The biological operability of stage III non-small cell lung cancer

Stage III non-small cell lung cancer represents a broad spectrum of anatomical and histological subsets of patients with differing biological characteristics and prognostic expectations. Our experience with 161 consecutive patients undergoing complete resection for Stage III non-small cell lung cancer at the M. D. Anderson Hospital and Tumor Institute from 1965 through 1980 includes 69 patients with T3 N0 or N1 disease and 92 patients with an N2 classification. The cumulative 5-year survival overall was 30%: 35.6% for the T3 N0 or N1 group and 26% for the N2 patients. Seventy-three patients had squamous cell carcinoma and 76, adenocarcinoma. Small numbers of patients had other miscellaneous classifications (N = 12). In the T3 N0 or N1 subset, 43% of the patients with squamous cell carcinoma (N = 37) and 23% of those with adenocarcinoma (N = 25) survived 5 years. In the N2 subset, 39% of the patients with squamous cell carcinoma (N = 36) and 14% of the group with adenocarcinoma (N = 52) achieved long-term survival. Failure of treatment was clinically documented in 61 patients. The first observed recurrence or metastasis was at a distant site in the majority of these patients. Operative intervention for patients with Stage III M0 non-small cell lung cancer is effective and reflects the impact and limitations of resection on disease progression. Adjuvant irradiation was not shown to improve the outcome over the results of operation alone. Effective systemic therapy will be required to produce substantial changes in end results.     

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.     

Novel therapies in non-small cell lung cancer

Over the last years, several new systemic cancer therapy strategies have been introduced to turn the growing insights of molecular aberrations involved in the development and progression of lung cancer into better treatment options fort the patients. This review presents some of the most important biological targets and biomarkers relevant in the treatment of non-small cell lung cancer. Especially EGFR mutations, anti-angiogenesis, multi kinase inhibition, vascular disrupting agents, vaccines, m-TOR inhibitors, TRAIL inhibition and several biomarkers are highlighted including current study results.     

Therapeutic advances in non-small cell lung cancer

Despite decades of research, therapeutic advances in non-small cell lung cancer (NSCLC) have progressed at a painstaking slow rate with few improvements in standard surgical resection for early stage disease and chemotherapy or radiotherapy for patients with advanced disease. In the past 18 months, however, we seemed to have reached an inflexion point: therapeutic advances that are centred on improvements in the understanding of patient selection, surgery that is undertaken through smaller incisions, identification of candidate mutations accompanied by the development of targeted anticancer treatments with a focus on personalised medicine, improvements to radiotherapy technology, emergence of radiofrequency ablation (RFA), and last but by no means least, the recognition of palliative care as a therapeutic modality in its own right. The contributors to this review are a distinguished international panel of experts who highlight recent advances in each of the major disciplines.     

Progress in lung cancer: Non-oat cell (non-small cell lung cancer)

Lung cancer remains the greatest killing cancer in the United States with 149,000 new cases expected in 1987. The present expected mortality rate is 87 per cent. More women in the United States died of lung cancer than breast cancer in 1986. Asymptomatic, early and curable lung cancer in high risk individuals is usually found by routine chest X-ray. So-called Stage I lung cancer was reported to have a 83 per cent survival rate at three years by Martini and Beattie in 1977 and 70 per cent five year survival rate subsequently. When the more than 30,000 volunteer males were enrolled in the National Cancer Institute, national lung program for screening, 223 unsuspected lung cancers were found. 47 per cent were Stage I with a survival rate at five years of over 76 per cent. The PMI-Strang/Memorial Sloan Kettering Cancer Center study found 53 cancers in its first screen and 235 lung cancers over the next eight years of the study. Forty per cent were Stage I with a five year survival rate of 70 per cent. Sputum cytology as compared to chest X-ray was of little additional value. Studies (Martini) of N1 lung cancer was found to have a 49 per cent survival rate following resection. The N2 group of lung cancers where the mediastinal tumor was surgically removable and followed by external radiation therapy had a 27 per cent survival rate at five years. Those tumors with solitary brain metastases where the solitary brain metastasis could be resected and the primary tumor controlled, gave a 27 per cent survival rate at six years. The group of advanced N2 disease where the mediastinum could not be completely cleared were a serious group of cancers. A study of 100 patients treated from 1977 to 1980 with surgery plus internal radiotherapy followed by external radiotherapy had an overall 22 per cent survival rate for four to eight years with most of the deaths occurring because of metastases outside the chest. More recently chemotherapy has been used pre-operatively for those individuals with advanced lung cancer in the chest then followed by a combination of surgery, internal radiotherapy, external radiotherapy and more chemotherapy, if chemotherapy sensitive. This is the so-called multidisciplinary approach. In our present early studies it seems that those so treated who are chemotherapy sensitive have a 44 per cent, two year survival rate in a group of patients considered to have extremely poor prognosis. Director Kriser Lung Cancer Center, Chief Thoracic Surgery, Director Clinical Cancer Programs, Beth Israel Medical Center Chief Medical Officer Emeritus, Attending Surgeon, Member of Board of Overseers, Memorial-Sloan-Kettering Cancer Center This report is the gist of a paper read by E.J.B. at the 87th Annual Congress of the Japanese Surgical Society, Tokyo, Japan, 1987.     

Aberrant methylation in non-small cell lung cancer

The potential of tumor suppressor genes (TSGs) to serve as clinical markers for disease detection, progression, and therapeutic response was evaluated by conducting a comprehensive review of the English-language scientific literature on aberrant promoter methylation of TSGs in non-small cell lung cancer (NSCLC). Genome-wide hypermethylation and silencing of TSGs are common features of cancer cells. Aberrant promoter methylation has been found in NSCLC, and research is now focused on the identification of specific genes that exhibit differential expression levels based on the methylation state. Aberrant methylation in NSCLC is observed in the early development of cancer and can be detected in DNA circulating in the blood or isolated from sputum. Therefore, methylation assays offer the promise of a noninvasive test for detecting cancer. In addition, the identification of cancer-specific epigenetic changes may be useful for molecular classification and disease stratification. Hence, the detection of cancerspecific methylation changes heralds an exciting new era in the diagnosis of cancer, its prognosis, and therapeutic responsiveness, and warrants further investigation in NSCLC.     

Pneumonectomy for non-small cell lung cancer

Purpose

To assess the mortality, complications and major morbidity of pneumonectomy for non-small cell lung cancer (NSCLC) and to establish the importance of various prognostic factors.

Methods

We reviewed retrospectively the hospital records of 71 consecutive patients who underwent pneumonectomy for NSCLC between 1992 and 2007 to evaluate the significance of risk factors for an adverse outcome. Patients were divided into two period groups according to the period when they were treated: early (1992–1999; n?=?47) and late (2000–2007; n?=?24).

Results

Both the 30-day and the in-hospital mortality rates were 4.2?% (3/71). Complications developed in 31.3?% (22/71) and overall 5-year survival was 23.1?%. Pathological stage III or more, T3 or more, and N2 or more were risk factors of an adverse outcome. Survival was not significantly influenced by histological type, the side of surgery, or curability. The 5-year survival rates for the early and late periods were 19.6 and 32.9?%, respectively. There were more patients with clinical N2 or 3 disease in the early period than in the late period (66.0 vs. 33.3?%).

Conclusions

Pneumonectomy is associated with acceptable overall morbidity and mortality; however, patients with pathological stage III or more, T3 or more, and N2 or more disease require special consideration. Pneumonectomy should be performed only in selected patients.     

Preoperative induction therapy in non-small cell lung cancer

The clinical significance of preoperative induction therapy for non-small cell lung cancer (NSCLC) is reviewed. As the survival rate in locally advanced NSCLC patients remains poor, preoperative therapy has been attempted in order to improve survival. Whereas some prospective phase II and phase III studies have demonstrated that preoperative cisplatin-based chemotherapy with or without concurrent radiation may improve the prognosis, the efficacy has not been established. Recently, some new chemotherapeutic agents such as paclitaxel and gemcitabine have been introduced, and it has been suggested that preoperative therapy using these new drugs may be more effective. To establish effective preoperative therapy regimens, more sophisticated, prospective, randomized studies in sufficient numbers of homogenous populations such as mediastinoscopy-proven stage IIIA, T1-2N2 patients should be conducted.     

Heavy-ion therapy for non-small cell lung cancer

Since carbon beam therapy for non-small cell lung cancer (NSCLC) was initiated in October 1996, seven trials have been conducted; three have already closed and the remaining four are ongoing. The local control rate, cause-specific survival rate, and overall survival rate of 141 patients with clinical stage I NSCLC were 82%, 58%, and 42%, respectively. Radiation pneumonia was rare (2.1%) and not serious. In the phase II clinical study, the local control rate achieved in 50 patients was 100%, with no radiation pneumonia, resulting in a 60% overall survival rate. Carbon beam therapy could be an alternative to surgery, especially for lung cancer patients of advanced age and/or with complications. For locally advanced lung cancer treated with carbon beam therapy, excellent local control comparable to that in stage INSCLC has been demonstrated and offers hopeful prospects for the treatment of lung cancer.     

Adjuvant chemotherapy for non-small cell lung cancer

The survival after complete resection for non-small cell lung cancer (NSCLC) is unsatisfactory. Until recently, the use of adjuvant therapy after resection for early stage disease has not been proven to improve survival. However, the efficacy of adjuvant therapy has been demonstrated in phase III prospective randomized trials. The appropriate use of adjuvant therapy, including biologic therapy, is currently under investigation.     

Targeted therapy for non-small cell lung cancer

The overall survival for the treatment of lung cancer patients is less than 15%, despite advances in chemotherapy, radiation therapy, and surgery, due to the inability to control metastatic disease. Over the past three decades, the genetics of lung cancer has been progressively delineated. Small molecule drugs or monoclonal antibodies have been developed that target and inactivate specific cancer-related proteins, such as growth factor receptors or their kinases. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of targeted therapies in its treatment.     

Multi-modality treatment of non-small cell lung cancer

Despite significant advances in radiation therapy techniques and a variety of newer chemotherapeutic agents, when multimodality treatment for stage I and II tumors has been tested by Phase III randomized prospective trials of adequate size, no significant survival advantage over surgery alone has been found in most instances. Modalities tested include preoperative radiation therapy, and postoperative chemotherapy and radiation therapy. Trials are presently underway to test preoperative chemotherapy for stages Ib, II, and T3NI (S9900) and to test adding surgery for patients with N2 disease who have been treated by chemotherapy and radiation therapy (INT 0139). Results of a recently completed trial (JBR10) will answer the question of whether postoperative chemotherapy is of benefit for patients with stages T2N0 or T1-2N1. Until these trials are completed, surgeons should resist the temptation to use newer but unproven therapies except within established approved protocols.     

Sleeve lobectomy for non-small cell lung cancer

Sleeve lobectomy is a procedure in which the involved lobe with part of the main stembronchus is removed. The remaining lobe (s) is reimplanted on the main stembronchus. This procedure is indicated for central tumors of the lung as an alternative to pneumonectomy. It is the aim of this study to describe the technique of sleeve lobectomy and to analyse the early postoperative results and late results (survival-recurrence) after sleeve lobectomy for non-small-cell lung cancer. MATERIAL AND METHODS: Between 1985 and 1999, 77 sleeve lobectomies for bronchogenic carcinoma were performed at the University hospitals Leuven. The most common performed sleeve lobectomy is the right upper lobe sleeve lobectomy (67.5%). In 6 patients a combined sleeve resection of the pulmonary artery was performed. The operative mortality was 3.9%. Two patients developed a broncho-pleural fistula. The five-year survival rate was 45.6%. In 5 patients, an anastomotic suture developed which required a completion pneumonectomy in 2. Thirteen patients developed local tumor recurrence. CONCLUSION: We conclude that sleeve lobectomy can be performed with an acceptable mortality and morbidity. Long term survival rate and recurrence rate are as good as after pneumonectomy. The operative mortality is lower when compared to pneumonectomy, exercise tolerance and quality of life are much better after sleeve lobectomy compared to pneumonectomy. For central tumours we believe that sleeve resection is the procedure of choice.