Controversies in the management of stage III non-small-cell lung cancer

Lung cancer remains the leading cause of death in the USA and is the most common cancer both in incidence and in mortality globally (1.35 million deaths annually). Non-small-cell lung cancer accounts for >80% of all lung cancers . About 35–45% of non-small-cell lung cancer patients present with locally advanced non-metastatic stage III disease. However, confirmed stage III disease represents a very heterogeneous group ranging from borderline surgical candidate with minimal mediastinal involvement to bulky mediastinal nodes or contralateral nodal involvement with significant controversy regarding optimal management in these various situations. This article specifically addresses the role of surgery, radiotherapy and chemotherapy in multimodal approach to treat stage III patients with N2/N3 involvement and controversies surrounding these recommendations.     

Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935

BACKGROUND AND OBJECTIVES: CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes. METHODS: Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy. RESULTS: Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041). CONCLUSIONS: These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse.     

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.     

长春瑞滨联合顺铂方案治疗晚期非小细胞肺癌

目的 研究长春瑞宾(NVB)联合顺铂(DDP)方案(NP方案)治疗晚期非小细胞肺癌(NSCLC)的疗效及毒副作用方法：91例经病理或细胞学诊断非小细胞肺癌患者，其中腺癌56例，鳞癌27例，肺泡细胞癌4例．大细胞肺癌3例；细胞学涂片为癌细胞1例。初治80例，复治11例；Ⅲ期32例(Ⅲa期2例，Ⅲb期30例)．Ⅳ期59例，采用长春瑞滨(NVB)25mg/m^2，第1、8天静滴；顺铂(DDP)90～loomg/m^2静滴，21天为1个周期结果：部分缓解(PR)37例，稳定(SD)30例，进展(PD)24例，总有效率为40．6％(95％CI：30．5％～50．7％)：中位进展期5月(95％CI：4～6月)，中位生存期13月(95％，CI：11～15月)，一年生存率52.7％(95％CI：42.4％～62．9％)。WHOⅢ Ⅳ度白细胞下降占40．7％，为主要血液毒性结论：长春瑞滨联合顺铂治疗晚期’NSCLC疗效确切，毒副反应性可耐受，价格适中，为符合国情的治疗晚期非小细胞肺癌的方案。     

不可切除Ⅲ A(N2)期非小细胞肺癌的术前化疗

目的探讨不能切除的ⅢA（N2）期非小细胞肺癌（NSCLC）的治疗方法。方法1999年1月至2002年12月,76例不可切除ⅢA（N2）期NSCLC患者接受诺维苯（NVB,25mg／m^23,第1,5天）加卡铂（300mg／m^2,第1天）2个周期的化疗,第二周期化疗后3周重新评估能否手术切除。对化疗效果达到部分有效（PR）或完全有效（CR）、估计能完全切除的64例患者行剖胸探查术;对化疗后评价为稳定（SD）和进展（PD）的12例患者行放疗。64例手术患者中,完全切除（肺叶或全肺切除加纵隔淋巴结清扫术,至少达到R3水平）56例,术后继续给予诺维苯加卡铂化疗2个周期;不完全切除8例,另加局部放疗。结果76例不可切除的ⅢA（N2）期NSCLC经诱导化疗后手术或放疗,中位生存期为18．6个月,1,2,3年生存率分别为64．2％、39．4％和25．6％。其中完全切除患者的中位生存期为28．2个月,1,2,3年生存率分别为70．4％、52．5％和38．6％。结论对不可切除的局部晚期NSCLC,如诱导化疗后可以手术,应首选外科治疗。     

A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903)

BACKGROUND:

This study sought to ascertain whether induction‐concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC).

METHODS:

Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m² and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible.

RESULTS:

Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment‐related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression‐free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021).

CONCLUSIONS:

The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC. Cancer 2012. © 2012 American Cancer Society.     

Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial

Background

The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid.

Patients and methods.

Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m² in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m² in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m² on day 2 was administered. All patients continued treatment with radiation therapy with 60–66 Gy concurrent with cisplatin 50 mg/m² on days 1, 8, 29 and 36 and etoposid 50 mg/m² on days 1–5 and 29–33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).

Results

From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively.

Conclusions

Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance.     

Multicenter phase II trial of accelerated cisplatin and high-dose epirubicin followed by surgery or radiotherapy in patients with stage IIIa non-small-cell lung cancer with mediastinal lymph node involvement (N2-disease)

To assess the therapeutic activity of accelerated cisplatin and high-dose epirubicin with erythropoietin and G-CSF support as induction therapy for patients with stage IIIa-N2 non-small-cell lung cancer (NSCLC). Patients with stage IIIa-N2 NSCLC were enrolled in a phase II trial. They received cisplatin 60 mg m(-2) and epirubicin 135 mg m(-2) every 2 weeks for three courses combined with erythropoietin and G-CSF. Depending on results of clinical response to induction therapy and restaging, patients were treated with surgery or radiotherapy. In total, 61 patients entered from March 2001 to April 2004. During 169 courses of induction chemotherapy, National Cancer Institute of Canada (NCI-C) grade III/IV leucocytopenia was reported in 35 courses (20.7%), NCI-C grade III/IV thrombocytopenia in 26 courses (15.4%) and NCI-C grade III/IV anaemia in six courses (3.6%). Main cause of cisplatin dose reduction was nephrotoxicity (12 courses). Most patients received three courses. There were no chemotherapy-related deaths. Three patients were not evaluable for clinical response. Twenty-eight patients had a partial response (48.3%, 95% CI: 36-61.1%), 24 stable disease and six progressive disease. After induction therapy, 30 patients underwent surgery; complete resection was achieved in 19 procedures (31.1%). Radical radiotherapy was delivered to 25 patients (41%). Six patients were considered unfit for further treatment. Median survival for all patients was 18 months. Response rate of accelerated cisplatin and high-dose epirubicin as induction chemotherapy for stage IIIa-N2 NSCLC patients is not different from more commonly used cisplatin-based regimen.     

Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer

Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.     

Survey on the treatment of non-small-cell lung cancer in Italy

Background:The results of the Italian part of an internationalsurvey on therapeutic preferences and opinions about prognosis of patientsaffected by non-small-cell lung cancer (NSCLC) are shown. Patients and methods:The investigation was conducted by the meansof a postal questionnaire aiming to gather information on preferences abouttreatment and beliefs about survival of three hypothetical patients affectedby NSCLC in different stages (T₂N₁M₀,T₂N₃M₀, M₁); three sources ofItalian physicians potentially treating patients affected by NSCLC were thetarget population: participants in the Adjuvant Lung Project Italy (Alpi)trial, a 20% random sample of the Italian Medical Oncology Association(AIOM) and representatives of almost all the pneumology wards in Italy. Results:Overall, there were 287 evaluable responses, 89%of respondents were males, mean age was 46 years, years from graduation 21 andcharge of patients per clinician 82. The most important result is the widevariation of answers both about therapy and prognosis. Expectations about sizeof prognosis improvement with a new chemotherapy seem to be excessive. Conclusions:The results are discussed in relation to the twinsurveys of Canada and England and Wales and to the meta-analyses on theefficacy of chemotherapy as an adjunct to primary treatment and onpostoperative radiotherapy in non-small-cell lung cancer.     

Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research

Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials'' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.     

Induction chemotherapy followed by concurrent standard radiotherapy and daily low-dose cisplatin in locally advanced non-small-cell lung cancer.

Both induction chemotherapy and concurrent low-dose cisplatin have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study was designed to investigate activity and feasibility of a novel chemoradiation regimen consisting of induction chemotherapy followed by standard radiotherapy and concurrent daily low-dose cisplatin. Previously untreated patients with histologically/cytologically proven unresectable stage IIIA/B NSCLC were eligible. Induction chemotherapy consisted of vinblastine 5 mg m(-2) intravenously (i.v.) on days 1, 8, 15, 22 and 29, and cisplatin 100 mg m(-2) i.v. on days 1 and 22 followed by continuous radiotherapy (60 Gy in 30 fractions) given concurrently with daily cisplatin at a dose of 5 mg m(-2) i.v. Thirty-two patients were enrolled. Major toxicity during induction chemotherapy was haematological: grade III-IV leukopenia was observed in 31% and grade II anaemia in 16% of the patients. The most common severe toxicity during concurrent chemoradiation consisted of grade III leukopenia (21% of the patients); grade III oesophagitis occurred in only two patients and pulmonary toxicity in one patient who died of this complication. Eighteen of 32 patients (56%, 95% CI 38-73%) had a major response (11 partial response, seven complete response). With a median follow-up of 38.4 months, the median survival was 12.5 months and the actuarial survival rates at 1, 2 and 3 years were 52%, 26% and 19% respectively. The median event-free survival was 8.3 months with a probability of 40%, 23% and 20% at 1, 2 and 3 years respectively. Induction chemotherapy followed by concurrent daily low-dose cisplatin and thoracic irradiation, in patients with locally advanced NSCLC, is active and feasible with minimal non-haematological toxicity. Long-term survival results are promising and appear to be similar to those of more toxic chemoradiation regimens, warranting further testing of this novel chemoradiation strategy.     

局部晚期非小细胞肺癌同步放化疗前诱导化疗的临床研究

目的:探讨局部晚期非小细胞肺癌同步放化疗与化疗的配合模式.方法:把符合入组标准的94例局部晚期非小细胞肺癌分为A、B、C三组,A组为直接同步放化疗组,放化疗后行辅助化疗4-6个周期;B组为同步放化疗前行诱导化疗2个周期,放化疗后行辅助化疗2-4个周期;C组为同步放化疗前行诱导化疗4个周期,放化疗后行辅助化疗0-2个周期.比较各组的疗效与毒副反应.结果:随访率95.7％,A、B、C组的有效率(ORR=CR+ PR)分别为67.7％、83.3％、66.7％,B组的有效率略高,无显著性差异(P=0.56).A、B、C三组患者的1、2年生存率分别为70.3％、71.4％、78.5％和37.6％、36.9％、38.8％,中位生存期分别为18.9个月、17.9个月和20.5个月(P =0.763).治疗毒性方面,3组患者恶心呕吐反应程度相似,A组患者中发生2级以上放射性食管炎比例(32.3％)少于B、C组(分别为50.0％、51.5％),A组患者发生3、4级骨髓抑制比例(29.0％)少于B、C组(46.7％、51.5％),A组患者发生2级以上放射性肺炎比例(67.7％)多于B、C组(53.3％、48.5％).结论:局部晚期非小细胞肺癌同步放化疗与化疗的配合尚难以确定其固定模式,诱导化疗的选择与应用需进一步研究.     

紫杉醇每周小剂量同步放化疗治疗Ⅲ期非小细胞肺癌

背景与目的：临床约2／3的Ⅲ期非小细胞肺癌患者确诊时已失去手术机会，单纯放疗或化疗疗效均不理想，5年生存率只有5％～10％。同步放化疗的不同治疗方法问有协同作用，可获得更好的局部控制率和生存率，有报道5年生存率为15．8％。但其毒副反应较大。本研究前瞻性比较两种同步放化疗方案治疗不能手术的Ⅲ期非小细胞肺癌的疗效及毒副反应，以期取得较佳疗效的同时，降低毒副作用。方法：48例不能手术的Ⅲ期非小细胞肺癌患者，随机分成两组，紫杉醇每周小剂量组（每周小剂量组）和3周紫杉醇＋顺铂（DDP）常规剂量组（对照组）。两组的放疗方法相同，均采用常规分割放疗。每次2．0Gy，每周5次，原发肿瘤灶总剂量60～64Gy。每周小剂量组在放疗同时给予紫杉醇每周45mg／m^2，连用6周；对照组给予紫杉醇135mg／m^2，第1、22天＋DDP 50mg／m^2第2～4天，第23～25天。结果：每周小剂量组和对照组的有效（CR＋PR）率分别为79％和75％（P〉0．05），而两组CR率分别21％和13％（P〈0．05）。1、2、3和5年生存率分别为83％、63％、38％、13％和63％、42％、17％、8％，差异接近显著性意义。紫杉醇每周小剂量组重度毒副反应小，但两组问差异无显著性意义（P〉0．05）。结论：紫杉醇每周小剂量同步放化疗方案组可降低毒副反应，并有望延长生存时间。     

顺铂联合紫杉醇同步放化疗治疗肺癌的临床研究

目的：研究顺铂联合紫杉醇化疗方案同步放化疗治疗非小细胞肺癌（NSCLC）的临床疗效。方法选择接受治疗的中晚期NSCLC患者118例,按照治疗方式将其分为观察组与对照组,每组各59例。对照组患者给予放射治疗,观察组给予顺铂联合紫杉醇同步放化疗。观察两组患者的疗效以及治疗前后C反应蛋白（CRP）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）等炎性因子水平,程序化细胞死亡分子5（PDCD5）蛋白水平和不良反应发生情况。结果观察组6个月疾病控制率（DCR）为77.97%,高于对照组的61.02%,差异有统计学意义（P﹤0.05）;观察组平均生存时间为（16.87±3.85）个月,高于对照组的（13.56±2.73）个月,观察组1年生存率为81.36%,高于对照组的61.02%,差异均有统计学意义（P﹤0.05）;观察组治疗后CRP、TNF-α、IL-6水平均低于对照组,PDCD5蛋白水平高于对照组,差异均有统计学意义（P﹤0.05）;观察组骨髓抑制,Ⅲ、Ⅳ级粒细胞减少发生率均高于对照组,差异有统计学意义（P﹤0.05）。结论顺铂联合紫杉醇同步放化疗治疗NSCLC患者的疗效优于单纯放疗,但其不良反应较单纯放疗严重。     

Novel treatment options in stage I non-small-cell lung cancer

In the last 5 years, the current management of stage I non-small-cell lung cancer has been challenged due to novel surgical approaches and advances in radiation technology. The outcome after a sublobar resection is promising, especially for tumors less than 2 cm. Other treatment opportunities are available for high risk patients with comorbidity and impaired pulmonary function. Stereotactic ablative body radiotherapy is a good alternative treatment to surgery, especially in elderly and comorbid patients. However, randomized evidence comparing sublobar resection and stereotactic radiotherapy is presently lacking. The most recent development in radiotherapy is hadron therapy with a presumed reduced toxicity because of its peculiar physical and biological effects. Promising thermal and microwave ablative techniques are in development and have specific niche indications.