非小细胞肺癌术后辅助化疗的临床研究

背景与目的 非小细胞肺癌术后辅助化疗一直是国内外的研究热点。本研究的目的是对比观察术后辅助化疗对非小细胞肺癌患者生存期的作用。方法 2000年6月～2003年12月，观察64例ⅠB～ⅢA期行完全性切除的非小细胞肺癌患者，包括接受术后长春瑞滨＋顺铂（NP）方案或紫杉醇＋卡铂（TP）方案化疗的化疗组和仅行术后观察的观察组，然后以Kaplan-Meier法对两组病例的1、2、3、4年生存率和中位生存时间进行分析。结果 化疗组的1、2、3、4年生存率分别为93．9％、84．6％、71．4％、58．4％，观察组分别为93．6％、83．1％、63．5％、43．1％，两组间3年和4年生存率差异均有统计学意义（P〈0．05）。化疗组与观察组中位生存时间分别为52个月和47个月（P〈0．05），无病生存时间分别为19个月和16个月（P〈0．05）。结论 术后含铂辅助化疗可以延长完全切除病灶的ⅠB～ⅢA期非小细胞肺癌患者的术后生存期。     

ⅠB期非小细胞肺癌术后辅助化疗的争议和共识

临床上有20％～25％的非小细胞肺癌（NSCLC）患者可手术治疗,但5年生存率也只有40％左右。辅助化疗是部分早期可切除肺癌的标准治疗方式,可使4％～15％的患者生存获益。但是,ⅠB期NSCLC是否能从辅助化疗中获益仍存在争议。近年来,多个临床研究评价了ⅠB期NSCLC辅助化疗的疗效,我们通过分析这些临床研究,寻找ⅠB期NSCLC的高危人群和辅助化疗的适应证。     

非小细胞肺癌术后辅助化疗现状与展望

 非小细胞肺癌（NSCLC）术后辅助化疗出现于20世纪70年代，随着各种新药及新的联合化疗方案的出现，NSCLC的术后辅助化疗亦在不断地进展，越来越多的证据显示术后辅助化疗能提高NSCLC患者的生存期生活质量，就NSCLC的术后辅助化疗现状进行了介绍并对其发展前景进展的展望。     

Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy: subgroup analysis of the adjuvant vinorelbine (NVB) cisplatin (CDDP) versus observation in the ANITA trial

Background

Data issued from the survival outcome in the ANITA trial are reported according to histology in observation (n = 433) and adjuvant chemotherapy arms (n = 407).

Methods

In the ANITA trial, patients with resected stage IB, stage II and stage IIIA NSCLC were randomly assigned to vinorelbine plus cisplatin or to observation. In this retrospective analysis, Kaplan–Meier plots and life tables were used to describe survival within each treatment arm and each histological subgroup: observation adenocarcinoma, observation non-adenocarcinoma, chemotherapy adenocarcinoma, chemotherapy non-adenocarcinoma.

Results

In the observation arm, adenocarcinoma appears to be a poor prognostic factor in patients with resected NSCLC with a median survival of 37.3 months and 45.5 months for non-adenocarcinoma. In the treatment arm, adenocarcinoma may be a predictive factor of efficacy for adjuvant chemotherapy with a larger benefit from adjuvant vinorelbine-cisplatin chemotherapy, even though other histological subtypes also benefit from this treatment. The absolute benefit on survival at 5-years of chemotherapy was 13.9% in adenocarcinoma and 5.8% in non-adenocarcinoma.

Conclusion

Efficacy of vinorelbine-cisplatin in adjuvant setting is independent from histology. The poor outcome of adenocarcinoma found in the observation arm was reversed by the positive impact of chemotherapy, possibly due to a higher chemosensitivity of this subtype.     

Neoadjuvant and adjuvant therapy of non-small cell lung cancer

Though surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), many patients who undergo complete tumor resection will die of recurrent disease. Chemotherapy and radiotherapy have been employed both individually and in combination in an effort to prevent local recurrence and extrathoracic metastatic disease. However, the administration of neoadjuvant or adjuvant therapy remains controversial. Phase II and III trials with traditional radiotherapy schedules and cytotoxic drugs have produced conflicting results. Novel approaches utilizing long-term administration of less toxic drugs and targeted biologic therapies are promising.     

Adjuvant chemotherapy for non-small cell lung cancer

Nearly half of all patients who undergo surgical resection of localized non-small cell lung cancer (NSCLC) will develop and ultimately die of recurrent disease. The postoperative radiotherapy (PORT) meta-analysis showed adjuvant thoracic radiotherapy to have a detrimental effect on survival in this patient population. A meta-analysis of early trials of adjuvant chemotherapy by the Non-Small Cell Lung Cancer Collaborative Group showed that while chemotherapy with alkylating agents was also detrimental, chemotherapy with cisplatin-based adjuvant chemotherapy was associated with an improved hazard ratio for death (HR = 0.87), equating to a 5 percent survival benefit at 5 years. However, the result was not statistically significant (p = 0.08). Recently, results have been reported for several large Phase III trials of adjuvant chemotherapy which differed with respect to the stage of resected disease included, the type of chemotherapy used and the use of post-operative radiotherapy. Three trials (IALT, JBR 10, and ANITA) that utilized cisplatin-based doublets showed a significantly positive survival benefit of adjuvant chemotherapy in patients with Stage II-IIIA NSCLC. The magnitude of this benefit, which was suggested to be 4-5 percent at 5 years in the meta-analysis and by the IALT study, may be as large as 8-15 percent as indicated by more recent studies with modern platinum-based doublet chemotherapy. These data indicate that medically fit patients with resected Stage II-IIIA NSCLC should be offered adjuvant chemotherapy with a modern cisplatin-based doublet.     

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.     

Ⅲ A-N2期非小细胞肺癌术后化疗随机对照研究结果

背景与目的 法国的IALT（International Adjuvant Lung Cancer Trial）显示术后辅助化疗使非小细胞肺癌（NSCLC）患者5年生存率提高5％，加拿大的JBR10和美国的CALGB9633的结果提示第三代化疗药物能进一步提高早期（ⅠB～ⅡB期）NSCLC术后的疗效。本研究的目的是探讨术后化疗对完全性切除术后ⅢA-N2期NSCLC患者生存期的影响。方法 1999年1月1日至2003年12月31日，术后确诊为ⅢA—N2期NSCLC患者150例，随机分为术后化疗组（79例）与单纯手术组（71例）。术后化疗组的患者接受长春瑞滨或紫杉醇＋卡铂化疗，每3周一次，共4周期。结果 术后化疗组86．1％（68／79）的患者接受了4个周期的化疗，没有患者死于与化疗相关的毒性作用。25％的患者出现Ⅲ～Ⅳ度白细胞减少，2％的患者出现发热型白细胞减少，恶心、呕吐的发生率分别为56％、35％。全组中位生存期为879天，1年、2年、3年总生存率为81％、59％、43％；无瘤中位生存期为620天，1年、2年、3年无瘤生存率为63％、45％、25％。术后化疗组中位生存期为897天，单纯手术组为821天（P=0．0527）；术后化疗组1年、2年、3年生存率分别为94．71％、76．28％、49．62％，单纯手术组分别为88．24％、60．13％、43．73％，其中1年、2年生存率的差异有统计学意义（z值分别为1．956、2．427，P均＜0．05）。脑转移为最常见的首发转移部位，占26．0％（39／150），其中术后化疗组为22．8％（18／79），单纯手术组为29．6％（21／71）（P〉0．05）。术后化疗组与单纯手术组中脑转移患者的中位生存期分别为812天、512天（P=0．122），2年生存率分别为66．7％、37．6％（P〈0．01）。全组出现脑转移后的中位生存期为190天。结论 ①术后化疗虽不能显著延长ⅢA—N2期NSCLC患者的中位生存期，但显著提高了1年、2年生存率。②术后化疗没有减少ⅢA-N2期NSCLC患者脑转移的发生率，但推迟了脑转移发生的时间。     

顺铂为主的联合化疗治疗晚期非小细胞肺癌120例近期疗效观察

 本文报告了我院1986年1月至1993年10月未用顺铂为主的联合化疗治疗晚期柞小细胞肺癌120例，取得了较好的近期疗效。完全缓解(CR ) 3例(2.5%),部分缓解(PR ) 38例(31.70a),稳定(NS) 49例(40.80a)，进展(PD) 30例(25肠)。有效率(CR+PR)为34.1%。主要毒副l反应为胃肠道反应和骨髓抑制。     

多西他赛联合卡铂治疗晚期非小细胞肺癌的疗效

背景与目的 化疗是治疗晚期非小细胞肺癌的主要方法.本研究旨在分析多西他赛加卡铂治疗晚期非小细胞肺癌的疗效.方法 本组共治疗64例ⅢB、Ⅳ期非小细胞肺癌,采用多西他赛75 mg/m2静脉注射,第1天,卡铂AUC=5静脉注射,第2天.结果 全组总有效率CR PR为42.6%,临床获益率CR PR SD为68.9%,中位生存期14个月,1年生存率45.23%.初治病例1年生存率48.84%,中位生存期14个月;复治病例1年生存率37.89%,中位生存期12个月,两组之间差异有统计学意义(P=0.0233).ⅢB期病例1年生存率44.86%,中位生存期15个月;Ⅳ期病例1年生存率39.75%,中位生存期12个月,两组之间差异有统计学意义(P=0.0354).腺癌、鳞癌患者的疗效差异无统计学意义.主要毒副反应为粒细胞下降、乏力、恶心呕吐及脱发等.结论 多西他赛联合卡铂方案治疗晚期非小细胞肺癌疗效可靠,副反应轻微,可作为晚期非小细胞肺癌的一线和二线治疗方案.     

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.     

NP方案治疗晚期非小细胞肺癌疗效观察

目的　观察NVB加PDD治疗晚期非小细胞肺癌疗效。方法　 1999年 7月～ 2 0 0 1年 8月我们应用进口长春瑞滨 (法国皮尔法伯制药公司生产 ) ,NVB 2 5～ 30mg/m2 ,d1,d8,溶于 0 .9%生理盐水15 0ml中快速静滴 ,再以 2 5 0ml0 .9%生理盐水快速静滴 ,DDP 4 0～ 5 0mg/d1,2 ,3,静脉滴注 ,同时给予水化。 2 1天为一周期。结果　本联合化疗方案治疗晚期非小细胞肺癌 4 0例 ,取得了较好疗效 ,其中CR 4例、PR 2 6例 ,总有效率 75 %。结论　NP联合方案治疗晚期肺癌是合理、方便、安全、有效的一种可行的方案 ,可以作为一线方案推荐临床推广。     

A Prospective Randomized Study of Adjuvant Chemotherapy in Completely Resected Stage III-N2 Non Small Cell Lung Cancer

Objective: To evaluate the effect of postoperative adjuvant chemotherapy on survival after complete resection of stage III-N2 non-small-cell lung cancer. Methods: From Jan. 1999 to Dec. 2003, one-hundred and fifty patients, who were diagnosed as stage III-N2 non-small cell lung cancer after operation, were randomly devided into chemotherapy group and control group. The former received four cycles of chemotherapy with NVB (25 mg/m2, D1, D5)/paclitaxel (175 mg/m2, D1) and Carboplatin (AUC=5, D1). Results: In chemotherapy group, 75.8% (68/79) of patients had finished the 4 cycles of chemotherapy and no one died of toxic effects of chemotherapy. Twenty-five percent of the patients had grade 3?4 neutropenia and 2% had febrile neutropenia. The median survival for the entire 150 patients was 879 d, with 1-year survival rate of 81%, 2-year survival rate of 59% and 3-year survival rate of 43%. There was no significant difference in median survival between chemotherapy and control group (897 d vs 821 d, P=0.0527), but there was significant difference in the 1-year and 2-year overall survival (94.71%, 76.28% vs 512 d, P=0.122), but there was significant difference in the 2-year survival rate between two groups with brain metastases (66.7% vs 37.6% P<0.05). The median survival after brain metastasis appeared was 190 days. Conclusion: Postoperative adjuvant chemotherapy does not significantly improve median survival among patients with completely resected stage II-N2 non-small-cell lung cancer, but significantly improves the 1-year and 2-year overall survival. It neither decreases the incidence of brain metastasis but put off the time of brain metastasis.     

新辅助化疗对围手术期非小细胞肺癌患者的影响

目的 研究新辅助化疗(MVP)是否影响非小细胞肺癌患者围手术期的安全性。方法 所有患者化疗方案均为MVP，即丝裂霉素(MMC) 长春碱胺(VDS) 顺铂(DDP)。将接受2周期术前新辅助化疗、根治性手术和2次术后化疗的患者与接受同样手术和4次术后化疗的患者进行比较。结果 在107例符合要求的病例中，新辅助化疗组有66例，对照组有41例，两组在性别、年龄、肿瘤分期、病理类型上均无统计学差异。新辅助化疗组患者的手术时间(P=0．262)、术中失血量(P=0．704)、术中输血量(P=0．811)、输血总量(P=0．074)比对照组患者略高，术后总引流量(P=0．061)稍低，但其差异均无统计学意义。两组术后死亡率(P=0．674)和并发症：心律失常(P=0．608)、支气管胸膜瘘(P=0．378)、肺炎(P=0．622)、呼吸衰竭(P=0．285)的比较亦均无统计学意义。结论 新辅助化疗对非小细胞肺癌患者围手术期的安全性无显著影响。     

Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer

Objectives

Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We evaluated whether the expression of heat shock protein 70 (Hsp70) is associated with clinical outcomes in patients with completely resected NSCLC who were treated with or without adjuvant platinum-based chemotherapy.

Patients and methods

Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA were included. Immunohistochemical staining for Hsp70 was performed on surgical specimens and survival rates were compared by Hsp70 expression and adjuvant platinum-based chemotherapy.

Results

Of 327 enrolled patients, Hsp70 expression was positive in 220 (67.3%). For patients who did not receive adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for patients who received adjuvant chemotherapy, those with Hsp70-positive tumors had a longer disease-free survival outcome than cases with Hsp70-negative tumors (not reached vs. 27.3 months; P = 0.002), although there was no significant difference in overall survival (97.0 vs. 58.9 months, P = 0.080). In the adjuvant chemotherapy group, multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death after adjusting for age, sex, performance status, pathologic stage, and histological type (disease-free survival: adjusted hazard ratio, 0.537; 95% CI, 0.362–0.796; P = 0.002; overall survival: adjusted hazard ratio, 0.663; 95% CI, 0.419–1.051; P = 0.080).

Conclusion

Hsp70 is a positive predictive factor in completely resected NSCLC with received platinum-based adjuvant chemotherapy.     

长春瑞滨联合顺铂治疗晚期NSCLC 110例临床观察

目的　观察长春瑞滨 (NVB) +顺铂 (PDD)联合化疗方案治疗晚期非小细胞肺癌的疗效及毒副反应。方法　自 1998年至 2 0 0 2年对 110例中晚期NSCLC进行NVB +PDD联合化疗 ,NVB 2 5mg /m2 ,第 1,8天用。PDD 6 0 80mg /m2 分三天用 ,2 1天为一个周期 ,至少应用两个周期。结果　全组总有效率为 4 7.3% ,其中初治有效率为 4 8.7% ,复治有效率为 4 3.8%。IIIa期有效率为 5 2 .2 % ,IIIb期有效率为 5 3.1% ,IV期有效率为 4 1.8%。腺癌有效率为 5 2 .3% ,鳞癌有效率为 4 6 .7%。 (P >0 .0 5 )。化疗副反应主要是白细胞降低及静脉炎。白细胞下降占 93.6 % ,主要是I,II ,III度 ,分别为 32 .7% ,38.2 % ,18.2 %。静脉炎发生率为 14 .5 %。结论　NVB +PDD方案治疗NSCLC疗效较好 ,毒副反应较轻 ,可以耐受。     

周剂量紫杉醇联合异环磷酰胺治疗晚期非小细胞肺癌23例

目的　评价周剂量紫杉醇与异环磷酰胺联合化疗治疗晚期非小细胞肺癌的疗效和安全性。方法　紫杉醇 5 0～ 65mg/m2 静脉滴注 ,第 1、8、15天 ,异环磷酰胺 1.3 g/m2 静脉注射 ,第 2～ 4天。每 2 8天重复 ,2～ 3周期为一疗程。使用紫杉醇前常规给予抗过敏等处理 ,异环磷酰胺使用后第 0、4、8小时给予美安解毒。结果　本组完全缓解 1例 ,部分缓解 8例 ,稳定 11例 ,进展 3例 ,总有效率为 3 9.1% ( 9/2 3 ) ,临床受益率为 87.0 % ( 2 0 /2 3 )。化疗后KPS评分显著提高 (P <0 .0 1)。随防 2 0例 ,中位生存期为 8.9月 ,1年生存率为40 % ( 8/2 0 )。全组毒性反应主要为血液学毒性和消化道反应 ,其中白细胞降低发生率为 69.6% ( 16/2 3 ) ,恶心呕吐发生率为 47.8% ( 11/2 3 )。结论　周剂量紫杉醇 +异环磷酰胺联合化疗对晚期非小细胞肺癌有较好的疗效 ,不良反应可耐受 ,安全性高 ,可在临床上推广应用。     

Ⅲ期非小细胞肺癌患者骨髓微转移与新辅助化疗及预后的关系

目的　研究Ⅲ期非小细胞肺癌患者骨髓中微转移与新辅助化疗及预后的关系。方法　选取Ⅲ期非小细胞肺癌患者 65例 ,随机分为新辅助化疗组 ( 3 2例 )及直接手术组 ( 3 3例 ) ,两组患者均于术中切取肋骨获得骨髓 ,应用RT PCR技术检测CK19mRNA及CEAmRNA的表达 ,并进一步分析两指标表达情况与生存期的关系。结果　新辅助化疗组及直接手术组患者骨髓中CK19阳性率分别为 18.8% ( 6/ 3 2 )、45 .5 % ( 15 /3 3 ) (P =0 .0 3 3 ) ,CEA阳性率分别为 2 5 .0 % ( 8/ 3 2 )、5 1.5 % ( 17/ 3 3 ) (P =0 .0 41)。CK19与CEA的表达具有正相关关系 (rs=0 .671,P <0 .0 0 1)。CK19及CEA共同阳性者化疗有效率为 0 % ( 0 / 5 ) ,共同阴性者为 5 6.5 % ( 13 / 2 3 ) (P =0 .0 44 )。CK19及CEA共同阳性者及共同阴性者中位生存期分别为 11和 2 7个月 (P =0 .0 0 0 6)。Cox模型分析提示 ,新辅助化疗组中化疗疗效、CK 19及CEA的阳性表达是影响患者预后的独立因素。无效的化疗较有效的化疗死亡风险增加 (P =0 .0 43 ) ,CEA及CK 19阳性表达者较阴性者死亡风险增加 (P =0 .0 2 1,P =0 .0 2 0 )。结论　新辅助化疗能降低Ⅲ期非小细胞肺癌患者骨髓微转移的发生率。骨髓微转移提示患者预后不良。     

A retrospective comparison of adjuvant chemotherapeutic regimens for non-small cell lung cancer (NSCLC): Paclitaxel plus carboplatin versus vinorelbine plus cisplatin

Background

Adjuvant chemotherapy with vinorelbine plus cisplatin (NP) has been demonstrated to increase overall survival in patients with stage II or IIIA non-small cell lung cancer (NSCLC). Although paclitaxel plus carboplatin (PC) failed to demonstrate efficacy in patients with stage IB NSCLC, an exploratory analysis suggested that patients with large tumors can benefit from adjuvant PC therapy.

Methods

Clinical outcomes of patients who received adjuvant NP or PC regimens after complete resection for their NSCLC were retrospectively compared.

Results

Of the 438 patients with completely resected NSCLC, 207 received PC and 231 patients received NP. The median relapse-free survival (RFS) was not significantly different, with 63.6 months for the PC group and 54.8 months for the NP group (P = .68). Overall survival also did not differ significantly between the two groups. The five-year overall survival rates were 73% (95% confidence interval (CI), 66–80%) in PC group and 71% (95% CI, 64–78%) in NP group (P = .71). In the subgroup analysis, RFS was comparable between the two groups across all variables. Analysis of the adverse events indicated that sensory neuropathy, alopecia, and myalgia are more frequent in the PC, while anemia, neutropenia, fatigue, anorexia, and vomiting are more common in the NP.

Conclusion

Although the adverse event profiles were different, the efficacy was comparable between the PC and NP regimens as adjuvant chemotherapy for NSCLC. While there is lack of prospective data, our retrospective data suggest that PC regimen can be considered as adjuvant chemotherapy for resected NSCLC.     

改进的多西紫杉醇联合顺铂方案治疗晚期非小细胞肺癌的临床观察

目的目前临床上广泛应用多西紫杉醇联合顺铂作为晚期非小细胞肺癌（NSCLC）的一线化疗方案，但传统3wk方案毒副反应较大。因此本研究为比较多西紫杉醇联合顺铂改进的3wk方案与传统3wk方案治疗晚期NSCLC的疗效、毒副反应及1a生存率。方法68例经组织学或细胞学确诊的Ⅲb或Ⅳ期NSCLC病人，随机分为两组，分别接受改进方案（A组）和传统3wk方案（B组）化疗。A组：多西紫杉醇总剂量按75mg／m^2，分2次分别于d1、d8，静脉滴注；每天顺铂25mg／m^2，静脉滴注，dl-d3，每3wk重复；B组：多西紫杉醇75mg／m^2，静脉滴注，d1，顺铂用法同A组，每3wk重复。2周期后评价疗效与毒副反应，并随访la生存率。结果两组均无CR，A组PR10例，SD20例，PD4例，总有效率为29.4％；B组PR11例，SD20例，PD3例，总有效率为32.4％；A组1a生存率为38．2％，B组1a生存率为35.3％，两组疗效（P=0．793）及1a生存率（P=0．801）差异无显著性。中性粒细胞Ⅲ／Ⅳ度减少A组17．6％；B组47．1％，两组差异有显著性（P=0．010）。结论多西紫杉醇联合顺铂改进的3wk方案治疗NSCLC与传统3wk方案相比，疗效相似，但血液学毒性明显下降，耐受性好。