ReviewChemotherapy, chemoresistance and the changing treatment landscape for NSCLC
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.
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