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The Oncologist, Vol. 13, No. suppl_1, 1-4, January 2008; doi:10.1634/theoncologist.13-S1-1
© 2008 AlphaMed Press

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Introduction

Paul A. Bunn, Jr.a, Nick Thatcherb

aUniversity of Colorado Cancer Center, Aurora, Colorado, USA; bDepartment of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom

Key Words. Non-small cell lung carcinoma • Antineoplastic agents • Angiogenesis inhibitors Protein kinase inhibitors • Antimetabolites

Correspondence: Correspondence: Nick Thatcher, M.B., B.Chir., Ph.D., F.R.C.P., Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK. Telephone: 44-161-446-3848/3749; Fax: 44-161-446-8000; e-mail: nick.thatcher{at}christie-tr.nwestnhs.uk

Received September 24, 2007; accepted for publication September 24, 2007.

Disclosure: N.T. has received honoraria and research support from AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Merck, and Roche. P.B. has received honoraria from OSI/Genentech/Roche, Eli Lilly and Company, AstraZeneca, Imclone/BMS, and Sanofi-Aventis.


   ABSTRACT
Top
 Abstract
Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 
Lung cancer is the most common cancer and a highly lethal disease, with improvements in survival rates being dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease. Non-small cell lung cancer (NSCLC) represents around 80% of all lung cancers, and unfortunately at diagnosis most patients have advanced unresectable disease with a very poor prognosis. Indeed, 30%–40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment. Current U.S. Food and Drug Administration–approved second-line treatments are docetaxel (a taxane), pemetrexed (a folate antimetabolite), and erlotinib (an epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]). Gefitinib, another EGFR TKI, currently has only limited use in North America and is not available in Europe. These and other new molecular-target-specific agents may have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Overexpression of EGFR is reported to occur in 40%–80% of NSCLC cases, and EGFR mutations are associated with a significantly higher response rate and longer duration of response following treatment with EGFR TKIs. Another option is antiangiogenesis: the growth and persistence of solid tumors and their metastases are angiogenesis dependent, and so antiangiogenic therapies have been developed, such as the use of TKIs that block the vascular endothelial growth factor receptor. In fact, many commonly used chemotherapeutic drugs have antiangiogenic activity. Ongoing studies are focusing on patient selection and targeted therapies, and there are many new agents undergoing clinical trials.


   INTRODUCTION
Top
 Abstract
 Introduction
Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 
Lung cancer is the most common cancer in the world today, in terms of both incidence (in 2002 there were 1.35 million cases diagnosed, representing 12.4% of all new cancers) and mortality (1.18 million deaths in 2002, or 17.6% of the world's total cancer deaths that year) [1]. It is a highly lethal disease: the 5-year survival rate measured by the Surveillance, Epidemiology, and End Results (SEER) program in the U.S. is 15% [2], and Europe's average is 10% [3], which is not a great improvement over the 8.9% observed in developing countries. Improvements in 5-year survival rates are dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease.

Non-small cell lung cancer (NSCLC)—consisting of squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma—represents around 80% of all lung cancers. Unfortunately, most patients have advanced, unresectable disease at diagnosis, which has a very poor prognosis. Before 1980, radiotherapy was thought to be the only option for advanced disease, but a few years before the turn of the millennium a meta-analysis of NSCLC trials demonstrated a survival benefit with platinum-based chemotherapy. Since then, meta-analyses have shown that platinum-based doublets can improve survival in stage II–IV NSCLC, and some data suggest that this may also be true in stage IB disease. New chemotherapy agents and better supportive care measures have allowed more patients to benefit from chemotherapy with less toxicity [4]. New "targeted therapies" directed against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways have also improved the prognosis for specific patient subpopulations. However, 30%–40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment.


   SECOND-LINE THERAPIES
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 Abstract
 Introduction
 Second-Line Therapies
Targeted Therapy
 Acknowledgments
 References
 
Docetaxel, a taxane and a semisynthetic analogue of paclitaxel, was approved by the U.S. Food and Drug Administration (FDA) for the second-line treatment of NSCLC after studies showed a response rate of 17% for previously treated patients, with a median survival time of 8 months. A weekly dosing regimen has been proposed as being more convenient and causing less adverse effects than the standard 3-weekly schedule, and recent trials have shown that while weekly docetaxel does not result in better survival rates when compared with a 3-week docetaxel regimen, it does produce better compliance and response rates, and a significantly lower rate of neutropenia [5–8].

In 2006, two other agents joined docetaxel as FDA-approved second-line therapies for NSCLC [9]. The first of these new chemotherapy agents to be approved was pemetrexed, a folate antimetabolite administered with folic acid and vitamin B12, which has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel [10]. In a randomized phase III study directly comparing docetaxel and pemetrexed in previously treated patients, the median survival time was 8.3 months for pemetrexed-treated patients and 7.9 months for docetaxel-treated patients. The response rates were 9.1% with pemetrexed and 8.8% with docetaxel, and both drugs were associated with a progression-free survival time of 2.9 months [11]. Pemetrexed has a more favorable safety profile than docetaxel, causing less alopecia, neutropenia, neutropenic infections, need for G-CSF, and hospitalization for neutropenic fever.

Erlotinib, the most recent EGFR tyrosine kinase inhibitor (TKI) to be approved for second- (and third)-line treatment of patients with locally advanced or metastatic NSCLC, has shown a survival advantage over placebo in NSCLC patients after first- or second-line chemotherapy. With an objective response rate of around 8%–12%, regardless of type or number of prior chemotherapy regimens, and a median survival time of 6.7–8.4 months (1-year survival rate of 30%–40%), results with erlotinib use are encouraging when compared with other therapies in similar heavily pretreated patients [12, 13].

The other FDA-approved EGFR TKI, gefitinib, currently has its use limited in the U.S. and Canada to patients who are currently benefiting, or have previously benefited, from gefitinib treatment, or those involved in an access program. The labeling was changed in June 2005 after a review of studies revealed that, unlike erlotinib, the survival benefit from gefitinib (hazard ratio, 0.89) failed to reach significance except in some subsets of patients (those of Asian ethnicity, those who have never smoked [14]). While gefitinib has been approved elsewhere internationally, it is not available in the European Union [15].


   TARGETED THERAPY
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 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
Acknowledgments
 References
 
Response rates to chemotherapy in NSCLC are modest, reflecting the disease's high molecular heterogeneity. Increased knowledge about these molecular properties has facilitated the development of targeted therapies for specific genetic profiles. Whereas chemotherapeutic drugs affect all dividing cells, agents that selectively target specific receptors, such as EGFR, act mainly on malignant cells, where such receptors are overexpressed compared with their limited role in normal tissue. These molecular-target–specific agents therefore have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells.

A range of new targeted therapies is being investigated, including (a) inhibitors of the proteosomal complex, (b) histone deacetylase, (c) mammalian target of rapamycin pathway, (d) the eicosanoid pathway, (e) the protein kinase C (PKC)/Ras/mitogen-activated protein kinase pathway, (f) Raf kinase isoforms, (g) cyclooxygenase-2, and (h) other growth factor receptor–mediated signaling. Other approaches have failed in phase III studies (e.g., PKC and matrix metalloproteinase inhibitors), but this may be due to lack of appropriate patient selection [16–19].

With such targeted therapies, it can be speculated that treatment could be chosen according to which would be most effective for the specific tumor, for example, 5-fluorouracil–derived agents could be used for tumors with a low level of expression of thymidylate synthase; cisplatin and carboplatin would be preferential for tumors with a low level of expression of excision repair cross complementing-1; gemcitabine would be more useful for tumors with a low level of expression of ribonucleotide reductase; and gefitinib and erlotinib would best be used for tumors with EGFR mutations or increased EGFR gene copy numbers [20].

Overexpression of EGFR is reported to occur in 40%–80% of NSCLC cases [21], and patients with somatic mutations of the EGFR gene have a significantly higher response rate to treatment with EGFR TKIs than patients with wildtype EGFR [22]. Additionally, of those patients achieving a partial response, patients with EGFR mutations show a trend toward a longer duration of response in comparison with patients without EGFR mutations. EGFR gene amplification detected by fluorescence in situ hybridization can also be used to select patients for EGFR TKI therapy [23, 24]. Other EGFR TKIs are currently under investigation in phase I/II trials, many of which have differing selectivities for the various members of the human EGFR family [25].

Higher response rates to EGFR TKIs have also been seen in other patient subgroups, such as women, those with an Asian background, never-smokers, and patients with adenocarcinoma. This may be a result of an association between these clinical characteristics and the EGFR mutations (usually amino acid deletions or substitutions) thought to occur on exons 19 and 21 [22, 26].

The VEGF pathway forms another target for treatment. It has been 35 years since tumor vasculature was first singled out as a good target for therapy development [27], and since then it has been shown that the growth and persistence of solid tumors and their metastases are indeed angiogenesis dependent [28]. Antiangiogenic therapy, such as the use of TKIs that block the VEGFR, aims to disrupt existing capillaries that feed a tumor and prevent new vessels from forming around it [28]. Studies using VEGF pathway inhibitors as monotherapy have demonstrated low objective response rates; antiangiogenic agents can be effective in inhibiting tumor growth, but in most studies they do not destroy tumors [29], although this can be overcome by combining angiogenesis inhibitors with cytotoxic therapies [30–35]. Bevacizumab, a monoclonal antibody targeting VEGF that was recently approved for the treatment of colorectal cancer, extended survival in a recent clinical trial when used in combination with chemotherapy for selected patients with NSCLC with nonsquamous histology and lacking brain metastases or bleeding [36]. Several small-molecule VEGFR TKIs have activity in NSCLC, and additional trials are in progress [37]. These antiangiogenic agents are also being studied in small-cell lung cancer. There is also evidence that many commonly used chemotherapeutic drugs have antiangiogenic activity [38]; the question is how best to administer these agents to use both their cytotoxic and antiangiogenic properties [39, 40]. Angiogenesis inhibitors are most effective with a dose schedule that maintains a constant concentration in the circulation [40], and the use of gene therapy to deliver antiangiogenesis genes has shown promise in preclinical models [35, 41, 42].

These types of advances in the understanding of molecular processes in NSCLC are driving new research. Screening patients for various factors before treatment may allow predictions about the clinical benefit of the treatment. For example, DNA in pleural effusion fluid can be used to detect EGFR mutations [43]. Another potential independent prognostic factor in patients with NSCLC is glucose metabolic activity, which closely reflects response to gefitinib therapy. As such, fluorodeoxyglucose (FDG)–positron emission tomography, an imaging method that uses the higher glycolytic rate of tumor cells, may be a valuable clinical tool; increased FDG uptake is an independent prognostic factor in patients with International Union against Cancer stage I/II NSCLC, and less distinctively so for stage III tumors [44, 45].

This supplement has been put together to provide an overview of currently available and investigational treatment regimens for NSCLC. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of ongoing studies, and there are many new agents undergoing clinical trials. These developments are moving the field into an era of optimism in taking on the many remaining challenges of managing NSCLC.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
References
 
The authors would like to thank Remedica Medical Education and Publishing, London, UK, for its support during the preparation of this manuscript.


   REFERENCES
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 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 

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