Lung cancer is one of the commonest cancers and cause of cancer related deaths all over the world. It accounts for 13 % of all new cancer cases and 19 % of cancer related deaths worldwide. There were 1.8 million new lung cancer cases estimated to occur in 2012.¹

In India, lung cancer constitutes 6.9 % of all new cancer cases and 9.3 % of all cancer related deaths in both sexes, it is the commonest cancer and cause of cancer related mortality in men, with the highest reported incidences from Mizoram in both males and females (Age adjusted rate 28.3 and 28.7 per 100,000 population in males and females, respectively). ²

Computed tomography (CT)is a best method for the detection and quantification of emphysema,^3,4 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.⁵ 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.⁶

Several lung cancer histologies exist, each with characteristic molecular and clinical features.⁷ A previous case–control study found an increased risk of squamous carcinoma associated with the clinical diagnosis of chronic obstructive pulmonary disease (COPD).⁸ However, the correlation between COPD (as defined spirometry) and emphysema is limited.^9,10 Present study was aimed to study prognostic value of CT-emphysema score & concomitant pulmonary pathologies (like pleural effusion, atelectasis, lymphangitic spread, pulmonary metastases etc.) on overall survival in patients with advanced Non-Small Cell Lung Carcinoma treated with chemotherapy.

Present study was single-center, retrospective study, conducted in department of radiodiagnosis, at Tata memorial center, 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. Study approval was obtained from institutional ethical committee.

Inclusion criteria

• Patients with histopathologically proven advanced nonsmall cell carcinomas of lung mostly adenocarcinoma treated with palliative chemotherapy AND 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

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.

CT-emphysema score, 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.¹¹ 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

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 occasionData 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.

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.

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 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

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 statistically significant association seen in OS with pleural effusion and extensive pulmonary metastases (p>0.05)

Table 3: Univariate & Multivariate analysis

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 1: 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 2: 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 statistically 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 3: Kaplan–Meier curve for overall survival and emphysema grade

Volume grade

It is nothing but observed functioning volume of both the lungs at base line scan. There is also association between volume of lung and OS, as the patients with optimum volume were showing increased OS with p value of 0.03(<0.05)

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

Lymphangitic spread

This is characteristic feature of adenocarcinoma though also seen in other histological types of carcinoma lung. In our study we only considered extensive lymphangitic spread. The association between this and OS is shown below. There is significant correlation between OS and lymphangitic spread. As the presence of diffuse lymphangitic spread leads to disease progression and reduced overall survival.

Figure 5: Kaplan–Meier curve for overall survival and pleural effusion

Pleural effusion grade and extensive pulmonary metastases:

Pleural effusion and extensive pulmonary metastases do not affect the overall survival and show no significant correlation with OS. Their correlation is as shown below with p-values of 0.9 and 0.5 respectively i.e.,>0.05.

Figure 6: Kaplan–Meier curve for overall survival and pleural effusion.

Figure 7: Kaplan–Meier curve for overall survival and extensive pulmonary metastases and OS

Concomitant pulmonary pathologies (like pleural effusion, atelectasis, lymphangitic spread, pulmonary metastases etc.) are seen in patients with advanced Non-Small Cell Lung Carcinoma treated with chemotherapy. A malignant pleural effusion (MPE) is often the first sign of cancer and it is a prognostic factor in patients with advanced disease. MPE can be a complication of any malignancy, but in patients with lung cancer, the frequency of MPE ranges from 7% to 23%.¹⁴

MPE is characteristic of advanced malignancies, but it may also appear in patients with a longer projected survival (e.g., those with lymphomas, including Hodgkin’s disease, and breast carcinoma). The quality of life in patients with MPE is usually compromised because of distressing symptoms, such as coughing, dyspnea, and chest pain.^15,16,17

More than half of lung cancer patients have metastatic disease at presentation. Bones, adrenals, brain, and liver are the common distant metastatic sites. Metastatic disease with a few exceptions is not amenable to surgical resection or any kind of potentially curative therapy.

In present study, 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.,¹⁷ Saing Kin et al.,⁴ and Laila A Mohsen et al.,¹⁹ respectively. These studies were also having p values <0.05.

We noted that, 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) 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, there is no significant correlation seen between pleural effusion and overall survival with p value of 0.5 (>0.05), this could be due to their majority of patients in study population were of stage III with PS 3 and above whereas in our study population most of the patients are of stage IV with PS of 1. 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.

As the Goddard semi-quantitative scoring system was used in the present study to evaluate the severity of emphysema in baseline CT scans. This visual scoring method is straight forward and can be performed rapidly because it does not require post-processing techniques, such as, lung segmentation, thresholding, or manual extraction for quantitative CT assessment.

Furthermore, previous studies have reported good agreement of semi-quantitative scores between expert readers for the assessment of presence and extent of emphysema, and subjective visual assessments were found to be well correlated with objective lung attenuation measurements obtained by two- or three-dimensional CT densitometry. Since all lung cancer patients undergo an initial chest CT scan for diagnosis and staging, this method might allow the routine quantitative assessment of emphysema in lung cancer patients without additional cost or radiation exposure.

There is statistically significant association between CT-emphysema score & concomitant pulmonary pathologies on overall survival (OS) in patients with advanced Non-Small Cell Lung Carcinoma treated with chemotherapy. There is significant correlation between OS and lymphangitic spread. As the presence of diffuse lymphangitic spread leads to disease progression and reduced overall survival. Pleural effusion and extensive pulmonary metastases do not affect the overall survival and show no significant correlation with OS.

Conflict of Interest: None to declare

Source of funding: Nil

1. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology and Prevention Biomarkers. 2016 Jan 1;25(1):16-27.
2. Malik PS, Raina V. Lung cancer: Prevalent trends & emerging concepts. The Indian journal of medical research. 2015 Jan;141(1):5.

3. Madani A, Zanen J, De Maertelaer V, Gevenois PA. Pulmonary emphysema: objective quantification at multi–detector row CT—comparison with macroscopic and microscopic morphometry. Radiology. 2006 Mar;238(3):1036-43.
4. Kim YS, Kim EY, Ahn HK, Cho EK, Jeong YM, Kim JH. Prognostic significance of CT- emphysema score in patients with advanced squamous cell lung cancer. Journal of thoracic disease. 2016 Aug;8(8):1966.
5. Smith BM, Pinto L, Ezer N, Sverzellati N, Muro S, Schwartzman K. Emphysema detected on computed tomography and risk of lung cancer: a systematic review and meta-analysis. Lung cancer. 2012 Jul 1;77(1):58-63.
6. Gullón JA, Suárez I, Medina A, Rubinos G, Fernández R, González I. Role of emphysema and airway obstruction in prognosis of lung cancer. Lung Cancer. 2011 Feb 1;71(2):182-5.
7. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization, International Agency for Research on Cancer, International Association for the Study ofLung Cancer, International Academy of Pathology, Pathology and Genetics of Tumours ofthe Lung, Pleura, Thymus and Heart. Pathology and Genetics of Tumours of The Lung, Pleura, Thymus and Heart. 2004.
8. Papi A, Casoni G, Caramori G, Guzzinati I, Boschetto P, Ravenna F, Calia N, Petruzzelli S,Corbetta L, Cavallesco G, Forini E. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax. 2004 Aug 1;59(8):679-81.
9. Bergin C, Müller N, Nichols DM, Lillington G, Hogg JC, Mullen B, Grymaloski MR, Osborne S, Paré PD. The diagnosis of emphysema: a computed tomographic-pathologic correlation. American Review of Respiratory Disease. 1986 Apr;133(4):541-
10. Gelb AF, Hogg JC, Müller NL, Schein MJ, Kuei J, Tashkin DP, Epstein JD, Kollin J, Green RH, Zamel N, Elliott WM. Contribution of emphysema and small airways in COPD. Chest. 1996 Feb 1;109(2):353-9.
11. Goddard PR, Nicholson EM, Laszlo G, et al. Computed tomography in pulmonary emphysema. Clin Radiol 1982;33:379-87. 10.1016/S0009-9260(82)80301-2
12. Froudarakis ME. Pleural effusion in lung cancer: more questions than answers. Respiration. 2012;83(5):367–76.
13. Chernow B, Sahn SA. Carcinomatous involvement of the pleura.An analysis of 96 patients. Am J Med. 1977;63(5):695–702.
14. Haas AR, Sterman DH, Musani AI. Malignant pleural effusions - management options with consideration of coding, billing, and a decision approach. Chest.2007;132(3):1036–41.
15. Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ. Management of a malignant pleural effusion: British thoracic society pleural disease guideline 2010. Thorax. 2010;65(Suppl 2):ii32–40.
16. Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ. Management of a malignant pleural effusion: British thoracic society pleural disease guideline 2010. Thorax. 2010;65(Suppl 2):ii32–40.
17. Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD. COPD prevalence is increased in lung cancer independent of age, gender and smoking history. European Respiratory Journal.2009 Feb 5.
18. Shaw AT, Kim D-W, Mehra R, Tan DSW, Felip E, Chow LQM, et al. Ceritinib in ALK- rearranged non-small-cell lung cancer. N Engl J Med 2014; 370 : 1189-97.