Hong Kong Respiratory Medicine

Dr. James Chung-man Ho, Prof. Wah-kit Lam
Department of Medicine, The University of Hong Kong
Burden of lung cancer in Hong Kong
Lung cancer has been the top cancer killer in Hong Kong over the past decade. From the Hong Kong Cancer Registry, lung cancer was the commonest cancer type in men (2,793 cases) and third commonest in women (1,443 cases) in 2008. Alarmingly, lung cancer accounted for the most common cancer mortality in both men (2,302 deaths) and women (1,195 deaths). The male to female ratio has remained 2:1, with median age at around 70 years old. Based on a local study conducted by the Hong Kong Thoracic Society, respiratory tract cancers ranked second highest as a cause of respiratory mortality (33.2%), and third highest for respiratory hospitalization (5.7%) and inpatient bed-days (9.2%) in 2005. 1 There was a modest reduction of age standardized mortality between 1997 and 2005 in both genders.

Histological cell type and cancer genetics
Traditionally, lung cancer is categorized pathologically into non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC), with distinct cancer biology and treatment algorithms. Microscopically, NSCLC is comprised of adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Notably, there has been a recent updated pathological classification of lung adenocarcinoma, with the removal of the category “bronchioloalveolar carcinoma”. 2 Similar to the worldwide trend, there has been growing proportion of NSCLC among all lung cancers, in particular, adenocarcinoma in Hong Kong. This could be partly explained in light of decreasing smoking prevalence, change in the composition of cigarettes, and evolution of diagnostic workup. Also, non-smoking related adenocarcinoma is becoming more evident clinically. In the past, treatment of lung cancer is largely driven by the distinction between NSCLC and SCLC, and clinical staging. With the advances in cancer therapeutics, accurate pathological categorization into exact cell types of NSCLC is becoming crucial in treatment decision. Furthermore, the knowledge of important driver mutations in adenocarcinoma, namely epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has revolutionized the treatment paradigm for NSCLC.3

Staging
The new international TNM staging system (7th edition) for lung cancer has been adopted in 2009. This revised staging was largely based on the survival data of more than 100,000 lung cancer patients in a study conducted under the initiative of the IASLC since 1998.4 With the newly defined TNM descriptors, the revised overall staging can provide better prognostic stratification. The following are some of the more clinically important highlights: (1) Primary tumour size (T): apart from the different cut-offs by size, tumours larger than 7 cm is now described as T3 rather than T2; (2) Satellite nodules in the same lobe: separate lung nodules within the same lobe as the primary tumour was previously described as T4. Under the new staging system, such satellite nodules will be defined as T3; (3) Malignant pleural or pericardial effusion: the so-called “wet IIIB” in the old staging describes malignant involvement of pleural or pericardial effusion, which is now defined as M1a; (4) Metastatic lung nodules beyond the same lobe as the primary tumour (M): such metastatic lung nodules ipsilateral to the primary tumour will be described as T4, while those contralateral lung nodules as M1a. Historically, the clinical staging of SCLC follows the Veterans staging system to distinguish between limited-stage versus extensive-stage disease. There are now more advocates for applying the new TNM staging system also to SCLC.
New advances in diagnostic techniques, notably endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), pleuroscopy and 18-FDG PET-CT scan, have contributed significantly to the accurate clinical staging of lung cancer.

Treatment algorithm (SCLC)
Curative surgical lung resection is seldom possible for SCLC, however, it should still be performed in rare cases of early resectable disease after thorough clinical staging. In patients with good performance status, upfront concurrent chemo-radiotherapy is the standard-of-care for limited-stage disease (LD). 5 The most effective chemotherapy regimen is still cisplatin and etoposide (PE). For patients with extensive-stage disease (ED), combination systemic chemotherapy (PE) is often administered, unless in those with extremely poor performance status. The potential survival benefit of prophylactic cranial irradiation (PCI) in both LD and ED has been well proven in those with complete or very good partial remission of extracranial disease. 6, 7

Treatment algorithm (NSCLC)
The overall treatment plan for NSCLC is still largely dependent on clinical staging. 8 Curative surgical lung resection (preferably lobectomy or pneumonectomy, rather than segmentectomy or wedge resection) is still the gold standard treatment for early resectable stage (I, II, selected IIIA) of disease in those with good surgical risks. In those with poor surgical risks due to co-morbidities (mainly cardio-respiratory), modern conformal thoracic radiotherapy with curative intent is often advised. The role of post-operative adjuvant cisplatin-based chemotherapy has been well-established with recent large-scale randomized controlled trials and meta-analysis, confirming an overall 5-year survival benefit of around 5% among those with stage II or IIIA resectable disease.9 For locally or regionally advanced disease (stage IIIA/B), combination chemotherapy (e.g. etoposide/cisplatin or paclitaxel/carboplatin) and radiotherapy is recommended, with concurrent chemo-radiotherapy preferred for those medically fit. In highly selected cases of stage IIIA disease, upon review by a multidisciplinary team, a neo-adjuvant approach with induction chemotherapy or chemo-radiotherapy prior to surgical resection can be considered. However, there is still controversy on the role of surgery on top of induction chemo-radiotherapy, especially those with curative intent.

For advanced or metastatic disease of NSCLC, the overall aim of treatment is palliative intent. Though not aiming at cure, the newer generation platinum-based chemotherapy and targeted therapy have been proven to achieve disease and symptom control, improve quality of life and prolong survival. The standard first-line systemic chemotherapy is a combination of platinum and one of the newer generation chemotherapy agents (e.g. paclitaxel, docetaxel, gemcitabine, pemetrexed), with a median survival of around 9-10 months. The choice of chemotherapy regimen is now driven by the histological cell type, with pemetrexed-based platinum doublet having superior efficacy and safety profile in adenocarcinoma of lung. 10 In order to enhance the clinical efficacy of systemic chemotherapy, anti-angiogenic therapy (bevacizumab, which is a monoclonal antibody against vascular-endothelial growth factor) has been added to standard first-line platinum doublet in selected population with advanced adenocarcinoma of lung. 11 In recent years, much has been known about the significance of EGFR mutations in driving lung carcinogenesis. It is now becoming the standard to know of the EGFR mutation status in order to decide on the most appropriate first-line systemic treatment. Among those with EGFR activating mutations (commonly exon 19 deletion or L858R mutation at exon 21), targeted therapy with EGFR tyrosine kinase inhibitors (TKI) (e.g. gefitinib or erlotinib) have been shown to be superior to standard platinum-based doublet chemotherapy, with median survival more than one year. 12, 13 The common toxicities of EGFR TKI include skin rash (acneiform rash) and diarrhea, while a relatively rare complication (< 1%) of pulmonary toxicity (interstitial lung disease) should be noted.

Conclusions
Over the past decade, there have been major advances in the molecular cancer biology, clinical staging techniques and treatment modalities for lung cancer. Especially for NSCLC, we are beginning to move into the era of molecularly-targeted treatment approach with personalized therapy.

References
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