (NSCLC) has been questioned due to the perceived potential for higher toxicity in this population, possibly attributable to progressive organ failure and comorbidities. This non-systematic review presents the authors' selection of key evidence for the use of chemotherapy for elderly patients with NSCLC. To date, single-agent chemotherapy with agents such as vinorelbine, gemcitabine, docetaxel, and paclitaxel has been a reasonable option. Data on non-platinum-based combinations are limited, but recent investigations of gemcitabine plus vinorelbine failed to show superiority over either agent alone. Retrospective subset analyses from large randomized trials suggest that the efficacy and tolerability of platinum-based combination chemotherapy are similar in both the elderly and their younger counterparts. Further phase III trials that specifically examine platinum-based combinations in selected elderly NSCLC patients are therefore warranted. The potential impact of new targeted therapies-alone or in combination with chemotherapy-is being investigated.     

以铂类为基础的两药联合方案治疗老年晚期非小细胞肺癌临床研究

目的 评价老年晚期非小细胞肺癌(NSCLC)患者接受以铂类为基础的两药联合化疗的疗效和安全性. 方法 对我院41例年龄≥70岁的老年晚期NSCLC患者应用以铂类为基础的两药联合方案化疗的情况进行了回顾性分析. 结果 41例患者中采用长春瑞滨方案的18例(43.9%),吉西他滨方案的9例(22.0%)、紫杉醇和多西紫杉醇方案各7例(17.1%).全组总有效率为19.5%,中位疾病进展时间和中位生存期分别为5.8个月和14.2个月,1年生存率为65.8%.化疗的主要不良反应为骨髓抑制,主要以白细胞和血小板减低为主,给予对症处理后可以恢复.患者无化疗相关死亡发生,有3例患者因出现Ⅲ～Ⅳ度骨髓抑制仪化疗1个周期. 结论 以铂类为基础的联合化疗方案治疗一般状况较好的老年晚期NSCLC疗效确切且耐受性较好.     

Chemotherapy for non-small cell lung cancer in elderly patients

STUDY OBJECTIVE: To determine the appropriate chemotherapy regimen for inoperable, chemotherapy-na?ve non-small cell lung cancer (NSCLC) in elderly patients. SETTING: National teaching hospital in Taiwan. DESIGN: We retrospectively analyzed data from our clinical trials for a total of 270 patients and compared them with the data from other studies, addressing the elderly in particular or providing subgroup information on age, to analyze the feasibility of current chemotherapy options for elderly patients and possible alternative approaches. RESULTS: The response rates and median survival times of fit elderly patients with NSCLC who were receiving appropriate new anticancer drugs for chemotherapy, including single-agent or combination treatment, were no worse than those of younger patients, and the response rates may have been even higher in the elderly patients, while survival time was slightly poorer in this group. The risk of adverse side effects, such as myelosuppression and peripheral neuropathy, may be higher in elderly patients, who also visit the hospital more frequently. Some items on the lung cancer symptom scale for elderly patients were rated as being slightly worse than those for younger patients after chemotherapy. CONCLUSION: Advanced age alone should not preclude chemotherapy. New single-agent drugs, and non-platinum-based or platinum-based doublets, can all be considered as appropriate treatment for selected fit elderly patients with advanced NSCLC.     

Meta-analyses of clinical trials in patients with non-small cell lung cancer. Minireview

Currently lung cancer is the most common worldwide cause of major cancer incidence and mortality. The treatment outcome is poor and there are still many questions which remain unanswered such as the interest of the best treatment schedule. To approach the answer what is the best treatment for patients with non-small cell lung cancer (NSCLC) we made a review of the published meta-analyses. Meta-analysis is a systematic approach to identification and abstraction of critical information from different randomized, controlled trials. The review of meta-analyses of clinical trials we had made showed that --in radically operated patients the postoperative radiotherapy should be detrimental if standard fields are used; postoperative chemotherapy with regimens based on cisplatin has an absolute benefit of 5% at 5 years survival; we can improve the survival of patients with locally advanced NSCLC using chemoradiation comparing to radiotherapy alone; chemotherapy with cisplatin can prolong the survival and improve the quality of life in patients with advanced NSCLC; platinum-based doublets remain the standard regimen in patients with advanced NSCLC; there is a slight but significant improvement in efficacy of gemcitabine plus platinum agent when compared with other platinum based comparators in regard to the survival and time to disease progression. In our dealing with NSCLC patients there are still many controversial opinions, and the meta-analyses are seldom the only way to find more effective treatment regimen, while the improvement in lung cancer treatment is a story of small steps.     

The role of chemotherapy in the treatment of unresectable stage III and IV nonsmall cell lung cancer

Modern platinum-based combination chemotherapy has played a major role in the therapeutic approach to unresectable stage III and IV NSCLC. Randomized phase III trials clearly documented a survival as well as palliative benefit to treatment in patients with stage IV NSCLC who have a good PS (PS 0-1). The optimal therapeutic approach in patients with poor PS (PS 2) has not yet been defined. Recent trials that focused on the elderly suggested that they receive benefits from chemotherapy that are similar to their younger counterparts. The benefit from chemotherapy seems to occur early (initial 3 to 4 cycles) and prolonged therapy is not indicated. Second-line therapy that is administered upon progression was shown to provide survival and palliative benefits. In unresectable stage III NSCLC, the addition of chemotherapy to TRT improves long-term survival and has the potential to cure a minority of patients. Although sequential and concurrent chemoradiotherapy approaches have improved survival in phase III trials, concurrent strategies seem superior in comparative trials. New techniques in radiation therapy, such as three-dimensional treatment planning, may allow safer administration of both modalities concurrently and allow higher doses of TRT to be delivered. In unresectable stage III and stage IV NSCLC, the role of the new "targeted" therapies is currently being defined in several randomized, phase III trials. It is imperative that physicians who care for patients with advanced NSCLC be aware of these trials and attempt to enroll their patients, if possible. It is only through the successful and timely completion of well-designed clinical trials that we will advance our knowledge of improved treatment options for our patients with this disease.     

Chemotherapy in advanced non-small cell lung cancer

Although patients with advanced non-small cell lung cancer (NSCLC) cannot be cured, cytotoxic chemotherapy in patients with reasonable performance status can improve overall survival and quality of life. No one regimen has demonstrated superior efficacy results, and platinum-based doublets remain the current standard of care. The toxicity profiles of acceptable regimens differ, allowing treatment to be tailored to a specific patient. The duration of first-line chemotherapy should not exceed four to six cycles. Second- and third-line treatment regimens also have established survival benefits, which has led to increasing improvements in overall survival for patients with advanced NSCLC. Treatment approaches in patients with borderline performance status remain controversial. Although the optimal treatment approach for elderly patients has not yet been established, it is clear that the elderly do benefit from chemotherapy, and fit elderly patients can be treated with the same regimens as younger patients. It is critical that all patients with advanced NSCLC be referred to medical oncologists. Patients considering chemotherapy must have a clear understanding of the expected benefits, limitations, and toxicities.     

胸腺素β4在老年晚期非小细胞肺癌中的表达及其对化疗疗效的影响

目的:探讨胸腺素β4(Tβ4)在老年晚期非小细胞肺癌(NSCLC)中的表达与临床病理学因素及一线含铂类化疗疗效的关系。方法:选取94例晚期的老年NSCLC患者病理组织标本,采用免疫组化的方法检测Tβ4的表达水平,分析临床病理特征,采用实体瘤客观疗效评价标准(RECIST)评价化疗效果,进行生存随访。分析Tβ4的阳性表达与无进展生存期(PFS)及总生存期(OS)的关系。结果:在94例老年晚期NSCLC患者中,Tβ4的高表达率为39.4%(37例/94例)。相关性分析表明,Tβ4的高表达与性别、分化程度、病理类型、TNM分期、化疗方案及T分期等因素无关(P<0.05),与化疗疗效(r=0.327,P=0.001)、PFS(r=0.387,P=0.002)及OS(r=0.404,P=0.001)显著相关。多因素Logistic回归分析表明,Tβ4表达为NSCLC患者疗效的影响因素(P<0.05)。COX多因素分析表明Tβ4表达水平是化疗反应率及PFS的预测因素(P<0.05)。结论:Tβ4的高表达与老年晚期NSCLC一线含铂化疗疗效及生存期相关。Tβ4对于老年晚期NSCLC一线含铂化疗方案的疗效预测具有一定的临床意义。     

厄洛替尼与化疗治疗晚期非小细胞肺癌的临床观察

目的观察厄洛替尼与含铂化疗方案治疗晚期非小细胞肺癌的疗效和安全性。方法对我院晚期NSCLC给予化疗组30例,服用厄洛替尼组27例定期随访,观察疗效与不良反应。结果 57例可评价疗效的患者中,化疗组30例:CR:0例,PR:6例,SD:10例,PD:14例;缓解率6/30(20%),疾病控制率16/30(53.3%);服用厄洛替尼组27例:CR:2例,PR:8例,SD:14例,PD:3例;缓解率:10/27(37.1%),疾病控制率24/27(88.9%);不良反应主要表现在骨髓抑制、胃肠道反应以及皮疹,发生率在化疗组和厄洛替尼组分别为76.7%、80%、13.3%及3.71%、40.7%、66.7%,三者之间均有显著性差异。结论厄洛替尼治疗晚期NSCLC患者的疗效较化疗组好,且安全性高。     

Monoclonal antibodies against EGFR in non-small cell lung cancer

Blockade of the epidermal growth factor receptor (EGFR) by monoclonal antibodies is a strategy to improve outcome in patients with non-small cell lung cancer. Cetuximab, a chimeric anti-EGFR monoclonal antibody, has been studied in combination with different chemotherapy protocols in both phase II and phase III trials in patients with advanced NSCLC. In the phase III FLEX trial, cetuximab added to cisplatin/vinorelbine resulted in an absolute overall survival benefit of 1.2 months compared to the same chemotherapy alone in patients with advanced EGFR-expressing NSCLC. In the second phase III trial, cetuximab added to carboplatin plus paclitaxed failed to improve progression-free survival but suggested a survival benefit similar to that seen in the FLEX trial. However, the benefit in survival reached statistical significance only in the FLEX trial. A meta-analysis that included patients from four randomized trials confirmed the efficacy of cetuximab when added to chemotherapy. Thus addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced NSCLC. Matuzumab and panitumumab have also been evaluated in phase II trials. Necitumumab is currently evaluated in combination with chemotherapy in two randomized phase III trials.     

Cisplatin-based chemotherapy in elderly patients with advanced stage (IIIB and IV) non-small cell lung cancer patients

Lung cancer continues to be the leading cause of cancer-related mortality and approximately 70% of patients present with locally advanced or metastatic disease at the time of diagnosis. More than 50% of lung cancer cases are diagnosed in patients over the age of 65 years. The doublet chemotherapies consisting of platinum plus one of the third-generation agents become currently the standard regimen, the first line chemotherapy The most of the available data regarding the optimal treatment of lung cancer comes from clinical trials in which the vast majority of patients are significantly younger than 65 years of age. We aimed to investigate whether there is any difference in tolerability and efficacy in between adult(<65 years old) and elderly(≥65 years old) patients who received cisplatin based chemoteherapy or chemoradiotherapy for stage IIIB and IV non-small cell lun cancer. We retrospectively evaluated the total 134 patients with advanced stage (stage IIIB or IV) NSCLC, in Ondokuzmay?s University, Faculty of Medicine, Department of Pulmonary Medicine between 2001 and 2004. The response rates were 30.3% in adults and 28.8% in elderly patients. The median survival was 13.6±1.4 months and 11.8±2.0 months for adults and elderly patients, respectively. The one-year, two year and five year survival rates were 37%, 9% , 4% for adult patients and 29%, 7%, 4% for elderly patients, respectively. There was no statistical difference between the groups. Percentages of grade 3-4 anemia (0% vs 6.6%) and grade 3-4 neutropenia (0% vs 4.4%) were higher in elderly patients than adult patients. Other toxic effects were similar among both of groups. In conclussion; standart cisplatin containing chemotherapy regimens (cisplatin plus gemcitabine or vinorelbine) can be used in elderly patients with advanced non-small cell lung cancer.     

Palliativ intendierte First-line-Chemotherapie des metastasierten nichtkleinzelligen Lungenkarzinoms

EGFR-TKI are established as an effective option for second- and third-line-treatment of advanced non-small cell lung cancer. The combination with chemotherapy in nonselected patients did not show an additional benefit compared with chemotherapy alone. With a combination of the EGFR antibody cetuximab or the VEGF antibody bevacizumab with chemotherapy a moderate improvement of overall survival was achieved. Results of comparative trials with molecular targeted therapies and classic chemotherapy as first-line treatment are currently only available for the EGFR-TKI erlotinib and gefitinib which showed impressively the superiority in response rate, progression-free survival, toxicity, and improvement of quality of life for EGFR-TKI in patients harboring an activating mutation of EGFR. For patients with unknown EGFR mutation status or wild-type EGFR the platinum-based chemotherapy combination is still the most effective treatment option.     

Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year survival rate. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. Several randomized trials now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year survival rate among patients with T1N0 disease after they had received adjuvant therapy with a combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11% rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0 disease. Two recently published meta-analyses have estimated a relative risk reduction in mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B 9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus, there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.     

Strategies for maintenance therapy in advanced non-small cell lung cancer: current status, unanswered questions and future directions

Systemic chemotherapy (CT) with platinum-based doublets result in modest improvements in both overall survival (OS) and quality of life in good performance status patients with advanced non-small cell lung cancer (NSCLC). However, although substantial progress has been made in the therapeutic options currently available for these patients, the overall outcome remains poor. Maintenance therapy for patients who achieved at least stable disease after first-line treatment has been an area of intense investigation in recent years as a way of improving outcomes in metastatic NSCLC. Several alternative strategies for prolongation of initial treatment have been evaluated. These include the prolongation of the initial combination CT regimen until disease progression, unacceptable toxicity or a predefined greater number of cycles, continuation with a lower intensity version of the first-line CT regimen or administration of a new active agent immediately after completion of the first-line therapy (switch-maintenance or early second-line therapy). Treatments that have been studied in randomized trials to date include CT, molecularly targeted agents, and immunotherapy approaches. Phase III trials have not revealed a survival benefit for extended first-line CT with combination regimens for more than 4-6 cycles. Nevertheless, early second-line therapy with pemetrexed in nonsquamous tumours and erlotinib have demonstrated to improve OS results, especially in select patient groups characterized by histology and/or molecular profile. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development.     

Clinical efficacy and safety of Huachansu injection combination with platinum-based chemotherapy for advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials

Background:Huachansu injection (HCS) is a widely used traditional Chinese medicine for advanced non-small cell lung cancer (NSCLC) to alleviate the adverse drug reactions (ADRs) and enhance the clinical efficacy of chemotherapy.Objective:To evaluate the efficacy and safety of HCS as an adjunctive treatment to platinum-based chemotherapy (PBC) for advanced NSCLC.Methods:A systematic review and meta-analysis were conducted according to PRISMA guidelines. A total of nine databases were searched to select randomized controlled trials (RCTs) of HCS plus PBC to treat NSCLC from inception to October 10, 2020. RCTs on HCS plus PBC vs PBC alone for advanced NSCLC were included. Dichotomous data were pooled as risk ratio (RR) with 95% confidence intervals. RCTs compared to HCS plus PBC vs PBC alone were included. Primary outcomes were objective response rate (ORR) and disease control rate (DCR), and secondary outcomes were survival rate, quality of life (QOL), and adverse drug reactions (ADRs). GRADE software was used to access the quality of evidence.Results:A total of 32 RCTs, including 2753 patients, were included. Compared to PBC alone, HCS plus PBC improved the ORR, DCR, 1- and 2-year survival rates, and QOL and alleviated neutropenia, thrombocytopenia, nausea, vomiting, anemia, liver injury, renal injury, and alopecia.Conclusions:Compared to PBC alone, HCS plus PBC improved the clinical efficacy and alleviated the ADRs in advanced NSCLC patients. Considering the limitations of the included RCTs, high-quality trials with longer follow-ups are needed to further confirm the results.     

老年与青年晚期非小细胞肺癌患者的临床特点及预后分析

目的 回顾性分析老年及青年晚期非小细胞肺癌(NSCLC)患者的临床特点、治疗及预后因素的异同.方法 收集北京大学临床肿瘤学院胸部肿瘤内科1995年3月至2007年5月住院的晚期NSCLC 399例,其中老年(≥70岁)256例,男199例,女57例;青年(≤45岁)143例,男77例,女66例,均接受一线化疗.采用Kaplan-Meier及Cox回归法分析生存期及其影响因素,疗效相关性分析采用χ~2检验.结果 (1)青年组及老年组均以男性、腺癌、Ⅳ期患者居多,但青年组与老年组相比,女性[46.2%(66/143),22.3%(57/256)]、腺癌[71.3%(102/143),54.7%(105/256)]、Ⅳ期患者[72.7%(104/143),61.7%(158/256)]所占比例高;青年女性吸烟率高达95.5%(63/66);(2)一线治疗的疾病控制率与年龄无关;含铂联合化疗有利于疾病的控制,符合世界卫生组织毒性分级标准3-4度血液学毒性的病例数两组无差异;(3)老年组中位无进展生存期(PFS)为149 d(95%CI为119.5～178.5 d),青年组中位PFS为126 d(95%CI为84.0～168.0 d),两组比较差异无统计学意义;(4)老年组中位生存期为398 d(95%CI为330.3～465.7 d),青年组中位生存期为424 d(95%CI为359.7～488.3 d);(5)东方肿瘤合作组评分为0～1、一线治疗达到疾病控制、以三代新药或靶向治疗为二线治疗者等因素是有利于生存的独立预后因素.结论 青年组中,女性、腺癌、Ⅳ期患者所占比例较老年组高;青年女性NSCLC发生率的增加可能与吸烟有一定关系;年龄与一线治疗的疾病控制率、PFS及总生存期均无相关性.     

Doublet Versus Single Cytotoxic Agent as First-Line Treatment for Elderly Patients with Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Background

The aim of this study was to perform a systematic review and meta-analysis of all randomized controlled trials that compared the efficacy of doublet versus single third-generation cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC).

Methods

Several databases including PubMed, Embase, and Cochrane databases were searched. The endpoints were overall survival (OS), time to progression (TTP), 1-year survival rate (1-year SR), overall response rate (ORR), and grade 3 or 4 adverse event (AE). We performed a meta-analysis of the randomized controlled trials using a fixed-effects model and an additional random-effects model when applicable. The results of the meta-analysis were expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95?% confidence intervals (95?% CI). A subgroup meta-analysis was performed based on chemotherapy regimens.

Results

Ten eligible trials involving 2,510 patients were identified. The intention-to-treatment (ITT) analysis demonstrated that doublet therapy was superior to single agent in terms of OS (HR?=?0.84, 95?% CI?=?0.71–1.00, p?=?0.053), TTP (HR?=?0.76, 95?% CI?=?0.60–0.96, p?=?0.022), 1-year SR (RR?=?1.17, 95?% CI?=?1.02–1.35, p?=?0.03), and ORR (RR?=?1.54, 95?% CI?=?1.36–1.73, p?=?0.000). Subgroup analysis also favored platinum-based doublet therapy in terms of 1-year SR (RR?=?1.40, 95?% CI?=?1.09–1.81, p?=?0.009) and ORR (RR?=?1.64, 95?% CI?=?1.38–1.96, p?=?0.000). Though gemcitabine-based doublet significantly increased ORR compared with single agent (RR?=?1.45, 95?% CI?=?1.23–1.71, p?=?0.000), it did not translate into an increase in survival benefits. In addition, more incidences of grade 3 or 4 anemia, thrombocytopenia, and neurotoxicity were observed in the doublet combination group. With respect to grade 3 or 4 neutropenia and nonhematologic toxicities such as diarrhea, fatigue, nausea, and vomiting, equivalent frequencies were found between the two groups.

Conclusions

Our results indicated that doublet therapy was superior to a single third-generation cytotoxic agent for elderly patients with advanced NSCLC. The optimal dosage and schedule of platinum-based doublet should be investigated in future prospective clinical trials. Gemcitabine-based doublet could be considered for elderly patients who were not suitable for platinum-based chemotherapy.     

Chemotherapy of non-small-cell bronchial carcinoma in elderly patients

The incidence of lung cancer increases with age, and non-small-cell histotypes account for approximately 85% of lung cancers in patients aged older than 65 years. Results of large multicentric trials provide no evidence that elderly lung cancer patients who receive systemic chemotherapy have a worse outcome than younger patients. There is, however, an underrepresentation of older patients in cancer treatment trials, at least in part due to the stringent eligibility criteria of these trials. Recent studies specifically designed for elderly patients with advanced non-small-cell lung cancer have shown that chemotherapy improves survival and disease-related symptoms also in this age group. However, the degree of comorbidity was found to affect both the tolerance to treatment and the survival outcome.     

晚期老年人非小细胞肺癌化疗的循证医学证据及思考

晚期老年人非小细胞肺癌化疗的问题,临床上一直存有争议。本文回顾了晚期老年人肺癌治疗的循证医学证据,展示了晚期老年人非小细胞肺癌化疗策略的演进过程,指出目前晚期老年人非小细胞肺癌的化疗策略为单药是基础、含铂双药是补充。同时,根据目前肺癌治疗的现状,对“老年人肺癌”这一概念提出一些思考和建议,提出“老年人肺癌”的问题实质是如何将肺癌临床水平的异质性进行有效细化,从而使得老年人肺癌的化疗有的放矢。     

Treatment of advanced non-small cell lung cancer in the elderly

Non-small cell lung cancer (NSCLC) is primarily a disease of the elderly. Although NSCLC is the leading cause of cancer death in the United States and the overall prognosis of this disease is poor, treatment improves survival compared with best supportive care, independent of the stage of disease. Elderly patients have a particularly poor prognosis with NSCLC compared with younger patients, likely due to age-related biases in referral and treatment patterns. There is an emerging literature regarding the tolerability of NSCLC treatments in elderly patients. In advanced disease, subgroup analyses of the elderly population participating in randomized clinical trials as well as elder-specific prospective randomized trials have demonstrated that elderly NSCLC patients derive equivalent survival benefit from the treatment of NSCLC as younger patients. This treatment is tolerable for "fit" elderly patients, and modified regimens are available for the more frail elderly patients. Evaluating the relative fitness of an elderly patient may be achieved through an assessment of functional ability. As the U.S. population ages and the incidence of NSCLC rises, an understanding of treatment options for elderly patients with NSCLC is vital for all clinicians involved in their clinical care.