Australian Doctor 16th June 2023 16JUNE2023 issue | Page 23

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About 25 % of all global lung cancers occur in never-smokers , with approximately 60-80 % of females diagnosed with NSCLC having never smoked . 1 Risk factors associated with lung cancer in people who have never smoked include exposure to passive smoke , cooking fumes , ionising radiation and radon gas , as well as inherited genetic susceptibility , occupational exposures and pre-existing lung disease . 1

While incidence rates have declined in men over the past few decades , lung cancer rates in women have increased ( see figure 4 ). 15 This may , in part , be due to the narrowing / converging of smoking rates for men and women , but other factors may also be involved .

PATHOPHYSIOLOGY AND PATHOGENESIS

LUNG cancer arises from the cells in the respiratory epithelium . The pathophysiology is complex and believed to be a combination of environmental exposures and an individual ’ s genetic susceptibility . 19

Histopathological classification is based on cellular and molecular subtypes and forms an important part of diagnosing and managing lung cancers .

Historically , lung cancer has been divided into two main histopathological groups : SCLC and NSCLC .

SCLC is a neuroendocrine carcinoma and accounts for up to 15 % of all lung cancers . 7 , 20 SCLC is characterised by rapid doubling time and early development of widespread metastatic disease , including to mediastinal lymph nodes , liver , bones , adrenals and brain . 20 About one-third of patients present with SCLC localised to the chest . 20 SCLC is frequently associated with a wide range of paraneoplastic syndromes , the most common is the syndrome of inappropriate secretion of antidiuretic hormone ( SIADH ) and ectopic adrenocorticotropic hormone ( ACTH ) production . 20

About 85 % of all lung cancers are NSCLCs , which are then further subdivided into three major subtypes : adenocarcinoma , squamous cell carcinoma ( SCC ), and large cell carcinoma , plus others not discussed in this article ( see figure 5 ). 1

Adenocarcinoma is the most common form of NSCLC ( see figure 5 ). It is the most common subtype in females , younger people and those who do not smoke . 1 , 21 Large cell carcinoma typically appears as a large peripheral mass , whereas SCC is usually found in the central parts of the lung .

Bronchioloalveolar carcinoma ( BAC ), a variant of NSCLC , was previously a distinct histological classification but has now been replaced with adenocarcinoma in situ , minimally invasive adenocarcinoma and invasive adenocarcinoma of the lung .

Other less common histologic subtypes include adenosquamous carcinoma , pleomorphic sarcomatoid carcinoma , large-cell neuroendocrine carcinoma , and carcinoid tumour . 1

Advances in genomic profiling has allowed lung cancers to be further

characterised and classified according to underlying genetic alterations and driver mutations that play a role in tumour growth and survival ( see table 2 ). There are now various targeted agents available and in development for use in patients with an oncogene driver , depending on the clinical setting . Once identified , these can then be exploited with specific targeted and other immunotherapy treatments . 1

The genetic and epigenetic pathways involved in the formation of lung cancer differ between smokers and never-smokers . Molecular epidemiology studies show different mutation patterns and frequencies between lung cancers in the two groups . There are also major clinical differences and responses to targeted therapies , suggesting lung cancer arising in never-smokers is a disease distinct from the more common tobacco-related forms . 21

DIAGNOSIS AND INVESTIGATIONS

EARLY detection and diagnosis of lung cancer improves the chances of survival . Patients can follow various routes to diagnosis , but primary care plays an integral part for many . 11 A 2019 cohort study of 894 patients reported 60 % had four or more GP attendances in the three months before diagnosis of NSCLC , 56 % had GP-ordered imaging ( chest X-ray or CT scan ), 39 % attended a respiratory physician and 11 % attended a cardiothoracic surgeon . 21A Lung cancer can present with a wide range of non-specific symptoms ( see box 3 ), making it difficult to recognise , particularly if there is coexisting respiratory disease . However , it is important to be alert to the possibility of lung cancer in patients with these types of symptoms , especially when they are persistent and occur in highrisk groups . 19

Early lung cancer can be largely asymptomatic , and patients may not be aware of obvious physical changes . Once symptoms do appear , they may be attributed to other aetiologies , leading patients to not seek further advice . 19 More than 60 % of patients with lung cancer have either Stage III or IV disease when diagnosed ( see figure 2 ).

Cancer Australia has developed a guide for GPs and other health professionals to assist in investigating symptomatic people with suspected lung cancer ( see box 4 and figure 6 ). This general guide helps support early and rapid referral into the diagnostic pathway and provides a flowchart for symptoms and signs of lung cancer , recommended investigations and referrals as well as timeframes for referral . 11 When lung cancer is suspected , order the initial investigations listed in box 4 . 11 , 19 Note that standard additional staging procedures usually undertaken by the lung multidisciplinary team include 18F-FDG PET scan and brain imaging ( preferably MRI or CT ).

A complete diagnostic and staging workup to evaluate the extent of disease is required ( see box 5 ), as this plays a major role in determining the choice of treatment . Molecular testing

20

and biomarker testing can inform the most appropriate treatment for NSCLC . 19

SURVIVAL AND SCREENING FOR LUNG CANCER

THE survival rate for lung cancer is poor compared with most other cancers , and diagnosis in Australians usually occurs once disease has metastasised . Late diagnosis is very important , given the significant decline in five-year survival rates from 68 % for Stage I at diagnosis down to 3 % for Stage IV at diagnosis ( see figure 2 ). 8 , 23

There is mounting recognition from ongoing national and international research of the effectiveness of targeted lung cancer screening . Without screening , most cases of lung cancer are likely to continue to be diagnosed at a late stage where treatment options are limited .

The Federal Government is considering advice on a national lung cancer screening program from the Medical Services Advisory Committee ( MSAC ) alongside Cancer Australia ’ s lung cancer screening program feasibility project . 24 A summary of the proposed element for the national lung cancer screening program appears in box 6 .

MANAGEMENT

LUNG cancer treatment requires a multidisciplinary approach , with management goals based on disease stage and patient fitness , involving surgery , radiotherapy , systemic treatments ( including chemotherapy , targeted therapies and immunotherapy ), with the benefits of the treatment balanced

19 , 25 against its morbidity and risks .

Depending on the pathology and staging of the disease , the treatment intent will first need to be established and will be either curative therapy or

Year Figure 4 . Lung cancer age-standardised incidence rates in Australia 1982 to 2017 ( by sex , all ages ).

Main lung cancer histological categories

SCLC 15 %

NSCLC 85 %

Figure 5 . Histological classification of lung cancer ( LCC , large cell carcinoma ; SCC , squamous cell carcinoma ; SCLC , small cell lung cancer ; NSCLC , non-small cell lung cancer ).

therapy to improve quality of life and / or longevity . 19

Non-curative therapy used to be considered “ palliative ” intent therapy ; however , with many systemic therapies now substantially reducing symptom burden , prolonging disease-free and overall survival , the goal is to keep patients with lung cancer living well with their cancer .

It is important to emphasise quality of life but not to confuse palliative intent treatment with terminal care , an oft-confused distinction that sometimes affects patients ’ willingness to engage with palliative and supportive care services early in their disease trajectory .

Generally , Stage I-III NSCLC is considered curable with either surgery or radiotherapy +/ - systemic therapy , with advanced Stage III disease not suitable for curative approaches or Stage IIIB or IV disease considered palliative . In Australia in 2011 , only 40 % of lung cancers cases were Stage III or earlier . 26

Early-stage disease

Surgical lobectomy remains the preferred treatment for medically fit patients with operable early-stage NSCLC . 25 Recent developments include resection via minimally invasive surgery that has fewer complications and similar oncological outcomes compared with open thoracotomy .

25 , 27

Radical radiotherapy or stereotactic ablative radiotherapy ( SABR ) can provide alternatives to surgery . 24 , 25 Modern radiation techniques allow early-stage lung cancers to be treated with higher ablative doses . SABR is now the standard of care for early-stage localised lung cancers where there are comorbidities

21 , 27 or other reasons to avoid surgery .

Evidence for benefit has emerged with modern targeted drugs ( such as osimertinib ) in the adjuvant treatment

NSCLC subtypes

Adenocarcinoma 40 %

SCC 25 %

LCC 15 %

Others 20 %

Table 2 . Frequency of gene mutations and alterations seen in NSCLC

EGFR KRAS FGFR1 PTEN DDR2 ALK HER2 MET BRAF PIK3CA AKT1 MEK1 NRAS RET ROS1

10 – 35 % 15 – 25 % 20 % 4 – 8 % 4 % 3 – 7 % 2 – 4 % 2 – 4 % 1 – 3 % 1 – 3 % 1 % 1 % 1 % 1 % 1 %

Source : Schabath MB et al 2019 1

Box 3 . Common lung cancer symptoms

• Cough ( new or changed ).

• Haemoptysis .

• Chest and shoulder pain .

• Shortness of breath .

• Hoarseness .

• Weight loss .

• Anorexia .

• Persistent or recurrent chest infection .

• Fever .

• Weakness .

• Bone pain . Source : Cancer Australia 2020 11 , Cancer Council Victoria and Department of Health Victoria 2021 19

Adapted from Schabath & Cote 2019 1 of resected Stage IB-IIIA adenocarcinomas with sensitising epidermal growth factor receptor ( EGFR ) mutations to help improve disease-free survival ( DFS ) after surgery , with improved DFS also seen with immune checkpoint inhibitors following surgery in selected patients . 28-30 Immunotherapy is also