Lung Cancer

Abstract

One third of all cancer-related deaths worldwide are caused by lung cancer, which accounts for more fatalities each year than breast, prostate, and colon cancers combined.1Parkin DM Global cancer statistics in the year 2000.Lancet Oncol. 2001; 2: 533-543Abstract Full Text Full Text PDF PubMed Scopus (2078) Google Scholar The greatest risk of developing lung cancer is associated with tobacco use,2Haus BM Ravazi H Kuschner WG Occupational and environmental causes of bronchogenic carcinoma.Curr Opin Pulm Med. 2001; 7: 220-225Crossref PubMed Scopus (17) Google Scholar and the World Health Organization (WHO) estimates that the number of tobacco-related deaths will have exceeded 2 million per year by 2010.3Alberg AJ Samet JM Epidemiology of lung cancer.Chest. 2003; 123: 21S-49SCrossref PubMed Scopus (672) Google Scholar Non-small cell lung cancer (NSCLC) is responsible for 80% of all lung cancer cases, and most patients present with inoperable locally advanced (stage III B) or metastatic (stage IV) disease. Unfortunately, the long-term prognosis for these patients remains poor because of the inability of systemic therapy to cure advanced disease. Chemotherapy has only a palliative role and a 5-year survival rate ranging from 8% to 15%.4Jemal A Murray T Wand E et al.Cancer statistics, 2005.CA Cancer J Clin. 2005; 55: 10-30Crossref PubMed Scopus (5431) Google Scholar Therefore, active treatment in conjunction with the minimization of side effects is a key goal. In the past few years, several studies have investigated the use of systemic therapy in this setting. In 1995, the NSCLC Collaborative Group's meta-analysis confirmed the palliative role of chemotherapy.5Non-Small-Cell Lung Cancer Collaborative Group Chemotherapy in non-small-cell lung cancer: a meta analysis using data on individual patients from 52 randomised clinical trials.BMJ. 1995; 311: 899-909Crossref PubMed Scopus (465) Google Scholar The results of 11 randomized trials showed that cisplatin-based chemotherapy produces 10% improvement in 1-year survival compared with best supportive care alone and determines benefits in terms of symptom control, quality of life,6Bunn Jr, PA Kelly K New chemotherapeutic agents prolong survival and improve quality of life in non-small-cell lung cancer: a review of the literature and future directions.Clin Cancer Res. 1998; 4: 1087-1100PubMed Google Scholar and cost-effectiveness in advanced NSCLC.7Jaakkimainen L Goodwin PJ Pater J et al.Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in non-small-cell lung cancer.J Clin Oncol. 1990; 8: 1301-1309Crossref PubMed Scopus (204) Google Scholar During the last 10 years, several new cytotoxic agents have become available; these include taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and topoisomerase 1 inhibitor irinotecan. Three of these new chemotherapy regimens (gemcitabine plus cisplatin, docetaxel plus cisplatin, and paclitaxel plus carboplatin) were compared with a reference doublet (paclitaxel plus cisplatin) in a randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG). The conclusion was that third-generation agents can moderately improve 1- and 2-year survival rates in patients with good performance status (PS) with NSCLC. No survival differences were observed in the four treatment arms, although the carboplatin-containing doublet was associated with lower toxicity.8Schiller JH Harrington D Belani CP et al.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002; 346: 92-98Crossref PubMed Scopus (4592) Google Scholar The major challenge of future chemotherapy in NSCLC is the increased efficacy of cytotoxic agents minimizing side effects. Pemetrexed, a multi-target anti-folate, is a novel drug recently introduced into clinical practice for the treatment of malignant pleural mesothelioma9Scagliotti GV Shin DM Kindler HL et al.Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.J Clin Oncol. 2003; 21: 1556-1561Crossref PubMed Scopus (241) Google Scholar, 10Vogelzang NJ Rusthoven JJ Symanowski J et al.Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.J Clin Oncol. 2003; 21: 2636-2644Crossref PubMed Scopus (2281) Google Scholar and NSCLC, and it could play an important role in this setting. The single-agent response rates in previously untreated NSCLC are 16% to 23%,11Clarke SJ Abratt R Goedhals L et al.Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non-small-cell lung cancer.Ann Oncol. 2002; 13: 737-741Crossref PubMed Scopus (120) Google Scholar, 12Rusthoven JJ Eisenhauer E Butts C et al.Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: a phase II study. National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol. 1999; 17: 1194Crossref PubMed Google Scholar whereas it is 39% to 45% in combination trials.13Manegold C Gatzemeier U von Pawel J et al.Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: a multicenter phase II trial.Ann Oncol. 2000; 11: 435-440Crossref PubMed Scopus (149) Google Scholar, 14Shepherd FA Dancey J Arnold A et al.Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group.Cancer. 2001; 92: 595-600Crossref PubMed Scopus (144) Google Scholar Trials comparing doublet-containing pemetrexed with cisplatin plus gemcitabine or with placebo plus best supportive care, after prior platinum treatment, are underway. A comparison between pemetrexed plus cisplatin and a non-cisplatin–containing arm could also be interesting.15Scagliotti GV Kortsik C Dark GG et al.Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small-cell lung cancer: a multicenter, randomized, phase II trial.Clin Cancer Res. 2005; 11: 690-696Crossref PubMed Scopus (31) Google Scholar Pharmacogenomics makes it possible to select specific patients on a genetic basis. Early results indicate that the applications of genomics in NSCLC could have a significant impact on therapeutic strategies and improve the survival of particular subpopulations of patients.16Rosell R Scagliotti G Danenberg KD et al.Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer.Oncogene. 2003; 22: 3548-3553Crossref PubMed Scopus (198) Google Scholar Several studies of pharmacogenomics concern two genes: RRM1 and ERCC1. RRM1 (ribonucleotide reductase M1 gene) has an impact on DNA damage and repair. When this gene is highly expressed, the resistance to gemcitabine is increased; when the level of RRM1 is low, cell lines become more sensitive to gemcitabine.17Bepler G Pharmacocogenomics: a reality or still a promise?.Lung Cancer. 2006; 54: 3S-7SAbstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar RRM1 mRNA expression could be a predictive marker of survival in patients treated with cisplatin plus gemcitabine, and genetic testing of RRM1 expression could be used to personalize chemotherapy. Another pharmacogenomic study showed that the excision repair cross-complementing group (ERCC1) gene is related to cisplatin activity. A recent phase III trial18Rosell R Cobo M Isla D et al.ERCC1 mRNA-based randomized phase III trial of docetaxel (doc) doublets with cisplatin (cis) or gemcitabine (gem) in stage IV non-small-cell lung cancer (NSCLC) patients (p) (Abstract).J Clin Oncol. 2005; 23: 7002Google Scholar compared docetaxel plus cisplatin versus docetaxel plus gemcitabine in stage IV NSCLC and showed that increased ERCC1 mRNA levels are linked with resistance to platinum-based chemotherapy. Based on the evidence that RRM1 and ERCC1 expression may result in chemoresistence, other trials, like MADeIT, were initiated. This trial was designed to tailor chemotherapy based on the expression of these genes. Patients with high levels of RRM1 expression received a chemotherapy doublet that did not contain gemcitabine, whereas those with low levels of RRM1 were treated with gemcitabine. The goal was to demonstrate that up-front patient selection can lead to the choice of the appropriate treatment and, potentially, improve outcome. Platinum-based combination therapy is the established standard of care in the treatment of NSCLC; therefore, all approaches to first-line chemotherapy seem to have reached a therapeutic plateau. An interesting new field of cancer research is the investigation of novel biological agents able to target different cell signaling receptors. Because of its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor are very important targets of biological agents. Bevacizumab is an anti-VEGF recombinant humanized monoclonal antibody that can bind and clear VEGF from the tumor microenvironment.19Presta LG Chen H O'Connor SJ et al.Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.Cancer Res. 1997; 57: 4593-4599PubMed Google Scholar It obtains additional antitumor activity because of its effects on tumor vasculature, interstitial pressure, and blood vessel permeability.20Jain RK Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.Nat Med. 2001; 7: 987-989Crossref PubMed Scopus (1700) Google Scholar In NSCLC, the high expression of VEGF is common and is associated with poor outcome.21Yuan JA Yu CJ Kuo SH et al.Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer.J Clin Oncol. 2001; 19: 432-441Crossref PubMed Scopus (196) Google Scholar, 22Volm M Koomagi R Mattern J Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer.Int J Cancer. 1997; 74: 64-68Crossref PubMed Scopus (231) Google Scholar Recent trials23Johnson D Fehrebacher L Novotny WZ Herbst R Randomized phase II trial comparing bevacizumab plus carboplatino and paclitaxel with carboplatino and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.J Clin Oncol. 2004; 22: 2184-2191Crossref PubMed Scopus (1752) Google Scholar demonstrated a statistically significant advantage in median survival favoring the combination of bevacizumab plus paclitaxel plus carboplatin versus paclitaxel plus carboplatin in the treatment of advanced chemotherapy-naïve NSCLC that presented neither hemoptysis nor central nervous system metastases. This is the first trial showing that the addition of a targeted agent to a standard cytotoxic doublet can prolong survival24Laskin JJ Sandler AB First-line treatment for advanced non-small-cell lung cancer.Oncology. 2005; 19: 1671-1676PubMed Google Scholar and, in the United States, this result has led to the use of bevacizumab in first-line treatment of advanced non-squamous NSCLC. A study testing two different doses of bevacizumab (7 vs 15 mg/m2) associated with chemotherapy has been completed recently. Several targeted agents are being investigated for the treatment of patients with thoracic malignancies. ZD6474 is an inhibitor of tyrosin kinase activity of the VEGF-2 and EGF receptors (EGFR).25Herbst RS Johnson BE Rowbottom JA et al.ZD6474 plus docetaxel in patients with previously treated NSCLC: results of a randomized, placebo-controlled Phase II trial (Abstract).Lung Cancer. 2005; 49: S35Abstract Full Text PDF PubMed Google Scholar A randomized phase II trial has shown that the addiction of ZD6474 to docetaxel prolongs median time to disease progression when compared with docetaxel alone.25Herbst RS Johnson BE Rowbottom JA et al.ZD6474 plus docetaxel in patients with previously treated NSCLC: results of a randomized, placebo-controlled Phase II trial (Abstract).Lung Cancer. 2005; 49: S35Abstract Full Text PDF PubMed Google Scholar This encouraging result justifies further study in a phase III setting. Sorafenib is an oral multi-kinase inhibitor that targets several serine/threonine and receptor tyrosine kinases via its effects on the RAF/MEK/ERK pathway at the level of Raf kinase, VEGFR-2 and PDGFR-ß. Several ongoing studies are evaluating the efficacy of combination chemotherapy with sorafenib. The clinical benefit of this agent has been demonstrated in a randomized, double blind, placebo-controlled phase III study among patients with renal carcinoma (RCC). Preliminary analyses of the sorafenib monotherapy data in NSCLC reveal disease-stabilizing effects similar to those observed in RCC. However, no benefit was demonstrated in NSCLC with other biological agents such as bexarotene,26Blumenschein GR Khuri F Gatzemeier U et al.A randomised Phase II trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer (NSCLC) (Abstract).J Clin Oncol. 2005; 23: 7001Google Scholar, 27Jassem J Zatloukal P Ramlau R et al.A randomized Phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patinets with advanced or metastatic non-small-cell lung cancer (NSCLC) (Abstract).J Clin Oncol. 2005; 23: 7024Crossref PubMed Scopus (194) Google Scholar ionafarnib,28Blumenschein G Ludwig C Thomas G et al.A randomized phase III trial of Ionafarnib /carboplatin/paclitaxel vs CP in chemotherapy naive patients with stage IIIB and IV NSCLC (Abstract).Lung Cancer. 2005; 49: S30Abstract Full Text PDF Google Scholar and aprinocarsen,29Lynch TJ Raju R Lind M et al.Randomised Phase III trial of chemotherapy and antisense oligonucleotide LY900003 (ISIS 3521) in patients with advanced NSCLC: Initial report (Abstract).Proc Am Soc Clin Oncol. 2003; 22: 623Google Scholar, 30Paz-Ares L Douillard J Koralewski P et al.Randomized Phase III tria of gemcitabine/cisplatin (GC) and protein kinase C (PKCa antisense oligonucleotide aprinocarsen in patients (pts) with advancesstage non-small-cell lung cancer (NSCLC) (Abstract).J Clin Oncol. 2005; 32: 7053Google Scholar but negative results could be the result of lack of selection of patients. Recent data have suggested that immunotherapy could have clinical utility in NSCLC. PF-3512676 is a synthetic, single-stranded oligodeoxynucleotide (ODN) molecule and is a toll-like receptor 9 (TLR-9) agonist that provides a targeted and specific modality of immunotherapy by activating plasmacytoid dendritic cells and B-lymphocytes. Data from a randomized phase II trial suggest that the addition of PF-3512676 to standard taxane/platinum chemotherapy for first-line treatment of patients with advanced NSCLC can increase objective response rate and prolong overall survival. These preliminary results indicate that PF-3512676 is able to provide a novel, safe, and effective treatment modality when combined with a platinum-based doublet, but confirmatory phase III trials are necessary.