Fluorescence bronchoscopy for early detection of lung cancer

Abstract

The conventional method of bronchoscopy has only a 30% sensitivity to detect early stage cancer in the central airways. For patients with positive sputum cytology who clearly harbor early cancers, repeat and lengthy sessions of bronchoscopies are required for accurate localization of these lesions. This leads to a significant delay in obtaining the diagnosis, postponing an appropriate treatment and reduces the chance for cure. There are valid reasons for improving the detection rate of early stage lung cancers. The number of individuals at risk forms a large population, the outcome of patients treated with early stage cancer has been shown to be better and bronchoscopic treatments, e.g. photodynamic therapy and electrocautery, are currently alternatives for surgical resection. Finding more early stage cancers by screening the population at risk and accurate staging to enable treatment at the earliest stage feasible, may improve the dismal prognosis of many patients. This article deals with the clinical background and current problems in early detection of lung cancer and discusses our expectations regarding new developments in bronchoscopy for early detection, accurate staging and treatment of lung cancer.

Introduction

Lung cancer is a global epidemic and number one killer among all cancers. Morbidity is high and cure rate is only 13%. Many lung cancer patients are diagnosed in a relatively advanced stage, precluding radical resection [1]. Surgery provides the best chance for cure if the tumor can be radically resected and when no lymph node or distant metastases is present. In only 25% of the population can the tumor be resected and half are ultimately cured. Even after curative treatment of their primaries, patients remain at risk for local recurrence, distant metastasis and subsequent primaries [2]. Treatment modalities, such as cisplatin-based chemotherapy and radiotherapy for unresectable lung cancer, are becoming part of the treatment strategy, achieving significant improvement of quality of life, longer median survival time and higher survival rate, if compared to palliative care alone [3], [4]. Gene susceptibility for both smoking and developing lung cancer make the management of the target population quite complex [5], [6]. Many lung cancer patients also suffer from smoking related diseases, such as COPD and their cardiovascular status is often poor. Reduced physical fitness hamper our abilities to apply the best treatment strategies because of treatment related morbidity. Smoking and cancer susceptibility of the individuals at risk also explains why, after previous curative treatment of cancer primaries in the aero-digestive tract, many remain at risk of developing subsequent primaries [7]. The rate of second primary cancer after a non-small cell lung cancer is in the order of 1–4%. Earlier study has shown a cumulative incidence for second primary lung cancer of 4% per year [8].

Invasive squamous cell cancer in the central airways gradually develops from normal mucosa and may be multifocal, the so-called field cancerization [9]. Research to reverse gradual progression of normal tissue towards cancer, e.g. chemoprevention studies and gene therapy, is currently one of the major activities in medical oncology [10], [11]. Inhaled carcinogens may cause cumulative genetic damage to the entire mucosa of smokers and ex-smokers. Genetic abnormalities gradually develop until morphological changes, such as dysplasia and carcinoma in situ, become morphologically apparent [12], [13], [14]. Patches containing 200–400 cell clones have recently been found to harbor early molecular changes similar to those seen in tumor cells [15]. Various molecular damage may indicate heterogeneity in the pathways of development towards cancer of multiple cells’ clones in the bronchial mucosa. The finding that these clonal patches may only contain 90,000 cells makes it quite obvious that conventional diagnostic methods, such as chest X-rays, CT scan and bronchoscopy, cannot be regarded as promising tools and are therefore inappropriate for early detection. These clones are far below the detection threshold of conventional diagnostic tests. It is therefore important to develop more sensitive and accurate diagnostic methods that can be applied in the target group for the detection of early stage lesions.

Surgical resection is proven to provide the best chance for cure. However, it is not always feasible because of the relative wasteful method of resection of healthy lung parenchyma. Many patients have limited pulmonary function suffering from COPD [6]. As parenchyma sparing techniques, such as surgical bronchoplasty and video-assisted thoracoscopic surgery, require clinical expertise, there will always be a need for less morbid alternatives for the standard surgical approach [16]. In early stage cancer of the central airways, fluorescence system has been shown to increase the yield of finding pre-invasive lesions [17], [18]. Central and proximal airway branches can be inspected with the fiberoptic bronchoscope during the conventional white light bronchoscopy and the additional use of the fluorescence imaging equipment has been shown to be feasible in clinical practice. Tumor margins are clearly visible and taking biopsy specimens becomes more precise. Techniques, such as thermal lasers, high frequency electrocautery, photodynamic therapy, cryotherapy and brachytherapy, can then be applied in a more accurate manner [16], [19]. Further study is needed to look for the most optimal method of fluorescence detection. The development of various imaging systems for optical biopsy may help us to understand carcinogenesis without the necessity to biopsy and thus, affect the natural history of disease [20].

Early diagnosis is aimed to find cancer at the earliest stage before patients become symptomatic. Hence, treatment of patients with occult cancer should not cause too much morbidity deteriorating quality of life. Many patients with early stage cancer can greatly benefit from less invasive and morbid treatment approaches, which offer a better quality of life. Less invasive diagnostic and therapeutic methods are indispensable elements for success in a lung cancer’ screening program and increase the value of early detection.