Non-small cell lung cancer - Clinical review

How to diagnose and manage this type of lung cancer plus the latest evidence on the role of smoking. By Dr Nadia Yousaf and Dr Sanjay Popat

Coloured x-ray: Bronchalveolar cancer is a subtype adenocarcinoma
Coloured x-ray: Bronchalveolar cancer is a subtype adenocarcinoma

Section 1: Epidemiology and aetiology

Lung cancer survival in the UK is among the lowest in the developed world1 and five-year survival has improved only marginally since the 1970s.

There is significant regional variation in incidence, with higher rates in Scotland compared with England, Wales and Northern Ireland.

Incidence in men in the UK has been falling since the 1970s, but in women, it has risen more than 70%.

Risk factors
A diagnosis of lung cancer is uncommon under the age of 40, with a median age at presentation of approximately 70 years.

Although the risk of lung cancer is directly related to the duration and number of cigarettes smoked, only a minority of smokers develop it.

A susceptibility focus on chromosome 6q23-25 has been identified, which confers a slightly higher risk for lung cancer and is linked to increasing tobacco use, although its clinical significance is uncertain.2

Up to 25% of cases worldwide are patients who have never smoked.3

Although meta-analyses have identified other environmental factors associated with increased risk, including passive smoking,4 radon exposure,5 cooking oil vapours and indoor coal and wood burning, the absolute cause for many individual patients is unknown.

Classification
Traditionally, lung cancer has been classified on the basis of histological appearance as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for about 85% of cases and encompasses differing histological subtypes, with squamous cell carcinoma (SCC) and adenocarcinoma accounting for up to 90% of cases.

Advances in molecular analysis have enabled a number of tumoral (somatic) genetic mutations to be identified. These are mutations in genes that encode for components of cell proliferation and survival signalling pathways. Their identification has significantly altered the treatment paradigm and prognosis in advanced lung cancer.

It has become evident that NSCLC is an umbrella term for a heterogeneous group of patients with significant variations in disease characteristics, particularly between smokers and non-smokers.

Section 2: Making the diagnosis

It has been hypothesised that screening high-risk patients might aid early diagnosis and help to reduce mortality. However, early trials did not show a mortality benefit from chest X-ray based screening.6,7

Low-dose CT-based screening has been proven to improve mortality in high-risk smokers by aiding early detection, but at the cost of a high number of false positives.8

Symptoms can be non-specific, especially in patients with comorbidities such as COPD. Recurrent chest infections in a smoker must be taken seriously and prompt a chest X-ray, because this is the most common presenting finding.

The development of a new cough or change in character of an existing cough is also common, as is weight loss. Chest/shoulder pain can also occur and is often a feature of local invasion. New-onset or progressive dyspnoea can be due to extrinsic or intrinsic airway obstruction, lymphangitis, pulmonary emboli or pleural/pericardial effusions.

Disease involving the recurrent laryngeal nerve may present with dysphonia. Fever may be due to obstructive pneumonia or less frequently, advanced disease.

A plain chest X-ray has a specificity of only 78% in detecting NSCLC so is not sufficient to exclude a diagnosis of cancer.13 When faced with a normal chest X-ray, all patients with suspected lung cancer should undergo a contrast enhanced CT scan.

Staging
Clinical staging is based on a contrast enhanced CT scan of the chest and abdomen (to include imaging of the liver and adrenal glands).

If disease appears localised and potentially treatable on CT, an FDG-PET scan should be used to exclude occult metastatic disease.

Surgical staging with mediastinoscopy or endobronchial ultrasound may also be required to confirm nodal involvement.

Results of these investigations allow patients to be staged according to the TNM system.

Brain imaging

The incidence of brain metastasis in patients with lung adenocarcinomas has been reported as almost 44% in autopsy studies.14 Brain imaging with contrast enhanced CT or MRI is recommended in patients due to undergo radical treatment.

Biopsy

A biopsy is essential for histological classification. Bronchoscopy can be used to biopsy endobronchial lesions or lymph nodes. Peripheral lesions are usually biopsied by transthoracic CT guidance.

Section 3: Managing the condition

Formal objective measurement of the airways, with full lung function tests and optimisation of lung function by treating any underlying obstructive lung disease, is required before embarking on any radical treatment plan.

Stage 1 or 2 disease
Lobectomy with systemic lymph node dissection and pleural lavage is considered the standard of care in early stage (1 or 2) disease.

Adjuvant chemotherapy with cisplatin and vinorelbine (or carboplatin/gemcitabine/paclitaxel) has been shown to improve overall survival in all patients with node-positive disease and may also be recommended in those with node-negative disease if the tumour is >4cm in size.15

If cisplatin is contraindicated, carboplatin is usually substituted.

In patients who are inoperable due to comorbidities, stereotactic radiotherapy using ablative doses is the standard of care, when technically feasible. Alternatively, high-dose conventional radiotherapy in combination with chemotherapy can be considered, but is rarely curative.16

Stage 3/stage 4 disease
The management of stage 3 disease is more difficult because this encompasses a diverse group of patients, from those with a large tumour without nodal involvement to those with contralateral nodal metastasis (N3).

Five-year survival rates vary from 24% to 9%.

Chemotherapy and radical radiotherapy are modalities of choice for these patients, delivered either concomitantly or sequentially, if the disease distribution can be encompassed in a radiotherapy treatment field and comorbidities allow. However, there may be a role for trimodality therapy, including surgery in selected cases (usually stage 3A).

Postoperative radiotherapy may reduce local relapse rate in patients who have a positive margin or incidental mediastinal lymph nodes (N2) discovered at surgery.17

If left untreated, patients with stage 3 disease unsuitable for radical treatment or with stage 4 disease have a poor prognosis, with a median survival of four to six months.

Treatment is contingent on histological subtype of NSCLC and the patient's epidermal growth factor receptor (EGFR) mutational status.

In patients without EGFR mutation, palliative chemotherapy with cisplatin and pemetrexed (primarily for adenocarcinomas)18 and vinorelbine/gemcitabine/paclitaxel/docetaxel (for SCC) is the standard of care.

At relapse, second-line treatment with docetaxel19 or erlotinib20 improves symptoms and survival when compared to best supportive care.

New developments
Molecular characterisation of tumours has shown that about 60% of adenocarcinomas have somatic mutations that can be inhibited with specific molecular targeted therapy.

Some of these are the current standard of care and many are in development within clinical trials. About 15% of patients, usually never-smokers with an adenocarcinoma, have a somatic mutation in EGFR.

These patients benefit from initial therapy with oral erlotinib or gefitinib, over cytotoxic chemotherapy, with response rates of more than 70% and significant improvements in progression-free survival.21

Somatic ALK gene fusions are a rare aberration, usually in young never-smokers with adenocarcinoma, and impressive responses have been reported with oral crizotinib, which resulted in fast-track approval of this drug in the US and Europe.22

Despite the targeted nature of these drugs, side-effects commonly occur, but are usually manageable with drug interventions or dose reductions (see table above) and generally less problematic than those with chemotherapy. Care must be taken when prescribing concomitant oral medication for many tyrosine kinase inhibitors because PPIs and drugs affecting the cytochrome P50 CYP3A4 may affect drug metabolism.

Section 4: Prognosis

Although the prognosis in patients with lung cancer remains poor, a number of recent advances have improved the prognosis in subsets of patients with NSCLC.

The use of EGFR tyrosine kinase inhibitors and crizotinib in patients with sensitising molecular abnormalities has markedly improved overall survival, from a median of nine months for most patients with stage 4 NSCLC to 24 months in EGFR mutant NSCLC treated with EGFR tyrosine kinase inhibitors.

A number of other mutations have now been identified and clinical trials of other targeted agents are under way.

Follow-up

Most of the guidelines recommend regular follow-up with imaging for these patients.

The aim is to detect recurrence or any second primary at an early stage, so that an intervention can be initiated, although the surveillance frequency and imaging modalities are not mandated.

 

Section 5: Case study

A 34-year-old male non-smoker presented in September 2011 with a five-month history of right subcostal pain, exertional dysponea, intermittent cough and poor appetite.

He was initially investigated with an ultrasound scan of the gall bladder. He then had a CT scan, which demonstrated a large lung mass with mediastinal lymphadenopathy and liver metastases.

The patient underwent a bronchoscopic biopsy, which demonstrated an adenocarcinoma. Molecular testing did not show an EGFR mutation, but there was insufficient tissue for further molecular analysis.

The patient started standard palliative chemotherapy with cisplatin and pemetrexed and completed six cycles of treatment in February 2012 with a partial response, but with typical chemotherapy side-effects.

Following this, a biopsy was arranged for further molecular analysis and an ALK fusion was confirmed.

Two months later, CT demonstrated relapse. However, because of the ALK fusion, the patient started crizotinib in April 2012, resulting in a rapid improvement.

Within two months, CT demonstrated an excellent partial response. The only major side-effect was decreased libido owing to hypogonadism, a common side-effect of crizotinib and easily reversed with testosterone therapy. His response has been durable and he continues to enjoy excellent quality of life.

Section 6: Evidence base

Clinical trials

  • Butts CA, Ding K, Seymour L et al. J Clin Onc 2010; 28(1): 29-34.
  • Rosell R, Carcereny E, Gervais R et al. Lancet Oncol 2012; 13(3): 239.
  • Kwak EL, Bang YJ, Camidge DR et al. N Engl J Med 2010; 363: 1693-703.

Guidelines

Online

 

  • Contributed by Dr Nadia Yousaf, specialist registrar in medical oncology, and Dr Sanjay Popat, consultant medical oncologist, The Royal Marsden Hospital, London.

 

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Review diagnosis of lung cancer in the past year and assess if early diagnosis could have been made by prompt X-ray.
  • Agree a practice protocol for referral to X-ray with cough.
  • Devise a health promotion poster for early presentation with cough.

Click here to take a test on this article and claim a certificate on MIMS Learning

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15. Butts CA, Ding K, Seymour L et al. J Clin Oncol 2010; 28: 29-34.

16. O'Rourke N, Roque IFM, Farre Bernado N et al. Cochrane Database Syst Rev 2010: CD002140.

17. Douillard JY, Rosell R, De Lena M et al. Int J Radiation Oncol, Biol, Physics 2008; 72: 695-701.

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