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Published on 15 April 2011

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Non-small cell lung cancer: Diagnosis and management

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Steve Williamson, MRPharmS (IPresc), MSc, FCPP
Consultant Pharmacist in Cancer Services
Northumbria Healthcare and North of England Cancer Network

Lung cancer is the fourth most common cancer in Europe and causes the most cancer deaths. In 2008 there were 288,118 new cases of lung cancer and 252,495 deaths from lung cancer in Europe.1

Highest mortalities are reported in eastern and northern Europe, with the Mediterranean countries having the lowest incidence and mortality. Lung cancer is rare under the age of 40 years and 85% of cases occur in those over the age of 60 years.2 The death rate from lung cancer remains close to the incidence rate, with very poor one-year and fiveyear survival rates.

Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases. NSCLC includes squamous cell carcinoma (48%), adenocarcinoma (38%) and large cell carcinoma (10-15%). Until recently the different NSCLC pathological types were considered to have a homogeneous clinical behaviour and were treated in the same way, but trials with pemetrexed highlighted differences in preferred choice of treatment depending on histology.3

Smoking is the most significant risk factor for lung cancer; not all smokers get lung cancer but the majority of patients with lung cancer have smoked. It is estimated that 86% of lung cancers in the UK result from smoking.4 Other risk factors include exposure to naturally occurring radon gas, industrial carcinogens including arsenic and some hydrocarbons, and asbestos.

Presentation and diagnosis
Early diagnosis of lung cancer is critical. Patients with symptoms suggestive of lung cancer should be examined by a member of a specialist lung cancer multidisciplinary team as soon as possible. Diagnosis is via imaging; chest X-ray and/or computed tomography (CT) scan of the chest and upper abdomen. A tissue biopsy will be taken, usually via a bronchoscopy (for central lesions), or guided needle biopsy for peripheral lesions. Positron emission tomography (PET) scanning (18F-deoxyglucose PET) is required for patients who are staged as candidates for surgery or for radical radiotherapy to rule out involved intrathoracic lymph nodes and distant metastases. Staging for NSCLC is based on the tumour, node, metastases (TMN) system.

Table 1 summarises the main stages of the disease.5

Treatment options
Surgery
The best chance of curing stage I and II disease is by surgery. Surgery involves resection of the tumour by lobectomy, bi-lobectomy or pneumonectomy. The surgery is challenging and has a 5% post-operative mortality rate. Patients can experience significant post-surgical complications including haemorrhage, respiratory failure, infection and arrhythmias.

There is an increasing role for adjuvant chemotherapy given after surgery to improve overall survival. A combination regimen with cisplatin and vinorelbine, is used most commonly. In clinical trials, this combination increased median survival to 65.7 months compared with 43.7 months in patients having no adjuvant chemotherapy (an 8.6% improval in overall survival at five years).6

Radiotherapy
Radical radiotherapy is the choice for early stage NSCLC patients who are not suitable for surgery. The way in which radiotherapy is administered can be significant; traditionally the total radiotherapy dose is calculated and the dose divided into smaller portions (fractions). The fractions are then given daily over three to four weeks. Research has focused on delivering the fractions more quickly in a schedule known as CHART (continuous, hyperfractionated, accelerated radiotherapy), with smaller doses of radiation given three times a day over 12 consecutive days. CHART has a small but significant survival advantage over traditional radiotherapy but has proved difficult to adopt in some European countries owing to constraints on services such as the availability of linear accelerators and the staff to operate them.

Chemotherapy
Platinum-based combinations have been the standard of care for firstline treatment of advanced NSCLC. In the UK, the National Institute for Health and Clinical Excellence (NICE) recommends a combination of a single third-generation drug plus a platinum compound (carboplatin or cisplatin) as first-line therapy chemotherapy for advanced NSCLC. The choice of the combination will vary according to clinician/centre preference. Table 2 details the different regimens used. The regimens are usually given for four cycles, unless there is evidence that the patient has progressive disease, in which case they are discontinued. Although effective palliation, survival benefit is modest; these drugs offer a 30-40% response rate and median survival of about 10 months.7

On progression, the patient is assessed for suitability for second-line chemotherapy, with docetaxel (Taxotere) or pemetrexed (Alimta) as single agents. The TAX317 trial of docetaxel versus Best Supportive Care (BSC) showed a clear survival benefit at a dose of 75mg/m2 and a 40% one-year survival rate for docetaxel versus 16% with BSC.13 However, a large proportion of patients experienced moderate to severe neutropenia with docetaxel. The antimetabolite cytotoxic agent, pemetrexed, had similar efficacy to that of second-line docetaxel.14 Pemetrexed has a slightly more favourable toxicity profile than docetaxel, but is more expensive. A large trial of a first-line combination of pemetrexed plus cisplatin offered a significantly longer survival than gemcitabine plus cisplatin (median of 12.6 months compared with 10.9 months) in patients with adenocarcinoma.15 This was the first time a difference in response to NSCLC chemotherapy depending on the disease histology had been shown and led to a change in the license of pemetrexed to reflect the increased activity in the non-squamous population. Pemetrexed is administered at a dose of 500mg/m2 every three weeks.

Targeted therapies
Erlotinib (Tarceva®)
Erlotinib was the first targeted therapy to have a significant impact in NSCLC. It is not a traditional cytotoxic agent, but a small molecule inhibitor of the epidermal growth factor receptor (EGFR). EGFR is part of the control mechanism of cell growth that is fundamentally disturbed in cancer. When EGFR is stimulated, a chemical message is generated that reaches the nucleus through a number of biochemical pathways. The common first step in these pathways is activation of a receptor-linked tyrosine kinase (TK). EGFR overproduction is common in NSCLC, i.e. lung cancer cells have too much EGFR and therefore have increased signals to stimulate growth and proliferation. Over-production of EGFR is associated with aggressive tumour cell biology, chemotherapy resistance and reduced survival.

Second- or third-line erlotinib in the BR21 study16 had a comparable survival benefit to docetaxel in the TAX317 study,8 but without the neutropenia and myelotoxicity associated with chemotherapy. Erlotinib was administered as a 150-mg, once-daily dose given until disease progression. The BR21 study showed that erlotinib increased the median overall survival from 4.7 months in the placebo arm to 6.7 months in the erlotinib arm. The percentage of patients surviving at 12 months was 31% and 22%, respectively. On reflection, this two-month increase in survival is modest, but there are many anecdotal examples of a small number of patients having a significant and prolonged response. The advantage of a targeted therapy in these cases is that, unlike traditional chemotherapy and its cumulative bone marrow toxicity, some patients can continue to take erlotinib for a long period of time. That is not to say that erlotinib does not have significant toxicities; the EGFR inhibitor toxicity profiles differ from those of traditional chemotherapy, with patients being prone to diarrhoea and severe skin reactions.

Early results from a trial targeting erlotinib to patients with EGFR mutations showed some promise; the OPTIMAL study compared firstline erlotinib with gemcitabine and carboplatin chemotherapy. Early results showed a response rate of about 84% with erlotinib and a response rate of about 37% with chemotherapy. The progression-free survival (PFS) for erlotinib was 13.1 months versus 4.6 months for chemotherapy17 but full trial results are needed to confirm these preliminary findings.

Gefitinib (Iressa®)
Gefitinib is another EGFR inhibitor that has been under investigation for some time; early trial results were not promising and slowed the development of the drug. More recently, when used in trials that specifically identified patients with EGFR-TK mutations, the benefit of gefitinib became clear. The Iressa Pan Asian Study (IPASS)18 trial investigated patients with adenocarcinoma histology who had never smoked or were very light smokers. The trial showed in the subgroup of EGFR-TK mutation-positive patients (n = 261), the main outcome – median PFS – was 9.5 months with gefitinib compared with 6.3 months for paclitaxel/carboplatin chemotherapy. The objective tumour response rate was higher for gefitinib (71.2% versus 47.3%). There was no statistically significant difference in the estimates of overall survival for patients. Gefitinib was shown to be inferior in patients without the EGFR-TK mutation. There has been some debate over the validity of using the IPASS trial to guide treatment of a Western population because the evidence for clinical effectiveness was derived mainly from a trial of gefitinib in East- Asian women who were non-smokers and had tumours with adenocarcinoma histology. However it is likely that that the efficacy of gefitinib depends on the EGFR-TK mutation status of the patient, and that EGFR-TK mutation-positive patients are likely to respond to gefitinib irrespective of their gender, ethnicity, smoking status or the histological subtype of their tumour.

Bevacizumab (Avastin®)
Another targeted therapy is bevacizumab (Avastin), which is licensed as an addition to platinum-based chemotherapy for the first-line treatment of patients with locally advanced metastatic or recurrent non-squamous NSCLC. Data from two large studies – ECOG 459919 and AVAiL20 – showed a small survival advantage when bevacizumab was added to standard combination chemotherapy. The ECOG study showed a median overall survival of 12.3 months in patients taking bevacizumab plus paclitaxel and carboplatin compared with 10.3 months for chemotherapy alone. However the AVAiL study using the gemcitabine and cisplatin regimen showed was no overall survival benefit for bevacizumab, despite improvements in PFS. These mixed trial results coupled with concerns over pulmonary haemorrhage caused by bevacizumab and the high drug acquisition cost can prove a barrier to its use.

Maintenance therapy
Erlotinib has expanded its role into maintenance after first-line chemotherapy for NSCLC. In the SATURN trial,21 erlotinib was given to patients with locally advanced or metastatic NSCLC who did not progress immediately after four cycles of platinum-based doublet chemotherapy. Erlotinib demonstrated improved PFS and median overall survival (OS). The mean PFS was 22.4 weeks in the erlotinib group compared with 16.0 weeks in the placebo comparator arm. Quality of life data from the trial did not suggest a detrimental effect from erlotinib compared with placebo, although it could be argued that patients need to be relatively fit and have good performance status before considering maintenance therapy. Pemetrexed also has benefit as maintenance therapy for patients with non-squamous histology. The OS rate for patients with NSCLC receiving maintenance pemetrexed was 15.5 months compared with 10.3 months for patients receiving placebo.22 Adverse events with pemetrexed included fatigue, nausea, loss of appetite, tingling or numbness in the hands and feet, and skin rash.

The future
There are many new agents in development. At the European Society of Medical Oncology (ESMO) conference in October 2010, the first evidence of use of the next generation of TK inhibitors was presented. Afatinib irreversibly inhibits EGFR and is active against EGFR mutations not sensitive to standard erlotinib or gefitinib. The placebo controlled LUX-Lung 1 trial23 tried to establish the role of afatinib in the patients who had failed to respond to a first-line TK. The study reported a 7% response rate in the treatment arm and a PFS benefit of 3.3 months versus 1.1 months. However, there was no difference in overall survival, which may have resulted from placebo patients in the trial crossing over to active treatment. More data are needed to establish the role of this new drug.

Conclusion
Lung cancer has very poor survival rates and remains the cancer that has the worst patient outcome. However progress is being made with newer targeted agents, which are continuing to make modest improvements in the average survival of patients.

References
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4. Cancer Research UK. 2008b. Lung cancer – risk factors. http://info.cancerresearchuk.org/ cancerstats/types/lung/riskfactors/ (accessed 03/03/11)
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17. Zhou C. Program and abstracts of the 35th European Society of Medical Oncology Congress, October 8-12, 2010; Milan, Italy: Abstract LBA13
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