Vol. 10 No. 3 April 1995 Journal of Pain and Symptom Management 237

Rev/ew Art/de

Management of Symptomatic Malignant Ascites with Diuretics: Two Case Reports and a Review of the Literature Subhash Sharma, MD, and Declan Walsh, MSc Palliative Care Program (S.X ) and Department of Hematolo~,/Medical Oncology (D. 141.), Cleveland Clinic Foundation, Cleveland, Ohio

Abstract Malignant ascites is a common complication of advanced cancey: It is associated with distressing symptoms and poor prognosis. Treatment may be aimed at the underlying cancer but is rarely successful. Th~apeutic success for the available symptomatic treatment options for ascites is often limited. Control of symptomatic malignant ascites is possible with the use of diuretics in selected patients, is well tolerated, and should be tried first. J Pain Symptom Manage 1995;10:237-242.

Key Words Malignant ascites, diuretics, advanced cancer

Introduction

Malignant ascites is a common cause of dis- tress and one of the most serious complications of advanced cancer. Ovarian, endometrial, breast, colon, gastric, and pancreatic carcino- mas cause over 80% of the cases. 1-5 In up to 20%, the ascites is due to tumors of unknown origin, 6'7 and these cases present the worst prognosis. ~ Patients with ovarian carcinoma de- velop ascites earlier in the course of the disease but live longer than those with other carcino- mas (mean survival > 10 months versus < 4 months) .7 With the exception of ovarian can- cer, the response of the ascites to treatment of the tumor is unsatisfactory' and treatment-re-

Address reprint requests to: Declan Walsh, MSc, Pallia- tive Care Program--T33, Department of Hematol- ogy/Medical Oncolo~', Cleveland Clinic Founda- tion, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Accepted for publication: June 15, 1994.

lated morbidity is common. Thus, the intent of most treatments for malignant ascites should be palliative.

We report two patients with ascites associ- ated with cancer (one cytology positive and one cytology negative), who were treated suc- cessfully using a combination of furosemide and spironolactone. Malignant ascites has pre- viously been considered unresponsive to di- uretics, 8-1° and there are only four previous case reports ~ ~-14 that describe beneficial effects of diuretics in malignant ascites. We discuss the role of diuretic therapy as one of many ap- proaches used to manage this complication.

Case Report 1 A 74-year-old woman presented in August

1991 with abdominal discomfort, bloating, and breathlessness, and was found to have massive ascites, a mild left hydronephrosis, and a left adnexal mass on pelvic ultrasound. Explor- atory laparotomy revealed a left ovarian cyst,

© U.S. Cancer Pain Relief Committee, 1995 0885-3924/95/$9.50 Published by Elsevier, New York, New "zbrk SSDI 0885-3924(94)00129-9

238 Shal)na and Walsh Vol. 10 :Vo. 3 April 1995

disseminated carcinomatosis involving the small bowel mesente W, lymphadenopathy, and a palpable mass in the pancreas. The pathology f rom the ovarian cyst, pelvic per i toneum, bowel serosa, and pancreas all showed invasive moderately differentiated mucinous adenocar- c inoma consistent with ovarian primaD'. The peri toneal fluid was chylous and cytology found to be positive for adenocarc inoma. The postoperative course was complicated by recur- rence of ascites. The pat ient preferred pallia- tion, refused chemotherapy, and was managed with oral furosemide 80 nag and spironolac- tone 100 mg daily. A dramatic response oc- curred with marked resolution of ascites and a weight loss of 15 kg over 3 months of diuretic treatment. No side effects were repor ted by the patient. No abnormal i D' of electrolytes or renal functions was noted, and there was no ortho- static hypotension. The ascites remained con- trolled until her death 4 months later of pro- gressive cancer.

Case Report 2 A 53-year-old woman presented with several

weeks' histo D' of right upper quadrant pain and weight loss. She denied any histo D, of al- coholism. The computer ized tomographic (CT) scan of the abdom en revealed a large liver mass and the CT-guided biopsy revealed moderately differentiated metastatic adenocar- cinoma. Colonoscopy revealed a large solita D' tubular adenomatous polyp at the hepatic flex- ure but no pr imary tumor. No significant re- sponse to chemothe rapy with 5-flurouracil, adriamycin, and mitomycin C was observed. The abdominal CT scan 4 months later was consistent with progression of disease in the liver and splenomegaly due to tumor involve- men t of the portal vein. Soon thereafter, esophagogas t roduodenoscopy showed esopha- geal varices and a deformity of the stomach and d u o d e n u m suggestive of extrinsic com- pression. Further metastatic workup failed to reveal the pr ima D, site. T u m o r markers such as alphafetoprotein, CA-125 and CA 19-9 were normal, and carcinoembD'onic antigen only slightly elevated at 5.1 (normal ~<2.3). She then received chemotherapy with carbopla t inum and an investigational agent but the liver dis- ease cont inued to progress. Four months later, she was found to be hypercalcemic (calcium,

11.1 m g / d L ) but responded well to intrave- nous mithramycin and hydration. Ascites, an- kle edema, and constipation developed 3 months later. The peri toneal fluid was negative for mal ignant cells. She was given furosemide 80 mg and spironolactone 200 mg orally daily. This reduced the ascites and was followed by a weight loss of 7 kg over 2 weeks. The furose- mide dose was later reduced to 40 mg on alter- nate days, while the spironolactone dose was left unchanged. Due to poor compliance with diuretics, she subsequently developed recur- rent ascites, and the furosemide dose was increased to 80 mg. Her modera te ascites re- mained clinically stable on this diuretic regi- men for ano ther 5 months when she was lost to follow-up. No adverse effects of diuretics oc- curred and the blood pressure, electrolytes, b lood urea nitrogen, and creatinine all re- mained normal.

Discussion

Ascites results ei ther f rom overproduct ion of fluid f rom visceral capillaries in the perito- neum, impaired drainage by visceral or dia- phragmat ic lymphatics, or both. 15 Involvement of diaphragmatic and mediastinal lymphatics by tumor a6 may be a significant factor in intrac- table ascites. The fluid can be a transudate or exudate. Malignant cells are more often found in exudative ascites and positive cytology is demonst ra ted in 26%-52% of cases. 7'17'1~ En- dothelial permeabili ty is increased in exudative ascites 9 resulting in increased protein concen- tration in the fluid. Fluid overproduct ion also occurs f rom areas on the peri toneal surface un- involved by tumor, z° Activation of the r en in - angiotens in-a ldosterone mechanism by reduc-

Table 1 Subtypes of Malignancy-Related Ascites and

Their Prevalence

Prevalence Subtype (%)

Massive liver metastases alone 53.3 Peritoneal carcinomatosis and massive

liver metastases 13.3 Heptaocellular carcinoma with portal

hypertension 13.3 Malignant chylous ascites 6.7

Modified from Table 1 i~l Hepatology 1988;8:1104-1109, with publisher's permission.

IJ)d. 10 No. 3 April 1995 Management of Aseites with Diuretics 239

tion in the extracellular fluid volume has been demonst ra ted in some and may have therapeu- tic implications. ~4

Chylous ascites may result f rom extravasation of chyle into the peri toneal cavi~ ~ due to lym- phatic obstruction by tumor. The prognosis for these patients depends on the t rea tment of the underlying disease. Lymphomas are the com- mones t cause of chylous ascites but pancreatic, breast, colon, prostate, ovarian, and renal cell carcinoma have all been implicated. 2~

Ascites should not be assumed to be a sequel- ae of the cancer until o ther c o m m o n causes such as cirrhosis, heart failure, and peritonitis are excluded. Once the diagnosis of mal ignant ascites is established, t rea tment is largely pal- liative and a imed at symptom control. Thera- peutic success is often limited. No standardized protocol exists for t rea tment of cancer patients with rapidly reaccumulat ing ascites and the fol- lowing approaches are implemented empiri- cally.

Diuretics Malignant ascites is associated with increased

renin activity, but the incidence of this abnor- mality' is unknown. The use of aldosterone an- tagonists, such as spironolactone 100-200 nag daily, ei ther alone or in combinat ion with a loop diuretic (e.g., furosemide 40-80 mg daily) may be able to provide adequate control. '~z They are often only temporari ly effective and dosage often needs to be increased. The max- imal ascitic reabsorption rate is 930 m L / 2 4 hr; 2'~ thus, the goal of therapy in patients with- out per ipheral edema is weight loss of 1 kg / day. If fluid is lost at a faster rate, there is a risk of intravascular volume depletion, diminished renal perfusion, azotemia, and hypotension. It is, therefore, impor tant to start diuretics in small dosage initially (e.g., furosemide 20 mg daily).

Paracgntesis Large volume paracentesis provides symp-

tomatic response, with significant hemody- namic changes, ~:~ but relief is only t e m p o r a l ' . No hemodynamic deteriorat ion occurs if para- centesis is combined with albumin infllsion. ~4 In a retrospective review of more than 300 pa- tients, Fisher ~~ did not find serious hypoten- sion following drainage of as much as 9 L of ascitic fluid. Occasionally, paracentesis to d ~ ~-

ness results in p e r m a n e n t control of ascites, z6 There are risks of hypovolemia, hypoprotein- emia, bowel perforation, and catheter- induced peritonitis. Paracentesis should be done with caution in loculated ascites. Permanent ly im- plantable ascitic drains have been used in re- current ascites ')7 but are associated with a high risk of sepsis. No comparat ive data are available on the use of diuretics versus paracentesis in mal ignant ascites.

Systemic Chemotherapy Ascites due to chemosensitive tumors such as

ovarian carc inoma or lymphoma often respond well to appropr ia te systemic chemotherapy. In a retrospective study based on a small n u m b e r of patients, Malik and colleagues 98 demon- strated complete remission or significant re- gression of ascites in 43% of patients r eceMng chemothera W for the underlying cancer (ovar- ian 46% and lymphoma 11%).

Intraperitoneal Chemotherapy Intraper i toneal ( I /P) drug administrat ion

achieves significantly higher drug concentra- tion in the peri toneal cavity including the dia- phragmat ic and peri toneal lymphatics than in- travenous drug administration. This approach may be more effective in achieving ascitic con- trol. I / P bleomycin, 29 cis-platinY 5FU and adriamycin:~l,32 have been used. All have shown only a partial response. Large studies on I / P chemothe rapy in mal ignant ascites are lacking. Systemic side effects f rom systemic drug ab- sorption occur.

Intraperitoneal Radio Colloids :~2p is the most widely used radionuclide for

mal ignant ascites with a repor ted response rate of 58%. :~~ Colloidal solutions of zinc ((~3Z) and gold (19~Au) have also been given but are as- sociated with a higher risk of complications, such as bowel necrosis. These agents also c a n t the risk of radiation exposure to health-care providers and need well-trained staff for ad- ministration.

lntraperitoneal lmmunostimulants Immunos t imulan t immunizat ion protocols

are based on the assumption that challenge with a particular infections agent, in a non-

240 Sharma and Walsh Vol. 10 No. 3 April 1995

pathogenic form, may activate cytotoxic T cells, macrophages, and natural killer cells, to pro- duce regression of peri toneal metastases and ascites. In a randomized study of nearly 200 patients with mal ignant ascites 34 treated with I / P OK-432, and extract of Streptococcus pyo- genes A3, ascites disappeared in 60%. Those treated with OK-432 also survived significantly longer than those managed with paracentesis and diuretics (10 months versus 3 months) . However, OK-432 t rea tment was effective mostly against cytology, positive ascites and was associated with side effects such as fever, chills, nausea, and abdominal distension. Moreover, these clinical responses were not reproduced in subsequent trials. Surgically conf i rmed tu- mor regression and significant reduct ion in as- cites has also been noted with the use of I / P Cownebac te r ium parvum. 35,36

Intraperitoneal Interfeq'on Some responses have been noted in resistant

ascites following I / P ot or ~ interferon. The mechanism is unclear but augmenta t ion of nat- ural killer cell activity in the peri toneal cavity has been noted. Fever, leukopenia, and flu-like symptoms are notable side effects. 37'38

Peritoneo-Venous Shunt ing (PVS) PVS, which was int roduced by LeVeen for

ascites due to alcoholic liver disease, may have a place also for mal ignant ascites. 2'a'9'~<~7 It in- creases physical mobility and obviates the need for repeated paracentesis by reducing abdom- inal distension. The cytologic status of the as- citic fluid should be considered in selection for PVS, as shunt life is significantly greater in cytologically negative ascites. 4° PVS may be associated with complications such as shunt blockage, venous thrombosis, disseminated in- travascular coagulation, heart failure, peri tone- al fibrosis with consequent intestinal obstruc- tion, and sepsis. T u m o r cells infused into the central venous system could produce massive early metastases 2'3-5'9'39'41'42 Case reports of

tumor embolization exist, though none have corrobora ted with systematic pos tmor tem pathological investigations. In 33 patients with mal ignant ascites treated with PVS, Souter and colleagues 4~ found clinically silent tumor em- boll in five of 12 who had autopsy. Contrain- dications include loculated ascites, jaundice

(serum bilirubin >10 mg%), infection, hemor- rhagic ascites or ascitic fluid protein content greater than 50 g /L , pseudomyxoma peritonei, and overt or subclinical coagulopathy.

Conclusion

The t rea tment of asymptomatic ascites should be aimed at the underlying cancer. In symptomatic cases with associated abdominal discomfort, early satiety,, and reduced mobility related to ascites, we believe that diuretics should be tried as first-line agents. Further studies are needed to evaluate their role in mal ignant ascites. Therapeut ic paracentesis should be done if ascites is associated with re- spiratory distress or if symptomatic ascites is resistant to diuretics. Per i toneovenous shunts are best avoided due to the higher risk of com- plications and morbidity. The role of intraper- itoneal immunost imulants needs to be evalu- ated fur ther with larger controlled studies.

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