INTRODUCTION:

The number of lung cancer cases has been increasing in Asia. Currently, the incidence and mortality from lung cancer have been reported to increase¹. In 2018, 1,225,029 lung cancer cases were reported in Asia alone. This is 58.8% of all cancer cases recorded worldwide. In 2018, 1,068,862 deaths were reported due to lung cancer in Asia, which is 60.7% of all deaths attributed to cancer worldwide²^-4. The data and information center from Globocan 2020 shows that the incidence of lung cancer in Indonesia in 2020 ranks third with 36,663 new cases (8.8%) of all cancers in both sexes combined and ranks first from top 5 most frequent cancers (ranked by cases) in males^5,6.

Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC)^7–11. Unfortunately, 75% of all patients with NSCLC are diagnosed at an advanced or metastatic stage which often concurrent with malignant pleural effusion (MPE), which is considered a complication in 40% of lung cancer cases^12,13. In MPE cases, NSCLC accounts for most MPE, while 40% is attributed to adenocarcinoma and 23% to squamous cell carcinoma. Only 17.6% of MPE cases were found to be caused by small cell carcinoma¹⁴.

MPE is an effusion related to malignancy, which is defined by the presence of malignant cells in cytology examination from pleural fluid or pleural biopsy. However, in several cases, MPE can also present without any cancer cells found in pleural fluid or pleural tissue. This effusion is called para-malignant effusion¹⁵. Some techniques can be used as palliative therapy to relieve dyspnea symptoms caused by MPE; these are (1) repeated thoracocentesis, (2) pleurodesis, and (3) placement of an indwelling pleural catheter¹⁶. Hence, from all of the techniques mentioned above, an ultimately ideal procedure has yet to be established, as those procedures still need to be performed multiple times, with prolonged hospitalization days and longer periods on catheter drainage.

Pleurodesis is a medical procedure that aims at the permanent adhesion of visceral and parietal pleura mechanically, chemically, and also minerally, in order to prevent fluid and air accumulation in the pleural space. Pleurodesis is indicated for MPE, recurrent pleural effusion, and recurrent pneumothorax. Pleurodesis acts as a long-term therapeutic procedure; thus, it can be performed as palliative therapy for MPE patients¹⁶. Standard procedure pleurodesis is a procedure that is performed by inserting a sclerosing agent through the thoracic drain and, then, after evacuated, assessed using a chest x-ray showing expanding lungs and absent trapped lung, with pleural fluid production <150ml/day. Meanwhile, rapid pleurodesis is a procedure that is performed by inserting a sclerosing agent through the thoracic drain and, then, after evacuated, assessed using a chest x-ray showing expanding lungs and absent trapped lung, without consideration of a minimal amount of liquid (<50ml/24 hours).

The exact pleurodesis procedure approach is still often be controverted. However, study on rapid pleurodesis conducted by Foo et al. (2020) suggests that rapid pleurodesis is a safe and effective option in the management of MPE. Based on Thai Foo’s research, All patients received a definitive pleural intervention with 86.7% of them discharged on the same day and 77.8% pleurodesis success at 6-months¹⁷. The British Thoracic Society Pleural Disease Guideline 2010 also reports that pleurodesis should not be postponed when, after evacuated, proved expanding lungs and absent trapped lung in chest x-ray (B)¹⁸. In literature data, especially in Asia, there is only limited research or publication showing the comparison between rapid and standard procedure pleurodesis outcome in MPE cases. Therefore, the objective of this research was to determine whether rapid pleurodesis is more efficient and effective than standard procedure pleurodesis in MPE patients.

MATERIAL AND METHODS:

Research design:

This study is an experimental study using a randomized posttest-only control group design devided into two groups: standard procedure pleurodesis and rapid pleurodesis. All of the samples utilized in this study were from the patients of Dr. Soetomo General Hospital Inpatient Unit, who were identified with MPE and required pleurodesis procedure. The study took ten months for completion. An approval from the ethics committee of Dr. Soetomo General Hospital was secured before conducting the study (number: 512/Panke.KKE/VIII/2017). Human subjects who participated in the study signed and provided informed consent.

The inclusion criteria were as follows: age older than 21 years old or married, patients with MPE, and willingness to participate in the study by submitting a written informed consent. The exclusion criteria were as follows: transudative pleural effusion due to hypoalbuminemia, tuberculosis pleural effusion, empyema, and pregnant women. A total of 25 samples were included in this study (13 for rapid procedure group and 12 for standard procedure group). The study conducted total sampling; the samples were taken from study populations eligible with inclusion and exclusion criteria.

Pleurodesis procedure:

Pleurodesis procedure is performed by inserting a sclerosing agent through the thoracic drain after fluid well evacuated. Standard procedure is preferred if the pleural fluid amount is less than 50ml/24 hours. On the other hand, rapid pleurodesis is performed without consideration of a minimal amount of liquid (<50ml/24 hours), but assessed with chest x-ray showing expanding lungs and absent trapped lung. About 20ml of lidocaine 20% inserted into the pleural cavity as a local anesthetic agent 15minutes before the procedure was carried out. We use sterile-talc 5mg with normal saline 50cc as talc slurry that inserted from the chest tube one time. The clamp is then attached to the chest tube for 2hours after injecting the talc slurry. The clamp is opened, and the chest drain is connected to a −20cm H20 pressurized suction. Clinical and side effects were observed in the samples. The chest tube can be revoked if the pleural fluid is less than 150ml/day, or there is no undulation on the water-sealed drainage bottle.

Successful pleurodesis procedure evaluated using several criteria such as complete, partial, failed, and not observed. Complete success is defined as having no accumulation of pleural fluid, as evidenced by chest x-ray for 1 month. Partial success is described as reaccumulation of pleural fluid less than 50% with dyspnea, as shown using a chest x-ray for at least a month. The failed category is explained as dyspnea occurring with reaccumulation of pleural fluid more than 50%, as determined using a chest x-ray for at least a month. The primary outcome is success in pleurodesis, and the secondary results are the length of stay, cost of treatment, and complications.

Statistical analysis:

Statistical analysis was conducted using the Mann-Whitney analysis test in order to estimate the comparisons between variables. The statistic software used is SPSS. The statistical analysis result showed that both procedures have the same effectivity if the significance value is p ≥ 0.05 (α = 5%).

RESULTS:

The characteristics of research sample:

The study subjects’ characteristics are presented in Table 1. The study took ten months for completion. Considering the inclusion and exclusion criteria, 25 MPE patients were determined to be qualified for the study, of which 13 were identified in the rapid procedure group and 12 in the standard procedure.

Based on the result from Table 1, it is known that there were more male MPE patients than female patients. The age interval of the subjects in this study was between 51 to 60 years. The majority of study subjects were smokers, have lung carcinoma and the hystopatologic type of adenocarcinoma.

Table 1: Study subjects’ characteristics.

Characteristic	Group		P-value
Characteristic	Rapid	Standard
Age (mean ± SD)	56.4 ± 13	57.08 ± 7	0.885
<30 years	1 (7.7%)	-
31–40 years	-	-
41–50 years	1 (7.7%)	1 (8.3%)
51–60 years	6 (46.2%)	7 (58.3%)
≥ 61 years	5 (38.5%)	4 (33.3%)
Gender
Male	8 (61.5%)	7 (58.3%)	1.000
Female	5 (38.5%)	5 (41.7%)
Smoking
Yes	7 (53.9%)	7 (58.3%)	0.821
No	6 (46.1%)	5 (41.7%)
Tumor types
Lung Ca	12 (92.3%)	11 (91.7%)
Urogenital Ca	-	1 (8.3%)
Others	1 (7.7%)	-
Histopathology
Adenocarcinoma	10 (77%)	8 (66.7%)
Squamous cell	1 (77%)	-
Unidentified	2 (15.3%)	4 (33.7%)
Performance score (mean ± SD)	87.5 ± 4.5	84.6 ± 5.1	0.225
Body weight (mean ± SD)	53.4 ± 8	57.5 ± 12.4	0.339
Pleural fluid LDH (mean ± SD)	1,385.5 ± 1,231.9	863 ± 659.8	0.295

Pleurodesis results:

In this study, complete success was defined as having no accumulation of pleural fluid, as evidenced by chest x-ray for 1 month, while partial success was described as reaccumulation of pleural fluid less than 50% with dyspnea, as shown using the chest x-ray, for at least a month. In the rapid procedure, ten patients (90.9%) were determined to have successful pleurodesis and one (9.1%) with failed pleurodesis; however, two were not evaluated as one patient died 25 days post-pleurodesis due to all progressive disease with secondary infection and the other patient was not assessed because she/he was lost to follow-up. In the standard group, nine patients (81.8%) were determined to have successful pleurodesis, two (18.18%) were failed, and one was not evaluated, as the patient died 17 days post-pleurodesis due to tumor progressive disease metastasis. The result of the Mann-Whitney test indicates no significant difference between the rapid and standard groups, with p-value 0.300 (p > 0.05), shown in Table 2.

Table 2: Pleurodesis results.

Primary outcome

Frequency in the rapid group

Frequency in the standard group

P-value

Evaluation criteria

Success

Complete success

Partial success

Failed

Not evaluated

10 (90.9%)

8 (72.7%)

2 (18.2%)

1 (9.1%)

9 (81.8%)

5 (45.4%)

4 (36.4%)

2 (18.2%)

0.300

The secondary biomarker data of pleurodesis are shown in Table 3. The results of the average (mean±SD) glucose level of patients with failed pleurodesis and successful pleurodesis were 56.67±56.88 and 71.74± 40.57, respectively. The results of the average (mean± SD) LDH level of patients with failed pleurodesis and successful pleurodesis were 2,104.33±1,854.50 and 917.32±743.53, respectively.

Table 3: Biomarker secondary data.

Variable	Pleurodesis	Mean ± SD
Glucose level	Failed	56.67 ± 56.88
Glucose level	Successful	71.74 ± 40.57
LDH level	Failed	2,104.33 ± 1,854.50
LDH level	Successful	917.32 ± 743.53

The secondary data from pleurodesis results were shown in Table 4. The results of the average (mean ± SD) hospitalization days of patients in the rapid group were 24.62±11.22 days, while in the standard group, it was 29.08±15.77 days. The average (mean±SD) cost in USD with patients in the rapid group was 1,700±893 USD, while in the standard group, it was 1,876±728 USD. The average (mean±SD) total fluid (ml) with patients in the rapid group was 7,400±3,327.41ml, while in the standard group, it was 7,375±4,151.25ml. The data was analyzed using two independent samples t-test. All the data showed that there was no significant difference for secondary outcomes included 0.420 (p>0.05), 0.590 (p> 0.05), 0.980 (p>0.05), respectively.

Table 4: Secondary data from pleurodesis result.

Secondary outcome	Rapid groups (mean ± SD)	Standard groups (mean ± SD)	P-value
Hospitalization days	24.62 ± 11.22	29.08 ± 15.77	0.420
Cost in USD	1,700 ± 893	1,876 ± 728	0.590
Total fluid (ml)	7,400 ± 3,327.41	7,375 ± 4,151.25	0.980

Pleurodesis results:

In this study, pain and fever are determined to be common complications of pleurodesis, shown in Table 5. In the rapid group, 1 patient (7.6%) was reported to have a fever, 12 patients (92.3%) with no fever, 9 patients (69.2%) with pain, and 4 (30.7%) with no pain. In the standard group, 3 patients (25.0%) had a fever, 9 patients (75%) with no fever, 9 patients (75.0%) with pain, and three patients (25.0%) with no pain.

Table 5: Pleurodesis complication.

Complications post-pleurodesis	Rapid group (n = 13)	Standard group (n = 12)	P-value
Fever
Yes	1 (7.6%)	3 (25.0%)	0.320
No	12 (92.3%)	9 (75.0%)
Pain
Yes	9 (69.2%)	9 (75.0%)	1.000
No	4 (30.7%)	3 (25.0%)

DISCUSSION:

Study subjects’ characteristics:

This study obtained more male MPE patients than female ones. This incidence in line with the number of lung cancer cases that was more frequent in males. However, this data is not consistent with the study conducted by Abrao (2020), In this single-center cohort study that included 288 patients with MPE, Of the 288 included patients, 62.5% were females¹⁹. This phenomenon could be attributed to the fact that, in Abrao’s research¹⁹, almost three-quarters of the pleural effusion patients had a tumor primary sites located in breast, lung, and gynecological.

Up until now, lung cancer is still the leading cause of pleural spread in male patients; meanwhile, in female patients, breast malignancy takes the major part. Both are the predominant cause of MPE, which accounts for 50%-65% of all origins. Lymphoma, genitourinary tumor, and gastrointestinal account for 25% of MPs. Moreover, pleural effusion caused by unknown primary tumors are about 11%^20-²². The age of patient between 20 to 75 years. Lung cancer survival is mostly determined by disease stage and treatment modality, and the five-year survival rate has been in a plateau of 15% for three decades. Despite aggressive treatment with concurrent chemotherapy and radiation, only 15% of patients survive 5 years²³^. The risk of lung cancer increases with age; at the age of 40, the risk will keep growing each year. This condition is caused by the impairment of DNA repair system and cell growth, there is data supporting that germline mutations in DNA repair genes increase the predisposition to the disease²⁴. Supporting this it has been shown that in ~2.5% of all cancer, a germline mutation in a DNA repair gene was associated with cancer development²⁴. The process takes place in a very long time. Thus the risk keeps increasing along with the age increase²⁵.

Most of the participants were smokers (56%). Smokers have been determined to have a 10–30 times higher risk for cancer compared with nonsmokers. The risk of lung cancer in the active smokers has increased 20 times compared to non-smokers. This is related to the number of cigarettes smoked, age of smoking and duration of smoking habits. With the research subjects without a history of smoking, it shows that there are other risk factors that cause lung cancer. Other risk factors are exposure to asbestos radon and air pollution. A person with asbestosis due to exposure at work has a high risk of suffering from lung cancer. Also, radon is a radioactive gas that is naturally present in nature, especially area with high granite content has a bigger risk of lung cancer. Passive smokers are also at risk of having lung cancer due to exposure to secondhand smoke²⁶^-29. Globally, there are 15%-20% males and over 50% females with lung cancer without a history of smoking³⁰.

This study obtained histology results using fine-needle aspiration biopsy (FNAB) in eight patients (3.2%), pleural fluid cytology examination in 14 patients (56%), and FNAB and cytology examination in three patients (12%). The positivity rate of pleural fluid cytology examination for MPE diagnosis is determined by some factors such as how tumor spreads and the location of the primary tumor. Various studies show that the positivity rate ranges between 40% and 87%³¹.

Pleurodesis result:

This study observed no significant difference between the rapid and standard groups, with a p-value of 0.300 (p > 0.05) (Table 2); this means that both procedures have the same effectivity (p≥0.05). Some other studies have also compared rapid pleurodesis with standard pleurodesis. A survey by Farrag et al. (2019) has also shown no marked difference³². Meanwhile, in a study by Foo (2021), 45 patients with MPE who underwent day case rapid pleurodesis rapid pleurodesis were examined; Pleurodesis success rates of 71.1% (32/45) and 77.8% (35/45) were achieved at 3 and 6-months. 31.1% (14) of patients died within 6 months¹⁷. Another study showed a similar result, which overall concludes that there is no marked superiority between the rapid pleurodesis group and the standard pleurodesis group¹⁸. Accordingly, procedure alternatives based on personalized treatment and the cost-effective issue can be the considerations in deciding which procedure will be performed.

Failed pleurodesis indicators are as follows: pleural fluid glucose < 60mg/dl, pleural fluid pH < 7.20, pleural fluid LDH > 600IU/L, massive pleural effusion, and unresponsive tumor to chemotherapy³³. The success rate of pleurodesis in was determined to be higher in patients with higher pleural fluid. Lower pleural fluid glucose in Table 3 indicates pleural thickening or metabolism increase in pleural fluid. Results in table 3 also determined that pleural fluid LDH in patients with successful pleurodesis is lower compared with that of patients in the failed pleurodesis category. It is in concordance with the research conducted by Shehata et al. (2015)³⁴. Pleural fluid lactate dehydrogenase (LDH) is a marker of inflammation or cellular injury³⁵. High LDH level indicates there has been a widespread inflammation process, acute inflammation, necrosis, and cell deaths in the pleural space. Therefore, the LDH level can be used to determine how severe the impairment created by tumor cells infiltrating into the pleural space. Moreover, LDH correlate with CRP and other inflammation markers suggesting a possible relationship between tissue damage and the infective status³⁶.

The average duration of hospital stay in this study differs from the survey done by Yildirim et al. (2005)³⁷, resulting in the mean duration of hospital stay in rapid group 2.33±0.62 days while in standard group 8.33± 4.85 days 8 (Table 4). The discrepancy likely occurred because subjects in this study were hospitalized not only due to MPE but also due to other concurring diseases. That phenomenon was determined to be the cause of prolonged hospital stay duration in this study; most of them were on account of the medical workup for the concurring infections and the definite diagnosis workup.

This study statistically showed that the duration of hospital stay in either group was not markedly different. The length of hospital stay in the rapid pleurodesis group is 5 days shorter on average compared with standard procedure pleurodesis. This difference could decrease the incidence of nosocomial infection and increase the quality of life of the patients. It is suggested that fast and effective pleurodesis may have caused less hospital-related morbidity³⁴. In addition, shorter hospital stay led to possibly a low-hospital cost. This was in accordance with the study published by Magdy that suggested an ultrasound-guided completion of the process of pleurodesis in a single session with a shorter duration of pleural fluid drainage and shorter hospital stay (can be done on a day-care basis) is efficient, safe, and cost-effective³⁸.

The result of the difference test using two independent samples t-test shows that there is no marked difference in total cost during hospital stay between the two groups, with the value of p 0.596(p > 0.05) (Table 4). This result might have occurred perhaps because subjects were not only hospitalized due to MPE but mostly also by other concomitant diseases. Thus, the total cost during a hospital stay is not markedly different because of the consequent disease treatments and the diagnosis workups required by the patients.

The test on the total pleural fluid volume before pleurodesis was done between both groups with a different value of 0.987 (p > 0.05) (Table 4). This result is concordant with the study done by Yildrim³⁷, the mean total pleural fluid volume drained during the procedure was not significantly different in both group.

The daily pleural fluid drained in the rapid pleurodesis group was at 410ml/day in the successful pleurodesis category and 300ml/day in the failed pleurodesis category. There has not been a guideline or recommendations on how much daily pleural fluid production is required for pleurodesis procedure.

Pleurodesis complications:

Complications that may be experienced are pain, tachycardia, tachypnea, pneumonitis, or respiratory distress (mainly after slurry talc administration), re-expansion lung edema which is mostly reversible, fever primarily related to pleuritis and disappear in <48hours, incomplete lung expansion and partially trapped lung, drug reaction, and neurogenic shock³⁹.

The result of the test showed that there was no significant difference in fever and pain complications between the rapid group and the standard group with a value of 0.322 and 1.000 (p > 0.05) respectively (Table 5). This result is different from the previous studies³⁴, that showed pain complications in nine patients (7%) and fever in 21 patients (16%), from a total of 131 patients observed in a sample. In the previous study, there is no explanation about the pain criteria included. That is the possible cause of the different results. In this study, all of the pain scales are considered pain complaints.

CONCLUSION:

The results showed that both of rapid pleurodesis and standard procedure pleurodesis in patients with MPE were no statistically difference. But we can still recommend rapid procedures because they have shorter hospital stays and incur lower costs.

CONFLICT OF INTEREST:

Nil.

ACKNOWLEDGMENTS:

The authors thank to Medical Faculty of Airlangga University for the funding and Dr. Soetomo Hospital Surabaya Indonesia to facilitate and support this research.

SUGGESTIONS:

It is recommended for further research to expand the sample by increasing malignant pleural effusion with causes of mediastinal tumors and small cell carcinoma, as well as by adding variations in pleurodesis materials such as povidone-iodine, 5-fluorouracil, and talc poudrage.

ETHICAL APPROVAL:

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. An approval from the ethics committee of Dr. Soetomo General Hospital was secured before conducting the study (number: 512/Panke.KKE/VIII/2017). Human subjects who participated in the study signed and provided informed consent.

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Received on 23.01.2023 Modified on 02.05.2023

Research J. Pharm. and Tech 2024; 17(1):333-339.

DOI: 10.52711/0974-360X.2024.00052