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Introduction: The Lung Cancer Burden
Lung cancer has been the most common cancer worldwide for the past few decades. It was also the most common cause of cancer deaths1. By 2008, lung cancer represented 12.7 per cent of all new cancers and 18.2 per cent of all cancer deaths. Overall, only 15.9 per cent of all Americans diagnosed with lung cancer survived more than 5 years2. In comparison, the 5 year relative survival of American colon and breast cancer patients during the same time period was 64.3 per cent and 89.0 per cent respectively.
In Singapore, lung cancer was the most common cancer among males for many years before it was overtaken by colorectal cancer a few years ago3. In females, lung cancer is the third most common cancer, after breast and colorectal cancer. In the 5 year period between 2006 and 2010, there were 6,119 new lung cancers diagnosed in Singapore residents, giving an average of 1,224 new cases a year. During the same 5 year period, there were 5,306 lung cancer deaths. This gives a survival rate of approximately 15 per cent, similar to the 15.9 per cent relative survival rates of lung cancer patients in the US. The number of lung cancer deaths was more than the combined number of deaths from breast and colorectal cancer.
The high number of lung cancer deaths is the result of the high incidence and the poor survival of lung cancer patients. The low cure rate of lung cancer is in turn due mainly to the fact that most patients are only diagnosed when the cancer is at an advanced stage. This is due to the lack of a good screening test for lung cancer, and the absence of symptoms in most early stage patients.
On the bright side, the incidence of male lung cancer in Singapore has declined since 1980's until today, reflecting the declining smoking prevalence in Singapore males. The female incidence however remained constant over the last 30 years. The number of males with lung cancer was two times that of females.
Screening for lung cancer
It has been well established that chest x-ray is not a good screening test for lung cancers. Several large randomised trials carried out in the 1960's and 70's were unable to demonstrate a reduction in lung cancer mortality with screening chest x-rays.
The lack of benefit with chest x-ray and the availability of CT scan led to the evaluation of low dose CT scan for lung cancer screening. In Nov 2010, the National Cancer Institute US announced the results of the National Lung Cancer Screening Trial (NLST), and published the results in Aug 20114. The NLST is a large randomised trial comparing annual low dose CT scan for 3 years with chest x-ray, and followed for a further 5 years. The screening population included 53,454 males and females age between 55 to 74 with a smoking history of at least 30 pack-years. These included current smokers as well as ex-smokers who had quit smoking within the previous 15 years.
The trial showed that low dose CT screening, when compared to chest x-ray, detected more lung cancers, identified a higher proportion of early stage I and II cancers, and reduced the relative lung cancer mortality by a statistically significant 20 per cent.
Screening for lung cancer (continued)
Although the NLST is considered a positive trial, screening with low dose CT has its limitations. The rate of positive screening tests was 24.2 per cent with low dose CT and 6.9 per cent with chest x-ray. Further evaluation of positive screening tests included mainly follow-up scans and biopsy. About 95 per cent of all positive screening tests in both groups were false positive. The number needed to screen with low-dose CT to prevent one lung cancer death was high at 320.
In the NLST, high risk individuals were screened with 3 annual CT scans and followed for 5 years. The optimum number of screening CT, the interval between scans and the duration of follow up is currently unclear. The definition of high risk individuals adopted in the NLST is not universally accepted. The high cost of CT screening, the cost of further evaluation for screen-positive individuals and radiation exposure are additional concerns.
Hence, it is difficult to recommend low dose CT screening for lung cancer on a population basis. However, it is reasonable to discuss and consider CT screening in motivated individuals with an increased risk of lung cancer who understand and accept the risk of false positive results and the possible need for further evaluation.
Post-surgery Adjuvant Chemotherapy
About 20-30 per cent of non-small cell lung cancers (NSCLC) are diagnosed at an early stage of the disease, i.e. stage I and II. Surgical resection (partial removal of one lung ) is the standard treatment. However, up to 50 per cent of patients who have undergone potentially curative resection develop recurrent disease and eventually succumb from advanced lung cancer. The most common sites of recurrence involve distant metastases, providing the rationale for adjuvant chemotherapy.
Early post-surgery adjuvant chemotherapy trials in the 1970's and 80's failed to improve the survival rates. The first positive adjuvant trial was presented in 20035, and since then several large randomized trials6,7,8 using modern cisplatin based chemotherapy confirmed the survival benefit of adjuvant chemotherapy. In the ANITA trial6, the overall survival benefit for all patients (stage IB to IIIA) at 7 years was 8.4 per cent. In the JBR10 trial7, adjuvant chemotherapy increased the 5 year overall survival of stage II patients from 44 per cent to 59 per cent.
At present, patients with post surgery stage II and III disease will be considered for adjuvant chemotherapy. Tumour node metastasis (TNM) factors that are classified under stage II or III disease include positive ipsilateral hilar and/or mediastinal nodes, large (>5cm) tumours or chest wall invasion. Four cycles of cisplatin and vinorelbine is considered standard. Other cisplatin-based doublets, including the combination of cisplatin and pemetrexed for adenocarcinoma, may be considered.
The benefit of adjuvant chemotherapy for stage IB patients is more modest. The toxicity of cisplatin-based chemotherapy for elderly patients and patients with multiple co-morbidities may be significant. In these patients, the risk benefit consideration of adjuvant treatment must be individualized.
Importance of Histology Subtypes in Non-Small Cell Lung Cancer (NSCLC)
Non-small cell lung cancer (NSCLC) includes the common subtypes of adenocarcinoma, squamous cell carcinoma and the large cell carcinoma.
Until a few years ago, the different subtypes of NSCLC were considered to have similar natural history and survival, and were treated with similar chemotherapy agents. Because of the above, there was very little incentive to subtype NSCLC. NSCLC NOS (Not Otherwise Specified) was a common histological diagnosis.
In a large randomized study9 published in 2002, 1,155 patients with advanced NSCLC were treated with four different chemotherapy doublets. All four chemotherapy regimens, considered state of the art treatments at that time, resulted in similar survival rates. The median survival was 7.9 months, 1 year survival was 33 per cent and the 2 year survival was 11 per cent (Figure 1).
In a more recent randomized trial10, gemcitabine (and cisplatin) was compared to a relatively new cytotoxic agent pemetrexed (and cisplatin) in 1,725 previously untreated advanced NSCLC. In this trial, the median survival was 10.3 months for both arms. However, when analysed according to histological subset, patients with adenocarcinoma and large cell histology had superior survival in the pemetrexed arm. In contrast, patients with squamous cell carcinoma had better survival in the gemcitabine arm. This was the first trial, published in 2008, to show that histology matters in the choice of cytotoxic agent in the treatment of NSCLC.
Histology is also important with the availability of newer targeted agents, including oral tyrosine kinase inhibitors against epidermal growth factors receptors (EGFR) which are more effective for patients with adenocarcinoma due to the higher prevalence of EGFR mutation (see below). Treatment with the anti-angiogenesis agent bevacizumab is contraindicated in patients with squamous cell histology because of the higher rate of fatal haemoptysis (coughing up of blood).
Because of the availability of these newer agents which are histology and/or mutation specific, the diagnosis of NSCLC NOS is no longer adequate. At present, further immunohistochemistry tests are indicated if the histological subtype is not obvious. Tumour mutation testing should be considered standard in patients with adenocarcinoma. These additional tests require the biopsy specimen to be large enough to provide adequate amount of tissues.
This has changed the way biopsy tissues are obtained. Radiology guided core needle biopsy is preferred over fine needle aspiration accepting a higher risk of a pneumothorax. Excision biopsy of a neck node is preferred over fine needle aspiration of the node.
Anti-angiogenesis Treatment in Advanced NSCLC
Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that binds the vascular endothelial growth factors (VEGF), preventing its binding the VEGF receptor. Bevacizumab is the main anti-angiogenic agent used in the routine treatment of various cancers, including ovarian, colorectal, primary central nervous system tumour, renal cell carcinoma and lung cancers.
The benefit of bevacizumab in lung cancer was established in a randomized trial11 published in in 2006, where 878 treatment naïve advanced NSCLC patients were treated with paclitaxel and carboplatin alone, or the same chemotherapy combined with bevacizumab. Patients with squamous cell histology were excluded, due to the high risk of fatal haemoptysis associated with the squamous cell histology observed in earlier trials.
In this trial, the addition of bevacizumab increased the response rate from 15 per cent to 35 per cent and the median survival from 10.3 months to 12.3 months. Common side effects associated with the use of bevacizumab include hypertension, thromboembolic events, bleeding tendencies and proteinuria. Potentially severe toxicities include gastrointestinal haemorrhage and perforation, and CNS bleeding.
Bevacizumab, combined with chemotherapy is currently indicated in the first line treatment of advanced non-squamous NSCLC. The use of this agent is limited by the modest benefit, potential side effects, the cost and most importantly the inability to pinpoint patients who are likely to benefit from bevacizumab.
Epidermal Growth Factor Receptors (EGFR) and Its Mutations
The availability of anti-EGFR drugs, the identification of activating EGFR mutations and the association with clinical sensitivity to tyrosine kinase inhibitors (TKIs), and the ability to test tumours for EGFR mutation in routine clinical practice in the last few years has changed the way we approach and treat advanced NSCLC.
Gefitinib (Iressa), an oral TKI against EGFR, was the first targeted agent approved for the treatment of NSCLC. Gefitinib at 250mg once daily was approved in 2003 based on two large phase II randomised studies. In these 2 trials, gefitinib results in a response rate of 10-20 per cent in previously treated advanced NSCLC. At that time, predictive factors were unclear for response and benefit from gefitinib. A second EGFR oral TKI, erlotinib (Tarceva) was approved one year later. Over the following few years, it was noted that EGFR oral TKIs were more effective in patients with adenocarcinoma, of East Asian origins, and who are never smokers.
In non-selected patients, only a small percentage of advanced NSCLC respond to EGFR TKI treatment. The molecular mechanism for response to oral EGFR TKI was only published12 one year after gefitinib was approved for clinical use. Patients with sensitizing mutation (exon 19 deletion and exon 21 point mutation) in the EGFR gene are associated with increased responsiveness to EGFR TKI treatment. EGFR mutations are present mainly in adenocarcinomas, and seldom (<5 per cent) in squamous cell carcinoma. Sensitising EGFR mutations are most commonly found (about 60 per cent) in East Asian patients with adenocarcinoma and who have never smoked13, and are less commonly found in Caucasian patients (about 10-15 per cent of adenocarcinomas).
In the large IPASS trial13, 1,217 East Asian patients with advanced adenocarcinoma and who were never smokers or were former light smokers were randomised to either upfront chemotherapy or single agent gefitinib (Figure 2). One tablet of gefitinib a day was found to be superior to combination chemotherapy in terms of response rate (43 per cent vs 32.2 per cent) and progression free survival (12 month progression free of 24.9 per cent vs 6.7 per cent). There was, however, no difference in overall survival.
The common side effects associated with gefitinib included skin dryness, pruritus, acne, nail changes (Figure 3) and occasional diarrhoea. Potentially fatal pneumonitis (Figure 4) occurs in less than 1 per cent of patients treated with gefitinib.
Since the IPASS study, there have been four additional randomised studies - comparing chemotherapy with gefitinib (2 studies) and chemotherapy with erlotinib (2 studies) - in patients with EGFR mutations. All studies showed oral EGFR TKI was superior to combination chemotherapy in progression free survival and response rate. However, none had shown an improvement in overall survival.
More recently, afatinib (BIBW 2992), a second generation irreversible oral EGFR TKI was shown in a randomised trial14 against first line cisplatin and pemetrexed to be superior in response rate and progression free survival in patients with EGFR mutation.
At present, all patients with advanced adenocarcinoma of the lung should be tested for EGFR mutation. This can be done on paraffin blocks / slides from biopsy specimen. In patients with sensitizing mutation, oral EGFR TKI is an option for first line treatment. In patients without a sensitizing EGFR mutation, conventional chemotherapy will be considered. Patients with EGFR mutation on oral TKI have a median overall survival of around 24 months. The overall survival is about 12 months for patients without EGFR mutation treated by chemotherapy.
Anaplastic lymphoma kinase (ALK) translocation and crizotinib
More recently, about 5 per cent of lung adenocarcinomas are found to have ALK translocation. Similar to EGFR mutation, ALK translocation occurs more frequently in never smokers with adenocarcinoma, but seems to occur in similar frequency in Caucasian and East Asian patients. Testing for ALK translocation can be done on paraffin embedded specimens. Patients with ALK translocation respond well to crizotinib15.
Randomised trials comparing crizotinib against chemotherapy are ongoing. Crizotinib was approved in Aug 2011 in the USA for the treatment of advanced NSCLC with ALK translocation.
Crizotinib is currently accessible in Singapore through the expanded access programme.
Dr Lim Hong Liang is a senior medical oncologist from Parkway Cancer Centre and has more than 25 years of experience. In addition to general medical oncology, he has a special interest in lung cancers, and head and neck cancers.
Dr Lim graduated from the National University of Singapore (MBBS) in 1986. He received his training in internal medicine and medical oncology at the National University Hospital Singapore (NUH). In 1992, he received further training in the Department of Thoracic Oncology at the Tokyo National Cancer Cantre Japan. Dr Lim was also trained in high dose chemotherapy and bone marrow transplant at the St Vincent’s Hospital in Sydney Australia in 1995.
Prior to joining the Parkway Cancer Centre, Dr Lim headed the Thoracic Oncology Service, Head and Neck Service and Bone Marrow Transplant Program at NUH. He was also the lead medical oncologist at the Tan Tock Seng Hospital Lung Tumour Clinic from 1996 to 2005. Before leaving for private practice in 2005, Dr Lim was the Chief of the Department of Haematology and Oncology and the Associate Chairman of the Medical Board of NUH.
To find out more about Dr Lim and his work, click here.
Endnotes
Endnotes:
1. GLOBOCAN 2008
2. SEER data, 2002 to 2008
3. Singapore Cancer Registry Interim Report 2006-2010
4. Reduced lung cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-405
5. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):351
6. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006;7(9):719
7. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352(25):2589.
8. Meta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol. 2005;23(22):4999.
9. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92
10. Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer. J Clin Oncol 2008;26: 3543-3551
11. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med. 2006;355(24):2542.
12. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129.
13. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947.
14. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harbouring EGFR-activating mutations (abstract #LBA7500). J Clin Oncol 2012.
15. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693