High-dose hyperfractionated accelerated radiotherapy in non-small cell lung cancer

The observation that improved local tumour control also results in increased survival rates, even in a disease such as non-small cell lung cancer (NSCLC), has fuelled the interest in strategies aimed at local tumour eradication. It has been demonstrated that a clear dose-response relationship exists for radiotherapy, i.e. higher doses of radiation lead to increased local tumour control. However, prolongation of the overall treatment time beyond 4-5 weeks renders radiotherapy less effective because of increased proliferation of tumour cells. It is therefore of interest to deliver as high doses as possible in short overall treatment times. An extreme example of this strategy is stereotactic body radiotherapy (SBRT), where a few large radiation doses, equalling very high biological doses, delivered in a short overall treatment time has resulted in at least 90 % tumour control in stage I NSCLC. However, when large volumes or critical normal structures such as the main bronchi are in the high-dose radiation volumes, more extensive fractionation schedules have been used, such as 70 Gy in 35 daily fractions of 2 Gy. As the overall treatment time than exceeds 4-5 weeks, hyperfractionated radiotherapy schedules have been introduced, which all delivered 2-3 relatively small fractions per day to total doses that are similar to the so-called standard regimen. Several randomized phase III trials and a meta-analysis based on individual patient data have demonstrated a superior 5-year survival with this strategy, without increased side effects. Our group has also shown that individualised hyperfractionated accelerated radiotherapy (INDAR) makes treatment with curative intent even in patients with large tumour volumes possible with few important side effects. Early results of INDAR with concurrent chemotherapy or with cetuximab are promising.     

The role of Bcl-2 family members in non-small cell lung cancer

The treatment of advanced nonsmall cell lung cancer (NSCLC) continues to pose great challenges for the thoracic surgeon. Current therapeutic strategies with chemotherapy and radiation are often ineffective adjuncts to surgery. Accordingly, preclinical research concentration has turned to molecular targets that may prove to be more effective. The Bcl-2 family consists of a homologous network of genes that regulate apoptosis or programmed cell death. Altered expression of members in this family leads to aberrant cell proliferation and malignant growth. This review will discuss the expression and significance of Bcl-2 family members in NSCLC and consider potential methods of intervention that are currently being tested and may have clinical applicability. In addition, the current experience with clinical trials involving Bcl-2 down-regulation in solid organ tumors will be summarized.     

Clinical parameters affecting prediction accuracy of postoperative lung function in non-small cell lung cancer

Despite significant development in chemotherapy and radiotherapy, surgery is still the cornerstone for curative lung cancer treatment. Accurate prediction of postoperative lung function is mandatory. The goal of this study was to identify important clinical factors affecting prediction accuracy of postoperative lung function for more careful patient selection. The medical records of non-small cell lung cancer patients undergoing pulmonary resection were reviewed. An accuracy index, apo/ppoFEV(1) was defined as the ratio of actual postoperative FEV(1) [apoFEV(1)] to predicted postoperative FEV(1) [ppoFEV(1)]. We used multivariate analysis to inspect the relationship between the accuracy index and seven tentative clinical factors: age, gender, preoperative FEV(1), time interval between operation and the first postoperative FEV(1), bronchodilator response (%), resected lung portion, and the number of resected lung segments. A total of 82 patients were analyzed. Accuracy index of quantitative perfusion lung scan-based prediction was better than that of simple calculation. Multivariate analysis identified the number of resected lung segments and preoperative FEV(1) as the significant clinical factors affecting the accuracy index (P=0.026 and 0.002, respectively). Preoperative FEV(1) and the number of resected lung segments are significant clinical factors affecting prediction accuracy of postoperative lung function.     

Clinicopathologic analysis of small-sized non-small cell lung cancer

We reviewed the data on 149 patients who underwent complete resection for small-sized (≤ 2 cm)peripheral non-small cell lung cancer at our institution between January 2002 and July 2010. Patients with small-sized lung cancer underwent a lobectomy in 121, segmentectomy in 13, and wedge resection in 15 cases. The overall and 5-year disease-free survivals were 89% and 82%, respectively. The 5-year disease-free survival of patients with tumors exceeding 1.5 cm was lower than that of patients with tumors 1.5 cm or smaller (p=0.01). The 5-year disease-free survival for patients without pleulal invasion was 87%, whereas it was 45% for those with pleulal invasion (p=0.004). The 5-year disease-free survival according to the serum level of carcinoembrionic antigen( CEA) were 82% for the normal group and 70% for the high group( p=0.007). Although the results were not significantly different, patients with tumors with high maximum standardized uptake value (SUV) on FDG-PET/CT showed a trend toward a lower 5-year disease-free survival rate( p=0.10). There were no recurrences in patients with ground-glass opacity (GGO) or GGO-dominant lesion including those who underwent sublober resection. Multivariate analysis showed that tumor size and pleural invasion were independent prognostic factors. Indication of sublober resection for solid-type small-sized non-small cell lung cancer (NSCLC) should be carefully determined considering tumor size, pleural involvement, serum carcinoembryonic antigen( CEA) level, and maximum SUV.     

Role of postoperative radiation therapy in stage IIIa non-small cell lung cancer

One hundred forty-six patients with pathological stage IIIa non-small cell lung cancer were retrospectively analyzed to determine whether postoperative radiation therapy improves survival and reduces locoregional recurrences. The survival rate of the overall group at 1, 3, and 5 years was 56%, 24%, and 17%, respectively. Regarding the type of resection and histology, we did not observe statistically significant differences. Patients with N0 and N1 disease were grouped and compared with the N2 group, and survival at 3 and 5 years was 41% and 27%, respectively, for the T3 N0-1 group and 17% and 15%, respectively, for the T3 N2 group (p less than 0.001 and p = 0.05, respectively). Eighty-six patients received postoperative irradiation (45 to 50 Gy) and 60 did not. We have not observed any improvement in survival with postoperative radiation therapy, except in those patients with N2 disease. Median survival time was 6 months for patients without irradiation and 15 months for those with irradiation (p = 0.071). According to locoregional recurrences, a slight benefit with postoperative radiation therapy was observed.     

The role of external radiation and brachytherapy in unresectable non-small cell lung cancer

The role of radiation therapy in the management of non-small cell lung cancer is rapidly changing. Preoperative radiation, with the exception of the superior sulcus tumor, has not been found to benefit patients. The issue of postoperative radiation in completely resected patients with non-small cell lung cancer remains controversial. Current postoperative trials suggest, however, that postoperative radiation in these patients prevents local recurrence and, in combination with chemotherapy, prolongs survival. Primary radiation therapy in inoperable non-small cell lung cancer is associated with a small but definite cure rate. Better definition of treatment volume, proper selection of dose-time, state-of-art treatment planning, and, whenever possible, intraoperative radiation have improved local control rates and decreased severe complications.     

N2期非小细胞肺癌的预后因素分析

目的 探讨有纵隔淋巴结转移(N2期)的非小细胞肺癌(NSCLC)的外科治疗疗效及影响预后的因素.方法 回顾性分析1999年1月至2003年5月手术治疗的117例N2 NSCLC患者(男性88例,女性29例,年龄29～79岁)的生存率,分析手术方式(肺叶切除、全肺切除、姑息性切除),病理类型(腺癌、鳞状细胞癌、混合癌、大细胞癌和其他类型),T分期以及术后综合治疗对预后的影响.结果 中位生存期为22个月,3年和5年生存率分别为28.1%和19.0%.年龄、性别、病理类型、围手术期化疗、术后放疗均未见与5年生存率有相关性.肺叶切除者的5年生存率为22.2%,全肺切除者为25.0%,均高于姑息性切除者的9.1%(P=0.001).T4期患者5年生存率为11.1%,低于T1-2期患者的37.5%(P=0.01).COX多因素分析示,手术方式和T分期与5年生存率相关.结论 外科治疗对T1-2 N2期NSCLC是最佳选择.对于T4期患者,由于不完全切除比例大,术前新辅助治疗比率低,手术提高长期生存率的效果有限.     

The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers, with patients having a poor prognosis. Approximately one third of NSCLC patients present with early-stage disease in which potentially curative resection and multi-modality therapy. Although adjuvant chemotherapy is the standard practice for patients with stages I-III breast and colorectal cancer, the therapeutic efficacy of adjuvant chemotherapy, following complete surgical resection of early stage NSCLC, has not been fully established. Several prospective randomized trials for patients with early stage NSCLC (stages I-IIIA) have confirmed a survival benefit with cisplatin-based adjuvant chemotherapy, as demonstrated in the 1995 meta-analysis performed by the NSCLC Collaborative Group. Studies from Japan have reported that adjuvant therapy with uracil-tegaful (UFT) afforded an improvement of 4% in the 5-year survival rate and a relative risk reduction of 26% in mortality at 5 years among patients with T1-2N0 (stage I) disease. In particular, the Japan Lung Cancer Research Group has demonstrated an improvement in the 5-year survival rate of 11%, favoring chemotherapy with UFT in the subset of patients with T2N0 (stage IB) disease. Two published meta-analyses based on abstracts have estimated a relative risk reduction in mortality of 11-13% at 5 years. The Lung Adjuvant Cisplatin Evaluation (LACE), which was based on a pooled analysis of five randomized trials, has demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with completely resected NSCLC. This benefit depended on stage, being greatest in patients with stage II or IIIA disease. This analysis has suggested that platinum-based adjuvant chemotherapy may have no benefit for patients with stage IA and only a marginal benefit for patients with stage IB. Thus, the information available at the current time supports the administration of adjuvant chemotherapy for patients who have undergone complete resection of stages IB-IIIA NSCLC. Further research is needed to define the role of adjuvant platinum-based chemotherapy and its use, in conjunction with chest radiotherapy as the treatment for patients with resected stages IB and IIIA NSCLC.     

Angiogenesis in non-small cell lung cancer

Two processes are necessary for a tumor colony to grow and become invasive: angiogenesis and basement membrane degradation. Angiogenesis is the formation of new blood vessels from the endothelium of existing vasculature, in response to the metabolic demand of the tumor. Assessment of the degree of tumor angiogenesis may improve risk stratification in patients with lung cancer, especially those with early-stage disease. In addition, the strategy of blocking the mechanism of angiogenesis may prove to be an effective therapeutic alternative for patients with nonsmall cell lung cancer. Clinical trials evaluating novel antiangiogenic agents, including antibodies to vascular endothelial growth factor (VEGF) and compounds directed at the tyrosine kinase receptor, are ongoing.     

Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis.

OBJECTIVE: To identify the prognostic significance of certain clinical, cellular and immunologic markers in resectable non-small cell lung cancer (NSCLC). DESIGN: A cohort of patients with resectable NSCLC was prospectively followed up for 8 years (100% follow-up). SETTING: A university hospital in a large Canadian city. PATIENTS: One hundred and thirteen consecutive patients who underwent surgical resection of primary NSCLC. MAIN OUTCOME MEASURES: Presence of peritumoral B lymphocytes (identified with antibody to CD20) and T lymphocytes (antibody to CD43), along with tumour markers (carcinoembryonic antigen [CEA], keratin, cytokeratin, S-100 protein, vimentin, chromogranin) and other factors such as age, sex, cell type, American Joint Committee on Cancer (AJCC) stage, histologic grade, DNA ploidy and S-phase fraction were correlated with survival. RESULTS: The mean age of patients in the study was 66.0 years; 60% were male. Histologic types of the tumours were: adenocarcinoma 57 (50.4%), squamous cell 47 (41.6%), adenosquamous 6 (5.3%) and large cell 3 (2.6%). AJCC stages were: I 66 (58.4%), II 20 (17.7%) and III 27 (23.9%). Histologic grades were: I (well differentiated) 31 (27.4%), II 50 (44.2%), III 29 (25.7%) and IV 3 (2.6%). Survival was 85% at 1 year (95% confidence interval [CI] 76%-90%), 44% at 5 years (95% CI 34%-53%) and 34% at 10 years (95% CI 22%-46%). Multivariate analyses using the Cox proportional hazards model for survival confirmed AJCC stage (p < 0.001) in all histologic subtypes to be the strongest factor of independent prognostic significance. It also revealed the presence of CD20-stained B lymphocytes (p = 0.04) in the peritumoral region of all tumours to be a positive prognostic factor. This relation was especially strong for nonsquamous cell carcinomas (p < 0.001). For squamous cell carcinomas, the immunohistochemical presence of CEA was of marginally negative prognostic value (p = 0.04). DNA ploidy and a high S-phase fraction showed no evidence of prognostic value for stage I tumours, but for stages II and III tumours there was strong evidence of prognostic value (p < 0.001 jointly). The evidence for DNA ploidy was especially strong in stages II and III squamous cell tumours (p = 0.008), and for a high S-phase fraction was strongest in stages II and III nonsquamous cell tumours (p = 0.002). CONCLUSIONS: AJCC stage remains the most important prognostic indicator from a variety of clinical variables and tumour markers in postoperative patients with resectable NSCLC. For nonsquamous cell lung carcinomas, the presence of peritumoral B lymphocytes was strongly associated with improved survival, suggesting an important role for humoral mediated immunity.     

Relevance of an intensive postoperative follow-up after surgery for non-small cell lung cancer

BACKGROUND: Although a minimal follow-up with periodic clinic visits and chest radiographs is usually recommended after complete operation for non-small cell lung cancer, the ideal follow-up has not been defined yet. Objectives of this prospective study were to determine the feasibility of an intensive surveillance program and to analyze its influence on patient survival. METHODS: Follow-up consisted of physical examination and chest roentgenogram every 3 months and fiberoptic bronchoscopy and thoracic computed tomographic scan with sections of the liver and adrenal glands every 6 months. Influence of patient and recurrence characteristics on survival from recurrence was successively analyzed using the log-rank test and a Cox model adjusted for treatment. RESULTS: Among the 192 eligible patients, recurrence developed in 136 patients (71%) and was asymptomatic in 36 patients (26%). In 35 patients, recurrence was asymptomatic and detected by a scheduled procedure: thoracic computed tomographic scan in 10 (28%) patients and fiberoptic bronchoscopy in 10. Fifteen patients (43%) had a thoracic recurrence treated with curative intent. From the date of recurrence, 3-year survival was 13% in all patients and 31% in asymptomatic patients whose recurrence was detected by a scheduled procedure. Asymptomatic recurrences (p < 0.001), female sex (p < 0.001), performance status 2 or less (p = 0.01), and age 61 years or younger (p = 0.01) were shown to be significantly favorable prognostic factors. CONCLUSIONS: This intensive follow-up is feasible and may improve survival by detecting recurrences after surgery for non-small cell lung cancer at an asymptomatic stage.     

The role of VATS for staging and diagnosis in patients with non-small cell lung cancer

Video-assisted thoracoscopic surgery is an effective and versatile tool for the diagnosis and staging of patients with lung cancer. Despite advances in imaging technology, including integrated positron emission tomography/computed tomography scans, the clinical staging of patients with lung cancer remains inaccurate. Tissue confirmation is critical for accurate staging and treatment of patients with lung cancer. Thoracoscopy is an excellent and often preferred approach to the biopsy of inferior mediastinal, anteroposterior window, and para-aortic lymph nodes, and has the added advantage of allowing simultaneous assessment of the pleural space, satellite lung nodules, and T status of the tumor. Thoracoscopic wedge resection is the preferred technique for diagnosing indeterminate solitary pulmonary nodules. In the era of computed tomography screening, most indeterminate lung nodules are less than 1 cm in size and pose unique challenges in determining malignant potential and obtaining a tissue diagnosis. Several techniques have been adopted to allow successful thoracoscopic biopsy of these subcentimeter lung nodules.     

影响非小细胞肺癌全肺切除术预后的因素

目的　探讨影响非小细胞肺癌患者全肺切除术预后的因素 ,为手术适应证的修正提供依据。　方法　回顾性分析行全肺切除术的 81例非小细胞肺癌患者的临床及随访资料。随访时间 5年以上。运用 χ2 检验、Kaplan Meier生存分析和COX模型多因素分析 ,对影响预后的因素进行单因素和多因素分析。　结果　本组患者肿瘤的组织学类型主要为鳞癌 (5 4 3% )、腺癌 (2 4 7% )和腺鳞癌(17 3% )。非小细胞肺癌全肺切除术后N0 、N1和N2 期患者的 5年生存率分别为 (2 0 8± 9 9) %、(15 4± 10 0 ) %和 (4 0± 2 8) % ,无围手术期死亡病例。术后合并症发生率为 2 2 2 %。单因素分析结果显示 :影响非小细胞肺癌患者全肺切除术预后的因素为年龄 ,术后合并症 ,肿瘤的组织学类型、部位和大小 ,胸壁侵犯和纵隔淋巴结转移。COX模型多因素分析结果显示 :影响患者预后的因素为术后合并症、肿瘤大小、胸壁侵犯和淋巴结转移状况。　结论　全肺切除术具有较高的术后合并症发生率。高龄、腺癌、心肺合并症和N2 期淋巴结转移是影响预后的不利因素。术前准确的肿瘤分期和心肺功能评估是病例选择的重要依据     

A quarter of a century experience with sleeve lobectomy for non-small cell lung cancer.

Objective: Sleeve lobectomy represents an effective and widely accepted surgical therapy for non-small cell lung carcinoma (NSCLC). We sought to review our experience in terms of mortality, early and late morbidity, and long-term survival evaluating the technical progresses overtime. Material and methods: From 1980 to 2005, 199 patients underwent sleeve lobectomy. Pathology revealed 167 (83.9%) squamous carcinomas, 23 (11.6%) adenocarcinomas, 7 (3.5%) large cell and 2 (1%) adenosquamous carcinomas. In 39 (19.6%) patients a vascular procedure was associated. Nineteen (9.5%) patients had preoperative radiotherapy, 14 (7%) preoperative chemotherapy and 10 (5%) chemoradiotherapy. Results: Overall postoperative mortality was 4.5% (n=9) and morbidity was 17.9% (n=34). Preoperative radiotherapy was identified as a significant risk factor for perioperative mortality (OR: 5.34, 95% CI: 1.16-24.47; p=0.03) and early anastomotic complications (OR: 3.73, 95% CI: 1.01-13.68; p=0.04). Overall 5-year survival rate was 39.7% and stage-by-stage analysis did not reach a significant survival difference. With growing skills the number of procedures, associated angioplasty and difficult sleeves (such as sleeve bilobectomy) increased. Also in term of mortality, in the last 10 years we had 0.8% of mortality rate. Conclusions: Sleeve lobectomy is a safe and effective therapy for selected patients with NSCLC. Vascular procedures and the use of induction chemotherapy did not increase mortality and morbidity; otherwise, the use of preoperative radiotherapy is not recommended. Overtime trend showed a significant lower mortality in the last period. This emphasises the importance of a learning curve and encourages the performance of this procedure in experienced centres.     

Surgical analysis for N 2 factor in non-small cell lung cancer

In this study we analyzed 33 cases which underwent complete surgical resection to assess the role of surgery in the treatment of patients with N 2 NSCLC. The 3 year survival rate was 33.3% and the median survival time was 26.1 months. The survival curve for patients with T 3 factor was statistically worse than those with T 1 or T 2 factor. Further, the survival curve for patients with p 2 or p 3 factor was significantly lower than than that for those classified as p 0. Patients classified with p 2 or p 3 had a survival rate under 2 years. Only one patient diagnosed as T 3 achieved 3 year survival. This patient had a pm1 tumor with p 0 factor. We thereby recommend that surgery should only be performed for those N 2 NSCLC patients diagnosed as T 1 or T 2 with a classification of p1 or less.     

The role of computed tomographic scanning in diagnosing mediastinal node involvement in non-small cell lung cancer

OBJECTIVES: The reliability of computed tomographic scanning in evaluating mediastinal node involvement is controversial because of the high false result rate. We attempted to identify significant factors responsible for false-positive and false-negative scans. METHODS: From August 1992 through April 1997, 401 patients with lung cancer who underwent major lung resection and systematic lymph node dissection were enrolled in this study. We retrospectively examined mediastinal node size, tumor location, maximum tumor dimension, the presence or absence of obstructive pneumonia, atelectasis, pulmonary fibrosis, and lymph node calcification on contrast-enhanced computed tomographic scans. We identified clinical and radiologic factors responsible for the false results by using univariate and multivariable analysis. RESULTS: Central tumor location proved to be a significant factor of false-positive scans. Elevated carcinoembryonic antigen level and larger tumor dimension were significant factors of false-negative scans. In patients with a peripheral tumor smaller than 40 mm and normal levels of serum carcinoembryonic antigen, sensitivity, specificity, positive predictive value, and negative predictive value were 6%, 93%, 8%, and 90%, respectively. The reliability of computed tomographic scanning in this low-risk subgroup was high in detecting N0-1 disease but low in diagnosing N2 disease. CONCLUSION: It is not possible to accurately diagnose N2 disease by using lymph node size on computed tomographic scanning alone, especially in patients with a central tumor, an elevated serum carcinoembryonic antigen level, or a tumor of 40 mm or larger. A preoperative invasive staging procedure is indicated in these populations and may not be indicated in the population with normal computed tomographic scan results without any of these risk factors.