New strategies for the management of malignant ascites NANCY PRESTON, BSc(Hons), RGN, ENB 237, Research Practitioner, Centre for Cancer and Palliative Care Studies, ICRlRoyal Marsden NHS Trust, Education and Conference Centre, Fulharn Rd, London SW3 SJJ, U K

PRESTON, N . (1995) European Journal of Cancer Care, 4, 178-183 New strategies for the management of malignant ascites

Intractable malignant ascites accounts for 6% of all hospice admissions. The onset of malignant ascites indicates a poor prognosis, hence minimal supportive therapy is indicated. This paper examines the method of control for malignant ascites presently available to patients, examines their limitations and proposes new strategies for managing intractable malignant ascites. Ascites is discussed in terms of its pathology-that is, as a form of lymphoedema. With this in mind treatment is proposed based upon principles incorporated into lymphoedema management. Nurses have taken a dominant role in the care of patients with lymphoedema and there appears no reason why ascites management cannot become the remit of nurses offering appropriate, but predominantly palliative therapy.

Keywords: malignant ascites, nursing care, treatment, causes.

Malignant ascites accounts for 6% of all admissions to hospices (Regnard & Mannix, 1989). Up to 20% of patients with peritoneal metastases may be affected (Klopp, 1984). The most common tumours to be involved are breast, ovary, colon, stomach, pancreas and bronchus. Ascites can be defined as an exudate into the peritoneal space due to a malignancy (Regnard & Mannix, 1989). Although a common symptom at initial diagnosis, which may resolve with chemotherapy, its manifestation in patients with relapsed disease often indicates a poor prognosis (Green- way et al., 1982). New strategies for managing ascites have been developed and these will be discussed in this article. Initially, the debilitating effects of ascites and the pathogenesis will be addressed, followed by both new and old approaches to management of ascites.

The debilitating symptoms that accompany ascites include indigestion, shortness of breath, loss of appetite, nausea and vomiting, abdominal distension, ankle oede- ma, fatigue, altered bowel habit, abdominal discomfort and problems with body image (Regnard & Mannix, 1989; Kehoe, 1991). All of these symptoms lead to a disruption

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in daily activities and lifestyle. Patients with distended abdomens may not want to be seen with such a manifestation of their dsease so apparent to the world. Some patients appear to remain active and it is their alteration in body image that prompts their request for treatment. Ultimately, the side-effects that are associated with ascites engulf the patient and relief must be sought. Many of these symptoms will be in addition to other side- effects already present in the patient with cancer. The debilitating symptoms that are associated with it can be resolved by removing the ascites, but there is no superior method of control and all have accompanying side-effects.

CAUSATIVE FACTORS

Malignant ascites cannot be attributed to a single cause, it is rather a combination of different factors. Whilst there is an over-production of fluid by tumour cells implanting in the peritoneal layer, this alone would not cause the accumulation. Fluid in the peritoneal cavity is returned to the circulation either directly by small capillaries or through the lymphatic system. Feldman [ 1975) demon- strated the dynamism of the lymphatic system in mice

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where the system could adjust to returning up to 50 times the normal amount of fluid from the abdomen back into the circulation. In ascites caused by cirrhosis, it has been shown that up to 20 litres of ascites can be returned to the circulation in a 24-hour period in man (Witte & Witte, 1983). Hence, over-production alone is not enough to generate ascites. Feldman (19751 demonstrated the lym- phatic pathway that re-absorption of ascites takes. Radiolabelled erythrocytes only leave the peritoneal cavity via the lymphatic system. Feldman noted that when mice were injected with a murine ovarian cancer cell line, there was a blockage of the lymphatic pathway at the diaphragm, characterized by a clumping of the erythrocytes along thc diaphragm. This implied that the fluid had no exit from the peritoneal cavity and a few days following demonstration of the blockage, ascites devel- oped. This would imply that ascites is primarily a condition that results from lymphatic obstruction rather than solely over-production. A subsidiary role in the formation of ascitcs may be the renin-angiotensin- aldosterone system. The ultimate convcrsion of angioten- sin into aldosterone through renin and a converting enzyme results in the retention of sodium. As sodium is retained there is decreased diuresis [Herlihy & Herlihy 1985). It is thought that a disruption in this system due to malignancy may increase fluid retention.

MANAGEMENT OF ASCITES

That ascites is a form of lymphoedema, in that lymphatic obstruction is a causative factor in producing the symptom, should have profound influence upon how ascites is managed. This suggests that techniques devel- oped in the management of lymphoedema of limbs in cancer, should offer a model of intervention and manage- ment for ascites. Lymphoedema management in the UK has fallen to nurses, carried out predominantly in day facilities. Experience gained by nurses in lymphoedema clinics has resulted in a key role for nurses in the care of patients with lymphoedema (Rose et al., 1993). Expertise is devolved to other nursing groups, incorporated into the role of breast care nurses, district nurses, oncology nurses and lymphoedema nurses within a clinic. Such nurses may find that their role could be crucial in managing patients with recurrent malignant ascites. What needs to be established, however, is the nature of interventions which may be valuable in relieving malignant ascites and the potential for nurscs to employ such techniques as part of their care.

Although there is no agreement about which is the superior method for control of malignant ascites, most

authors appear to agree that minimal supportive therapy is indicated (Garrison et al., 1986; Belfort et al., 1990), although most methods employed have failed to abide by this rule. The recognized means of control include diuretics, intraperitoneal therapy, paracentesis and perito- neovenous shunts. Regnard & Mannix (1989) published a flow diagram describing the decision steps made in choosing a treatment appropriate to an individual patient.

DIURETIC THERAPY

Diuretic therapy has been dismissed by many authors as ineffective in controlling malignant ascites (Oosterlee, 1980). Yet other authors have found success in their use with similar patient groups (Greenway et al., 1982). The discrepancies in success from different authors may be due to differences in dosing. From the literature showing ef- fective use of diuretics, control is achieved using quite high doses of diuretics. A relatively high dose of diuretics is recommended by Regnard & Tempest (1992). In studies where diuretics were found to be of little effect, the doses of diuretics used were not quoted, and it may be that patients were not given a therapeutic dose.

Randomized studies evaluating the role of diuretics in malignant ascites have not been carried out. If the renin- angiotensin-aldosterone mechanism is involved in the formation of ascites, dluretics such as spironolactone should be able to control ascitcs at least in part. It achieves this by competing with aldosterone for receptors on the proximal tubule, inhibiting the effect of aldosterone (Herlihy & Herlihy, 1985). Greenway et al. (1982) in a series of 15 patients showed control in 13 patients, thereby supporting the role of the renin-angiotensin-aldosterone system in contributing to ascites formation. The success of dmretics may, however, be due to redistribution of fluid (Regnard & Tempest, 1992). Using high dose levels of diuretics may result in imbalance of serum electrolytes, but the study by Greenway et al. (1982) appeared to show that this was not the case. They did, however, report a higher incidence of nausea and vomiting related to the use of spironolactone.

In one study, diuretic therapy was used in conjunction with water immersion with patients with ascites as a result of cirrhosis of the liver (Fort et a]., 1991). Water im- mersion results in immobilization of extracellular/extra- vascular fluid, with improvement in cardiac output, and increased excretion of salt and water (Fort et al., 1991). Water immcrsion in this study was found to be of additional benefit to these patients. The authors com- ment that patients’ feelings of well-being and mood were improved, but no formal assessment of this was carried

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out. Patients with advanced cancer may be unable to bathe due to restricted mobility, but for those who could this may offer a relaxing method for control of their ascites.

INTRA-PERITONEAL THERAPY

The success of intraperitoneal chemotherapy is likely to be dependent upon the sensitivity of the tumour. If a patient is still deemed sensitive to systemic doses of chemotherapy then they are likely to respond to intraper- itoneal doses of chemotherapy. Many patients with malignant ascites have chemotherapy-resistant tumours, and those with sensitive tumours may benefit from intravenous administration as this lessens the risk of infection, bleeding and chemical peritonitis which may accompany intraperitoneal use (Baker & Weber, 1993).

The use of biological modifiers has been under trial with ascites. In a series by Bezwoda et al. (1989) using Interferon-a2b, control was achieved in five out of 13 patients. All the responders were patients with ascites only, i.e. no tumour masses. Many patients with recurrent ascites have disseminated disease and the response rate for this poor prognostic group needs further evaluation. The use of all biological modifiers is still very much under review in relation to ascites.

Batimastat (BB94), from a new class of drugs known as the metalloproteinase inhibitors, has been introduced into randomized clinical trials against diuretic therapy in the treatment of malignant ascites. Metalloproteinase inhibi- tors are primarily aimed at limiting malignant progression. Patients with ascites were chosen to examine this drug because of the success observed in controlling ascites in animal stuctes (Brown, 1993). These studies are awaiting completion.

REPEATED PARACENTESIS

Patients presenting with abdominal distension thought to be due to malignant ascites need to have this diagnosis confirmed. This is done through cytology, where fluid removed at drainage is examined for malignant cells. Ascites can result from other medical conditions; hence, it is imperative to demonstrate that the ascites have oc- curred due to malignancy. Any drainage of the peritoneal cavity has the risk of bowel perforation. As the fluid builds up so the bowel can float upwards. Insertion should be carried out with ultrasound guidance (Ross et al., 1989), where the largest area of fluid can be identified and marked for drainage.

Drainage is carried out under local anaesthetic and can be uncomfortable to the patient. Furthermore, paracent-

esis, although offering relief from symptoms, is only tem- porary and the fluid will re-accumulate. Repeated drainage may result in protein depletion, hypotension and infection (Kehoe, 1991). Belfort et al. (1990) points out that many patients with intractable ascites spend their preterminal and terminal days in a less than optimal state, requiring frequent hospital admissions for drainage.

In an attempt to reduce hospital admissions, Belfort et al. (1990) designed a protocol whereby the catheter for drainage was left in the patient for them to take care of at home. The catheter was cared for as a stoma would be and a stoma nurse was incorporated into these patients’ care. The researchers felt the patients benefited from this approach, although a formal assessment of patients’ feel- ings and symptoms was not recorded. The main risk of such an approach would be infection, but with antibacter- ial cover only one patient developed peritonitis and two a mild cellulitis. This approach successfully controlled the build up of ascites in 14 out of 17 patients. Such an ap- proach does involve a great deal of involvement by the patient, and formal assessment of the patients’ feelings need to be evaluated, as does the incidence of peri-tonitis in a larger group of patients.

PERITONEOVENOUS SHUNTS

Peritoneovenous shunts were developed for use with patients with intractable ascites as a result of cirrhosis of the liver. This method involves implanting a catheter under the skin running from the peritoneal cavity back into the general circulation usually via the superior vena cava or right atrium. The two sections are connected by a one-way valve, allowing fluid to move in one direction only. Fluid moves upward due to changes in intrathoracic and intraperitoneal pressure achieved through normal breathing. A pressure of 3 crn of water is required to open the valve (LeVeen et al., 1974). Patients are asked to wear abdominal binders and carry out breathing regimes where they breath against a pressure for 15 minutes, four times a day in order to maximize the pressure changes (LeVeen et al., 1974). Peritoneovenous shunts are physiologically based in that it avoids problems of protein depletion. There are two main types of shunt: LeVeen and Denver. Both have been involved in clinical studies with patients with malignant ascites, but neither has proved superior (Oosterlee, 1980). They differ in that the Denver shunt has a valve that can be massaged each day to increase the flow and to push through debris in the catheter that may otherwise occlude it.

Both are usually inserted under local anaesthetic and a review of the literature of studies using shunts on at least

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20 patients showed a 65-88% success rate (Baker K\ Weber, 1993). However, two studies reported little or no benefit to their patient groups. This represents a major difference in findings. The use of shunts has to be balanced by the potential risks, which can be numerous. The major ones include fluid overload resulting in pulmonary oedema or heart failure, disseminated intravascular coagulation, infection and tumour cell infusion (Kehoe, 1991 ). Further- more, there is the complication of shunt malfunction, where the shunt may become kinked or blocked by debris. It is contra-indicated for patients with either bloody or mucinous ascites to have shunts, because of their increased risk of occluding the shunt. Although this method may achieve palliation of the symptoms related to ascites, no measurement has been made of how well patients recover from such an operation, nor how an indwelling shunt alters their body image and feeling of well-being.

POTENTIAL FOR NEW STRATEGIES I N THE MANAGEMENT OF MALIGNANT ASCITES

None of the strategies for managing malignant ascites has as yet proved to be effective, and all involve side-effects or possible detrimental effects. A more systematic study of ascites is needed and new strategies for dealing with the problem of ascites explored. Care for a patient with malignant ascitcs should involve few risks. These patients have a poor prognosis, usually only a couple of months (Baker & Weber, 1993). All methods of control currently being used have either dubious efficacy or side- cffects that may outweigh their benefits. While diuretic therapy seems the most innocuous of these treatments there are no randomized clinical trials to show its efficacy. Greenway et al. (1982) showed an increase in nausea and vomiting, and more work on electrolyte depletion should be carried out. Intraperitoneal therapy will undoubtedly be associated with side-effects. Many treatments are expen- sive and result in prolonged hospital admissions. Intraper- itoneal therapy may only be an option for patients with sensitive disease or small volume disease. Patients with intractable ascites are unlikely to fall into either of these groups. Peritoneovenous shunting shows good response rates in controlling the return of malignant ascites. However, these studies have failed to address the overall effect upon well-bcing of having a shunt and undergoing a general anaesthetic if required. As long as insertion of a shunt is associated with potentially fatal side-effects, its use in a patient population with such a poor prognosis appears misplaced. Finally, repeated paracentesis weakens a patient and involves frequent hospital admissions, where as the aim of care for many patients at this time is to

optimize the time they have left at homc with their families.

Treatment should offer few side-effects and aim to reduce the morbidity associated with ascites. With this as our aim, we are undertaking research to evaluate ways to delay the re-accumulation of ascites. The study has drawn upon existing work from human and laboratory studies, and hopes to apply some of the principles associated with lymphoedema management to the control of ascites. The work involves intermittently raising intraperitoneal pressure, through the use of breathing cxcrcises and ex- ternal pressure applied from an abdominal binder worn by the patient, to assist the turnover of ascites back into the general circulation. Repeated paracentesis results in low- ering of pcritoneal pressure, which may further disrupt the lymphatic output. This could be compensated for through cxercises to increase abdominal pressure and by wearing a binder to increase pressure. It is hypothesized that fluid movement through patent or partially patent lymphatic pathways in the diaphragm may be enhanced, thus delay- ing the re-accumulation of ascitic fluid.

This approach is based on the fact that malignant ascites is primarily a problem of lymphatic obstruction. The lymphatic system controls the flow of fluid through lymphatic vessels through three main mechanisms. Lymph vessels appear to have a spontaneous contracti- lity. This causes pressure to develop in lymphatic vessels which helps to propel the lymphatic fluid. It has been shown in animals that increased intraluminal pressure results in increased contractility. This pressure may be a result of increased fluid or of extrinsic methods, including pressure generated from the contraction of neighbouring muscles. Pressure changes between the thoracic and abdominal pressures further assist the flow of lymph from the abdominal cavity (Olszewski, 1985).

Increased abdominal pressure has been shown to be directly proportional to uptake of fluid from the abdomen (Zink & Greenway, 1977). Two studies with patients with ascites as a result of cirrhosis of the liver showed that the turnover of ascitcs back into the circulation was directly proportional to the intra-abdominal pressure, which was in turn proportional to the volume of ascites (Milani et a]., 1994; Pozzi et al., 1994). It appears that when the abdomen is under the greatest pressure so the rate of absorption is increased. Unfortunately, once the fluid is drained this pressure is lost and so probably is the contractility of lumens in the lymphatic system. Zink & Greenway (1977) proposed that this explains why it appears that the more a patient is drained, the more they require drainage, due to the disruption of the pressure involved in maintaining lymphatic flow.

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P R E S T 0 N Management of malignant ascites

Work is being undertaken to find optimal ways of maintaining the intra-abdominal pressure, thereby in- creasing lymphatic turnover following drainage of as- cites. The lymphatic system should not be overloaded by absorbing this excess fluid, because patients with ascites due to cirrhosis of the liver tolerate an increased lymphatic flow through the thoracic duct of 8-10litres per day, as opposed to 1-2 litres in patients without ascites (Witte & Witte, 1983). One method of increasing abdominal pressure is through wearing an abdominal binder. The binder could be applied following drainage in order to increase the pressure, as the fluid re-accumulates sooner, so that the time to drainage should be increased. Another method may be to optimize the changes on pressures achieved through breathing. Normal breathing is sufficient to allow passage of ascites along a peritoneove- nous catheter. LeVeen et al. (1974) found they could increase this pressure by wearing abdom-inal binders and by getting patients to breath against a pressure. If patients increase the pressure in their abdomen throughout the day through breathing exercise regimes, as well as wearing a binder, then they may optimize their remaining lymphatic channels.

Research is now underway to find out what breathing exercises do increase abdominal pressure and how much an increase in pressure is gained by wearing a binder. Patients admitted for routine drainage of their ascites are asked to participate in the study. This involves having a pressure gauge introduced through their drainage catheter to record pressure changes. The patients are asked to carry out different breathing regimes and the pressures recorded. Hopefully, from this data a useful regime of exercises can be developed that can be used with patients with recurrent ascites. We hope to test this regime against diuretic therapy to see which regime can most effectively help delay the re-accumulation of ascites. Our aim would not be to ’cure’ ascites, but to reduce the number of times a patient needs to be admitted for drainage of their ascites. Furthermore, we aim to evaluate what effect different treatments have upon patients’ well-being and to assess the impact on activities of daily living. Thls will be done through both questionnaires and semi-structured inter- views. There is a dearth of information regarding the effect of ascites upon well-being and daily lifestyles. Previous studies, although taking the length of time for fluid reaccumulation to occur as an end point, have failed to address patients’ views and symptoms associated with different treatments. If the aim of treatment is minimal intervention such a simple approach, based upon the pathophysiology of the disease, could be a major break- through for the management of patients with intractable

malignant ascites. However, data must be recorded regarhng the effectiveness of this approach. As with lymphoedema management, if those techniques prove to be effective nurses will be well placed to incorporate them into day-to-day patient care, whether at home, in a hospital or in a hospice. If we can offer minimal supportive therapy wherever the patient wishes to receive it, we will be going some way to meeting the needs of a patient group who currently have few options for care.

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