Malignant ascites: past, present, and future

COLLECTIVE REVIEW

Malignant Ascites: Past, Present, and Future Rony A Adam, MD, FACOG, Yehuda G Adam, MD, FACS and water retention, hepatic lymph production, and microvascular permeability for macromolecules.2 Under physiologic conditions, at least two-thirds of peritoneal fluid reabsorbs into open-ended lymphatic channels of the diaphragm and is propelled cephalad by the negative intrathoracic pressure. The fluid proceeds through mediastinal lymph channels into the right thoracic duct and empties into the right subclavian vein. Scintigraphic studies have documented this route of flow.3 In cases of disseminated intraabdominal cancerinduced ascites, the pathophysiology is multifactorial. Increased production of peritoneal fluid is induced by the tumor. Increased microvascular permeability of tumor vasculature is the main factor in malignant ascites formation. Beecham and colleagues4 observed marked neovascularization of the parietal peritoneum, but not of the omental or mesenteric fat, in patients with malignant ascites and ovarian carcinoma. The amount of ascites production correlates with the extent of neovascularization. Senger and associates5 isolated a glycoprotein from ascitic fluid of experimental animals that is responsible for increased vascular permeability of small blood vessels. Subsequently Garrison and colleagues6 demonstrated that cell-free malignant ascitic fluid caused protein leakage from the omentum of healthy animals. This 45-kd glycoprotein is responsible for increased neovascularization and vascular permeability. Vascular endothelial growth factor (VEGF) and vascular permeability factor (VPF) also play an important role in a tumor’s ability to metastasize and influence the aggressiveness of neoplasms.7 The VEGF/VPF binds specifically to receptors on endothelial cells; receptors are activated by tyrosine phosphorylation.8 Review of the literature supports the fact that angiogenesis promoted by VEGF is associated with fluid accumulation in human tumor effusions,9 and malignant ascites is accompanied by high levels of VEGF. Zebrowski and associates10 reported markedly increased VEGF levels in the ascitic fluid obtained from gastric, colon, and ovarian cancer patients compared with levels in nonmalignant cirrhotic ascites serving as controls. Xu and associates8 blocked tyrosine kinase activity of the receptor for VEGF/VPF with a novel protein tyrosine kinase inhibitor PK-787 and suc-

Those cases of dropsy which are treated by incision or cautery, if the water flows rapidly all at once, certainly prove fatal. Hippocrates (Aphorisms section VI:27)

Except in breast and ovarian cancer, the presence of malignant ascites in patients with neoplastic diseases frequently heralds the terminal phase of cancer. It is a poor prognostic indicator, with a median survival time ranging from 1 to 4 months.1 Elimination of fluid accumulation in a symptomatic patient can and will enhance the quality of life and may prolong survival. Increased intraabdominal pressure with resulting pain, anorexia, dyspnea, reduced mobility, and pseudoobstructive symptoms create a miserable existence. The palliation of malignant ascites using assorted treatment options— which are adequate in patients with cirrhotic ascites— unfortunately have been inconsistent, temporary at best, and generally unsatisfactory. During the last few years our understanding of the etiology of malignant ascites has changed. This new information modifies our therapeutic approaches of neoplastic effusions. The aim of this review is to discuss the available therapeutic options and to emphasize the impact of our evolving understanding of tumor biology on the clinical management of patients with malignant ascites. PATHOPHYSIOLOGY Fluid accumulation in the peritoneal cavity is dependant on the amount of fluid generated and the rate at which it leaves the abdominal cavity. When fluid production exceeds its clearance, free transudate will accumulate. Under physiologic conditions, transudation of plasma through the capillary membranes of the peritoneal serosa continuously produce free fluid to lubricate the serosal surfaces. This fluid production is under the influence of portal pressure, plasma oncotic pressure, sodium

Received July 3, 2003; Revised January 13, 2004; Accepted January 16, 2004. From the Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA (RA Adam) and Herzeliya, Israel (YG Adam). Correspondence address: Rony A Adam, MD, Department of Gynecology and Obstetrics, Emory University School of Medicine, 69 Jesse Hill Jr Dr, SE, Atlanta, GA 30303.

© 2004 by the American College of Surgeons Published by Elsevier Inc.

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Abbreviations and Acronyms

MMP ⫽ matrix metalloproteinase VEGF⫽ vascular endothelial growth factor VPF ⫽ vascular permeability factor 5-FU ⫽ 5-fluorouracil

cessfully inhibited malignant ascites formation of VEGF/VPF- dependent ovarian carcinomas. Tumor necrosis factor and administration of monoclonal antibody generated against VEGF receptors also prevented the recurrence of malignant ascites.11,12 These observations confirm that specific VEGF receptor inhibitors and tumor necrosis factor inhibit the interaction between VEGF and its receptor, preventing malignant ascites formation. Matrix metalloproteinases (MMP) are used by tumor cells to break down and remodel tissue matrices during the process of metastatic spread.13 Matrix metalloprotein inhibitors represent a new therapeutic approach to the treatment of disseminated cancer. These inhibitors not only prevent metastatic spread, but they block angiogenesis, prevent local invasion, and enable stromal encapsulation of tumor cells. Increased matrix metalloproteinase activity is detected in a wide variety of cancers and seems to correlate to their invasive metastatic potential and aggressiveness.14-16 Levels of certain MMPs such as stromelysin-3 and gelatinase are elevated in tumorassociated stroma compared with noninvolved tissue. When synthetic MMP inhibitors were given intraperitoneally to mice with ovarian or colon cancer-induced malignant ascites, the effusion resolved and survival improved.17 These observations in regard to the genesis of malignant ascites certainly may influence clinical management of malignant effusions. Another major factor in the formation of malignant ascites is lymphatic obstruction. When intraperitoneal technetium sulphur colloid was given to patients with neoplastic ascites, no radioactivity was detected above the diaphragm in 85% of patients.18 This suggests that diaphragmatic lymph channels are obstructed by tumor invasion. When the main thoracic duct is invaded by cancer, chylous ascites develops because the thoracic duct drains the abdominal viscera.19 In Budd-Chiari syndrome, obstruction of the hepatic venous outflow tract by tumor results in intraperitoneal fluid accumulation. In conclusion, based on currently available experi-

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mental and clinical data, tumor-produced specific proteins combined with mechanical obstruction are responsible for malignant ascites formation. Rational and effective treatment approaches in the future should consider blocking angiogenetic components and eliminating or at least reducing the obstructive elements. DIAGNOSIS Frequently, ascites is the first physical sign of a malignant intraabdominal process. Garrison and coworkers6 reported that 52% of patients have obvious ascites at the time of initial cancer diagnosis. In most instances, ascites can be diagnosed by a careful history and physical examination. Ultrasonography and abdominal CT are frequently used and are able to detect free peritoneal fluid if its volume is greater than 100 mL.20 Malignant ascites is indistinguishable by physical examination from ascites caused by benign conditions. Radiographic techniques also have limitations on their ability to distinguish the two. Cirrhosis, congestive heart failure, nephrosis, tuberculosis, pancreatitis, and peritonitis from pyogenic organisms, to mention a few, can produce intraabdominal fluid accumulation. Indeed, differentiating between malignant and nonmalignant ascites might be somewhat challenging without invasive testing. Abdominal paracentesis with analysis of the ascitic fluid should be used in most cases where there is doubt. Abdominal tap can be performed safely and its results are available in a few hours.21 The aspirated fluid should undergo microscopic, chemical, and cytologic analysis.The cell count provides immediate information about possible bacterial infection. Samples with a predominance of neutrophils, greater than 250 per mm3 are suggestive of infection. Gram stains and culture for bacterial, fungal, and acid fast organisms are mandatory. If the serum-ascites albumin gradient, calculated by albumin concentration of ascitic fluid minus serum albumin concentration, is less than 1.1 g/mL, portal hypertension can be safely ruled out.22 Ascitic fluid amylase content helps to detect pancreatic ascites and gut perforation.23 Ascitic fluid pH, lactate concentration, and tests for fibronectin and cholesterol have been proposed, but subsequent studies have not been found to be clinically useful.24,25 Colli and colleagues26 reported an 82% accuracy of sialic acid determination in ascitic fluid to differentiate between malignant and nonmalignant ascites. More recently, Tangkijvanich and associates27 noted that presence of telomerase is a specific discriminatory marker in malignant ascites. Telomerase activity is detected in 81% of malignant

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effusions, with a sensitivity of 76% and specificity of 95.7%. Human gonadotropin-␤ is frequently elevated in malignant ascites and has been combined with cytology with a diagnostic yield of 89.5%.28 Cell blocks from centrifuged specimens of ascitic fluid should be submitted for cytology. Unfortunately, ascitic fluid cytology is diagnostic in only 50% to 60% in reported series.29,30 Tumor markers, especially CEA, CA-125, and alphafetoprotein, can be useful in diagnosing the primary tumor in malignant ascites, although they lack specificity. Torresini and coworkers31 combined the CEA test and cytopathologic examination to improve the diagnosis of neoplastic versus nonneoplastic ascites in 130 patients. In 67 patients with epithelial tumors, only 53.7% had positive cytology. When combined with elevated ascitic CEA levels (⬎11.0 ng/mL) accuracy increased to 85.1%. So they suggested supplementing evaluation of cytologically negative ascitic fluid with CEA determination. Caution should be exercised when interpreting CEA levels in ascites in the presence of leukocytosis or hepatic failure. Elevated serum CA-125 levels are suggestive of ovarian cancer-induced ascites in the presence of an adnexal mass in postmenopausal women. Analysis of ascitic fluid does not always provide accurate pathologic diagnosis. In this subgroup of patients, laparoscopy can be used to obtain a tissue diagnosis.32 Schweiger and colleagues33 suggested percutaneous fluid aspiration or biopsy with CT fluoroscopic guidance in cases that are otherwise difficult or unsafe to attempt under ultrasound or conventional CT guidance. This approach was successful in 10 of 13 patients. Chang and associates34 used endoscopic ultrasound-guided fine needle aspiration to diagnose malignant ascites in a patient with gastric carcinoma in whom CT scan did not show any evidence of ascites. TREATMENT With the exception of ovarian carcinoma, malignant ascites is frequently a terminal event and, as such, life expectancy in most patients is limited. The aim of therapy is palliation and improvement of quality of life. But, in a small selected subgroup of patients, aggressive combined therapy may result in longterm survival. During the last decade, several novel and innovative approaches have been developed. Experimental and clinical results are variable, but encouraging.

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Diuretics

In general, malignant ascites remains refractory to medical treatment. Reduced sodium intake with the diuretic combination spironolactone and a loop diuretic, the initial treatment of choice in cirrhotic ascites, is rarely effective. Sharna and Walsh35 recommended the use of diuretics as first line treatment in selected patients because therapy of the underlying cancer is rarely successful. Greenway and coworkers36 used increasing doses of spironolactone up to 450 mg daily and succeeded in resolving clinically detectable ascites in 14 of 17 patients within 4 weeks of treatment. So it is likely that increased aldosterone concentration contributes to the formation of malignant ascites. It is interesting that patients with malignant ascites from massive hepatic metastases respond well to spironolactone, suggesting that these patients behave more like those with cirrhotic ascites. Caution in the use of diuretics is warranted because high drug levels may result in renal failure. Paracentesis

Evacuation of the accumulated fluid from the tense distended abdominal cavity substantially improves comfort, physical activity, and symptoms of pain and shortness of breath. Use of therapeutic paracentesis dates back to Greek civilization. In the mid 19th century, Beethoven underwent this procedure.37 Paracentesis involves considerable patient discomfort, protein loss, and fluid deprivation. In most cases, there is rapid reaccumulation of fluid necessitating frequent repeat abdominal taps. Many patients with malignant ascites who have undergone earlier extensive surgical procedures develop peritoneal adhesions and, consequently, fluid loculations, which may result in incomplete taps and increased risk. Visceral and vascular injury can occur with repeated paracentesis. Septic complications, despite rigorous sterile precautions, may occur with occasional fatal consequences. Hypotension directly related to the procedure is not uncommon, and ascitic fluid leak may also result. Despite these complications, in a recent Canadian study on attitudes of physicians treating malignant ascites, 98% preferred paracentesis as the initial management of malignant effusions. In 61%, the favored treatment was diuresis.38 To overcome the problems of frequently repeated paracentesis, indwelling peritoneal drainage catheters were introduced. Lee and colleagues39 inserted 45 cath-

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eters under ultrasonographic guidance in 38 patients, with immediate symptomatic relief. But, two fatal hypotensive episodes occurred, and one-third of the patients who were followed developed catheter-related sepsis. Five catheters were removed because of blockage and two were ineffective because of loculated ascites. To reduce septic complications Richard and associates40 used a Pleurx tunneled catheter (Denver Biomaterials) in 10 patients. The catheter was placed with combined ultrasonographic and fluoroscopic guidance. Although the reported series is small, no catheter-related infections were noted, and the mean patency duration was 70 days. Belfort and associates41 reported on 17 patients treated with a permanently implanted silicone elastomer drain. Complications include one case of peritonitis and abdominal wall cellulitis in two patients. Radioisotopes

Therapeutic radioisotopes emit particulate radiation that typically travels short distances in body tissues, where it either destroys or damages surrounding cells in the area. Radioactive gold AU-198 was one of the first isotopes used for intracavitary application to treat malignant ascites. Dybecki and colleagues,42 in 1958, reported on 566 patients treated with intraperitoneal AU198. In 47%, production of ascitic fluid was significantly decreased. When the injected dose was increased (up to 150 mCi), the ascites was eliminated completely in most of the patients. The dose escalation resulted in a substantial increase of bowel complications, mostly intestinal obstruction. AU-198 is a mixed beta and gamma emitter with a short half-life and as such, its use is now considered hazardous. 32 P chromic phosphate is a beta emitter. Intraperitoneal use of 32P has advantages. The radioactivity generated by this isotope is in close contact with tumor cells on the serosal linings of the peritoneal cavity and with cancer cells present in the effusion. Macrophages fix the beta- emitting colloidal particles on the serosal lining, where they destroy malignant cells. An added advantage is that maximal tissue penetration of 32P is 8 mm, compared with 3.8 mm of AU-198 with a longer half-life.43 After paracentesis, a 10- to 20-mCi dose is injected. Often, 99mtc sulfur colloid is instilled before the 32P to verify proper dispersion of the isotope in the peritoneal cavity. Intraperitoneal injection of 32P in the presence of significant intraabdominal adhesions may result in intestinal necrosis from uneven distribution of the isotope,

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and this is the most important contraindication to its use.44 Jacobs and colleagues45 reported that one-third of patients with malignant ascites treated with intracavitary 32 P responded with complete cessation of their effusion. The response rates reported by others vary between 30% and 80%.45-47 Of 313 patients with ovarian cancer treated with intracavitary 32P, 22 (7%) developed intestinal obstruction and 2 (0.6%) died.48 The major limitation of intracavitary 32P is limited tissue penetration. When tumor masses are present in the peritoneal cavity, the therapeutic effect of intracavitary 32P installation is minimal. So the ideal patients are those with diffuse peritoneal seeding or those in whom the ascitic fluid is cytology positive, without evidence of gross cancer deposits. Intracavitary chemotherapy

Intraperitoneal chemotherapy allows direct exposure of tumor cells to high concentrations of cytotoxic drugs without increasing systemic toxicity. A cytotoxic drug is considered appropriate for intraperitoneal administration if its molecular weight is high enough not to permit easy transfer through the peritoneal plasma barrier. Although the drugs are sequestered within the peritoneal space, they eventually are systemically absorbed. For this reason, safe dosing is, for the most part, identical to intravenous doses. There are three major impediments of intraperitoneal chemotherapy, including limited penetration (about 1 mm) into tumor nodules, nonuniform drug distribution, and the difficulty and dangers of longterm peritoneal access.49-51 The intracavitary approach is more effective when the tumor has been responsive to earlier systemic therapy, especially in patients with metastases of ovarian or breast origin. Because of limited drug penetration, therapeutic yield is best with minimal or microscopic tumor load. Intraperitoneal chemotherapy is an effective way to palliate malignant ascites. By destroying the surface cancer, it induces a progressive fibrotic process, which eventually will cover all malignant deposits and noninvolved parietal and visceral peritoneal surfaces, and this process will prevent formation of both peritoneal and neoplastic fluid. Eventually, the abdominal space ceases to exist because of massive adhesions. If the sclerotic process is not complete, it may produce fluid loculations that will interfere with uniform drug distribution, may cause ob-

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struction, and makes subsequent paracentesis difficult and risky.49,50 One of the earliest single agents used for intraperitoneal application is mechlorethiamine (nitrogen mustard), a polyfunctional alkylating agent. The first clinical trials took place in the early 1940s. After the ascitic fluid is evacuated, 0.2 to 0.4 mg/kg mechlorethiamine diluted in 100 mL of normal saline is injected intraperitoneally. This compound causes severe peritoneal irritation. Weisberger and associates52 reported no reaccumulation or decreased formation of malignant ascites after intracavitary nitrogen mustard in 8 of 11 patients. Experience with intraperitoneal Thio-TEPA is rather limited. After paracentesis 0.6 to 0.8 mg/kg thioTEPA diluted in 2 liters normal saline is instilled into the peritoneal cavity weekly. Twenty-three patients with malignant ascites were treated by Appelqvist and coworkers53 with intracavitary thioTEPA; one-third experienced temporary partial response. Intestinal obstruction developed in five patients (22%), and in 60% of the autopsied patients, massive intestinal adhesions were present. The overall response rates in published studies were between 32% and 58% when intracavitary therapy was given in conjunction with systemic chemotherapy.54,55 Locally, a less irritating agent is cis-diammine dichloroplatinum (cisplatin), an inorganic complex formed by an atom of platinum surrounded by chlorine and ammonia atoms in the cis position. This agent is very effective in treating ovarian cancer. Its intraperitoneal concentration is 30 times greater than when it is given intravenously. Large intraabdominal doses can be delivered with low systemic toxicity, it has no cross resistance with other drug combinations used to treat ovarian cancer, and it does not irritate the peritoneal surfaces.56-58 Despite these favorable characteristics, results in patients with malignant ascites from metastatic cancer of gastrointestinal primaries are not encouraging. Jones and colleagues59 used intraperitoneal cisplatin in patients with gastric cancer with a high risk of relapse. Adjuvant therapy with cisplatin did not influence the pattern of relapse or length of survival, but in half of the patients with malignant ascites, resolution of the effusion was achieved without major complications. Markman and Kelsen60 used a combination of intracavitary cisplatin and mitomycin for control of malignant ascites secondary to peritoneal mesothelioma in 15 patients. Seven (47%) experienced control of the ascites from 2 to 73

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months, especially those patients with small residual disease after surgical debulking. 5-Fluorouracil (5-FU) is used intraperitoneally as a single agent or in combination with other chemotherapeutic drugs. 5-FU administered intraabdominally is metabolized by the liver, so high intraperitoneal doses are well tolerated.51 Schilsky and associates61 treated 31 patients with malignant ascites using a 5-FU and cisplatin combination intraperitoneally every 28 days. Nine of the 15 patients with nonbulky disease had resolution of the ascites, and at least 50% reduction of peritoneal studding at repeat laparotomy. Adriamycin has very limited tissue penetration and triggers severe chemical peritonitis. Because of its corrosive activity, its intraperitoneal use is confined to produce adhesions and to obliterate the peritoneal cavity.62 This effect is similar to that of tetracycline or talc injected into body cavities. Intraperitoneal bleomycin reportedly can be given safely with few systemic side effects. Although this agent seems to be effective in controlling malignant pleural effusions, it is less active for malignant ascites. Response rates as high as 69% have been reported in decreasing ascites, but complete response rates around 20% seem more realistic.63 Mackey and colleagues64 studied 15 patients with recurrent malignant ascites who were treated subsequent to paracentesis with intraperitoneal triamcinolone hexacetanide, a slowly metabolized corticosteroid. Symptomatic ascites recurred in 13 of 15 patients, but the interval between paracentesis was extended from 2.5 days to 17.5 days and patient well being was significantly improved. Mitomycin C alone or in combination with etoposide in patients with malignant ascites secondary to gastrointestinal cancer is promising, especially in conjunction with peritoneal hyperthermia.65,66 Shunting procedures

To overcome the need for repeat distressing paracentesis and the resulting protein and fluid depletion Mulvani,67 in 1955, designed a peritoneal vesical catheter. The ascitic fluid drained into the bladder through a catheter and was eliminated through the urine. Because of frequent complications including peritonitis and catheter blockage, this procedure did not become popular. In 1974, Leveen and associates68 introduced the concept of peritoneovenous shunting. This shunt drains ascitic fluid into the superior vena cava. Fluid removal is

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based on the intraperitoneal and thoracic superior vena cava pressure differential and is performed through a pressure sensitive, one-way disc valve encased in a polypropylene housing. Initially the shunt was designed to drain nonmalignant ascites, but it subsequently became one of the most popular procedures managing malignant effusions. To overcome the main drawback of frequent occlusion, a variant, the Denver shunt, was designed by Lund and Newkirk.69 The heart of this system is a subcutaneous manually compressible silicon pump chamber containing two miter valves. The valves are open at a positive pressure of 1 cm water, and they prevent detectable reflux.70 There have been no prospective randomized studies comparing the patency rates of the two systems, but the impression based on clinical experience is that there is no significant difference between them and the incidence of occlusion is essentially the same.71-73 The authors reviewed 31 published series, a total of 968 peritoneal venous shunts, and found that 70% of shunts (680 patients) offered effective palliation. Because the goal of this surgical intervention is palliation, its use in patients whose life expectancy is less than a month is not justified. Patients with hemorrhagic or chylous ascites or those with loculated malignant effusion cannot benefit from the procedure. Advanced cardiac or renal failure is a relative contraindication because hemodilution and volume overload accompany peritoneovenous shunting. Elevated bilirubin levels (⬎6 mg/dL) are contraindications because of the markedly increased risk of intravascular coagulation.74 Portal hypertension, massive pleural effusion, and coagulation disorders are relative contraindications.75,76 Initial concern about the use of a shunt in treating malignant ascites centered around propagating the tumor. In practice, only infrequent case reports of these problems have been described. In cirrhotic patients, a major complication of peritoneovenous shunting was rapid development of disseminated intravascular coagulopathy. This problem in patients with malignant ascites is infrequent. The explanation of this phenomenon is that reinfusion of large volumes of ascitic fluid cause dilution of circulating coagulation factors and it introduces soluble collagen into the circulation, initiating disseminated intravascular coagulopathy. Discarding two-thirds of the ascitic fluid before shunting can prevent this complication.77 The complication rate of peritoneovenous shunting is estimated between 25% and 40%.71,78 Kinking of the

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catheter at its entrance to the internal jugular vein and occlusion of the valve by debris or fibrin deposits are the most common complications, occurring in one-third of patients.76,79 Ascitic leak from the insertion site, sepsis, gastrointestinal bleeding, tumor dissemination, and disseminated intravascular coagulopathy can occur. The reported perioperative mortality is between 10% and 20%. Reported median survival varies between 52 and 266 days, which reflects patient selection. Cheung and Raaf 79 reported that in patients whose ascitic fluid was negative for malignant cells, the median survival was 140 days compared with 26 days in the positive cytology group. In all reported studies, patients with ovarian and breast cancer who undergo peritoneovenous shunting have the best response rate (ⱖ50%); patients with gastrointestinal cancers fare worse (10% to 15%). Among 51 patients with nongynecologic malignant ascites undergoing shunting procedures reported by Bieligk and associates,80 the median survival time was 52 days. In conclusion, shunting is not without risks and complications, but in well selected patients with reasonable life expectancy who are symptomatic, in whom other treatment alternatives have failed, shunting can provide reasonable palliation. Biologic agents

The discovery of vascular endothelial growth factor has changed our concept of the genesis of malignant ascites.9 Malignant intraabdominal conditions associated with increased VEGF activity include epithelial ovarian, gastric, colon, and pancreatic carcinomas, and omental and hepatic metastatic diseases. Initial phase I and II clinical trials with angioinhibitory therapy, such as anti-VEGF antibodies, anti-VEGF receptor antibodies, tumor necrosis factor, and metalloproteinase inhibitors have been reported. Antitumor activity has been noted in patients with advanced disease with or without ascites.8-10 Blocking the tyrosine kinase activity of the receptor of VEGF with inhibitor protein PTK-787 inhibited malignant ascites formation in ovarian carcinomas.9 Tumor necrosis factor inhibits the interaction of VEGF and its receptor and prevents reaccumulation of ascites in a mouse model.11 Metalloproteinase inhibitors are not cytotoxic but are only cytostatic, so in clinical practice they are used in conjunction with chemotherapeutic agents. They do show synergistic effects with conventional chemother-

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apy.16 Batimastat is one of the early metalloproteinase inhibitors used in clinical trials on patients with malignant ascites. In xenograft models of human colon cancer, its use led to marked inhibition of local and regional tumor growth and significant inhibition of angiogenesis.81 In patients with malignant ascites, batimastat was well tolerated and effective.82 The drug was well absorbed by the intraperitoneal route, and a response was observed in five of eight evaluable patients with advanced malignant disease and malignant ascites.83 There is improved bioavailability reported for marimastat, a second generation matrix metalloproteinase inhibitor. Although no studies to date address the issue of palliation of ascites, marimastat showed no overall survival advantage in two recent randomized studies of colorectal or pancreatic cancer.84,85 The use of immunomodulators in treating malignant ascites dates back to the early 1980s. The first immunotherapeutic agent, OK-432, a lyophilized powder of sustrain Streptococcus pyogens A3 was introduced and tested by Katano and Torisu.86-88 They injected OK-432 intraperitoneally in 77 patients with malignant ascites of gastrointestinal origin. Subsequent cytologic examination of the peritoneal fluid revealed disappearance of cancer cells and increased number of neutrophils, macrophages, and lymphocytes 4 to 7 days after injection. Complete disappearance of ascites was observed in 43 patients (56%). Cell-mediated immunity is responsible for cancer destruction in the effusion and as the number of tumor cells decreased, the ascitic fluid protein levels decreased as well. Further accumulation of peritoneal effusion, as a result, was suppressed. In 1998, Katano and Murisaki89 reported on 400 patients with malignant ascites treated with intraperitoneal OK-432. The data showed that OK-432 therapy induced a reduction of effusion in 60% of cases and significantly prolonged survival in responsive patients. Reduction of the original tumor mass was observed in 20% of patients. Current data suggest that the antitumor activity of OK-432 is the result of both cell-mediated and cytokine-induced activity. Side effects are mild to moderate and include fever, chills, malaise, nausea, and abdominal distention. A combination of OK-432 and interleukin-2 (IL-2) was given to patients with malignant ascites from gastric cancer. Of the 22 evaluated patients 18 (82%) exhibited complete or partial responses, showing disappearance of cancer cells and decreased ascites.90 Gebbia and colleagues91 treated 23 patients with ma-

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lignant pleural and peritoneal effusions with intracavitary beta-interferon. Three of 15 patients with peritoneal effusions (20%) had complete resolution of their ascites at 30-day followup. Partial resolution, defined as less than 50% reaccumulation of fluid and no need for reaspiration, was noted in another three patients. The treatment was well tolerated, with mild and transient discomfort in 3 patients out of the entire group of 23. Twenty patients with gynecologic cancer-induced malignant ascites received intracavitary mitoxantrone. After abdominal tap, 20 mg mitoxantrone was instilled intraperitoneally; one to four doses were given as clinically indicated. Twelve of the 20 patients (60%) demonstrated palliation of the ascites, but 8 patients developed small bowel obstruction. Whether this complication was the result of disease progression or related to the treatment is unclear.92 Based on experience in treating cancer with radiolabeled antibodies targeting tumor- specific antigens, several studies have focused on intraperitoneal application to eliminate or decrease malignant ascites. Phase I and II studies of intraperitoneal radioimmunotherapy were conducted in ovarian and breast cancer patients with chemotherapy resistant ascites, using a anti-mucin monoclonal antibody 2G3, labeled with 131I. Nine patients received intraperitoneal iodine-labeled 2G3 in therapeutic doses (up to 150 mCi total dose) without significant side effects. Three of four patients who received doses greater than 50 mCi did respond, with temporary resolution of their ascites.93 Hyperthermic chemotherapy

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. In vivo studies have demonstrated that thermal advantage is maximized at temperatures between 40.5° and 43°C. Tissue penetration improved and drug resistance was reduced by hyperthermia.94 When cisplatin and etoposide were perfused in heated saline solution (41.5° to 42°C) into patients with disseminated gastric and colon cancer, ascites disappeared in four of five patients.95 Fujimoto and associates65 reported on 15 patients with refractory gastric cancer with peritoneal metastasis treated by intraperitoneal hyperthermic chemotherapy. Three patients died of peritoneal recurrence and one of pericardial metastasis. Of the remaining 11 patients with less extensive peritoneal metastasis, 5 survived without recurrence.

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When hyperthermic infusion is followed by extensive cytoreductive surgery, improved survival has been achieved in selected patients. One hundred nine patients with peritoneal carcinomatosis were recruited for a prospective phase II clinical trial. After resection of all gross disease, a 2-hour intraoperative mitomycin C infusion was carried out at 40.5°C. Treatment related morbidity and mortality were 35% and 8%, respectively; overall survival at 1 year was 61% and at 3 years, 32%. Hematologic toxicity occurred in 20% of patients.66 In a similar study, cisplatin was added to mitomycin C in 32 patients with advanced digestive and ovarian cancer. In 11 of 12 patients with malignant ascites, complete resolution was observed. Median survival in this group of patients was 11.2 months.96 Aggressive combined treatment approach

It is well documented that optimal results with intracavitary chemotherapy can be achieved when peritoneal spread is microscopic. The main disadvantages of chemotherapeutic agents are limited tissue penetration and unequal intraperitoneal distribution when infused or perfused. Aggressive cytoreductive surgery combined with intraoperative hyperthermic chemotherapy in a well selected patient population with malignant ascites could overcome those limiting factors.97 The procedure aim is to remove all visible evidence of tumor and leave the patient with microscopic residual disease. To achieve this goal, all involved peritoneal surfaces have to be removed, and fixed parts of the gastrointestinal tract with cancer desposits have to be resected.98 After completion of the resection and before performing the necessary intestinal anastomosis, hyperthermic chemotherapy is begun. This approach assures uniform intraperitoneal drug distribution. The agents used are mitomycin C, 5-FU, cisplatin, taxol, or gemcitabine, depending on tumor histology. Patient selection is of utmost importance. Histopathology to assess tumor invasive potential, peritoneal tumor load and its distribution, feasibility of complete eradication of the cancer by cytoreductive surgery, preoperative CT scan, and, of course, the patient’s general condition are all major factors in selecting patients for this rather formidable therapeutic undertaking.99 Surgical debulking, which leaves large foci of metastatic disease behind, does not provide lasting benefit. When gross metastatic deposits were left and immediate intraoperative hyperthermic chemotherapy with mitomycin

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C was performed, 1-year survival was only 39%, even though 75% of malignant ascites was resolved.100 The same group updated their experience and reported on 84 patients with peritoneal carcinomatosis of gastrointestinal origin. Malignant ascites was found in 39 of these patients (46%). Operative mortality was 6% and hematologic toxicity was mild. In patients with malignant ascites, median survival was only 7.6 months, in contrast to those without ascites, in whom median survival reached 27.7 months.101 To emphasize the necessity of complete removal of all visible metastatic disease, Shen and associates66 compared the results of resection of all metastatic deposits greater than 5 mm versus incomplete removal in 109 patients. When only microscopic disease was left, 3-year survival was 68%, in contrast to 21% when resection was incomplete. Patients with malignant ascites fared worse; presence of effusion was an independent negative prognostic factor. Similar results were reported by Beaujard and colleagues102 on 86 patients with digestive tract cancer and peritoneal carcinomatosis; median survival time was 16 months for the resected group versus 6 months for patients with incomplete resection. DISCUSSION Malignant ascites is a collection of protein-containing fluid within the peritoneal cavity associated with cancer. Ovarian, endometrial, breast, colonic, gastric, and pancreatic carcinomas make up more than 80% of tumors that cause malignant ascites from intraperitoneal seeding. Understanding of the pathophysiology of malignant ascites has evolved during the last decade. Discovery of tumor-derived new glycoprotein complexes has changed our concept of the genesis of malignant effusions. Vascular endothelial growth factor, vascular permeability factor, and matrix metalloproteinases play an important role in the pathogenesis of malignant ascites. Neovascularization and increased capillary permeability, permitting macromolecular transit through the endothelial linings of the newly formed capillary endothelium, compounded with the aggressive invasive phenotype of neoplastic cells and increased potential for metastatic spread, contributes to ascites formation. Lymphatic obstruction caused by tumor invasion of the open ended diaphragmatic lymph channels with the increased fluid production result in malignant fluid accumulation in the peritoneal cavity. Indeed, experimental models and clinical trials confirm that a new therapeutic approach

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Figure 1. Algorithm for the therapeutic approach of malignant ascites. The primary factor determining the mode of therapy for ascites is prognosis. Other factors include tumor type, tumor bulk, response before chemotherapy, and the general condition of the patient.

combining inhibiting agents with cytotoxic chemotherapy may be the preferred management for treating malignant ascites. The presence of ascites, in most instances, can be established by history and physical examination. If it is in doubt, ultrasound or CT can be diagnostic. Malignant ascites is rarely distinguishable by physical examination from ascites caused by benign conditions. In 50% of patients, the presence of ascites is the first clinical sign of an underlying abdominal neoplastic process. Paracentesis frequently affords a cytologic diagnosis, and at the same time results in significant symptomatic relief. The fluid’s appearance, protein content, chemical analysis and the search for infectious causes, cell content, and tumor markers assist in establishing the correct diagnosis. On occasion, laparoscopic, ultrasonographic, or CTguided biopsy is needed for final histologic diagnosis. Extensive search for the original tumor is justified only when it influences clinical management. When the neoplastic nature of the effusion is determined, many factors influence the optimal therapeutic

intervention. The aim is palliation in the majority of patients; only in a selected subgroup is it to improve survival. The histology and aggressiveness of the cancer, its response to earlier therapeutics, the extent of peritoneal spread, overall prognosis, and the patient’s general condition will influence the planned management of this heterogenous group of patients. The benefits of the planned therapy must balance favorably against the risks of the procedure (Fig. 1). Therapeutic use of paracentesis to relieve abdominal pressure and its related symptoms has been used for many centuries. Although abdominal discomfort, fluid and protein depletion, ascitic fluid leaks, peritonitis, and occasional hemorrhage are well known complications of repeat paracentesis, a recent survey of Canadian oncologists revealed that despite its drawbacks, peritoneal taps are the most popular procedures to palliate malignant ascites. Many patients developed peritoneal adhesions from earlier operations, with resulting fluid loculations that render abdominal tap ineffective and potentially hazardous. Nevertheless, in patients with advanced, aggressive, bulky, chemotherapy-

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resistant tumors with symptomatic ascites, paracentesis will improve quality of life and as such, provides acceptable palliation. The yield of diuretics in malignant ascites is reportedly low, but the complications and discomfort from diuretic administration are minimal, so diuretics can be considered a first line treatment in selected patients. Patients with massive hepatic metastases with ascites behave like those with cirrhosis and respond well to spironolactone. The problem with radiopharmaceuticals, such as AU198 or 32P, is their limited tissue penetration. With dose escalation, the incidence of bowel complications becomes prohibitive. Homogeneous isotope distribution within the peritoneal cavity is essential. Loculations are a contraindication for intraabdominal use of radioisotopes because it can result in bowel wall necrosis. The ideal candidate for intracavitary isotope therapy is the patient with diffuse peritoneal cancer involvement or with cytologically positive ascites without evidence of bulky intraabdominal disease. The success rate in controlling malignant ascites varies between 30% and 80% depending on patient selection. Intracavitary chemotherapy is an attractive concept; it can achieve high drug concentrations at the site of the disease, while plasma concentrations and systemic toxicity remain low. Intraperitoneally administered chemotherapeutic agents have dual actions: direct cytotoxic effect on the tumor itself and sclerosing the peritoneal surfaces. The sclerosing process initiates fibrosis of the peritoneal lining and obliterates the peritoneal space, preventing future fluid formation. The negative aspect of this sclerosing action is its high incidence of mechanical bowel obstruction. Therapeutic success yield varies between 30% and 60%. Patients with diffuse peritoneal seedings are the best candidates for this modality. Hyperthermia enhances the cytotoxicity of chemotherapeutic agents administered intraperitoneally. Experience with hyperthermic intracavitary chemotherapy, especially after surgical debulking procedures, is increasing. When it is used intraoperatively, homogeneous distribution of the agent is ensured. Mitomycin C with or without cisplatin, or cisplatin and etopisode with hyperthermia in patients with gastric, colon, and ovarian cancer-induced ascites have produced encouraging results. In addition to controlling malignant ascites, patient survival is improved in selected cases. In the 1980s peritoneovenous shunting became very

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popular, but complications and shunt malfunctions have dampened enthusiasm for this procedure, despite relatively high success rates. Roughly 70% of patients with malignant ascites respond to the shunting procedure. The complication rate varies between 25% and 45%. There are few contraindications for the procedure, and perioperative mortality is between 10% and 20%. Of course, therapy is purely symptomatic and has no impact on length of survival. If the patient is expected to survive more than 3 months and has failed other therapeutic alternatives, shunting is the best available method for lasting palliation. Immunomodulators have been used clinically since the 1980s. OK-432, a streptoccocal extract, was used in large series of patients with malignant ascites. More than 400 patients were treated with intraperitoneal OK-432, with a 60% reduction of the ascitic fluid and a 20% incidence of significant decrease of tumor mass, with mild side effects. Survival of the treated group increased to a mean of 10.2 months, compared with 3.1 months for controls. It seems that for patients with malignant ascites from a gastrointestinal primary, OK-432 is an acceptable therapeutic alternative. Two other immunomodulators, beta-interferon and mitoxantrone, were used intraperitoneally in small reported series, with a 50% success rate. Clinical experience to date with these agents is limited. Discovery of VEGF/VPF and the role of matrix metalloproteinase in the genesis of malignant ascites have recently opened new therapeutic possibilities in managing malignant effusions. In phase I and II studies, blocking VEGF/VPF with specific antibodies, anti-VEGF receptor antibodies, or with tumor necrosis factor and metalloproteinase inhibitors produced encouraging results in the control of malignant ascites. The metalloproteinase inhibitors batimastat and marimastat have resulted in inhibition of tumor growth and angiogenesis. Their clinical use in controlling malignant ascites, is expected to expand in the near future, pending additional trials. Finally, aggressive cytoreductive surgery combined with intraoperative hyperthermic chemoperfusion is reserved for a small selected subgroup of patients with malignant ascites. Results of this complex procedure depend on careful patient selection and adherence to basic surgical debulking principles, leaving the patient with only microscopic disease, and then selecting the best available agent for intraoperative hyperthermic che-

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moperfusion. In well selected patients, using meticulous surgical technique, results are very encouraging. Mortality is acceptable and this procedure not only controls ascites, but longterm survival is possible. In conclusion, malignant ascites encompasses a group of patients with heterogeneous pathology, and the results of available treatment alternatives are inconsistent. Changing concepts about the genesis of malignant effusions influence not only our understanding but the clinical management of this devastating condition. Along with the currently available, largely unsatisfactory treatment alternatives, these new discoveries might change our present clinical management of malignant ascites.

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