Malignant Pleural Effusions

Patients with a cancer diagnosis endure multiple complications and stresses, particularly when disease progresses. Unfortunately, the treatments themselves can also result in debilitating side effects that further increase their suffering.

One of the disease developments associated with cancer is malignant pleural effusion (MPE), which affects approximately 15% of patients with cancer.¹ A pleural effusion is a collection of fluid between the parietal and visceral pleural layers surrounding the lung.^2-6 For the most part, when patients are diagnosed with an MPE, they are in the advanced stages of their disease. MPE is estimated to occur in about 150,000 people with cancer per year in the United States.⁷ The normal pleural space contains 10 to 20 mL of fluid, which acts as a lubricant, allowing the lungs to move smoothly when the patient is breathing. Each day, approximately 5 L or more of pleural fluid is produced and moves throughout the pleural space.^3,8 Pleural effusion occurs when more fluid is produced than is absorbed from the space. Pleural effusions can also arise from other causes besides cancer, such as congestive heart failure, cirrhosis of the liver, tuberculosis, or with a pulmonary embolism, or after open heart surgery. This article will deal only with MPE.

Localized causes of fluid buildup in the pleural space tend to be from either the tumor itself causing increased permeability of the membranes or other causes related to obstruction. For example, the tumor may obstruct veins or lymph drainage pathways, allowing fluid to accumulate in the space; main stem bronchus tumors may obstruct the bronchus, causing atelectasis and an effusion from reduced pleural pressure; obstruction from pneumonia can cause an effusion; and finally a tumor may obstruct the thoracic ducts, producing a chyle effusion.⁹ These are the presumed reasons fluid is unable to flow through the pleural space as it normally would and remains trapped there.

Many malignancies can lead to the development of lung disease or lung metastasis, which could lead to MPE; however, the most common malignancies are adenocarcinoma of the lung, metastatic breast cancer, ovarian cancer, advanced lymphoma, and mesothelioma.^3,8,10-13 Patients who have developed an MPE often present with sudden severe shortness of breath, with or without chest pain, and also a dry cough, all ultimately affecting their quality of life.¹⁴

Diagnosis

Confirming a pleural effusion, let alone an MPE, can occasionally prove challenging. As mentioned above, many different medical conditions can cause a pleural effusion; thus, validating that the excess fluid in the pleural space is from a malignant cause can be a little more difficult. On physical exam, the patient will have decreased breath sounds on the affected side and there will be dullness over the affected side to percussion.¹² A lateral decubitus chest x-ray, or more particularly a computed tomography (CT) scan of the chest, is necessary to confirm an increased volume of fluid in the space. On x-ray, effusions could demonstrate a meniscus sign, which appears concave at the top of the effusion.⁸ Thoracic ultrasound will more than likely demonstrate excess fluid buildup in the pleural space, and this method is useful should the clinician need to remove some of the fluid for diagnostic testing. Ultrasound is also useful in diagnosing small effusions, detecting thickening of the pleura or diaphragm, or when patients can only be in a recumbent position, such as those in critical condition.¹²

Next, a sample of the fluid should be obtained to determine if the fluid is an exudate or a transudate. In a hallmark article regarding transudates and exudates, Richard Light and colleagues distinguished between the two by defining a transudate as happening for mechanical reasons that prevent the fluid being reabsorbed, and an exudate as happening when some other disease is influencing the pleural surface, such as inflammation or a malignancy.¹⁵

A sample of at least 50 mL of fluid should be obtained for testing. If the pleural effusion is transudative, usually indicating that the cause of the effusion is systemic (such as one of the benign conditions listed above), the condition itself should be treated systemically to reduce further development of pleural effusions. If the effusion is exudative, however, it is generally from a more local cause and therefore the treatment should be local as well. The “Light criteria,” developed by Richard Light, are what most clinicians use to differentiate between transudative and exudative effusions.⁹ A patient will need to meet one or more of the following lab values to be diagnosed with an exudative effusion:
• Protein level >0.5 in either the pleural fluid or serum
• Lactose dehydrogenase (LDH) level >0.6 in either the pleural fluid or serum
• Pleural fluid LDH level more than two-thirds the upper limit of normal for serum LDH⁹
Other tests can also be performed to differentiate an exudate in the pleural fluid: cell count and differential; glucose; pH; cytology; and cultures for bacteria, mycobacteria, and fungus in the fluid as well. As noted by Light, cytology of pleural fluid is one of the quickest ways to determine an MPE, with an approximate 60% diagnostic accuracy.^8,9,11 Pleural fluid that is grossly bloody is often a sign of malignancy if trauma has been ruled out. Tumor markers of pleural fluid have been analyzed but have shown little promise in detecting MPE. Markers CA 15-3 and CYFRA 21-1 are probably the best, but they are not sensitive or specific enough to really help.¹⁰ Testing the fluid for sensitizing epidermal growth factor receptor mutations is one of the newer exams, and it may assist in determining which drugs will have a more favorable response on the tumor.^8,16,17 Pleural biopsy is probably the final approach for diagnosing an MPE, with radiology-guided biopsy via CT scan the best way to obtain a suitable specimen with the least morbidity to the patient.¹² Clinicians can also obtain a pleural biopsy in the OR when performing one of the surgical procedures mentioned below. Once the type of effusion is diagnosed, a local treatment, such as pleurodesis or a pleural catheter, can be initiated as described later in this article.

It is important to consider that patients diagnosed with MPE generally have only 3 to 12 months to live, as it is a metastatic process that occurs close to the end of a patient’s life.^1,12-14,18 Patients with breast and ovarian cancer or lymphoma may receive systemic treatment (chemotherapy) to treat their disease, which may help in treating the MPE. Patients with lung cancer or mesothelioma may also receive chemotherapy, but the benefit is limited, so clinicians must determine the benefits versus the risks for these patients.^10,18 A good deal of research has been conducted regarding administration of certain types of systemic chemotherapeutic agents while the patient still has fluid in the pleural space. Research on methotrexate has determined that, given its structure and pharmacokinetics, this drug is best administered when the pleural space is empty in order to decrease toxicity to the patient. Recently, studies were conducted with pemetrexed, since its structure and some pharmacokinetics are similar to those of methotrexate and because this drug is often used in the treatment of non–small cell lung cancer and mesothelioma. Researchers and clinicians have not really reached a consensus regarding pemetrexed; some clinicians feel it is necessary to drain the pleural effusion before the patient receives pemetrexed, and others feel it is safe to give the pemetrexed even if the effusion has not been drained.¹⁹ Anecdotally, clinicians prefer that the effusion be drained prior to any treatment. Since systemic treatment may take time to show any value, local treatments to relieve symptoms may have to be utilized in the interim.

Nurses can assist during this early diagnosis phase by reassuring the patient, completing a thorough examination, and providing oxygen for comfort for the patient’s shortness of breath and antianxiety medications as needed. The nurse should encourage the patient to take rest periods to conserve energy and to eat small meals of high-caloric foods to increase energy.⁶ The nurse can also educate the patient regarding diagnostic testing and the methods that might be used to reduce the MPE.

Therapeutic Options for Treating Malignant Pleural Effusion

Medical Thoracentesis

Medical thoracentesis is a temporary measure that entails placing a catheter into the pleural space under ultrasound guidance to obtain fluid specimens (diagnostic thoracentesis) or to drain the space of fluid to provide symptom relief (therapeutic thoracentesis). Because of the obstructive or osmotic reasons mentioned previously that prevent the fluid from exiting the space, along with the fact that fluid continues to be produced in the space, fluid will reaccumulate without a more permanent therapeutic procedure.^11,13,18,20 To prevent patient discomfort and reexpansion pulmonary edema, fluid should be removed slowly and should not exceed 1500 to 2000 mL at a time. Reexpansion pulmonary edema occurs in less than 0.5% of cases in which too much fluid is removed too fast, causing the affected lung on that side to reexpand too rapidly. In the absence of pleural pressure monitoring, which is often not used in these cases, the clinician should pay attention to the patient and any complaints of chest pain during the procedure.^3,11,20

Medical thoracentesis can be performed by medical doctors, pulmonologists, and/or radiologists. It is best completed under ultrasound guidance, but the spot can be marked via ultrasound to enable the thoracentesis to be performed at a later time; however, studies show that there is a greater risk of pneumothorax when the procedure is performed in this manner. A chest x-ray should always follow a thoracentesis so that the clinician can determine if the fluid was successfully removed from the space and the patient has not developed a pneumothorax during the procedure.¹¹ The patient should be instructed to report any sudden chest pain or shortness of breath to his or her clinician and monitored for signs and symptoms of chest pain, shortness of breath, hypotension, and infection. Because this procedure can be performed on an outpatient basis, patients will need to be educated on the signs and symptoms of any issues and whom to contact should a problem develop.

Thoracentesis can be performed more than once on a patient. If it is determined that a patient has a small, slowly reaccummulating effusion, the clinician may decide that thoracentesis is the therapeutic option of choice to control the patient’s MPE. Ideally, it will need to be done only a few times. The clinician may decide to use thoracentesis to control an actively dying patient’s MPE to avoid a more invasive procedure. Another complication of thoracentesis, especially when repeated on a regular basis, is fluid loculation, where adhesions and scar tissue form as a result of the repeated procedures. In this situation, fluid is compartmentalized into smaller areas and all of the fluid cannot be removed with just 1 procedure.^3,11,20 Tissue plasminogen activator (TPA) has been used to try to break apart these adhesions, with moderately good results; however, the scar tissue may reform at a future time.^3,20

Placing a chest tube into the pleural space can assist the clinician in draining the effusion. The most common chest tube for this purpose is called a pigtail catheter, a 10-14 French, silicone catheter placed under fluoroscopic guidance. This type of procedure is usually performed on critically ill or palliative patients, who cannot undergo a more invasive procedure. The catheter itself can be connected to a closed chest drainage system or to a bag that has a one-way valve. Fluid can be drained from the space as needed without causing too much difficulty for the patient, and it provides symptom management for shortness of breath.^21,22 Patients should be monitored for pneumothorax post procedure. Patients with this type of catheter can be cared for at home by hospice or palliative care nurses, who can monitor them for tube dislodgement and infection. Larger-bore chest tubes are rarely used for this procedure, mostly due to discomfort for the patient and the complicated drainage systems needed.

Surgical Procedures

Thoracic surgeons sometimes perform an extrapleural pneumonectomy, involving resection of the lung, pleura, diaphragm, and pericardium, which works because it essentially removes the pleural space. This surgery, which is generally reserved for patients with mesothelioma, has high morbidity with a long recovery time and large prolonged air leaks. For optimal outcomes, patients must be in fairly decent shape prior to this surgery, but because many of them are close to the end of their life, they most likely would not be a candidate for this procedure. Compared with pleurectomy, which might also assist in eliminating the pleural space, the extrapleural pneumonectomy has the best outcomes.^12,13,20,23

Another procedure that eliminates the pleural space is pleurodesis.^10,12,13 The first clinician to perform this procedure, which was described in the Journal of Thoracic Surgery in 1935, was Norman Bethune, a thoracic surgeon from Montreal, Canada. Bethune and several other surgeons knew that causing scar tissue to form in the pleural space would assist in the removal of the space. In their research, they tried many tactics, including packing the space, stitching the lung to the parietal pleura, mechanical irritation, heat, elastic bands, tape, and finally products such as gases, and dusting the pleura with talc powder. They found the most beneficial method to be iodized talc powder, blown in with a blower under thoracoscopy.²⁴

The modern-day version of this procedure is video-assisted thoracoscopic surgery (VATS) pleurodesis via insufflation or talc poudrage, in which a patient is taken to the operating room under general anesthesia and any adhesions or scars are broken up via thoracoscope, biopsies are taken if needed, and talc is applied to all surfaces using a specialized atomizer to blow it into all areas. All this results in chemical pleurodesis, where scar tissue causes the two surfaces of the parietal and visceral pleural layers to adhere together. Then a chest tube is placed for drainage. The patient is usually kept in the hospital overnight for monitoring, including vital signs and drainage from the chest tube, as well as chest x-ray to rule out pneumothorax. Pleurodesis has been shown to be about 78% effective, with few patients experiencing failure or re-effusion. Following this procedure, about 5% to 9% of patients develop adult respiratory distress syndrome (ARDS), which is assumed to be related to the size of the talc particles used during the procedure—larger talc particles (>15 μm) being better for the patient.^3,8,11,12,25

Pleurodesis can also be performed “at the bedside” via a chest tube placed into the pleural space and attached to a collection chamber. Once all fluid has been drained from the space, irritants are introduced through the chest tube to cause scar tissue to form. Many products have been tried over the years: bleomycin, doxycycline, tetracycline, and betadine, to name a few. Studies again have shown that talc achieves the best results. To make the process easier, the talc is made into a slurry and injected into the space via the chest tube, which is then clamped for several hours. In the past, clinicians would have the patient change position throughout the time the talc was in the space to attempt to get the slurry on all of the surfaces; however, research has found this to be unnecessary. Generally, after several hours the tube will be unclamped and allowed to drain for about 24 hours, at which time it is removed. Talc slurry studies have shown this procedure to be about 71% effective.^3,8,11,12,25

After performing a Cochrane review, researchers determined that talc inserted via slurry or insufflation techniques proved to be the best of any of the substances tried.²⁶ Pleurodesis seems to show best results and not demonstrate future failure if apposition is maintained between the visceral and parietal pleural surfaces when the sclerosing agent is being placed in the space to stimulate inflammation and future fibrosis. This information could assist clinicians in determining the course of treatment for a patient, as oftentimes after an MPE is drained for the first time, the lung does not adequately reexpand to allow for pleurodesis.^27,28

A tunneled pleural catheter (TPC) is a 15.5 French, silicone catheter with a cuff placed into the pleural space. These catheters can be placed by thoracic surgeons, radiologists, and, more recently, interventional pulmonologists, as an outpatient procedure done under moderate sedation and local anesthetic. The catheter has a one-way valve at the end to prevent pleural fluid from exiting and air from entering the space.^10-12,17 A postprocedure chest x-ray should confirm placement of the catheter, the fluid amount in the space after drainage, and the absence of pneumothorax. Patients and/or family members are taught to drain the catheter of a prescribed amount of fluid a prescribed number of times per week using vacuum bottles provided by the company. Some insurance policies cover visiting nurses to assist patients with this procedure. This method of treating an MPE allows patients to care for themselves at home. It immediately relieves the symptom of shortness of breath and can be used even if there is no apposition between the visceral and parietal pleural surfaces. Spontaneous pleurodesis can occur with these catheters. Because they are a foreign object in the presumably mostly empty space, and because the patient is on a routine drainage schedule, the catheter is constantly physically irritating the surface of the lining and causing inflammation, resulting, hopefully, in spontaneous pleurodesis, which occurs in about 50% of patients with a TPC after approximately 2 months’ time. The chances of a spontaneous pleurodesis occurring are better if there is apposition between the 2 layers; however, clinicians prefer the TPC method, even if the fluid is loculated or there is a trapped lung, because it achieves symptomatic relief of the effusion.^12,17,29

Nurses can be helpful during the decision to use a TPC for treatment by first educating the patient regarding the catheter placement process. Nurses are also heavily involved in educating both the patient and the caregiver regarding management of the TPC as well as setting up visiting nurses to assist and getting supplies for drainage of the catheter for the patient.

Education should include possible complications. Catheters are a foreign object and can be a site of infection. Although draining the catheter and changing the dressing are done under sterile conditions, patients still need to know signs and symptoms of infection to report. TPCs can become clogged with fibrin by-products at the site of the one-way valve. TPA has been used to break up fibrin, and patients need to be educated when to call the clinician. If spontaneous pleurodesis occurs, then catheters can be removed as the effusion amount decreases. There have been reports of catheters fracturing during removal, so clinicians must be aware of how to handle this situation. There have also been reports of seeding of the cancer along the catheter, and some clinicians continue with chemotherapy in the hope of preventing this occurrence.^3,17,30

A few other methods for treating MPE are either older and not used much, or are very new and still being studied. One older technique is pleuroperitoneal shunt. In this technique, a catheter is placed into the pleural space with a one-way valve and a pump connected to a catheter that goes to the peritoneal space. The patient is taught to press on the pump several times a day, and this shunts the pleural fluid into the peritoneal space. Because of the high occlusion rate with these catheters and the likelihood of infection, clinicians seldom use this method.^3,10,11,17

A newer technique still being studied is placement of a port (similar to a venous access port). The patient and caregiver would be taught to access the port with a Huber needle and drain the effusion into a vacuum bottle. The idea is very similar to a TPC, only there is nothing on the outside of the body until the port is accessed for drainage, and the same issues that cause problems for TPC could occur with these ports.³¹

Another new technique is cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITHOC) perfusion, similar to a technique used for intraperitoneal tumors. A study was completed in Germany in 2012 with 16 patients—8 patients with mesothelioma and 8 patients with pleural thymoma. After cytoreductive pleural surgery, the patients were perfused with heated chemotherapy into the pleural space. The surgical procedure and the chemotherapy went well, with no real leakage of chemotherapy into other areas, as happens in some intraperitoneal cases, probably because of fewer anastomoses in the pleural area. Overall, the thymoma patients did better than the mesothelioma patients, probably due to their better prognosis.³²

Future Directions

Clinicians are frustrated that treatment for patients with MPE has changed little since 1935. Ultimately, one would hope the goal would be to cure the patient of his or her pleural metastasis, but in the meantime, clinicians should be cognizant of the fact that most of these patients are close to the end of their life and they need a treatment that deals with their symptoms, does not require as much hospitalization, and is the most cost-effective.

Many research studies have been conducted to determine the best means of treating MPE, ie, either talc pleurodesis or TPC. Other studies have examined the cost of VATS talc pleurodesis versus TPC and have found that VATS is more expensive due to the cost of the operating room, anesthesia, at least 1 or 2 days of in-hospital recovery time, and normal postoperative complications, such as air leakage, pain, etc, which could keep the patient in the hospital longer than planned. TPC, on the other hand, is an outpatient procedure with minimal anesthesia, and patients can return home to care for themselves and their catheter after proper education. TPC does have “hidden” costs, however, such as visiting nurses and supplies for draining the catheter 3 to 4 times per week.^33-35

Another trend is to pay more attention to patient outcomes and quality of life. Several research studies reviewed patients’ quality of life based on the type of MPE treatment. These studies found that patients were more satisfied when they had a TPC; their symptoms were relieved and they were able to care for the catheter at home, increasing their quality of life. Research is also looking at the outcomes of relieving shortness of breath, pain, and other symptoms and how those outcomes for patients are being met.^14,17,36

The information reviewed implies there will be new technology, surgeries, chemotherapy, and/or biotherapy drugs developed to assist in treating malignant pleural effusions. Oncology nurses will pay close attention to the research and learn to work with any new procedures that will help their patients. However, for now, clinicians need to treat patients with individualized therapy that relieves their symptoms and allows them to enjoy their remaining life in a quality manner.

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