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Lung Cancer

The Evolving Role of Chemotherapy and Predictive Markers in Early-stage Non-small-cell Lung Cancer

Eric W Humke1 and Heather Wakelee2

1. Instructor of Medicine; 2. Assistant Professor of Medicine, Department of Medicine, Division of Oncology, Stanford Cancer Center, Stanford University School of Medicine


Lung cancer continues to be the leading cause of cancer mortality worldwide. The utility of traditional chemotherapy has reached a plateau in both the metastatic and adjuvant settings. However, we have entered an era of better targeting of both traditional cytotoxic agents and newer compounds for select subsets of patients based on genetic analysis of the tumour. Substantial evidence supports the use of adjuvant chemotherapy in both stage II and stage III non-small-cell lung cancer (NSCLC), but it remains unclear which combination of either traditional or targeted therapies will work best for an individual patient. The use of chemotherapy and targeted therapies in patients with resected stage I NSCLC remains controversial because we cannot predict who benefits from its usage. This article focuses on the evolving role of predictive biomarkers in early-stage NSCLC and summarises the trials that are prospectively evaluating the use of those biomarkers to individualise treatment of NSCLC.

Keywords Early-stage non-small-cell lung cancer, chemotherapy, predictive markers

Disclosure: Eric W Humke has no conflicts of interest to declare. Heather Wakelee has received research funding from Genentech BioOncology, Bayer, AstraZeneca, Eli Lilly and Company, Novartis and Pfizer. Received: 23 March 2010 Accepted: 17 February 2011 Citation: European Oncology & Haematology, 2011;7(2):109–15 Correspondence: Heather Wakelee, Thoracic Oncology, 875 Blake Wilbur Drive, Room 2233, MC 5826 Stanford, CA 94305, US. E:

Lung cancer is the leading cause of cancer mortality worldwide. Surgery remains the optimal treatment for early-stage non-small-cell lung cancer (NSCLC); however, five-year survival rates for resected NSCLC without additional treatment range from 20 to 40% for stage IIIA disease to 70 to 80% for stage IA disease.1

Mortality occurs most

commonly from recurrences at sites outside the lung, suggesting that the cancer had spread before surgery.

These analyses are still based on empiric treatment and do not address the question of who will benefit the most from therapy and who may be harmed. The ultimate goal of adjuvant NSCLC treatment is to predict which patients will benefit from the use of chemotherapy, targeted therapy and radiation therapy, and to individualise therapy based on the patient’s tumour characteristics, including histology and genetic analysis. Recently, trials have begun to use novel biomarkers as a first step towards individualised adjuvant therapy.

In this article, we will give a brief historical background on the use of chemotherapy in the adjuvant setting, followed by previously investigated biomarkers to guide adjuvant therapy and end with a discussion of ongoing clinical trials to address the important question of how to personalise adjuvant therapy.


The goal of systemic therapy in patients with resected NSCLC is to eradicate the prior seeded micrometastases to improve overall survival. Several clinical trials and meta-analyses have shown improved survival in resected NSCLC with different combinations of chemotherapy.2–7

History of the Use of Chemotherapy in Resected Non-small-cell Lung Cancer Initial use of chemotherapy in NSCLC was only for metastatic disease. In 1991, an international panel recommended against the routine use of adjuvant chemotherapy outside of clinical trials.8

Four years later a

meta-analysis was undertaken to investigate the role that chemotherapy after surgery had played in trials up to that point.9 Fourteen trials were evaluated and the meta-analysis showed a 5% improvement in five-year survival but failed to reach statistical significance. Owing to this encouraging result and the established benefit of adjuvant chemotherapy in multiple other solid tumours, several follow-up studies were initiated.

The follow-up clinical trials validated the use of adjuvant chemotherapy in resected NSCLC.10

The major adjuvant trials are

beyond the scope of this article; however, they are highlighted in Table 1.

Although not all the trials were positive, a large meta-analysis of the data has reaffirmed the use of adjuvant chemotherapy. The Lung adjuvant cisplatin evaluation (LACE) meta-analysis was conducted to identify treatment options for post-operative chemotherapy.5


from 4,584 patients were pooled from the five largest adjuvant trials (Adjuvant lung project Italy [ALPI],11 Association [ANITA],3 cancer trial [IALT]2

Big lung trial [BLT],12 and JBR.104 corresponding to a five-year overall survival benefit of 5.4% from 109

Adjuvant International Trialist International adjuvant lung

). The overall hazard ratio (HR) was 0.89,

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