Central Annals of Gerontology and Geriatric Research

Cite this article: Venkatachalam J, Abisheganaden J, Chen S, Lim AYH, Tai DYH, et al. (2015) Lung Cancer in Asian Octogenarian Population. Ann Gerontol Geriatric Res 2(2): 1026.

*Corresponding authorAkash Verma, Tan Tock Seng Hospital, Department of Respiratory and Critical Care Medicine, 11 Jalan Tan Tock Seng, Singapore, 308433, Tel: 65-63573790; Fax: 65-63573087; Email:

Submitted: 26 February 2015

Accepted: 22 March 2015

Published: 24 March 2015

Copyright© 2015 Verma et al.

OPEN ACCESS

Keywords•Octogenarian•Elderly•Timeliness•Bronchoscopy

Cancer (lung)

Research Article

Lung Cancer in Asian Octogenarian PopulationJonathen Venkatachalam, John Abisheganaden, Shuyu Chen, Albert YH Lim, Dessmon YH Tai, Soon Keng Goh, Ai Ching Kor and Akash Verma*Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore

Abstract

Aim: Evaluate the clinical, radiological, and prognostic features in lung cancer amongst elderly patients.

Method: A retrospective study of patients diagnosed with lung cancer between January 2011 and December 2013, looking at demographics, CT findings, histopathology results, therapy, and survival was done. Features among young (≤60 years), and octogenarians (≥80 years) were compared.

Result: 177 patients were diagnosed with lung cancer out of which 51 were ≤ 60 years old, and 27 were ≥ 80 years old. These were analysed (n=78). 70 (89.7%) presented with advanced and 8 (10.2%) with early stage cancer. Octogenarians were significantly different from younger patients in terms of male predominance 21 (78%) vs. 26 (51%) in younger patients, p=0.02. Greater proportion of patients had fibrotic changes 3 (11%), scarring 9 (33%), peripherally located lung cancer 17 (63%) and past history of tuberculosis 6 (22%) in octogenarians as compared to young patients, p=0.03& p=0.01. Octogenarians 3 (11%) were treated with chemotherapy less frequently than the younger patients 29 (57%), p=0.0001, however no difference in survival was seen. Among octogenarians, 4(14.8%) survived >2 years, 7(26%) 1-2 years, &13(48.1%) survived <1 year. Features of peripheral tumour, left lower lobe involvement, early stage, and radiotherapy correlated with survival of ≥ 2 years in this group.

Conclusion: Lung cancer presents peripherally in octogenarians making the service of transthoracic needle aspiration an essential pre-requisite for all hospitals managing such patients. Fibrotic changes, scarring, and past tuberculosis correlated with lung cancer in this population. There was no difference in survival between octogenarians & younger patients. This helps to dispel nihilism surrounding the treatment of lung cancer in the elderly. Peripheral tumour, left lower lobe involvement, early stage, and radiotherapy correlated with better survival.

INTRODUCTIONElderly population is on the rise which is due to multiple

factors, such as baby boomers reaching retirement age, longer life expectancies associated with accessibility to healthcare advances, lower birth rates in developed and affluent economies, and smaller family structures. Singapore is no different. Singaporean population is living longer, and, in aggregate, ageing more rapidly. The life expectancy at birth for the overall population of Singapore was 82.5 years in 2013, one of the highest worldwide. It was 79.1 years a decade ago [1,2]. In addition, the proportion of seniors in Singapore is expected to grow from 9% to 24%, in a span of 20 years, from 2010 to 2030. This is in comparison to Japan where the proportion of seniors increased from 10% to 23%, within 25 years, from 1985 to 2010 [3]. More than half of patients diagnosed with lung cancer are above 65 years old and

rise in ageing population implies challenging rise in the demand of the lung cancer management related healthcare resources in the span of next 20 years.

For a long time nihilism influenced treatment decisions in patients with advanced non-small cell lung cancer due to poor survival rates, and since most of these patients are elderly, they are affected more by this nihilism than younger population. Though two thirds of new cancers occur in the elderly, only a third gets enrolled in cancer treatment trials [4,5]. Since the elderly population is systematically excluded by most cancer trial protocols, it becomes difficult to predict outcomes of emerging cancer treatment amongst the elderly [6]. Studies also show that elderly patients do not have as many definitive diagnoses made or receive treatment as younger patients diagnosed with lung cancer. Chemotherapy is avoided in them due to perceived poor

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tolerance even though survival advantage has been demonstrated despite the side effects [7,8]. Elderly population has also been reported to be affected by delay in their diagnosis and treatment more than younger population [9]. In addition, mortality has been reported to be higher in the elderly patients with lung cancer, the median survival reported significantly lower (37.8 vs. 57 weeks; P=0.009) compared to younger patients in one study [10].

The current study was done to assess the clinical and radiological features along with survival in Asian octogenarian population presenting with lung cancer.

METHODS The current study was part of an audit as a quality-of-

care initiative performed on patients who were consecutively diagnosed and managed for lung cancer. Patients were identified from the data base of the patients who were diagnosed with lung cancer and managed accordingly by the department of Respiratory medicine between January 2011 to December 2013. All patients who underwent diagnostic evaluation and referred to medical oncologist for further opinion and treatment were included. Retrospective review of demographics, Computed Tomography (CT) findings, and type of diagnostic technique employed, pathological result, and number of procedure required to reach conclusive diagnosis, time from 1st CT imaging of the chest to start of treatment, and survival was done.

Definitions

We defined “younger patients” as those ≤ 60 years old, and patients’ ≥ 80 years of age were defined as “octogenarians.”

Patients between 61-79 years of age were excluded from the analysis. Survival was calculated as time from the date of pathological diagnosis-to-date of death or the date of last follow-up.

Data analysis

We used software (SPSS, version 17; SPSS, Chicago, Ill) for all statistical analyses. The results were compared using a Wilcoxon two-sample test or Fisher exact test. P values were two sided and considered indicative of a significant difference if less than .05. Kaplan-Meier curve with log-rank test was used to analyse survival.

RESULTS 177 patients were diagnosed with lung cancer with median

(range) age of 69 (38-93) years and 112 (63.2%) being older than 65 years of age at presentation. Out of these 51 were ≤ 60 years old, and 27 were ≥ 80 years old. Clinical characteristics of this group (n=78) are presented in Table 1.

Comparison between young (≤ 60 years old), and ≥ 80 years old patients

Octogenarian (n=27) were significantly different from younger patients (n=51). There were more hypertensive patients in the octogenarian group 15 (56%) vs. young 9 (18%), p=0.0009. Octogenarian had tuberculosis (TB) in the past more frequently 6 (22%) than reported by younger patient 2 (4%), p=0.01. Fibrotic changes and scarring was common in octogenarian 3

(11%) & 9 (33%) as compared to young 0 & 6 (12%), p=0.03. Peripheral tumour was the commoner radiographic finding in octogenarians 17 (63%) vs. younger patients 19 (37%), p=0.03, (Figure 1). Treatment initiation showed a trend for delay in the octogenarians 60 (19-61) vs. 36.5 (6-150) days, p= 0.09.

Octogenarians showed male predominance 21 (78%) vs. 26 (51%) in younger patients, p=0.02. No difference in the proportion of patients with advanced stage disease in each group was seen. Octogenarians and younger patients had 24 (88.8%) vs. 46 (90.6%) patients with advanced disease, p= 1.0. Octogenarians 3 (11%) were treated with chemotherapy less frequently than the young 29 (57%), p=0.0001, Table 2, however no difference in survival was seen among these groups (Figure 2).

Among octogenarians, 4(14.8%) survived >2 years, 2 (50%) of which had advanced stage cancer. Seven (26%) survived 1-2 years, 6 (85.7%) of which had advanced disease, &13(48.1%) survived <1 year, all of whom had advanced disease. Features of peripheral tumour, left lower lobe involvement, early stage, and radiotherapy correlated with survival of ≥ 2 years in this group (Table 3).

DISCUSSIONAge at which lung cancer presents may be increasing [11-

15]. This seems true both for Asian and Caucasian population. Investigators from Korea have observed that age at which lung cancer presents has been increasing in Asian population with the mean age at presentation of 62.0 ± 10.75, 64.1 ± 9.37 and 65.2 ± 9.45 years in the period of 2000-03, 2004-07, and 2008-

Characteristics No. of patients (%), median (range)Age 58 (38-93)GenderMale 49 (63)Female 29 (37)SmokingCurrent smoker 21 (27)Never smoker 27 (35)HistologyAdenocarcinoma 46 (59)Squamous cell carcinoma 6 (8)Small cell carcinoma 4 (5)Co-morbiditiesDiabetes 9 (12)Hypertension 24 (31)Ischemic heart disease 10 (13)Chronic obstructive lung disease 11 (14)Old tuberculosis 8 (10)StageAdvanced (stage III-IV) 70 (89.7)Early (stage I-II) 8 (10.2)TherapyTyrosine kinase inhibitors 22 (28)Chemotherapy 32 (41)Radiotherapy 32 (41)Surgery 9 (12)Survival 293 (6-1361)

Table 1: Clinical Characteristics of Patients (n=78).

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Figure 1 Representative case of an 81 year old male patient with peripherally located lung cancer.

≤ 60N=51

≥ 80N=27 P value

A B A & BAge 54 (38-60) 84 (80-93) 0.0005Males 26 (51) 21 (78) 0.02

Radiological featuresFibrotic changes 0 3 (11) 0.03Scarring 6 (12) 9 (33) 0.03Calcified granuloma 4 (8) 3 (11) 0.68Pleural thickening 9 (18) 7 (26) 0.39Peripheral tumour 19 (37) 17 (63) 0.035Central tumour 14 (27) 4 (15) 0.26Discreet mediastinal lymph node 14 (27) 11 (41) 0.30

Mediastinal infiltration 14 (27) 3 (11) 0.14Effusion 16 (31) 9 (33) 1.0

Site of cancerRight upper lobe 19 (37) 10 (37) 1.0Right middle lobe 5 (10) 3 (11) 1.0Right lower lobe 5 (10) 4 (15) 0.71Left upper lobe 14 (27) 5 (19) 0.42Left lower lobe 5 (10) 4 (15) 0.71

DelaysCT-∆Procedure time (days) 4 (-34-58) 5.5 (-5-55) 0.32CT- Start of treatment (days) 36.5 (6-150) 60 (19-61) 0.09

Diagnostic proceduresCervical FNAC 4 (7.8) 1 (3.7) 0.65Thoracentesis 13 (25.4) 9 (33.3) 0.59Transthoracic needle aspiration 21 (41) 12 (44.4) 0.81Bronchoscopy 12 (23.5) 4 (14.8) 0.55EBUS-TBNA 0 1 (3.7) 0.34

HistologyAdenocarcinoma 33 (65) 13 (48) 0.22Squamous cell carcinoma 2 (4) 4 (15) 0.17Small cell carcinoma 3 (6) 1 (4) 1.0Others 4 (7.8) 0 0.29NSCLC 8 (15.6) 8 (29.6) 0.23

Smoking history

Table 2: Subgroup analysis of young patients (age ≤ 60 years), and octogenarians (age ≥ 80 years).

Never smoker 19 (37) 8 (30) 0.61Current smoker 16 (31) 5 (19) 0.28

Co-morbiditiesDiabetes 4 (8) 5 (19) 0.26Hypertension 9 (18) 15 (56) 0.0009Ischemic heart disease 4 (8) 6 (22) 0.08Chronic obstructive lung disease 5 (10) 6 (22) 0.17

Old tuberculosis 2 (4) 6 (22) 0.01Stage

Advanced (stage III-IV) 46 (90.1) 24 (88.8) 1.0Early (stage I-II) 5 (9.7) 3 (11.1) 0.41

TherapyExon 19 7 (14) 0 0.08Exon 21 6 (12) 2 (7) 0.70Tyrosine kinase inhibitors 18 (35) 4 (15) 0.06Chemotherapy 29 (57) 3 (11) 0.0001Radiotherapy 21 (41) 11 (41) 1.0Surgery 7 (14) 2 (7) 0.48Survival 279 (6-1328) 303 (15-1361) 0.63Data presented as number of patients (%), or median (range)

Figure 2 Kaplan-Meier curve showing survival difference among younger (n=51) and octogenarian (n=27) group. X-axis shows time in years.

10 respectively [12]. Similar findings have been reported on Caucasian population [13-15]. A study from England reported the mean age of 71 years (range 31-95) in lung cancer patients and commented it to be a common disease in the elderly with 43% of patients aged 75 or over at presentation [11]. In our cohort of 2011-2013, the median age was 69 years in keeping with the observation of Korean and British investigators. However this increase in median age of lung cancer presentation could be due to combination of greater incidence of lung cancer in the elderly and the increase in ageing population. A study from Turkey reported the median age of 59 years (range 35-88 years) in the lung cancer population [10], which suggests that this observation could be a reflection of differences in life expectancy between the countries.

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2) patients with discrete mediastinal node enlargement in whom the size of the nodes can be measured; 3) central tumour with normal mediastinal nodes; and 4) those with a peripheral tumour with normal mediastinal nodes [16-20]. Distinguishing these groups is particularly useful in defining the need and selection of invasive diagnostic & staging tests [16]. For example, in the first and second groups, Endo-Bronchial Ultrasound Guided Needle Aspiration (EBUS-TBNA) can often confirm both the stage of disease and the diagnosis with minimal, if any, additional risk. In the last two groups because of lack of mediastinal nodes enlargement, conventional bronchoscopy and Transthoracic Needle Aspiration (TTNA) respectively are the most appropriate diagnostic modalities. The studies looking at the distribution of these 4 categories in lung cancer in the elderly are sparse. However it has been described that peripheral type of presentation is commoner, seen in 62% of patients with the rising proportion over time (49.7% vs. 63.7% vs. 73.7%; P < 0.01) over the period of 2000-03, 2004-07, and 2008-10 respectively [12]. Our findings are consistent with these reports as 63% of octogenarians had peripherally located tumour.

The clinical implication of these radiological differences among the elderly lie in their impact on the healthcare policies and resource allocation planning of the hospitals by keeping themselves well equipped with the service of TTNA as it is likely to be required more frequently in keeping with rising ageing population and greater proportion of peripherally located tumour in these patients.

Our data also revealed that fibrotic changes, scarring, and a past history of tuberculosis were more common in octogenarian group. Previous history of TB and chronic inflammation has been reported to be associated with the development of lung cancer [21,22]. Our findings support the view that underlying pathophysiology may involve chronic inflammation and cell senescence due to aging rather than exposure to carcinogens or somatic mutations. However this requires further study and validation.

Treatment delay

A trend toward longer delay in starting the treatment was seen without reaching statistical significance. The most common cause for delay was “refusal of treatment” by the patient instead of age related selection bias for diagnostic work-up or therapeutic intervention as described by other investigators [11]. Clear causes of refusal could not be found due to lack of explicit documentation and retrospective nature of the study. The longer waiting times for surgery seen for elderly patients and those with co-morbidities have been reported [9,23]. The conceivable reasons described are that such patients often require relatively more preoperative tests, consults or preparation for the operating room [23].

One of the commonest reasons given for refusal of treatment by our patients was, wanting to try Traditional Chinese Medicine (TCM) or herbal medication instead. This may reflect the socio-cultural beliefs of our local population. Though we did not specifically explore any specific treatment preferences in the rest of our lung cancer patients, it’s likely that many of them would have taken some alternative form of complementary medicine.

N=27 < 365 daysN=13

> 730 daysN=4 P Value

Age 84 (80-93) 83 (81-89) 0.33

Male 11 (84.6) 2 (50) 1.0

Radiological features

Fibrotic changes 2 (15.3) 1 (25) 0.39

Scarring 6 (46.1) 1 (25) 1.0

Calcified granuloma 1 (7.6) 1 (25) 0.27

Pleural thickening 6 (46.1) 0 0.54

Peripheral tumour 6 (46.1) 4 (100) 0.01

Central tumour 6 (46.1) 5 (23) 0.50Discreet mediastinal lymph node 5 (38.4) 1 (25) 1.0

Mediastinal infiltration 2 (15.3) 0 1.0

Pleural Effusion 5 (38.4) 1 (25) 1.0

Site of cancer

Right upper lobe 4 (30.7) 0 1.0

Right middle lobe 2 (15.3) 0 1.0

Right lower lobe 3 (23) 1 (25) 0.49

Left upper lobe 2 (15.3) 1 (25) 0.39

Left lower lobe 1 (7.6) 2 (50) 0.04

Histology

Adenocarcinoma 7 (53.8) 2 (50) 0.58Squamous cell carcinoma 0 1 (25) 0.14

Small cell carcinoma 1 (7.6) 0 1.0

Smoking history

Never smoker 3 (23) 2 (50) 0.14

Current smoker 4 (30.7) 0 1.0

Stage Advanced (stage III-IV) 12 (92.3) 2 (50) 0.04

Early (stage I-II) 1 (7.6) 2 (50) 0.04

Therapy Tyrosine kinase inhibitors 2 (15.3) 1 (25) 0.39

Chemotherapy 2 (15.3) 0 1.0

Radiotherapy 4 (30.7) 3 (75) 0.04

Surgery 0 1 (25) 0.14

Table 3: Subgroup analysis of patients by survival < 1 year and > 2 years in octogenarian population (n=27).

Data presented as number of patients (%), or median (range)

Radiological features

Lung cancer in the Octogenarian population manifested at a peripheral location more frequently than discreet mediastinal lymph node, central tumour, mediastinal infiltration, or effusion. American College of Chest Physicians (ACCP) describes four categories with respect to intrathoracic radiographic characteristics in patients with lung cancer: 1) Patients with mediastinal infiltration that encircles the vessels and airways;

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Perhaps if the treating physician had reassured patients keen on TCM that its possible for them to receive both chemotherapy, radiotherapy or surgery as well (provided that there are no interactions), uptake of treatment could have been better in this group of patients.

Another common reason cited was patients stating that they were ‘too old’ for getting treatment. This may reflect the treating physicians’ beliefs that this may be a rational reason to refuse treatment. Perhaps a more comprehensive discussion should take place citing evidence that age does not have a detrimental effect on the safety of diagnostic procedures or outcome of treatment for lung cancer. This reassurance has to be provided to patients especially in the elderly in order to ensure that they are making a truly informed decision about their care.

An area of concern that we noticed was the general paucity of documentation for reasons for refusal of treatment amongst the elderly. In cases where younger patients had refused treatment, comprehensive documentation in the notes clearly stating various reasons given for refusing treatment as well as assurances of patient’s mental capacity to make those decisions were found. However, in case of older patients, reasons for refusal of treatment were usually documented simply as ‘advanced age’ or ‘too old’. In four cases, family members were allowed to be surrogate decision makers who decided that the patients were ‘too old’ for further diagnostic procedures or treatment despite no previous documentation to suggest any underlying cognitive impairment or lack of mental capacity in these patients. These shortcomings may reflect the treating physicians’ preconceived notions and nihilism about treatment of lung cancer in the elderly and are the areas amenable to improvement. Further study are needed to identify the true causes of refusal. Focus group discussion may be of help in this area.

Therapy

Chemotherapy was administered specifically less frequently to octogenarians as compared to younger population. This reflects specific bias against chemotherapy in this group likely due to concerns of greater risk of toxicity. Of the estimated 1.2 million people with lung cancer worldwide, approximately 300 000 have a diagnosis of Non-Small Cell Carcinoma (NSCLC) and are aged 70 years or older [24,25]. Many patients in this subgroup are not offered cyto-toxic treatment because of concerns about tolerability and the high risk-to-benefit ratio. It is believed that elderly patients are less likely than younger patients to tolerate potential toxicity of chemotherapy due to the age-related reduction in the functional reserve of many organs and co-morbid conditions [26,27]. Cisplatin-containing regimens for lung cancer have been shown to provide a slight advantage over supportive care without anti-neoplastic drugs (a 6-week increase in median overall survival) but can induce severe toxic effects [28]. Consequently, this treatment is frequently deemed contraindicated in elderly patients.

Survival

No difference in survival between younger, and octogenarian population was seen. This was interesting in view of the fact that octogenarians received chemotherapy less frequently than the rest of the patients. It can be argued that had the octogenarians

received chemotherapy, their survival may have been lower due to toxicity, but it could be higher by virtue of greater response rate can also be a valid argument. It has been shown that chemo-radiotherapy for the elderly does not result in improved survival when compared with those who had radiotherapy alone [29]. However, some investigators have demonstrated the survival advantage with chemotherapy in the elderly (>70 years old) despite the side effects [7,8]. In a recent randomised controlled trial that was performed on 200 elderly patients above 70 years old with inoperable stage 3 NSCLC, those receiving chemo-radiotherapy had improved survival over those who received radiotherapy alone [30]. Median overall survival for the chemo-radiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5-33·6) and 16·9 months (13·4-20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47-0·98, p value=0·0179). Though this came at a cost of increased haematological complications and infections in the chemo-radiotherapy group, the authors concluded that chemo-radiotherapy offered clinically significant benefits over radiotherapy alone. In our cohort, the sub-group analysis of octogenarians showed better survival (≥ 2 years) in patients with peripheral tumour, left lower lobe involvement, early stage, and radiotherapy. This may be a reflection of the effect of the early stage of lung cancer on survival. Correlation of radiotherapy with better survival in the context that radiotherapy was the most predominantly administered therapy to this group implies the benefit of offering some form of treatment to them. In view of the published literature supporting the survival advantage with chemotherapy [7,8] or chemo-radiotherapy [30] in this group, it is conceivable that addition of chemotherapy to their treatment regimen may confer improvement in survival.

Our study has limitations as it is a retrospective single centre study. Due to the retrospective nature, we could not identify the causes of refusal of therapy clearly. Another limitation is that although all patients who undergo diagnostic evaluation are referred to medical oncologist for further opinion and treatment in our centre, however, there are some patients who are deemed unfit even for the diagnostic procedure for a suspicious lesion on the imaging studies and are not referred for any treatment. These patients are either bedbound, have dementia, or are dependent in activities of daily living. Since we only looked at those lung cancer patients who underwent diagnostic procedure, followed by therapy, we may have missed this group. However in our anecdotal experience, such patients are very few in number. The strength of our study is that it provides insights into clinical and radiological features of lung cancer which has higher mortality rate than four most common cancers combined, in a subset of population that is under-represented in trials, and in which published literature is sparse, but which is expected to consume significant healthcare resources in the foreseeable future.

In conclusion, lung cancer is a disease of elderly population and as the population ages; age at presentation is likely to increase. Lung cancer presents peripherally in octogenarians making the service of TTNA an essential pre-requisite for all hospitals managing such patients. Fibrotic changes, scarring, and past tuberculosis correlate with lung cancer in this population. Delay in starting treatment occurred but was attributable to patients` refusal of treatment. There was no difference in survival between octogenarians & younger patients. Octogenarians with early

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Venkatachalam J, Abisheganaden J, Chen S, Lim AYH, Tai DYH, et al. (2015) Lung Cancer in Asian Octogenarian Population. Ann Gerontol Geriatric Res 2(2): 1026.

Cite this article

stage cancer, peripheral tumour, left lower lobe involvement, and treated with radiotherapy correlated with better survival. This helps to dispel nihilism surrounding the treatment of lung cancer in the elderly and should encourage local physicians to have detailed discussions with the elderly patients and their families to understand true cause behind their refusal for treatment and provide support to overcome these.

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