Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent ‘cancer immunoediting’ has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment.     

Novel Taxane Formulations and Microtubule-Binding Agents in Non–Small-Cell Lung Cancer

Antitubulin agents are among the most active drugs for the treatment of Non—Small-cell lung cancer. The taxanes paclitaxel and docetaxel are highly active and frequently used for adjuvant therapy after resection of localized disease and in combination with radiation for locally advanced disease and treatment of patients with advanced disease. Despite their benefits, these drugs have significant problems, including toxicity and limited efficacy. Recently, new taxane formulations and novel antitubulin agents have been developed. In some cases, these drugs have reduced toxicity with preserved efficacy. In other cases, these agents have potentially unique activity and have now advanced to late-stage trials. This review evaluates 2 novel paclitaxel formulations, albumin-bound paclitaxel and paclitaxel poliglumex. New antimicrotubulin agents, including the epothilones, colchicine-binding antivascular agents, and vinca alkaloids, are also discussed.     

Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC

The first generation of clinical trials of targeted agents in non-small cell lung cancer (NSCLC) treatment has concluded. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors, represent a further chance for tumor control and symptom palliation. In chemotherapy-naive, advanced, nonsquamous NSCLC patients, the combination of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab with chemotherapy was demonstrated to produce better survival outcomes than with chemotherapy alone. The relative failure of first-generation targeted therapies in lung cancer may be a result of multilevel cross-stimulation among the targets of the new biological agents. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of the synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. In a recent phase I/II trial, the combination of erlotinib and bevacizumab demonstrated very promising activity in the treatment of advanced NSCLC pretreated with chemotherapy. Whether the multitargeted approach is best performed using combinations of selective agents or agents that intrinsically target various targets is a matter of debate.     

Targeted therapy in advanced non-small cell lung cancer (NSCLC): Where do we stand?

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.     

表皮生长因子受体通路阻断治疗晚期非小细胞肺癌

 化学治疗晚期非小细胞肺癌（NSCLC）疗效已达到平台，靶向药物是进一步提高疗效的关键。表皮生长因子受体（EGFR）信号异常在NSCLC的发生和进展中起重要作用，已成为抗肿瘤治疗的常用靶点。研究显示，小分子口服EGFR酪氨酸激酶抑制剂吉非替尼和厄洛替尼毒副作用轻微，对化疗失败的NSCLC患者可以改善症状、提高生活质量、延长生存。此外，抗EGFR单克隆抗体西妥昔单抗（cetuximab）在晚期NSCLC的一线和二线治疗中均显示出令人鼓舞的疗效。第二代靶向治疗药物---多靶点抑制剂，可同时阻断肿瘤多个信号传导，临床试验初步结果表明，毒副作用可以耐受，治疗晚期NSCLC有较好的应用前景。     

Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer

Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC.     

Current trends in the treatment of advanced non-small cell lung cancer (Review)

Several advances have been made in the treatment of advanced non-small cell lung cancer in the last few years. Combined modality therapies utilizing chemotherapy have improved survival of patients with locally advanced disease (stage III) when compared to either radiation or surgery alone. New chemotherapeutic agents, used alone or in combination, have also made a strong impact in patients with metastatic disease (stage IV). Ongoing randomized trials will certainly define new treatment standards and hopefully improve the outcome of patients with advanced non-small cell lung cancer.     

New approaches in systemic treatment of advanced colorectal cancer: the molecular targets era

The prognosis of advanced colorectal cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. In this review, the authors examine the most important trials with monoclonal antibodies and tyrosine kinase inhibitors in the treatment of advanced colorectal cancer.     

New approaches in systemic treatment of advanced colorectal cancer: the molecular targets era

The prognosis of advanced colorectal cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. In this review, the authors examine the most important trials with monoclonal antibodies and tyrosine kinase inhibitors in the treatment of advanced colorectal cancer.     

New Treatment Options for Lung Adenocarcinoma - in View of Molecular Background

Lung cancer is the leading cause of cancer related mortality all over the world, and a number of developments have indicated future clinical benefit recently. The development of molecular pathology methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. The most significant changes in the treatment of NSCLC revealed in new pathologic classification and in the introduction of molecularly targeted therapies, which include monoclonal antibodies and small molecule tyrosine kinase inhibitors. The side effects of these agents are generally better tolerated than those of conventional chemotherapy and show higher efficacy. The most important factor follows: histology subtypes, gene mutation status, patients’ selection, drug toxicities and occurence of drug resistance. In the advanced disease, the hope of cure is less than 3 %, but improvements in survival have been clearly achieved. Some years ago the median lung cancer survival rate was 10–12 months, now in case of available specific molecular targets, a significant increase in median survival rates to 24–36 months has been achieved. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. This review focuses on the rationale for targeted agents and new treatment possibilities in case of advanced lung adenocarcinoma.     

Treatment of non-small-cell lung cancer: state of the art and development of new biologic agents

Conventional treatment of non-small-cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of NSCLC patients. Although neoadjuvant and adjuvant therapies in early stages are under investigation and some progress has been achieved in the management of locally advanced and advanced disease, treatment outcomes for NSCLC are still to be considered dismal. The majority of patients affected from NSCLC experience metastatic disease and optimization of chemotherapy is unlikely to produce further substantial survival improvement, with symptom relief and quality of life still being the primary goal of treatment. Based on this background, clinical investigation of novel treatment strategies is mandatory. As our understanding of tumor cell biology has increased and several molecular targets for NSCLC have been identified, a number of new biologic agents have been developed. Targeted therapy describes treatment strategies that focus on cell signaling and other biologic pathways involved in tumorigenesis. Several targeted agents have been introduced in clinical trials in NSCLC, the majority in advanced disease, and some phase III studies have already produced definitive results. Currently, the minority of these new agents offer promise of improved outcomes and negative results are more common to be reported than positive ones. However, important lessons can be learned from this first generation of clinical trials that should be considered the first step of clinical research in this field.     

Targeted therapies for advanced non-small-cell lung cancer: current status and future implications

Lung cancer remains the leading cause of malignancy-related mortality worldwide, with over one million cases diagnosed yearly. Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers. Because lung cancer is typically diagnosed at an advanced stage, chemotherapy (CT) is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving survival of patients, and treatment outcomes must still be considered disappointing. Hence, considerable efforts have been made in order to identify novel targeted agents that interfere with other dysregulated pathways in advanced NSCLC patients. In order to further improve the results of targeted therapy, we should not forget that lung cancer is a heterogeneous disease with multiple mutations, and it is unlikely that any single signaling pathway drives the oncogenic behaviour of all tumours. The relative failure of some targeted therapies may be a result of multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. We summarize the most promising research approaches to the treatment of NSCLC, with particular attention to drugs with multiple targets or combining targeted therapies.     

Screening for non-small cell lung cancer

Lung cancer is the leading cause of cancer mortality and is usually discovered at an advanced stage, when treatment is generally not effective. Many researchers have investigated the value of screening for lung cancer, which would theoretically allow earlier detection and more effective treatment. Unfortunately, no trials of screening strategies for lung cancer have shown a mortality benefit, and as a result, no major medical organization currently recommends screening. Research continues to seek proof of the benefit of screening as new techniques are developed, including low-dose spiral computed tomography (CT), autofluorescence bronchoscopy, and advanced techniques of sputum analysis. Although there are promising data on the sensitivity of these newer screening methods, especially low-dose CT, for detecting early lung cancer, none of the published trials are controlled, and they have not yet proven a decrease in mortality. There are ongoing randomized, controlled trials aiming to demonstrate a mortality benefit. Patients who are interested in being screened for lung cancer should be encouraged to participate in well-designed clinical trials whenever possible.     

非小细胞肺癌靶向治疗研究进展

目前肺癌的生物靶向药物抗表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)已成功地应用于肺癌临床治疗.但肺癌分子生物学机制十分复杂,新的生物靶点药物在临床中的重要作用日益受到关注.本文对上述分子生物学标志物在肺癌治疗中的作用及其相关临床研究进展进行综述.     

Investigational agents for epithelial ovarian cancer

Ovarian cancer is the leading cause of gynecologic cancer deaths and accounts for 4% of women's cancer diagnoses and 5% of all cancer mortalities. Despite the ability of current chemotherapy and cytoreductive surgery to put patients in remission, most patients with advanced cancer will eventually relapse. Many advances in the treatment of ovarian cancer have been reported in the past several years and a historical background is provided. Attention will then turn to analogs of current chemotherapeutic agents, new cytotoxic drugs, targeted molecular therapy, intraperitoneal therapy and immunotherapy. This review will give a perspective on current drugs, potential agents and upcoming clinical trials.     

Investigational agents for epithelial ovarian cancer

Ovarian cancer is the leading cause of gynecologic cancer deaths and accounts for 4% of women’s cancer diagnoses and 5% of all cancer mortalities. Despite the ability of current chemotherapy and cytoreductive surgery to put patients in remission, most patients with advanced cancer will eventually relapse. Many advances in the treatment of ovarian cancer have been reported in the past several years and a historical background is provided. Attention will then turn to analogs of current chemotherapeutic agents, new cytotoxic drugs, targeted molecular therapy, intraperitoneal therapy and immunotherapy. This review will give a perspective on current drugs, potential agents and upcoming clinical trials.     

Cost-effectiveness of chemotherapy for nonsmall-cell lung cancer

After decades of research into its prevention and treatment, lung cancer remains the leading cause of cancer death in North America and Europe. Approximately 75% of all new lung cancer diagnoses are of the nonsmall-cell subtype, and less than 25% of these patients are potentially operable upon first detection. First-generation cisplatin-based chemotherapy regimens for patients with metastatic disease achieved a median survival of 175 days, with 15 to 20% of patients alive at 1 year.In recent years, vinorelbine, gemcitabine, paclitaxel, and docetaxel have emerged as promising agents in the treatment of advanced nonsmall-cell lung cancer. Evidence from randomized trials demonstrates that when these agents are combined with cisplatin, the objective tumor response is 25 to 40%, with a median overall survival approaching 300 days. In addition, recent studies have shown that single-agent docetaxel improves survival and quality of life in patients with platinum-refractory nonsmall-cell lung cancer. Since these modest but important improvements in the management of nonsmall-cell lung cancer are achieved at a significant cost, cost has emerged as a major consideration in health policy decision-making. This article reviews the pharmacoeconomic literature to provide guidance on the cost-effective use of chemotherapy in the treatment of advanced nonsmall-cell lung cancer.     

Nouvelles thérapeutiques ciblées dans les glioblastomes

The efficacy of the standard treatment for glioblastomas (surgical resection combined with radiotherapy and chemotherapy) is so far somewhat limited with a median survival rate of about 15 months. The development of new therapeutic approaches is therefore needed. In recent years, new-targeted drugs have been developed to strengthen the therapeutic arsenal in cancer treatment. Molecular targets are based on the biological and molecular characteristics of the cancer cell, such as hyperexpression of the EGF receptor, activation of the PI3K/Akt and Ras/Raf pathways. Unfortunately, results from glioblastoma trials have been disappointing so far. On the other hand, early clinical results using antiangiogenic agents appear very promising. It can be hoped that in the next few years these agents might transform the dismal prognosis of glioblastomas.     

Ongoing and future trials of biologic therapies in lung cancer

Lung cancer is the leading world-wide cause of cancer death. The care rate remains less than 15% despite improvements in surgery, radiotherapy and chemotherapy. The majority of deaths can be attributed to systemic metastases. Chemotherapy prolongs survival but produces few complete responses and survival at 5-years is rare. Molecular advances have provided many new targets for lung cancer therapy. Many new agents have been developed to attack these targets. This article describes current and proposed trials for these new targeted therapies in both small cell and non-small cell lung cancers.     

Evidenced-based medicine and future direction of Taxol

Taxol was introduced for the clinical treatment of several solid tumor malignancies in the 1990s. It has been established that primary chemotherapy based on Taxol is the standard for non-small cell lung cancer and epithelial ovarian cancer. After initial chemotherapy containing doxorubicin, sequential administration of Taxol for advanced or metastatic breast cancer is recommended by the Food and Drug Administration in the United States. Taxol-based chemotherapy and/or concurrent chemoradiation for head and neck cancer, esophageal carcinoma, urothelial and prostate cancer are under investigation, but these trials have not produced evidence showing that they are superior to the present standard treatment for these malignancies. Although phase I/II trials of Taxol combined with new agents such as vinorelbine, topotecan, CPT-11 and others may demonstrate efficacy to a certain extent for some solid tumor malignancies, a phase III study will be required in the next stage. Taxol combined with other agents focusing on molecular targets will be an important approach in next decade. Inhibition of signal transduction by a noncytotoxic agent such as herceptine has the potential to enhance the cytotoxic effect of Taxo.