Chronic obstructive pulmonary disease (COPD) and lung cancer are major medical challenges. As COPD and lung cancer are the leading cause of increased morbidity and mortality in the world and so in India. Emphysema, one of the classic subtypes of COPD, is characterized by abnormal and permanent enlargement of airspaces distal to terminal bronchioles and the destruction of the alveolar walls. ^1,2

Pulmonary emphysema and chronic bronchitis are important components of chronic obstructive pulmonary disease (COPD). Emphysema often simultaneously exists with chronic bronchitis in the COPD population, and from a clinical point of view, they are generally considered as one entity. Although a tissue diagnosis of emphysema is possible, in advanced cases it can usually be confidently diagnosed on the basis of the patient's history, physical findings, pulmonary function, and imaging results. Smoking is having an obvious relation between both diseases, and the resulting chronic inflammation likely plays an important shared role in the pathogenesis of COPD and lung cancer.^1,2

Computed tomography (CT)is a best method for the detection and quantification of emphysema,^2,3 and emphysema diagnosed with routine CT has also been reported to be associated with an increased risk of lung cancer independently of smoking history and airflow obstruction.⁴ Furthermore, presence of emphysema detected by CT in all stages of non-small cell lung cancer (NSCLC) and small cell lung cancer patients has adverse prognostic impact have reported by recent studies.^5,6 Present study was aimed to study CT emphysema score as a prognostic indicator in advanced non-small cell lung carcinoma treated with chemotherapy.

Present study was single-center, retrospective study, conducted in department of radiodiagnosis, at Tata memorial centre, Mumbai, India We retrospectively identified 285 consecutive patients with advanced NSCLC (stages IIIB and IV) that received palliative chemotherapy at between January 2011 and December 2016. All these patients had histologically proven adenocarcinoma. Study approval was obtained from institutional ethical committee.

Inclusion criteria

• Patients with histopathologically proven advanced non-small cell carcinomas of lung, mostly adenocarcinoma treated with palliative chemotherapy
• CT/PET CT thorax images of the patients available for evaluation

Exclusion criteria

• Patients who had undergone pulmonary resection
• Incomplete patient records
• Baseline imaging without chemotherapy

This is a retrospective observational study of the data of 285 patients who had baseline PET-CT or CECT and underwent treatment for lung cancer at our institute. The patient data was extracted from a prospectively managed institutional data base and the baseline PET- CT or CECT scans were retrieved from the institutional PACS system for analysis.

Medical records were reviewed to extract the Patient details and tumour characteristics. Patient information included age, sex, performance status (PS), smoking habit, stage, pre-treatment staging, treatment data including whether the patient received chemotherapy, chemotherapy regimen, metastatic pulmonary lesions, lymphangitic spread, pleural effusion, functional grade, collapse grade and overall survival (OS).

Emphysema is considered on the basis of imaging done at the baseline using CT scan or PET CT scan which is characterized as areas of low attenuation that contrast with the normal attenuation of surrounding lung parenchyma on CT.

The scans were acquired in helical mode using the same scanning protocol on a 16-slice CT Scanner (Siemens Somatom Sensation 16; Siemens Somatom Definition). The following acquisition parameters were used in the scanning protocol: 1 mm collimation, 120–140 kV, 75–350 mA, 0.75–1 s scan time and 1–2mm slice thickness. All scans were performed caudocranially with arterial contrast enhancement using bolus tracking. In the descending aorta, to avoid blurring due to breathing movement, spoken instructions were used to achieve end inspiration (‘‘breathe in and hold your breath’’). Axial slices of 1 mm were reconstructed. For lung-volume measurement, manual volumetry was used. Data sets for the lung were imported in a soft tissue kernel (B30 F).

CT-emphysema score:

This is also known as Goddard score. Emphysema severity was assessed by subspecialty-trained chest radiologist according to the Goddard scoring system using CT images acquired at time of diagnosis.⁷

Calculation of emphysema score

Each lung was divided into three areas, that is, upper, middle, and lower lung fields. An upper section was taken 1 cm above the superior margin of the aortic arch, A middle section 1 cm below the carina, and A lower section approximately 3 cm above the top of the diaphragm

Emphysema is detected on CT images as low attenuation regions that contrast with surrounding normal lung parenchyma. Each area was graded using a 5-point scale, as follows;

1. No emphysema (score 0),
2. ≤ 25 % emphysema (score 1),
3. ≤ 50 % emphysema (score 2),
4. ≤ 75 % emphysema (score 3) and
5. 75 % emphysema (score 4).

Scores from the six regions were added to calculate a total score, which resulted in a possible minimum and maximum score of 0 and 24, respectively. Because 9 5 % of nonsmokers in previous studies had lungs with less than 5 % emphysematous involvement,⁸ total CT-emphysema scores of 0 and 1 were assumed to represent the absence of emphysema. Two independent radiologists have evaluated the images in the same manner and on separate occasions and their readings have been recorded. Repeatability of scoring was done by one of the authors on 2 separate occasions.

Data was analysed using SPSS 21 statistical package (IBM). For descriptive statistics the results were expressed as mean ± standard deviation (SD). Patients’ anthropomorphic measurements, disease characteristics, and pathological features were compared to the morphmetrics using evaluated using Fisher’s exact test or analysis of variance techniques when the number of groups exceeded two. The associations between emphysema score and associated comorbidities with OS were performed using the Kaplan–Meier method and compared with the log-rank test. Significant univariate variables were included in a multivariate logistic regression analysis to adjust for other confounding factors such as age and/or tumor stage. Cox proportional hazard regression models were used for multivariate analysis to assess the association of body composition measurements for significant patient characteristics. For all statistical tests, P-values at or below 0.05 were considered significant

Figure 1: Right lung volume calculated as 2114.5 cc                        Figure 2: Total lung volume calculated as 3204 cc

Figure 3: Topogram and CT cuts at upper, middle and lower levels depicting the divisions of lungs for calculation of emphysema score

CT emphysema scores were analyzed for the 285 lung cancer patients treated at our hospital. The majority of patients were male (males =159, 55%, females=126, 45%) and the mean age was 54 years. Histopathology of all the patients was adenocarcinoma. 59 (20.7%) of total patients were

smoker out of which 54 (92%) were males. 268(94%) patients had an ECOG of 0 or 1 and 17 patients had an ECOG of 2 or more. Majority of the patients (96.9%) had stage IV cancer while remaining were stage III.

Table 1: General characteristics

In our study population,134 patients (47%) were having emphysema while other 151 patients (53%) were having normal lungs. Total emphysema score of 0 or 1 was considered as no emphysema, since 95% of nonsmokers in previous studies had lungs with <5% emphysematous involvement.

125 patients of study population were having collapse lung which were graded as mild, moderate and severe and rests were having normal lungs. Extensive lymphangitic spread was seen in 50 patients and rests (235) were having no lymphangitic spread. Pleural effusion with mild, moderate and severe grades was found in 46 patients while other 239 patients were having no pleural effusion.

Table 2: Radiological findings

The mean follow-up was 54 months, during which time a total of 210 (73.6%) patients experienced progression and 218 (76.4%) patients died.

The mean overall survival was 20.97 months with no statistical difference between male and female. The mean OS in emphysematous patients were 12.3 months and in non- emphysematous patients were 28.8   months.

Table 3: Survival

Difference in OS was found to be statistically significant in patients with respect to their age, smoking status, CT emphysema score, functional lung capacity, collapse grade, volume grade, lymphangitic spread and comorbidity score on the univariate analysis (p value 0.010, <0.001, 0.007, <0.001, <0.001 and <0.001 respectively).

In multivariate analysis all the above-mentioned parameters except age show statistically significant difference in OS with p value <0.05. There is no statistical significant association seen in OS with pleural effusion and extensive pulmonary metastases (p>0.05)

Table 4: Univariate & Multivariate analysis

There is statistical significant difference between increased age with overall survival having p value of 0.01. Difference in OS was found to be statistically significant in patients with respect to smoking history with p value of 0.010.

Table 5: Cox proportional hazard model for OS

Functional lung capacity grade:

In this, we divided both the lungs into 6 regions in similar way used in calculation of emphysema score. Each region has been given as grade of 3 if it is optimally functional, 2 if is borderline functional, 1 if it is poor and 0 if it is nonfunctional.

Test of equality of survival distributions for the different levels of Functional grade.

Figure 4: Kaplan–Meier curve for overall survival and functional grade

Collapse grade:

In this, opposite to the functional score, we gave the grades of 0, 1, 2 and 3 if the region appeared to be optimally functional, partially collapsed, borderline collapsed and completely collapsed respectively. We found correlation between them and OS as below

Test of equality of survival distributions for the different levels of collapsed grade.

Figure 5: Kaplan–Meier curve for overall survival and collapse grade

There is significant association between functional grade, collapsed grade and overall survival. Patients with optimum functional grade show increased OS. It is inversely related to collapse grade, stating that patients with decreased functional volume, associated with collapse are having increased collapse grade with decreased OS, means as collapse grade increases functional grade decreases and OS decreases.

Both above grades i.e, functional and collapse grades show p values of 0.007 and 0.001 respectively (p value <0.005) suggesting significant association.

CT Emphysema score and overall survival:

There is statistical significant association with p value <0.001 between emphysema score and overall survival. This suggest that patients with increased emphysema score means having more emphysema at the base line scan will show decreased overall survival compared to the patients with decreased emphysema score or no emphysema.

Figure 6: Kaplan–Meier curve for overall survival and emphysema grade

We considered all the parameters and calculated single grand total score labeled as total comorbidity score which includes, Functional grade, Collapse grade, Extensive metastases, Effusion grade, Emphysema grade, Volume grade & Smoking history. This grand total score shows significant statistical association with overall survival with p value of <0.001. This is shown below

Figure 7: Kaplan–Meier curve for overall survival and grand total score

In present study, CT emphysema score was assessed as a potential novel risk factor for clinical outcomes in 285 patients with lung cancer. We noted several findings of interest and compared with multiple similar studies available in literature.

In our study out of 285 patients majority of the patients were males 159 (55.7 %) and 126 (44 %) patients were females. The mean age was 54 years. In the other studies, mean age was also found to be in the range of 55 to 68 years such as Hee Young Lee et al.,⁹ (mean age – 68 years), Saing Kin et al.,³ (mean age – 69 years) & Smith BM et al.,¹⁰ (mean age – 69 years).

We used mean CT emphysema score as 4; at this value we come to know that there is significant correlation between emphysema score and OS. As the emphysema score increases there is decrease in OS with p value of less than 0.001(<0.05 significant). This is supported by the previous studies who considered mean emphysema scores as 6.6, 6.3 and 3 by Hee Young Lee et al.,⁹ Saing Kin et al.,³ and Laila A Mohsen et al.,¹¹ respectively. These studies were also having p values <0.05.

Functional capacity grade is considered in our study by considering the functional volume of lung. It is calculated by dividing the lungs into 6 regions same as divided in calculating the CT emphysema score. If all the 6 regions are functional then grade becomes 6 and any segment is nonfunctional then we calculated grade by subtracting the number of nonfunctional segments from the total 6 segments.

In our study, there is good correlation between functional grade and overall survival with p value of 0.007 (<0.05). As more the functional grade more is the functional reservoir of lungs and more the OS.

It is in opposite to the functional grade, i.e, the total collapsed lung which is not taking part of normal lung function in respiration. It is either due to pleural effusion or tumor infiltration. It is calculated by dividing the lungs into 6 segments like above; collapse grade is equal to the number of nonfunctional segments. There is also significant correlation between collapse grade and OS. As more the collapse grade less is the functional grade and less the OS. In our study, p value is 0.001(<0.05)

However this is in contradictory to the previous study done by Yilmaz Bulbul et al.,¹² which proved that presence of atelectasis in advanced NSCLC had better prognosis as compared to lungs without atelectasis. This could be due to their exclusion criteria like patients who had resectable lung cancer, who received prior chemotherapy or radiotherapy, who had no definitive histologic diagnosis and, who had bad performance status (ECOG 3 or 4) whereas in our study we included all the above patients. This might affect the results

In our study patients with lymphangitic spread were showing lower OS with p value of 0.001. Thus we can take this parameter as factor affecting prognosis in advanced lung cancer. All the above studies did not consider this as the prognostic significance but in our study we proved that lymphangitic spread decreases the survival outcome of patients.

In our study we cannot find the relation between overall survival and extensive pulmonary metastases. It is showing p value of 0.9 (>0.05). This parameter was also not considered by the above previous studies however we found that majority of advanced lung carcinoma patient with extensive pulmonary metastases show good response to chemotherapy and there is decrease in metastases burden in subsequent follow up imaging.

The present study has several limitations that require consideration. First, the number of patients included was small, although the study populations are homogeneous in terms of histology, stage, and treatment. Furthermore, we cannot analyze the value of the emphysema distribution (i.e., one area with >75% emphysema vs. diffuse emphysema across multiple regions) because no patient had localized emphysema. Finally, detailed information regarding the smoking status after cancer diagnosis cannot be obtained since this study was conducted in retrospective manner. It has been reported that smoking status after cancer diagnosis affects prognostic outcomes.^13,14

In conclusion, a higher CT emphysema score, as determined using baseline CT scans, was found to be associated with poor prognosis in patients with advanced adenocarcinoma lung cancer. Furthermore, our findings suggest CT-emphysema score could be used to better predict prognosis in advanced lung cancer. We can also use CT based functional and collapse grades for assessment of prognosis in newly diagnosed cases of lung cancer.

Conflict of Interest: None to declare

Source of funding: Nil

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