Adjuvant treatment of non-small-cell lung cancer: how do we improve the cure rates further?

Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.     

非小细胞肺癌术后EGFR-TKIs治疗研究进展

肺癌是全球新发癌症发病率最高的癌症,也是中国最常见和致死率最高的癌症。其中85%为非小细胞肺癌（NSCLC）,手术是早期患者的主要治疗手段,术后的标准辅助治疗为化疗。但部分患者从辅助化疗中获益十分有限,而且化疗的不良反应也严重影响了患者的生活质量和依从性。表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKIs）的出现改变了晚期NSCLC患者的治疗模式,而术后辅助EGFR-TKIs治疗也已成为了国内外的研究热点。本文将对NSCLC术后EGFR-TKIs治疗的效果、安全性以及尚未解决的问题进行探讨。     

非小细胞肺癌术后辅助化疗研究进展

完全切除的非细胞肺癌(NSCLC)是否需要术后辅助化疗是多年来肺癌治疗领域的研究热点,随着各种新药及新的联合化疗方案的出现,几项大型随机临床试验论证了含铂类药物术后辅助化疗可以延长患者生存期,从而奠定了肺癌术后辅助化疗的地位,但目前术后辅助化疗的预后和其疗效预测仍有很多末知因素.     

Topoisomerase II alpha expression and the benefit of adjuvant chemotherapy for postoperative patients with non-small cell lung cancer

Background  

Adjuvant chemotherapy has been shown to improve survival rates of postoperative patients with non-small cell lung cancer (NSCLC). Biomarkers could help select an appropriate chemotherapy for NSCLC patients or predict the efficacy of chemotherapy. The objective of this study was to explore the possible prognostic and predictive role of topoisomerase II alpha (TopIIα) expression level in postoperative NSCLC patients who received adjuvant chemotherapy.     

p53 status predicts the efficacy of postoperative oral administration of tegafur for completely resected non-small cell lung cancer.

Although postoperative adjuvant therapy for non-small cell lung cancer (NSCLC) had not been reported to be effective, it has been reported recently that oral administration of tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil, FT) may improve the postoperative prognosis. In the present paper, to examine whether p53 status affects the efficacy of FT as postoperative adjuvant chemotherapy for NSCLC, a total of 236 consecutive patients with completely resected pathologic stage I-IIIa NSCLC were retrospectively reviewed. p53 status was determined by immunohistochemical staining. For all patients, the 5-year survival rate of patients with FT administration (FT group) was 78.1%, being significantly higher than that (69.1%) of patients without FT administration (control group) (P=0.046). For patients without immunohistochemical evidence of p53 overexpression, the 5-year survival rate in the FT group was 87.1%, being significantly higher than that (74.0%) in the control group (P=0.036). This demonstrates an improvement of postoperative prognosis by FT administration. On the other hand, for patients with p53 overexpression, there was no significant difference in the postoperative prognosis between the FT group and the control group (5-year survival rate 63.2% and 60.1%, respectively; P=0.514), demonstrating that FT administration was not effective for these patients. In conclusion, p53 status may be useful for predicting the efficacy of postoperative adjuvant chemotherapy using FT. A prospective randomized study stratified by p53 status is needed to clarify the effect of postoperative FT administration.     

ACR Appropriateness Criteria® postoperative adjuvant therapy in non-small cell lung cancer

Therapeutic options for postoperative adjuvant treatment for patients with non-small cell lung cancer (NSCLC) continue to evolve, and may include postoperative radiotherapy (PORT) and chemotherapy, alone or in combination. The use of platinum-based adjuvant chemotherapy has been demonstrated to confer an improvement in overall survival in patients with completely resected, stage N1 or N2 NSCLC, in several randomized trials and 2 meta-analyses. Consideration may also be given to adjuvant chemotherapy in patients with node-negative NSCLC, when the primary tumor is >4 cm, based on subset analyses of recent prospective studies. The precise role of PORT is less well defined. Older randomized studies indicated that the toxicity of PORT outweighed the potential improvement in local control, but studies using more modern radiation techniques show significantly reduced toxicity, inferring that select patients may benefit. Relative indications for PORT include the presence of mediastinal lymph nodes, positive surgical margins, and considerations with regard to the extent and type of resection. This study by the lung cancer expert panel of the American College of Radiology summarizes the recent evidence-based literature that addresses the use of postoperative adjuvant radiotherapy and chemotherapy in patients with NSCLC, illustrated with clinical scenarios. The sequencing of radiotherapy and chemotherapy is discussed, along with issues regarding radiotherapy dose and fractionation, and the appropriate use of intensity modulated radiation therapy and particle therapy.     

辅助化疗在早期可手术非小细胞肺癌治疗中的地位

肺癌患者术后复发转移是临床治疗失败的主要原因,因此亟待一种更系统的治疗手段来完善患者的治疗计划,以降低复发率、延长生存期。辅助化疗(包括新辅助化疗、术后辅助化疗、靶向药物辅助化疗)应运而生。本文就辅助治疗领域的研究进展进行综述。     

非小细胞肺癌辅助靶向治疗进展

目前术后Ⅱ~ⅢA期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者推荐进行术后辅助化疗,但在带来生存获益的同时,化疗毒性难以忽视,寻找新的高效、低毒、个体化治疗方案迫在眉睫。表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI）依靠其高效低毒的特点,目前在晚期非小细胞肺癌得到广泛应用,为了探索更加有效的治疗模式,国内外学者进行了大量的尝试,试图将靶向治疗延伸到术后辅助治疗的范畴。以期真正指导临床实践,使非小细胞肺癌患者术后能够从靶向治疗获益,提高术后生存率。      

非小细胞肺癌术后多元化辅助治疗模式的研究进展

可手术切除Ⅱ-Ⅲa及Ⅲb（T3N2M0）期（IASLC/UICC第8版TNM分期）非小细胞肺癌（non-small cell lung cancer,NSCLC）推荐术后辅助化疗,但化疗毒性难以避免,且患者生存获益有限,仍具有较高的复发转移和死亡风险。在精准医疗时代,表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI）开启个体化辅助治疗的新篇章。本文将对NSCLC术后辅助化疗、放疗、EGFR-TKI靶向治疗、抗血管生成治疗、免疫检查点抑制剂治疗及中医药治疗进行综述,多元化辅助治疗模式的探索有望延缓术后复发转移,使NSCLC患者生存获益最大化。     

Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.The ASCO-JSCO Joint Symposium was held in Kyoto, Japan, on October 29, 2004.     

Combination of carboplatin and gemcitabine is a safe and feasible regimen in adjuvant therapy for stage II and IIIA NSCLC

BACKGROUND: Recently, several randomized trials have shown that postoperative adjuvant treatment improves survival among patients with completely resected non-small cell lung cancer (NSCLC). Platinum-based chemotherapy has been reported to be effective for patients with postoperative stage II to IIIA. PATIENTS AND METHODS: In the present study, 5 patients with completely resected stage IIB and IIIA received carboplatin AUC 4 on day 1 and gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks for six cycles as adjuvant chemotherapy. RESULTS: No early or toxic deaths were observed. All patients were administered 6 cycles completely and safely. Three patients had grade 3 neutropenia and three had grade 2 thrombocytopenia. One patient had grade 3 neutropenia on day 8 in the 2nd and 3rd cycle, and the medications were postponed for a week. Non-hematological toxicity including alopecia and neuropathy were not found. CONCLUSION: In the present study, the combination of carboplatin and gemcitabine has been a safe and feasible regimen in adjuvant therapy for stage II and IIIA NSCLC.     

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。     

EGFR敏感突变Ⅱ~ⅢA期非小细胞肺癌治疗的研究新进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）为发病率最高的恶性肿瘤,Ⅱ~ⅢA期患者为潜在可根治人群。目前,围手术期的标准治疗为化疗,而表皮生长因子受体（epidermal growth factor receptor,EGFR）敏感突变的患者,新辅助或辅助靶向治疗可提高无病生存期（disease free survival,DFS）,但是否能带来生存获益,尚未明确。ⅢA（N2）期NSCLC患者术后辅助放疗可带来生存获益,而不可手术切除的局部晚期NSCLC患者,同步放化疗后durvalumab维持治疗成为新标准。在驱动基因突变人群中的免疫治疗还有待于进一步探索,免疫治疗联合化疗可能为方向之一,而抗血管生成治疗不适宜在术后辅助治疗。      

Ⅲa期非小细胞肺癌术后辅助治疗的临床应用

背景与目的Ⅲa期非小细胞肺癌(non-small cell lung caner,NSCLC)单纯根治性手术获益有限,目前倡导多学科综合治疗,但术后放疗的价值仍不清楚。本文比较分析Ⅲa期NSCLC术后化疗和术后放疗+化疗的生存期及副反应。方法分析2003年12月-2007年6月大连医科大学第一附属医院收治的具有完全随访资料的Ⅲa期NSCLC 患者52例。术后化疗组23例,术后放疗+化疗组29例。术后化疗组采用铂类为主的联合化疗方案,联合化疗药包括吉西他滨、长春瑞滨、多西他赛,化疗共4周期。术后放疗+化疗组采用序贯放化治疗,化疗2-4周期后加用放射治疗,放射治疗采用三维适形放疗(3D-CRT),靶区剂量50 Gy,化疗共4周期,化疗方案同单纯化疗组。观察Ⅲa期非小细胞肺癌术后辅助治疗对生存期的影响及毒副作用,分析疾病进展原因。结果术后化疗组、术后放化疗组中位生存时间为32.5个月 vs 31.9个月,差异无统计学意义(P=0.371)。两组中位无进展生存时间为11.0个月 vs 17.0个月,差异有统计学意义(P=0.044)。两组1、2、3年生存率为87%、61%、33% vs 93%、69%、45%。不良反...     

p53 Status Predicts the Efficacy of Postoperative Oral Administration of Tegafur for Completely Resected Non-small Cell Lung Cancer†

Although postoperative adjuvant therapy for non-small cell lung cancer (NSCLC) had not been reported to be effective, it has been reported recently that oral administration of tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil, FT) may improve the postoperative prognosis. In the present paper, to examine whether p53 status affects the efficacy of FT as postoperative adjuvant chemotherapy for NSCLC, a total of 236 consecutive patients with completely resected pathologic stage I–IIIa NSCLC were retrospectively reviewed. p53 status was determined by immunohistochemical staining. For all patients, the 5-year survival rate of patients with FT administration (FT group) was 78.1%, being significantly higher than that (69.1%) of patients without FT administration (control group) (P=0.046). For patients without immunohistochemical evidence of p53 overexpression, the 5-year survival rate in the FT group was 87.1%, being significantly higher than that (74.0%) in the control group (P=0.036). This demonstrates an improvement of postoperative prognosis by FT administration. On the other hand, for patients with p53 overexpression, there was no significant difference in the postoperative prognosis between the FT group and the control group (5-year survival rate 63.2% and 60.1%, respectively; P=0.514), demonstrating that FT administration was not effective for these patients. In conclusion, p53 status may be useful for predicting the efficacy of postoperative adjuvant chemotherapy using FT. A prospective randomized study stratified by p53 status is needed to clarify the effect of postoperative FT administration.     

Adjuvant therapy for resected non-small cell lung cancer

Surgery remains the initial treatment for patients with early-stage non-small cell lung cancer (NSCLC). The frequent occurrence of distant metastases and local regional failure after surgical resection would indicate that additional treatment is necessary. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. This was followed by a new generation of randomized phase III trials some of which have reported a benefit for chemotherapy in the adjuvant setting. Based on the results of these trials, platin-based chemotherapy has become the standard of care for resected stages II and IIIA NSCLC. The role of postoperative radiation therapy remains to be defined. In the future, improvement in survival outcomes from adjuvant treatment is likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Gene expression profiles and proteomics are techniques being used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. Increasing the understanding of the molecular makeup of lung cancer will hopefully increase cure rates for patients by maximizing the efficacy of the adjuvant therapy.     

Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer.

PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC. METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis. RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001). CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.     

Adjuvant treatment of lung cancer: current status and potential applications of new regimens

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers diagnosed worldwide. Surgical resection offers the best chance for cure for those patients diagnosed with early-stage disease; however, the vast majority of patients will eventually relapse. Despite complete surgical resection, recurrences are likely due to undetectable microscopic disease at diagnosis, making these patients potential candidates for effective adjuvant therapy. Postoperative radiation therapy may actually have a detrimental effect in patients with NO-N1 disease and has been shown to possibly prevent local recurrences in patients with N2 disease. Although results from a large meta-analysis of data on adjuvant chemotherapy suggested an absolute benefit of 5% at 5 years from cisplatin-based chemotherapy, a rate similar to that seen in breast and colon cancers where adjuvant chemotherapy is a standard of care, the use of adjuvant therapy in NSCLC remained controversial. In addition, results of the International Adjuvant Lung Cancer Trial (IALT), which compared adjuvant cisplatin-based chemotherapy to observation in patients with resected stage-I-IIIA NSCLC, suggested that adjuvant therapy had the potential to prevent a substantial number of deaths each year. Two recently reported landmark studies have demonstrated the survival advantages of adjuvant therapy for patients with early-stage NSCLC. Docetaxel, one of the most active agents for advanced NSCLC, is also regularly used for locally advanced disease as part of neoadjuvant or combined-modality regimens. As recent findings have established the value of adjuvant chemotherapy for early-stage NSCLC, agents such as docetaxel warrant rigorous evaluation in this setting.     

Postoperative radiation therapy for patients who have resected non-small cell lung cancer

The role of adjuvant postoperative therapy for patients who have resected non-small cell lung cancer (NSCLC) has been controversial. Recent large trials and meta-analysis support a modest, but significant, survival benefit for postoperative adjuvant chemotherapy. Postoperative radiation therapy has little potential benefit in patients who have N(0) or N(1) disease and should not be used routinely in these patients. There are suggestions of benefit for patients who have N(2) disease, but adequately powered trials have not been conducted to demonstrate a possible small, but clinically worthwhile, survival benefit in this subgroup. Central nervous system relapse has emerged as an increasing problem for patients who have NSCLC; trials of prophylactic cranial irradiation are underway in several cooperative trial groups.     

Highlights from the Tenth World Conference on Lung Cancer

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus. Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity. Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.