ⅠB期NSCLC术后辅助化疗争议及病理预后因素

ⅠB期非小细胞肺癌(NSCLC)为早期肺癌,目前最有效的治疗手段为手术治疗.然而,肿瘤的复发仍严重影响ⅠB期非小细胞肺癌患者的术后长期生存.ⅠB期NSCLC患者能否从辅助化疗中获益仍存在争议,本文就ⅠB期NSCLC患者术后辅助化疗存在的争议及影响预后的病理学特征做一综述.     

Ⅰb期非小细胞肺癌患者术后辅助化疗现状及研究进展

肺癌的发病率和死亡率均居全球癌症之首,且发病率逐年上升,根据组织病理学分类可将其分为非小细胞肺癌和小细胞肺癌。非小细胞肺癌占肺癌的75%-80%。I期NSCLC,手术是治疗的标准方式,尽管接受了根治性手术,Ⅰb期术后5年生存率约60%,主要的失败原因为远处转移和局部复发,虽诸多研究证明Ⅱ、Ⅲ期NSCLC术后辅助化疗可使患者生存获益,但Ⅰb期NSCLC患者术后是否化疗尚存在争议,本文对Ⅰb期NSCLC患者术后辅助化疗现状及研究进展做一综述。     

Ⅰ期非小细胞肺癌预后因素和术后辅助治疗进展

近年来,随着影像学技术的发展、肿瘤疾病谱的演变,越来越多的Ⅰ期非小细胞肺癌(NSCLC)患者被发现与治疗.Ⅰ期NSCLC的术后辅助治疗已成为热点.现指南推荐ⅠB期含高危因素患者术后使用含铂类的两药联合辅助化疗.尽管如此,近30％的Ⅰ期患者术后会出现局部复发或远处转移.众多预后因素提示Ⅰ期NSCLC中可能存在一部分未发现的高危患者,同时Ⅰ期NSCLC的术后辅助治疗已进入平台期.现有的研究已经开始探讨靶向辅助治疗和免疫辅助治疗的可行性.本文对近几年Ⅰ期NSCLC预后因素和术后辅助治疗的进展进行综述.     

表皮生长因子受体酪氨酸激酶抑制剂用于非小细胞肺癌术后辅助治疗的研究进展

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKI）在晚期EGFR突变阳性的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中的疗效肯定,但EGFR-TKI能否提高完全切除的NSCLC术后辅助治疗疗效不确切。部分研究发现在可切除的Ⅰ~Ⅲ期EGFR敏感突变肺腺癌患者中,辅助TKI治疗有使无疾病生存（disease free survival,DFS）获益的趋势,另一部分临床研究未能证实EGFR-TKI在术后辅助治疗有获益。造成各研究结果不一的原因很多,如人群选择、EGFR-TKI使用时长、耐药等。国内外目前一些设计比较合理的,对比EGFR-TKI化疗辅助治疗Ⅱ~ⅢA期EGFR敏感突变的NSCLC临床研究正在进行,值得期待。目前,早期NSCLC术后TKI辅助治疗仅限于临床试验,不建议作为临床常规治疗。     

非小细胞肺癌患者对术后辅助化疗的评价和选择

[目的]了解已接受术后辅助化疗的非小细胞肺癌（NSCLC）患者对辅助化疗的评价和选择倾向。[方法]调查2006年11月1日-2009年3月31日间接受术后辅助化疗的NSCLC60例。调查内容包括患者对辅助化疗的评价,患者在假设病理ⅠB期、Ⅱ期和Ⅲ A期条件下可接受辅助化疗带来的最小生存率和中位生存期。[结果]93.3％患者认为辅助化疗值得做。约70％患者愿意接受辅助化疗以获得生存期延长1年或者5年生存率提高10％。曾出现化疗重度毒副反应、Ⅲ A期和经济状况差的患者要求辅助化疗带来的生存获益更高。[结论]多数患者能够接受术后辅助化疗带来的益处和毒性反应．     

树突状细胞抑制ⅠB期非小细胞肺癌术后复发和转移初探

背景与目的：ⅠB期非小细胞肺癌（NSCLC）术后生存率较差,有必要进行辅助治疗。树突状细胞（DC）是体内功能最强的专职抗原递呈细胞,可有效诱导静止T细胞增殖和应答,促进细胞毒性T淋巴细胞和辅助性T淋巴细胞的生成,是机体免疫反应的启动者和参与者。本研究初步探讨DC联合化疗治疗根治性术后ⅠB期NSCLC患者的生存率。方法：选择根治性手术ⅠB期NSCLC患者66例,按照1∶2随机分为DC联合化疗组和单纯化疗对照组,研究组22例,采用体外培养外周血单个核细胞来源的DC及细胞因子激活的杀伤细胞（CIK）后回输患者体内,同时联合化疗。对照组44例,接受单纯化疗。结果：DC联合化疗组22例患者的3年生存率为87.50%,4年生存率为77.78%;对照组分别为85.10%和61.28%,两组差异有显著性（P=0.0419）,提示DC联合化疗有延长ⅠB期NSCLC术后患者生存时间的趋势。DC联合化疗组毒副反应轻微。结论：DC生物免疫治疗联合化疗可使术后ⅠB期非小细胞肺癌患者获益。     

ⅠB期非小细胞肺癌完全切除术后辅助治疗方式的研究进展

原发性肺癌是肿瘤相关死亡率较高的恶性肿瘤之一，非小细胞肺癌约占原发性肺癌的85%。近年来，由于医疗技术水平的提升和健康体检的普及，早期非小细胞肺癌检出率逐渐提高。早期NSCLC的治疗方式主要是手术切除和辅助治疗，但ⅠB期患者在肿瘤完全切除术后的辅助治疗及随访管理存在诸多争议。这篇综述聚焦于ⅠB期NSCLC患者完全切除后辅助化疗、靶向及免疫治疗选择的关键问题，同时探讨了筛选早期NSCLC高危患者的生物标志物及预后因子。     

干扰素与化疗对Ⅰ期非小细胞肺癌术后治疗的疗效比较

目的比较干扰素与化疗对Ⅰ期非小细胞肺癌患者治疗的疗效。方法2001年1月～2005年1月可供分析的Ⅰ期NSCLC术后干扰素治疗患者106例及ⅠB期NSCLC术后化疗病例74例为研究组,同时随机抽取单独手术病例112例为对照组,行对照研究。结果Ⅰ期NSCLC患者干扰素组和对照组1～5年生存率分别为100.0%(106/106),97.8%(87/89),93.4%(57/61),83.3%(25/30),76.2%(16/21)和88.4%(99/112),79.3%(73/92),71.9%(41/57),66.7%(28/42),59.3%(16/27)。显示两组患者1～3年生存率有显著性差异(P<0.05),4～5年生存率无显著性差异(P>0.05)。ⅠB期NSCLC患者干扰素组1～2年生存率明显高于化疗组,具有显著性差异(P<0.05)但3～5年生存率两组无显著性差异(P>0.05)。ⅠB期NSCLC患者化疗组与对照组1～5年生存率的比较均无显著性差异(P>0.05)。干扰素组主要毒副反应是注射部位不同程度的红肿和疼痛,化疗组主要毒副反应是骨髓抑制及消化道反应。结论干扰素可以提高Ⅰ期非小细胞肺癌患者的1～3年生存率,但对长期生存率无影响,ⅠB期非小细胞肺癌患者术后化疗不利于提高生存率。ⅠB期非小细胞肺癌患者术后单独应用干扰素短期疗效强于单独应用化疗。     

肺癌化疗进展

第十届世界肺癌大会于 2 0 0 3年 8月 10日～ 14日在加拿大温哥华市召开 ,来自世界各地的专家、学者交流了近年来肺癌领域的研究进展 ,重点展示了 2 1世纪肺癌的临床研究状况 ,如肺癌的预防、早期发现、肺癌的分子生物学及临床治疗等。非小细胞肺癌(NSCLC)的治愈率不高 ,5年生存率仅 10 %～ 15 %。为提高疗效 ,有关NSCLC的化学治疗已涉及到与各种治疗的联合 ,本次会议也进行了广泛的讨论。例如 ,放、化联合疗法中 ,ⅢA和ⅢB期患者如何从紫杉醇(TAX) /卡铂 (CBP)联合放化疗方案中获益 ;对完全手术切除的NSCLC ,多数报告辅助化疗并…     

Ⅰ期非小细胞肺癌术后预后的多因素分析

背景与目的 Ⅰ期患者尤其是Ib期术后非小细胞肺癌(non-small cell lung cancer,NSCLC)患者能否从辅助化疗中获益备受争议.2009年第7版肺癌TNM分期发表.本研究的目的是明确新版TNM分期对Ⅰ期NSCLC患者的价值,以及评估术后辅助化疗是否能提高早期肺癌患者的生存率.方法 研究纳入了上海市胸科医院1998年6月-2010年6月早期NSCLC完全切除术的433例患者,按照新的分期标准重新分期.把新分期的参数与其它已被证明与肺癌预后相关的因子结合起来,进行多因素分析.研究纳入变量包括年龄、性别、吸炯史、病理类型、手术切除方式(叶切、双叶切、袖切和全切)、肿瘤大小(肿瘤最长径)、T分期、淋巴管血管癌栓和辅助化疗.结果 女性患者3年生存率优于男性(89.22％vs 77.53％,P=0.001,8).老年患者预后不佳,≥70岁的NSCLC患者3年生存率为70.64％,＜70岁为85.85％,P=0.000,1).肿瘤最长径≤2 cm患者的3年生存率优于＞2 cm且 ≤3 cm患者(95.15％vs85.71％),肿瘤最长径＞3 cm且≤5 cm及＞5 cm且≤7 cm者3年生存率为74.80％vs 60.47％(P＜0.000,1).多因素分析显示年龄、性别、血管癌栓、病理类型、胸膜侵犯是影响生存期的预后因素.结论 对Ⅰ期NSCLC患者而言,肿瘤最长径及病理类型是独立的预后因素.腺癌患者的生存期优于其它病理类型.女性和非吸烟患者结局较好.Ib期患者可能从术后辅助化疗中获益.     

Chemotherapy in stage I+II non-small cell lung cancer

Although surgical resection offers the best chance for long-term survival for patients with non-small cell lung cancer (NSCLC), the limited number of resectable patients and the presence of micrometastatic disease is limiting the effectiveness of this modality as sole treatment. Results of randomized trials demonstrated a survival benefit for preoperative (neoadjuvant) cisplatin-based chemotherapy in patients with stage IIIA NSCLC compared to surgery alone. In stage I+II NSCLC preoperative chemotherapy, although still experimental, clearly offers encouraging results. However, there is no evidence of its superiority over adjuvant chemotherapy. Moreover, for adjuvant therapy a benefit has not been established yet. Possibly current ongoing or recently finished trials may change the recommendations on adjuvant or neoadjuvant therapy for completely resected or resectable early disease in the future.     

Induction chemotherapy for resectable non-small-cell lung cancer

Lung cancer remains the leading cause of cancer death in American men and women. Non-small-cell lung cancer (NSCLC) accounts for 85% of these cases. Although surgery is the best curative approach for resectable NSCLC, long-term survival for patients with operable disease remains poor. More than half of patients who initially present with stage I to IIIA disease experience relapse of metastatic disease. Postoperative adjuvant therapy has been evaluated in several randomized trials, and provides a survival benefit. It appears reasonable to look to induction chemotherapy, or preoperative chemotherapy, to provide a similar improvement in survival with early treatment of micrometastatic disease. Multiple trials of induction therapy have been carried out with encouraging results. The use of various induction regimens with chemotherapy alone or chemotherapy combined with radiotherapy for stage IIIA NSCLC is under investigation. Randomized trials are under way to better define the role of induction therapy in the multimodality treatment of NSCLC.     

Consensus development conference on the medical treatment of non-small cell lung cancer: treatment of the early stages

Surgery remains the mainstay of treatment for early non-small cell lung cancer (NSCLC) but more than 80% of recurrences occur within 2 years from radical surgery. The pattern of recurrence may differ by histology with more local recurrences seen for patients with squamous cell carcinoma and more distant metastases seen in patients with adenocarcinoma. A number of studies demonstrate that dissemination of cancer cells at levels much below those detected by any current available imaging techniques, including PET scanning also, affect prognosis of patients with clinical early-stage NSCLC. The current clinical evidence does not recommend adjuvant chemotherapy and/or radiotherapy in completely resected stage I-II-IIIA for N1. There are few randomised trials available for analysis of neo-adjuvant chemotherapy involving patients with resectable stage III disease; overall these trials suggest that induction chemotherapy (with or without radiation) improves survival, particularly in those patients who undergo significant downstaging. Heterogeneous study populations limit the ability to define the optimal patient population who would most benefit from this approach. There is no conclusive evidence that neo-adjuvant chemotherapy in early NSCLC is associated with an increased post surgical morbility and mortality. Additional trials are needed. More recently neo-adjuvant chemotherapy has been tested in resectable stage I-II NSCLC and proved to be feasible and better tolerated than adjuvant chemotherapy. Several randomised trials are currently ongoing. In the next future the role of targeted biological therapies as agents acting on minimal residual disease should be explored.     

The Rationale for Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer

The past decade has witnessed renewed interest in studies exploring the benefits of adjuvant (postoperative) chemotherapy (± radiation therapy) in patients with resected non-small cell lung cancer (NSCLC). Recently completed adjuvant trials have included a heterogeneous group of patients with resected stages I to IIIA NSCLC. With rare exception, the published results of these studies indicate adjuvant chemotherapy imparts a significant overall survival advantage. Subset analyses suggest survival benefit occurs primarily in patients with resected stage II or IIIA and is less likely to occur in stage I patients. This apparent lack of survival benefit in stage I patients was seemingly validated in a prospective trial conducted by the Cancer and Leukemia Group B in which stage IB patients were randomized to observation or adjuvant carboplatin and paclitaxel. Survival at 5 -years was identical in the two arms of this trial. By contrast, two contemporary postoperative chemotherapy trials also conducted exclusively in stage I NSCLC patients yielded positive survival results. The divergent outcome of the prospective trials along with the negative subset analyses has created uncertainty as to the utility of postoperative adjuvant chemotherapy in stage I NSCLC. Herein we review the data underlying this controversy and offer a proposed algorithm to aid the clinician in selecting patients whom we believe may benefit from adjuvant chemotherapy. The treatment algorithm is based on currently available tumor- and host-related factors that affect prognosis.     

The new era of immune checkpoint inhibition and target therapy in early-stage non-small cell lung cancer. A review of the literature

Surgery is the best option for patients with early stage non-small cell lung cancer (NSCLC). However, the rate of local and metastatic recurrences following surgery alone is high, especially in NSCLC patients with N2 lymph node involvement. A recent American study showed that 60% of lung cancers are diagnosed in an advanced stage, and less than 20% are diagnosed in an early, resectable stage. The same study reported the 5 year survival of patients with stage IV NSCLC was 6% compared to 50% in patients with resectable NSCLC depending by stage. The addition of adjuvant or neoadjuvant chemotherapy only improves 5 year survival by 5%-10%. Recently, immunotherapy with or without chemotherapy and novel targeted therapies have yielded excellent results, in terms of both progression-free survival and overall survival, in advanced NSCLC. Published studies have shown a benefit in using immunotherapy and targeted therapy in both the adjuvant and neoadjuvant settings with many further studies still ongoing. Here we review the published data on immunotherapy and targeted therapy in the adjuvant and neoadjuvant settings in patients with operable NSCLC.     

Adjuvant treatment of stage IB NSCLC: the problem of stage subset heterogeneity

While 5-year survival rates in patients with stage IB non-small-cell lung cancer (NSCLC) are historically modest (40% to 67%), adjuvant chemotherapy trials including this subgroup have shown little evidence of chemotherapeutic benefit. This article reviews the available data regarding adjuvant chemotherapy following surgically resected stage IB NSCLC, framed within the context of present and future proposed definitions of this diagnosis. The discussion addresses limitations of the current staging system and how this contributes to the mixed results seen with adjuvant treatment. In addition, the authors consider current treatment options for stage IB NSCLC and review planned clinical trials for stage I disease designed to exploit new pharmacogenomic findings.     

The role of chemotherapy in early-stage (stage I and II) resectable non-small cell lung cancer

For patients with stage I or II non-small cell lung cancer (NSCLC), surgical resection is considered the standard of care. Although surgery achieves long-term survival in many patients, a significant proportion experience locoregional or distant recurrence. Five-year survival rates after resection for stage I and II NSCLC range from 38% (T3 N0) to 67% (T1 N0). Efforts at improving survival for early-stage NSCLC patients have focused on the use of chemotherapy administered postoperatively (adjuvant) or preoperatively (neoadjuvant or induction) to eradicate micrometastatic disease. The majority of trials examining adjuvant chemotherapy have not found a survival benefit. A meta-analysis examining the role of chemotherapy in the treatment of NSCLC found a 5% absolute improvement in 5-year survival associated with the use of adjuvant cisplatin-based chemotherapy (P =.08). Chemotherapy administered before surgery or definitive irradiation has improved survival rates in patients with stage III NSCLC. The role of induction chemotherapy in stage I and II NSCLC is currently under investigation.     

Adjuvant chemotherapy in early-stage non-small cell lung cancer

Approximately 80% of lung malignancies are non-small cell lung carcinoma (NSCLC). Patients diagnosed with early-stage disease (about 30% of patients) undergo surgery, but up to 50% develop local or distant recurrence. In an effort to improve survival for patients with resectable NSCLC, chemotherapy has been explored in the adjuvant setting. Several adjuvant trials were launched in the mid 1990s after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the International Adjuvant Lung Cancer Trial (IALT) study, with 1,867 patients included, confirmed the benefit of postoperative chemotherapy in resected NSCLC. More recently, modern platinum-containing doublets showed a 10% to 15% overall benefit compared to no adjuvant treatment. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.     

Neoadjuvant Immunotherapy for NSCLC: Current Concepts and Future Approaches

Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy. However, these patients continue to have a high risk of recurrence and death. Unfortunately, there has been little progress in the treatment of resectable NSCLC over the past several decades. Neoadjuvant therapy, which has been considered as an approach to improve survival in patients with resectable NSCLC, is a hotly debated topic. A systematic review of 32 randomized trials involving 10,000 patients revealed that there was no difference in survival between preoperative and postoperative chemotherapy. Because of such results and the theoretical concern about resectable tumors progressing on relatively ineffective neoadjuvant chemotherapy, and thus becoming unresectable, neoadjuvant chemotherapy fell out of favor, and many clinicians preferred adjuvant chemotherapy after surgery. However, neoadjuvant therapy has been revived in the past couple of years, with emerging data from various ongoing trials suggesting that neoadjuvant immunotherapy may have significant efficacy and could potentially improve the survival of patients with resectable NSCLC. In this review article, we discuss the evidence supporting the role of neoadjuvant immunotherapy in the multimodal management of resectable NSCLC. We summarize early results of ongoing clinical trials and highlight the challenges in adopting a uniform definition of treatment “success.” We address hurdles to be overcome for seeking regulatory approval for neoadjuvant immunotherapy and establishing it as a standard of care. Finally, we provide some perspectives for the future.     

Clinical issues in the management of non-small-cell lung cancer and the role of platinum-based therapy

Although the benefits of chemotherapy have been established for treating non-small-cell lung cancer (NSCLC), several clinical issues remain. Currently, doublets offer the maximum benefit in terms of balancing efficacy with tolerability to patients with advanced-stage disease. The optimal duration of therapy continues to be evaluated, and several agents have emerged for treating patients with recurrent advanced NSCLC. Chemotherapy benefits for populations underrepresented in clinical trials, such as elderly patients and patients with poor performance status, also need to be established. Although combination therapy with carboplatin/paclitaxel is one regimen of choice for treating advanced NSCLC, there may be ways to optimize its delivery schedule including use of weekly administration of paclitaxel and monthly administration of carboplatin. In addition, biologic approaches are being investigated to determine if these agents may be appropriate for treating patients with advanced NSCLC and how best to administer them. In resectable stage IIIA disease, benefits of preoperative chemotherapy and chemotherapy/radiation therapy followed by surgery continue to be evaluated. Although associated with esophageal toxicity, in non-resectable stage IIIA/IIIB disease, concurrent chemotherapy/radiation therapy has emerged as the schedule of choice. Yet, benefits of higher radiation dosage need evaluation. Based on phase II studies, preoperative chemotherapy with or without radiation may benefit patients with early-stage disease, but studies have been inconclusive, yielding mixed results. Recent trials of adjuvant chemotherapy following surgical resection in early-stage NSCLC have yielded conflicting results, with some trials showing no benefit to adjuvant therapy. Trials under way will determine the future of adjuvant or induction chemotherapy in treating this patient population.