Elsevier

Lung Cancer

Volume 71, Issue 1, January 2011, Pages 3-10
Lung Cancer

Review
Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC

https://doi.org/10.1016/j.lungcan.2010.08.022Get rights and content

Abstract

Management of patients with lung cancer continues to pose a considerable challenge to today's oncologist. While treatment may be curative in the early stages of the disease, the majority of patients are not diagnosed until the tumor has progressed beyond the primary site. Most patients face an intensive and invasive treatment regimen comprising surgery, radiotherapy, or chemotherapy, or combinations thereof depending on disease stage/performance status. Most will require chemotherapy even if their initial surgery is potentially curative; for those with advanced disease, chemotherapy may be their only treatment option. Moreover, the majority of patients will require multiple lines of therapy as their cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. Resistance to current chemotherapeutics available for the management of non-small cell lung cancer (NSCLC) represents one of the most significant barriers to improving long-term outcomes for this vulnerable patient group. Future management may lie in individualizing therapy through careful selection of appropriate agents based on the likelihood of response and the development of resistance. A number of biomarkers are emerging that predict response to current therapeutics; work is ongoing to develop appropriate algorithms based on such markers to guide treatment selection. In addition, novel chemotherapeutics are in development including new platinum analogs such as picoplatin (a cisplatin analog), ABT-751 (a sulfonamide) and tubulin binding agents (TBAs) such as the epothilones, providing hope for the future.

Introduction

Lung cancer is one of the most common cancers and cause of cancer-related death among adults, with a 5-year survival rate from the time of diagnosis of around 15% in the USA [1], [2]. In 2002, there were >1.3 million individuals living with lung cancer globally, with an almost equivalent number of deaths at ∼1.2 million [3]. The most recent estimates for the USA suggest that >222,000 individuals will be diagnosed with cancer of the lung and bronchus, with >157,000 individuals dying prematurely as a result of the disease in 2010 [2]. New cases and estimated deaths are anticipated to remain higher among men than women (new cases 116,750 and 105,770, respectively; deaths 86,200 and 71,080, respectively) [2]. However, data from the USA suggests that mortality due to lung cancer appears to have declined among men and stabilized among women in recent years, a situation that may be linked to the continued high relative rate of tobacco use among women [2], [4]. Improved and earlier diagnosis, the availability of novel effective chemotherapeutic agents, advancing surgical techniques, and declining smoking rates may all be contributing factors to the gradually improving outcomes for this disease. However, the rate of decline in the mortality rate associated with non-small cell lung cancer (NSCLC) still lags considerably behind that observed for other prevalent cancers such as those of the breast, prostate, colon and rectum [5]. The predominant form of the disease, NSCLC, accounts for >80% of all cases of lung cancer and is the focus of this review.

The management of NSCLC requires a multidisciplinary approach. Patients will generally require a combination of surgery, radiotherapy and/or chemotherapy, depending on their stage, resectability and overall performance status [6]. Chemotherapy is now recognized as an important component of treatment for all stages of the disease, including patients with completely resected, early stage disease, who benefit with improved survival rates when adjuvant platinum-based chemotherapy is given [7], [8], [9]. However, the majority of patients (77%) are not diagnosed until the disease has spread beyond the primary site; approximately 55% of patients have metastatic (stage IV) disease at diagnosis [1]. For these patients, chemotherapy forms the foundation of their treatment and is critical in determining their survival and quality of life. Platinum-based therapy is the mainstay of chemotherapy for NSCLC and is usually given in combination with a tubulin binding agent (TBA; including the taxanes [paclitaxel, docetaxel] and vinca alkaloids [vinorelbine, vincristine]), a camptothecin analog (irinotecan, topotecan), gemcitabine, or pemetrexed.

Despite an expanding panel of chemotherapy agents and emerging data regarding the most effective ways to deploy such agents, tumor cell resistance to chemotherapy agents (chemoresistance) continues to pose a significant challenge in the management of human neoplasms. This paper will review the molecular mechanisms that drive chemoresistance to the agents most commonly used in the treatment of NSCLC, and will examine ways in which such mechanisms can be avoided or overcome.

Section snippets

Chemoresistance is a problem for all oncologists and their patients

Chemoresistance may be innate or acquired and may apply to a single agent or to a class of agents with the same/similar antineoplastic mechanisms of action. Chemoresistance is a multifaceted problem with diverse clinical manifestations that requires an understanding of both the basic mechanisms and the evolution of such resistance as the cancer progresses.

A range of cellular mechanisms that give rise to chemoresistance to taxanes have been identified as depicted in Fig. 1 [10], [11], [12].

Chemoresistance in NSCLC

Chemoresistance is common in NSCLC. In one study of 3042 NSCLC patient tumor cultures, extreme or intermediate resistance to carboplatin was documented in 68% (1056/1565) of samples and cisplatin resistance was documented in 63% (1409/2227) of samples [13]. Resistance to doxorubicin, etoposide, gemcitabine, vinorelbine, paclitaxel, docetaxel, and topotecan was reported in 75, 63, 72, 42, 40, 52 and 31% of samples, respectively [13]. All NSCLC patients will eventually develop resistance to the

Overcoming chemoresistance in NSCLC

Chemoresistance represents a considerable barrier to improving outcomes for patients with all stages of NSCLC; from those with early resectable disease eligible for adjuvant chemotherapy to those with advanced metastatic disease whose only treatment is chemotherapy. A variety of strategies have been evaluated and continue to be explored to optimize the efficacy of chemotherapeutics in the management of human NSCLC, including treatment holidays and rechallenge, switching to a different agent

New chemotherapeutics for NSCLC

A variety of agents are currently in development for the treatment of advanced NSCLC (Table 2) [64], [65], [66], [67]. A number of platinum analogs are in early clinical development including picoplatin (a cisplatin analog). This agent has demonstrated clinical activity among patients with platinum-refractory small cell lung cancer in a Phase II trial [64] and in a Phase III trial as a second-line treatment following platinum therapy [65]. A Phase II study is ongoing among patients with NSCLC

Conclusions

Chemoresistance against the panel of agents currently available for the treatment of NSCLC is a formidable barrier to improving outcomes for this group of patients. Many of the traditional resistance mechanisms described in other solid tumors have also been reported in preclinical and clinical NSCLC studies. In order to better manage patients with NSCLC, biomarkers predictive for response to treatment have been identified with the aim of ensuring patients receive the most active treatment

Conflicts of interest statement

Professor Chang has received research funding from pharmaceutical companies Bristol-Myers Squibb, AstraZeneca, Esai and Pfizer, and served on the advisory boards of Pfizer, AstraZeneca and Eli Lily in the past 12 months.

Acknowledgements

The author takes full responsibility for the content of this publication and confirms that it reflects his viewpoint and medical expertise. He also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Bristol-Myers Squibb did not influence the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript.

References (79)

  • P. Sève et al.

    Is class III β-tubulin a predictive factor in patients receiving tubulin-binding agents?

    Lancet Oncol

    (2008)
  • Y. Xu et al.

    Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity

    Ann Oncol

    (2002)
  • P. Ceppi et al.

    ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine

    Ann Oncol

    (2006)
  • M.J. Edelman

    Novel cytotoxic agents for non-small cell lung cancer

    J Thorac Oncol

    (2006)
  • A.M. Mauer et al.

    A phase II study of ABT-751 in patients with advanced non-small cell lung cancer

    J Thorac Oncol

    (2008)
  • E.S. Kim et al.

    Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial

    Lancet

    (2008)
  • N. Thatcher et al.

    Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)

    Lancet

    (2005)
  • M.J. Horner et al.

    SEER cancer statistics review, 1975–2006

    (2009)
  • A. Jemal et al.

    Cancer statistics 2010

    CA Cancer J Clin

    (2010)
  • D.M. Parkin et al.

    Global cancer statistics, 2002

    CA Cancer J Clin

    (2005)
  • A. Jemal et al.

    Cancer statistics, 2008

    CA Cancer J Clin

    (2008)
  • A. Jemal et al.

    Annual report to the Nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control

    J Natl Cancer Inst

    (2008)
  • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Non-small cell lung cancer....
  • R. Arriagada et al.

    The International Adjuvant Lung Cancer Trial Collaborative Group: cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer

    N Engl J Med

    (2004)
  • T. Winton et al.

    Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer

    N Engl J Med

    (2005)
  • L. Gatti et al.

    Overview of tumor cell resistance mechanisms

    Methods Mol Med

    (2005)
  • Y. Matsumoto et al.

    Enhanced expression of metallothioneins in human non-small-cell lung carcinomas following chemotherapy

    Anticancer Res

    (1997)
  • T. Hida et al.

    Glutathione S-trasnferase pi levels in a panel of lung cancer cell lines and its relation to chemo-radiosensitivity

    Jpn J Clin Oncol

    (1993)
  • K. Azuma et al.

    Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with a combination of cisplatin/docetaxel and concurrent thoracic irradiation

    Cancer Chemother Pharmacol

    (2009)
  • K.A. Olaussen et al.

    DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy

    N Engl J Med

    (2006)
  • C. Schettino et al.

    The potential role of pharmacogenomic and genomic in the adjuvant treatment of early stage non small cell lung cancer

    Curr Genomics

    (2008)
  • A.C. Vilmar et al.

    ERCC1 and histopathology in advanced NSCLC patients randomized in a large multicenter phase III trial

    Ann Oncol

    (2010)
  • G. Belper et al.

    RRM1-modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small cell lung cancer

    J Clin Oncol

    (2006)
  • R. Rosell et al.

    Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients

    Clin Cancer Res

    (2004)
  • A. Al Omari et al.

    Genetic variability in DNA repair and clinical outcome in stage III non-small cell lung cancer (NSCLC) treated with concurrent platinum-based chemoradiation

    J Clin Oncol

    (2009)
  • R. Rosell et al.

    BRCA1: a novel prognostic factor in resected non-small-cell lung cancer

    PLoS ONE

    (2007)
  • R. Rosell et al.

    Customized treatment of non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression

    PloS ONE

    (2009)
  • P.A. Andrews et al.

    Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of ovarian carcinoma

    Cancer Commun

    (1990)
  • R.J. Parker et al.

    Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation

    J Clin Invest

    (1991)
  • Cited by (377)

    View all citing articles on Scopus
    View full text