Essay: Clinical Profile and Risk Factors for Lung Cancer Among Young Filipino Adults

INTRODUCTION
Lung cancer is one of the leading causes of death worldwide. As of 2012, there are 1.8 million new cases globally and 1.5 million deaths attributable to this disease, with North America, Europe and East Asia having the highest rate of mortality.1
It usually occurs in patients of advanced age with the highest incidence in the 6th and 7th decade of life. Majority of this cancer is caused by cigarette smoking. Cigarette smokers are 15 to 30 times more likely to get lung cancer or die from it than those who do not smoke. 2 However, in the United States, 7,300 nonsmokers die from lung cancer each year, mostly from second hand smoking.3 Aside from cigarette smoking, other factors implicated in the development of lung cancer include: occupation lung carcinogens, asbestos, coal dust, radiation, in-door and outdoor pollution.4
In the recent years, there are more and more young adults, aged 45 years and below, who developed lung cancers. The incidence was reported to be 1.2 ‘ 6.2% in less than 40 years age group, 5.3% among < 45 years of age and 13.4% among 50 years or less. Many of them were never smokers and have not lived long enough to get exposed to secondhand smoking and other carcinogens.5
In 2010, VM Medina et al6 reported that lung cancer was among the cancers showing an increasing trend in the Philippines in both female and male population. Both populations showed an annual percentage change (APC) of 0.5%. This was attributed to increasing per capita consumption of cigarettes. According to the latest WHO data published in April 20117, lung cancer deaths in the Philippines reached 8,518 or 2.2% of total deaths. The age adjusted Death rate is 15.46 per 100,000 of population ranks Philippines # 80 in the world. There have been many reports of lung cancer among the young and nonsmoking population in our country but still, the incidence is not reported. Several local studies have been done on lung cancer in the Philippines however none regarding lung cancer among the young.
OBJECTIVES OF THE STUDY
The objectives of the study are to determine the demographic and clinical profile of young adults diagnosed to have lung cancer and to identify which of these can best predict development of lung cancer.
Specifically, the aims of this study are:
1. To determine the demographic profile of these patients in terms of age, gender, smoking history, duration of smoking, occupation, family history, area of residence, eating habits, environmental exposure.
2. To determine the clinical profile of these patients in terms of clinical presentation, histologic type of lung cancer, size of tumor, staging upon diagnosis, EGFR mutation, performance status, radiologic findings, laboratory findings, treatment , overall survival.
3. To identify which of the demographic factors can best predict the likelihood of the disease.
SIGNIFICANCE OF THE STUDY
Identification of the demographic profiles of young adults who are prone to develop lung cancer can increase the clinician’s index of suspicion that can result to earlier screening and detection of lung cancer. Furthermore, determining the clinical profile of these patients may aid the clinician in the prognostication of the disease.
REVIEW OF RELATED LITERATURE
Lung cancer is the most common cancer in men and third among women worldwide. As of 2012, there were 1.82 million new cases globally and 1.56 million deaths due to lung cancer representing 19.4% of all deaths from cancer. 1
In the Philippines, lung cancer deaths reached 8,518 or 2.02% of total deaths according to the latest WHO data published in April 2011.7 Philippines is one of the 192 countries worldwide with the most number of people with lung cancer. This was attributed to high smoking rates with an estimated 17.3 million tobacco consumers in the country.8
Lung cancer usually occurs in older people 65 years or older.4 The average age at diagnosis is 71 years. 9 The rate of new cases in 2011 showed that men develop lung cancer more often than women (64.8 and 48.6 per 100,000 respectively) and blacks are more likely to develop this disease. 10
Lung cancer typically does not cause signs and symptoms in its earliest stages. Signs and symptoms occur only when the disease is advanced hence the higher the mortality. Signs and symptoms may include: persistent cough, hemoptysis, dyspnea, hoarseness, chestpain, weight loss, body malaise, recurrent infections, new onset wheezing, and other symptoms pertaining to possible distant spread of the disease such as bone pain, neurologic changes, jaundice and Lymphadenopathies. 4
It was established that majority of lung cancers is caused by cigarette smoking. It contributes to 80% of lung cancer deaths in men and 90% in women. Exposure to secondhand smoke causes approximately 7,330 lung cancer deaths among non-smokers every year. Non-smokers have a 20-30% greater chance of developing lung cancer if they are exposed to secondhand smoke at home or work. 10 Radon gas which is produced by decaying uranium naturally occurring in soil and rocks contributes 10% of lung cancer cases, about 9-15% percent for occupational exposures including asbestos, arsenic, nickel, silica, polycyclic aromatic hydrocarbons and 1-2% for outdoor air pollution. With the interactions of these exposures, the combined attributable risk for lung cancer can exceed 100%. 4,10
There are two general types of lung cancer: (1) Non-small cell lung cancer (NSCLC) which comprise about 85-90% of cases and is the umbrella term for several types of lung cancers that behave in a similar way including squamous cell carcinoma, adenocarcinoma and large cell carcinoma and (2) Small cell lung cancer. Squamous cell carcinoma is often linked to a history of smoking. Adenocarcinoma is the most common type among non-smokers, women, and younger people. Small cell lung cancer is less common and almost exclusively occurs in heavy smokers. 4
Recently, more young adults and even non-smokers were diagnosed with lung cancer. The incidence of lung cancer in the young is around 1.2 to 6.2% under 40 years, 5.3% under 45 years and 13.4% under 50 years.11 There is no clear criterion in defining ‘young’ in lung cancer. Many published studies used age less than 40, 45 or 50.12 In this study, ‘young adults’ is defined as diagnosed with lung cancer at ’45 years of age. Lung cancer in the young may have a different biology with a set of unique characteristics compared to published data in more common older patients.
In the study of Hsu et al11, the median age of patients with lung cancer was 39.1 years and 51.4% of them were women. The most common initial clinical presentation was cough (54.2%) followed by dyspnea (19.4%) and chestpain/ tightness (17.4%). Six patients (4.2%) were asymptomatic, with abnormal chest image findings during health examination. Sixty-two patients (43.1%) had a history of cigarette smoking and 34.7% of which were current smokers. Low BMI, stage IV disease, anemia at diagnosis, and male gender were the negative prognostic factors for young patients with advanced NSCLC.
Radiologic findings in younger patients seen in the study of Sanjay13 include mass lesion (60.3%), pleural effusion (43.8%), collapse/consolidation (19.2%), mediastinal widening (12.3%), rib lesion (1.4%) and cavitation in the lung (1%) as was also seen in the older patients.
Younger people tend to have more advanced lung cancer at the time of diagnosis, most of whom were diagnosed with stage IV disease. In the study of Skarin et al14, 15% had stage I/II, 17% stage IIIA, 22% stage IIIB and 45% stage IV disease at the time of diagnosis. Even in the study of Hsu et al, 40 patients had stage IIIB and 104 had stage IV disease upon diagnosis. It is possible that lung cancer in young patients has worse prognosis because of its aggressive biological behavior and underlying genetic differences.15
Sanjay et al13 found that squamous cell carcinoma was the most common histological subtypes in both older and young age groups but squamous cell carcinoma was more frequently diagnosed in older patients than in younger patients. However, in the study conducted by Skarin et al14, the most common histopathology was adenocarcinoma (46%), followed by small cell carcinoma (14%), squamous cell carcinoma (12%), large cell undifferentiated (8%) and other types (20%). Considering that it takes decades to develop cancer after starting to smoke, it is possible that in young patients there would be less smoking-related squamous carcinoma and therefore more adenocarcinoma than in older age group.15
Young people with lung cancer are more likely to be never smokers than people who develop lung cancer later in life. Overall, 10-15% of people with lung cancer have never smoked and 50% are former smokers.12 Kreuzer et al16 showed that duration of smoking and amount smoked significantly increased odds ratios for lung cancer.
Heredity likely plays a role in developing lung cancer in the young. Studies are now geared towards identifying genes that may predispose young people to develop lung cancer. Inherited factors include polymorphisms on chromosomes 5, 6 and 15. Acquired mutations in lung cells also result with exposure to environmental factors such as tobaccos smoke. Acquired gene changes such as TP53, p16 tumor suppressor genes and KRAS oncogenes are thought to be important in the in the development of non-small cell lung cancer.4
EGFR mutation is also linked to lung cancer susceptibility in never smokers.2 Many patients with adenocarcinoma harbor mutations of the EGFR which is highly sensitive to EGFR tyrosine kinase inhibitors such as Gefitinib, Erlotinib and Cetuximab.15 Targeted therapy with these agents could help improve the overall survival of lung cancer patients.
Kreuzer et al16 demonstrated in his study a threefold increase in risk of lung cancer in subjects younger than 46 years if relatives were also affected by lung cancer and no elevated risk in older people. Other studies showed mendelian codominant inheritance of rare autosomal gene that produces earlier age of onset of cancer. Schwartz et al17 showed 7.2 fold increase in risk of lung cancer in a first degree relative in the young age group (40-59 years) even when adjusting for smoking, occupational, and medical history of each family member. In older age groups however, a positive family history of lung cancer did not increase lung cancer risk.
Despite the advances in treatment, including surgery, chemotherapy, radiotherapy and epidermal growth factor receptor tyrosine kinase inhibitor therapy, the 5-year survival rate is only 9 to 20%, specifically 54% for cases detected when the disease is still localized and only 4% for distant tumors.10 In the study conducted by Skarin et al14, the median survival was 1 year with 2 and 5 year survivals of 30% and 18% respectively. Five year survival was related to stage of disease: 60% for patients with stage I, 58% for stage II, 36% for stage IIIA, 10% for stage IIIB, and 3% for stage IV disease. Factors that adversely affected survival included advanced stage of disease, poor PS, duration of symptoms for more than 3 months, and 5% or greater body weight loss.
METHODOLOGY
This is a retrospective cross-sectional study involving young adults diagnosed to have lung cancer in the outpatient department as well as inpatient in San Pedro Hospital from 2010 ‘ 2015.
The following are the inclusion criteria:
1. Adult patients aged 18 years to 45 years old
2. Histologic diagnosis of lung carcinoma including small cell carcinoma as well as non-small cell carcinoma (adenocarcinoma, large cell carcinoma and squamous cell carcinoma).
The following are the exclusion criteria:
1. Suspected lung cancer without histologic diagnosis
2. Patients diagnosed to have lung cancer with incomplete charts
Data gathering will commence upon the approval of the ethics committee. All OPD charts and Inpatient medical records from January 2010 to present will be obtained from the hospital Medical Records and OPD clinic of participating clinicians. These charts will be reviewed.
Demographic Profile
The following demographic data will be obtained from the charts: age upon diagnosis, gender, occupation, ethnicity, diet (vegetables, fruit, preservatives, meat, fish), smoking history, duration of smoking (for smokers), exposure to smoking, environmental exposure (to asbestos, indoor pollution, cooking fumes, burned wood, chimney, ionizing radiation, smoke from vehicles, driving), and family history of malignancy (pulmonary or non pulmonary).
Clinical Profile
The clinical data will include histologic diagnosis, staging of the disease, initial presentation, laboratory data at diagnosis (including presence of anemia, leukocytosis, hypoalbuminemia, liver function test, creatinine, Epidermal Growth Factor Receptor (EGFR) mutation, Eastern Cooperative Oncology Group Performance Status (ECOG PS), presence of comorbidities, and initial treatment given.
Statistical Method
Descriptive analysis of both the demographic and clinical profiles will be done by determining the frequency and percentages. Significant risk factors will be identified using the univariate analysis. Further risk analysis using multiple logistic regression and odd risk ratio will be applied on further risk analysis.
RESULTS
Table 1: Demographic profile of young patients with lung cancer
Number of patients (N) Percentages (%)
Age upon diagnosis
Gender
Male
Female
Occupation
Office work
Indoor
Smoking
Current
Never smoke/no exposure
Ex-smoker
Passive smoker
Ethnicity
Place of residence
Urban
Rural
Height
Weight
Body Mass Index (kg/m2)
Table 2: Clinical Profile of young adults with lung cancer
Features Number of patients (N) Percentages (%)
Signs and symptoms upon diagnosis asymptomatic
cough
dyspnea
chest pain/ chest tightness
hemoptysis
back pain
weight loss
clubbing
Unexplained fever, headache, body malaise
pallor
edema
dysphagia
hoarseness
bone pain
lymphadenopathies
hepatosplenomegaly
wheezing and stridor
super vena cava obstruction
soft tissue mass
focal neurologic signs
papilledema
ECOG Performance Status 0
1
2
3
4
Radiologic Findings mass
hilar enlargement
pleural effusion
consolidation or collapse
mediastinal widening
bony lesions
pericardial effusion
persistent pneumonia
cavity or coin lesions
Laboratory Results anemia
leukocytosis
thrombocytopenia
hypoalbuminemia
abnormal liver function
elevated serum LDH
hypercalcemia
Table 2: Clinical Profile of young adults with lung cancer continued
Features Number of patients (N) Percentages (%)
Tumor Type Non-Small Cell
Squamous
Adenocarcinoma
Large
Small Cell
Immunohistochemistry EGFR
KRAS mutation
p53 mutation
cytokeratin
TTF-1
CD56
Stage at Diagnosis Non-small cell carcinoma
I
II
IIIA
IIIB
IV
Small cell carcinoma
Limited
Extensive
Table 3: Risk factors associated in developing lung cancer
Number of patients (N) Percentages (%)
Smoking History Non-smoker
Passive smoker
Current smoker
Former smoker
Pack-years <10 years 11-19 years 20-29 years 30-39 years ’40 years Environmental Exposure burned wood coal cooking fumes asbestos ionizing radiation smoke from vehicles Diet vegetables fruits fish/ seafoods meat preserved/ cured foods Prior Lung Disease chronic bronchitis emphysema tuberculosis bronchial asthma Comorbid conditions diabetes hypertension dyslipidemia coronary artery disease hyperuricemia renal diseases History of cancer in the family lung cancer breast prostate ovaries endometrium brain stomach colon Table 4. Univariate analysis Significant Features Hazard Ratio (95% confidence interval p value Table 5. Multivariate analysis Significant Features Hazard Ratio (95% confidence interval p value REFERENCES 1. Lindsey A, Bray F, Siegel R, Ferlay J, Tieulent J, Jemal A. Global cancer statistics, 2012. http://onlinelibrary.wiley.com/doi/10.3322/caac.21262/full (accessed 2015 April 14). 2. Fauci et al. Harrison’s Principle of Internal Medicine, 18th ed. 2012. 3. Centers for Disease Control and Prevention. Cigarette smoking in the United States http://www.cdc.gov/tobacco/campaign/tips/resources/data/cigarette-smoking-in-united-states.html (accessed 2015 May 15). 4. American Cancer Society. Lung Cancer (Non-Small Cell). http://www.cancer.org; (accessed 2015 April 6). 5. Hsu C, Chen K, Shih J, Ho C, Yang C, Yu C, Yang P. Advanced non-small cell lung cancer in patients aged 45 years or young: outcomes and prognostic factors. BMC Cancer 2012, 12:241. 6. Medina et al. Cumulative incidence trends of selected cancer sites in a Philippine population from 1983 to 2002: a joinpoint analysis. http://www.researchgate.net/publication/43050428. (accessed 2015 May 10). 7. Philippines: Lung Cancers. http://www.worldlifeexpectancy.com/philippines-lung-cancers (accessed 2015 May 15). 8. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence in 2012. http://www.cancerindex.org/Philippines (accessed 14.4.15). 9. Eldridge, L. How many people die from lung cancer each year?. http://lungcancer.about.com/od/whatislungcancer/f/lungcancerdeaths.htm. (accessed 2015 April17). 10. American Lung Association. Lung cancer fact sheets. http://www.lung.org/lung-disease/lung-cancer/resources/facts-figures/lung-cancer-fact-sheet.html. (accessed 2015 April 10). 11. Hsu C, Chen K, Shih J, Ho C, Yang C, Yu C, Yang P. Advanced non-small cell lung cancer in patients aged 45 years or young: outcomes and prognostic factors. BMC Cancer 2012, 12:241. 12. Bonnie J. Addario Lung Cancer Foundation. Lung cancer in young adults. https://www.lungcancerfoundation.org/2014/08/lung-cancer-in-young-adults/. (accessed 2015 May 2). 13. Sanjay R, Prasad R, Verma S. Comparison between young and old patients with bronchogenic carcinoma. Journal of Cancer Research and Therapeutics. January-March 2009; 5(1): 31-35. 14. Skarin A, Herbst R, Leong T, Bailey A, Sugarbaker D. Lung cancer in patients under age40. Lung Cancer. 2001; 32: 255-264. 15. Zhang et al. Multicenter analysis of lung cancer patients younger than 45 years in Shanghai. 2010 August. Cancer. 3656-3662. 16. Kreuzer M, Kreienbrock L, Gerken M, Heinrich J, Bruske-Hohlfeld I, Muller K, Wichmann HE. Risk factors for lung cancer in young adults. American Journal of Epidemiology. 1998; 147 (11): 1028-1037. 17. Schwartz A, Yang P, Swanson M. Familial risk of lung cancer among nonsmokers and their relatives. American Journal of Epidemiology. 1996; 144(6): 554-562. 18. Gauderman W, Morrison J. Evidence for age-specific genetic relative risks in lung cancer. American Journal of Epidemiology. 2000; 151 (1): 41-49. APPENDIX A DATA COLLECTION FORM Name: Code: Age: DEMOGRAPHICS 1. Age 2. Age upon diagnosis of lung CA: 3. Gender: Male ____ Female ____ 4. Occupation 5. Height 6. Weight 7. Body Mass Index 8. Nationality 9. Ethinicity CLINICAL PROFILE 1. Clinical Manifestations upon diagnosis ____ asymptomatic ____ cough ____ dyspnea ____ chest pain/ chest tightness ____ hemoptysis ____ back pain ____ weight loss ____ clubbing ____ pallor ____ edema ____ dysphagia ____ hoarseness ____ bone pain ____ Lymphadenopathies ____ Hepatosplenomegaly ____ wheezing and stridor ____ super vena cava obstruction ____ soft tissue mass ____ focal neurologic signs ____ papilledema ____ unexplained fever, headache and body malaise 2. Performance status upon diagnosis according to Eastern Cooperative Oncology Group (ECOG) performance scale ____ 0 ____ 1 ____ 2 ____ 3 ____ 4 ____ 5 3. Radiologic findings ____ mass ____ persistent pneumonia ____ hilar enlargement ____ cavity or coin lesions ____ pleural effusion ____consolidation or collapse ____ mediastinal widening ____ bony lesions ____ pericardial effusion 4. Laboratory results ____ anemia ____ leukocytosis ____ thrombocytopenia ____ hypoalbuminemia ____ abnormal liver function ____ elevated serum LDH ____ hypercalcemia 5. Histologic findings ____ Non-small cell carcinoma ____ Small cell carcinoma ____ Adenocarcinoma ____ Squamous cell carcinoma ____ Large cell carcinoma 6. Immunohistochemistry ____ EGFR ____ KRAS mutation ____ p53 mutation ____ cytokeratin ____ TTF-1 ____ CD56 7. Stage of the disease upon diagnosis Non-small cell carcinoma ____ 0 (Carcinoma in situ) ____ I ____ II ____ IIIA ____ IIIB ____ IV Small cell carcinoma ____ Limited ____ Extensive RISK FACTORS 1. Smoking history ____ Non-smoker ____ Passive smoker ____ Current smoker: ____ Pack years ____ Former smoker ____ Pack years 2. Environmental exposure ____ burned wood ____ coal ____ cooking fumes ____ asbestos ____ ionizing radiation ____ smoke from vehicles 3. Diet ____ vegetables ____ fruits ____ fish/ seafoods ____ meat ____ preserved/ cured foods 4. Prior lung disease ____ chronic bronchitis ____ emphysema ____ tuberculosis ____ bronchial asthma 5. Comorbid conditions ____ diabetes ____ hypertension ____ Dyslipidemia ____ coronary artery disease ____ hyperuricemia ____ renal diseases 6. History of cancer in the family ____ lung cancer ____ breast ____ prostate ____ ovaries ____ endometrium ____ brain ____ stomach ____ colon APPENDIX B Eastern Cooperative Oncology Group (ECOG) Performance Scale 0: fully active, able to carry on all predisease performance without restriction 1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature 2: ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3: capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4: completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5: dead APPENDIX C TNM Classification for Non-Small Cell Lung Cancer Primary tumor (T) TX Primary tumor cannot be assessed, or the tumor is proven by the presence of malignant cells in sputum or bronchial washing but is not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor ‘ 3 cm in greatest dimension, surrounded by lung or visceral pleura, no bronchoscopic evidence of invasion more proximal than the lobar bronchus (not in the main bronchus); superficial spreading of tumor in the central airways (confined to the bronchial wall ) T1a Tumor ‘ 2 cm in the greatest dimension T1b Tumor > 2 cm but ‘ 3 cm in the greatest dimension
T2 Tumor > 3 cm but ‘ 7 cm or tumor with any of the following:
‘ Invades visceral pleura
‘ Involves the main bronchus ‘ 2 cm distal to the carina
‘ Associated with atelectasis/obstructive pneumonitis extending to hilar region but not involving the entire lung
T2a Tumor > 3 cm but ‘ 5 cm in the greatest dimension
T2b Tumor > 5 cm but ‘ 7 cm in the greatest dimension
T3 Tumor > 7 cm or one that directly invades any of the following:
Chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium;
Or tumor in the main bronchus < 2 cm distal to the carina but without involvement of the carina
Or associated atelectasis/obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; or separate tumor nodule(s) in a different ipsilateral lobe
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in the ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion
M1b Distant metastasis
APPENDIX C
TNM Classification for Non-Small Cell Lung Cancer continued
Anatomic stage/prognostic groups
Stage T N M
Ia T1a N0 M0
T1b N0 M0
Ib T2a N0 M0
IIa T1a N1 M0
T1b N1 M0
T2a N1 M0
T2b N0 M0
IIb T2b N1 M0
T3 N0 M0
IIIa T1 N2 M0
T2 N2 M0
T3 N2 M0
T3 N1 M0
T4 N0 M0
T4 N1 M0
IIIb T4 N2 M0
T1 N3 M0
T2 N3 M0
T3 N3 M0
T4 N3 M0
IV T Any N Any M1a or 1b
APPENDIX D
Staging of Small Cell Lung Cancer
Limited Stage
– confined to only one lung, and may have spread to the area between the lungs (the mediastinum), and/or to nearbylymph nodes, but not to other regions of the body
Extensive Stage Small Cell Lung Cancer
– has spread to the other lung, to lymph nodes on the other side of the chest, or to distant regions of the body such as the brain.