Postoperative Severe Lung Failure and Functional Variations in Lung Cancer Patients with Different Extent of Resection: A Pilot Study .

sample of 75 patients who underwent surgery for lung retrospectively studied about respiratory function and arterial gasanalysis .Data were collected and after A subgroups comparative analysis was performed between group who underwent lobectomy vs group who underwent sub-lobar resection represented by either wedge or segmentectomy. Lung failure was categorized as severe for PaO2< 50 mmHg or non severe for PaO2 >50 mmHg.


Introduction
Lung cancer it is the leading cause of cancer death worldwide. It is classi ed as non small cell that includes squamous, adenocarcinoma, large cell and small cell lung cancer. All histotypes are often associated with COPD .
The latter is de ned as an in ammatory bronchial chronic condition characterized by air ow limitation that is not fully reversible and it is usually caused by exposure to noxious particles or gases predominantly cigarette smoking, though other exposures such as biomass fuels are an important cause. It is the major cause of morbidity and mortality worldwide. It is frequently a comorbidity in lung cancer patients.
The relationships between in ammation, air ow limitation, and lung cancer are known but not fully clari ed (1) By far the main avoidable cause of both COPD and lung cancer is tobacco smoke which contains several chemicals more than 5,000 identi ed, including tobacco-speci c carcinogens such as nitrosamines, nitric oxide, benzopyrene.
By contrast smoking cessation is recognized to be the main tool to improve by itself the prognosis of the diseases and lung function (2).
Lung failure is a possible complication of both diseases and it often occurs after surgery (3) Lung cancer and COPD are often associated share the same initial pathogenesis (4) Lung cancer survival has reached partial improvements in the last few decades. Poor outcomes are linked to late clinical presentation, yet early diagnosis can be challenging as lung cancer symptoms are common and non-speci c.
Furthermore it is vital in assessing lung cancer risk to look carefully at lifestyle factors and past medical history The aim of our study is to investigate the effects of the type of surgery in lung cancer patients on lung failure development to determine the variables in uencing severe lung failure development and to detect the functional and respiratory changes after surgery comparing the two subgroups.

Methods
From 2019 to 2020, 65 patients were retrospectively analyzed who underwent thoracic surgery for lung cancer. This is a monocentric study based on the collaborations between thoracic surgeons and pulmonologists.
The age and demographic data were recorded as well as functional data, types of surgery, tumor staging, hospitalization time.
Patients underwent different lung resection by mini-thoracotomy approach meaning and incision of 3-4 inch between the ribs, some had lobectomy by thoracotomy and some others underwent sub-lobar resection by mini-thoracotomy .
All patients performed spirometry before and after surgery with detection of post-bronhodilator values, an arterial blood sample was also done with hemogasanalysis that was performed at baseline, 15 days after surgery and at three month check(GEM 3000 device,USA). The COPD assessment test was also applied and it was considered positive in case of score>10 according to GOLD guidelines.
The spirometry was performed by body plethysmography (Jaeger system masterscreen, Germany) as follows: brie y, ow sand dynamic volumes were measured by the pneumotacographic method and volumes and resistances by the plethysmographic method. Data recorded were post-bronchodilator Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), recorded as liters and percentage of predicted. The time for post-bronchodilation was 25 minutes obtained by salbutamol 400 µg. The techniques followed the American Thoracic Society and European Respiratory Society task force guidelines (5). Lung failure is categorized as severe (PaO2<50 mmHg) or non severe.
The sub-analysis included a group who underwent lobectomy(35) and group with sub-lobar resection (40).The study was approved by S.Andrea-Sapienza Ethic Committee, and a consent form was obtained by each patient.

STATISTICAL METHOD AND ANALYSIS
The normality of the data was assessed by the Kolmogorov-Smirnov test and values were expressed as mean and standard deviation (SD) or median and interquartile range, as appropriate. A sub-analysis was performed to compare subgroup of patients as described previously.
For this purpose Mann-Whitney test or Fisher's test was applied as appropriate and signi cance p level was set at <0.05 A logistic regression analysis was performed to correlate functional data and type of surgery with severe lung failure. Subsets of patients depending on type of surgery and their association with different grade of lung failure was detected by contingency table test and odds ratio calculation.
ANOVA test one way was eventually performed for repeated measurements to compare the changes in respiratory function before and after surgery between groups.
All data were acquired by SPSS version 24.0(USA)

Results
Overall data revealed 40 wedge resections and 25 lobectomies.
The prevalent stage was IA2 and prevalent hystotype was adenocarcinoma At baseline table 1 displays the following Patients are still alive except for 4 patients who died of whom 3 underwent lobectomy and 1 underwent wedge resection.
In Table 2 a logistic regression analysis revealed the following data: Table 2 Dependent variable: severe lung failure Only the type of resection and COPD affected signi cantly the dependent variable that was severe lung failure. The OR was 2.8 about lobectomy and 2.1 about COPD in uence(p<0.04 and p<0.03 respectively ). Table 3 contingency table with determination of odds ratio of the relationship between patients treated with sub-lobar resection(group 0) versus patients treated with lobectomy (group 1) with the risk of severe lung failure development and showed a signi cant increased risk in patients treated by lobectomy lobectomy with higher risk of long lasting oxygen supply(p<0.005) . Realationship : type of surgery and CAT>10 vs severe lung failure An increased risk was also found associated with a positive CAT score with an OR 2.8 (p<0.04). Table 4 Difference between group 0 (sub-lobar resection) and 1(lobectomy) Differences between group 0 and group 1 were signi cant about hospitalization time(p<0.03) with a longer time in patients treated by lobectomy. The groups were comparable for COPD ,age and pack-year. A signi cant difference in PaO2 value was also found(p<0.03)at 15 days post-surgery and after three months from surgery (p<0.04) showing an improvement only in the group treated with a limited resection .
In group 0 (sub-lobar resection) 60% of patients gave up oxygen after 3 months from surgery, compared with 45% in group 1. Table 5 Changes of FEV1 and FVC before and after surgery: comparison between group treated by sub-lobar resection G0 and group treated by lobectomy Differences were observed abut the variations of of changes of the main functional parameters before and after surgery comparing the two subgroups ,group 0 sub-lobar resection and group 1 lobectomy. A greater lost of functional values was observed in the second group and the difference was signi cant for both FEV 1 and FVC (p<0.001).

Discussion
Patients are often concerned about the prospect of using oxygen therapy postoperatively, and this factor may affect their choice about lung cancer treatment.
Our study showed important ndings concerning the need of oxygen therapy after surgery and pointed out which variables are associated with the clinical outcome Notably a higher percentage of patients who recovered from lung failure was found at post-surgery check in the group who underwent wedge sub-lobar resection. The CAT questionnaire major than 10 was also associated with a higher risk of severe lung failure meaning that concurrent COPD exacerbation may in uence post-surgery complications. The development of respiratory failure after surgery is a frequent occurrence with a long-lasting need of oxygen therapy but after three months from surgery patients treated with sub-lobar resection returned to acceptable PaO2 values without oxygen supply. The presence of COPD was indeed a factor affecting lung failure development and was more present in group high oxygen intensity.
Smoking habit is the main avoidable cause of both COPD and lung cancer as we know from previous studies (4).
COPD and lung cancer have a common origin sharing in ammation as main associated feature(4).
For NSCLC, surgical resection is the standard treatment for stage I-II disease; patients with IB or II disease are being offered adjuvant chemotherapy. Some patients with a stage IIIA tumor are suitable for surgery but often receive pre-or post-operative radiation and/or chemotherapy (6). Depending on their extent, pulmonary resections lead to permanent loss of pulmonary function. In healthy people, resections up to a pneumonectomy are remarkably well tolerated.
Consistenly with the literature our ndings suggest that COPD could in uence the respiratory failure development but the extension of the removed parenchyma in uence even more the functional values decrease and as a consequence it in uences the outcome (7).
Indeed, we found a major change in FEV1 and FVC in patients who underwent lobectomy as well as a worse hospitalization time. The risk of respiratory failure precludes lung surgery in many patients with severe chronic obstructive pulmonary disease. It is generally agreed that a minimum value of forced expiratory volume in 1 second (FEV1) is required preoperatively (2 l before pneumonectomy and 1.5 l in case of lobectomy, respectively). Variable cutoff values of FEV1(ranging from 35-80%) have been arbitrarily chosen to assess the severity of COPD and to predict the risk for pulmonary complications. By using receiver-operating characteristic analysis, Licker et coll con rmed that the best cutoff value of FEV1 for predicting respiratory complications was 60% (7,8).
The risk of respiratory failure in COPD may preclude lung surgery in many patients with severe chronic obstructive pulmonary disease may be a drawback in patients who undergo thoracic surgery for lung cancer .
We found that COPD irrespective of FEV1 value itself in uences the post-operative outcome (9).
The presence of COPD is not an absolute contraindication to surgery as we know from the literature since lobectomy for cancer can be performed successfully also in selected patients with chronic obstructive pulmonary disease (10). However the grade of air ow limitation and concurrent cardiovascular abnormalities are associated with an increased morbidity (11,12). A PaCO2 alteration along with FEV1 early decrease may be observed ,mainly among patients who died after surgery (13,14,15). In the present study a worse arterial oxygenation level was observed in the group undergoing more extensive resection.
Previous studies compared lobectomy with pneumonectomy but not lobectomy with sub-lobar resection (16,17). Predictors of complications may include age ,gender, history of smoking, type of resection aside from FEV1 value (18,19,20). Our population was mainly former smokers and pack-year did not affect signi cantly lung failure occurence.
The results show us that COPD is the main comorbidity affecting the quality of life and the possibility of complications that could be partially reversed by bronchodilators and smoking cessation (21,22,23). As far as surgery techniques is concerned one possible approach in lung cancer surgery treatment is the video assisted thoracoscopy (VATS) approach that has a signi cantly lower rate of complications compared with thoracotomy (28% vs 45%, p = 0.04) (24).Other valid approaches that we used are minithoracotomy or lateral muscle sparing thoracotomy suitable for different extent of resection. Our study is the result of an interdisciplinary cooperation notably between pulmonologist and thoracic surgeon allows to better manage the patient undergoing lung cancer treatment consistently with previous studies (25)Greater loss of function in the sense of a decrease of FEV1 and FVC was observed in patients treated with lobectomy leading to a greater lung failure percentage and longer hospitalization time. A recovery from lung failure after three months along with a lower hospitalization time was observed notably in patients treated with sub-lobar resection.

Conclusions
Our study highligths the in uence of COPD and extent of lung parenchyma resection on respiratory failure development. The majority of patients treated with a more conservative surgery recovered more easily from lung failure .COPD was the main comorbidity able to affect the outcome along with the type of surgery.
The greater changes of functional parameters was notably observed in cases treated with lobectomy.
Considering the results we advise a screening of high risk patients to nd an early diagnosis in order to promote a sparing parenchyma resection considering equal oncological radicality to reduce postoperative complications. Moreover being a pilot study more patients will be recruited in early future.  Changes of FVC before and after surgery