MALIGNANT ASCITES

DR. VARUN GOELMEDICAL ONCOLOGIST

RAJIV GANDHI CANCER INSTITUTE, DELHI

INTRODUCTION

Malignant ascites (abnormal accumulation of fluid in the

peritoneal cavity ) is a manifestation of end stage events in a variety of cancers and associated with significant morbidity.

Its onset and progression is associated with deterioration in quality of life (QoL) and a poor prognosis.

The malignancies most commonly associated with malignant ascites include

1. gynecologic malignancies,

2. gastrointestinal malignancies,

3. breast cancer and 4. carcinoma of

unknown primary. Among the

gynecologic malignancies, ovarian carcinoma predominates.

It has been considered pathognomonic for the diffuse implantation throughout the peritoneal cavity.

But the actual tumor burden and location of the disease can vary quite dramatically.

In patients with malignancy-related ascites

only 2/3 - have peritoneal carcinomatosis.

remaining 1/3 - nonmalignant causes e.g secondary to portal hypertension or lymphatic obstruction.

as in cases of massive liver metastases or lymphoma, respectively.

Differentiation between neoplastic and nonneoplastic causes of ascites can be challenging.

indistinguishable by physical examination and radiographic appearance

Unless associated with overt evidence of peritoneal carcinomatosis

PATHOPHYSIOLOGY

Not completely understood

Mechanical: obstruction of lymphatic drainage due to tumor growth

Cytokines: protein production causing increased vascular permeability leading to excess fluid accumulation (i.e. VEGF)

Hormonal: decreased removal of fluids due to lymphatic obstruction –reduced circulating blood volume –activation of renin-angiotensin system –sodium & fluid retention

Proposed pathophysiology involved in malignant ascites development

SIGNS & SYMPTOMS

Abdominal distension, pressure, fullness SOB, dyspnea, orthopnea Early satiety, nausea, vomiting Heartburn Peripheral edema Reduced mobility (i.e. bending, sitting

upright)

ASSESSMENT

DIAGNOSIS

Ultrasound or CT likely required to demonstrate small volumes of free peritoneal fluid

Diagnostic paracentesis to determine type of ascites with newly diagnosed cases

Identifying etiology is essential to determining interventions required

ASCITIC FLUID ANALYSIS

Visual inspection Grossly bloody fluid –malignancy. Cloudy fluid suggests infection. Milky fluid suggests chylous ascites –

often associated with malignancy, especially lymphoma.

Chemical analysis of ascitic fluid transudate and exudate - Division has

not proven to be beneficial for malignant ascites.

test useful for distinguishing malignant from cirrhotic causes of ascites is the serum-to-ascites albumin gradient.

Serum to ascites albumin gradient ≥1.1 g/dL - portal hypertension with 97% accuracy,

whereas a lower gradient indicates a lack of PHT and possibly the presence of a malignancy

Cytology presence of malignant cells - specificity 100%. gold standard for the diagnosis. The sensitivity of cytology is only 60%, as not all tumors

shed cells into the peritoneum. Patients with ascites due to advanced hepatocellular

cancer, massive liver metastases, and lymphoma have uniformly negative cytology.

Immunohistochemistry can help distinguish cancer cells from nonmalignant cells

such as mesenchymal cells. have not replaced cytology as the gold standard for the

diagnosis of malignant ascites.

Other tests which can be done To differentiate between malignant versus

nonmalignant ascites, sialic acid levels, HCG-β levels, VEGF levels, telomerase activity, fibronectin, and cholesterol levels.

To link the presence of ascites with an underlying primary malignancy CA 125, CEA and Added benefit is unclear CA 19-9

improvement in the sensitivity and specificity for the diagnosis of malignant ascites, but not recommended for routine clinical use.

Inspite of investigations, among patients diagnosed with malignant ascites, 20% will have tumors of unknown primary origin

Advances in imaging and immunocytochemical analysis, will continue to influence a decline in the number of cases of malignant ascites associated with carcinoma of unknown primary.

Laparoscopy and biopsy - a safe and minimally invasive techniques to help establish primary tumor diagnosis , esp. in women with good performance status who have no

apparent cause for ascites.

PROGNOSIS The presence of malignant ascites has a

strong negative prognostic import, different for different malignancies.

One retrospective study reviewed experience with malignant ascites over 10 years.The gastrointestinal malignancies associated

with the poorest prognosis gastric carcinoma (median survival of 1.4 months), pancreatic cancer (median survival of 1.4 months)

and colon cancer (median survival of 3.7 months).

Ascites of ovarian origin has a better median survival than all other cancer groups.

Ayantunde AA, Parsons SL. Ann Oncol.2007;18(5):945–949.

other prognostic factors especially in the nonovarian cancer groups low serum albumin, liver metastases, and elevated serum bilirubin.

Parsons SL, Lang MW, Steele RJC. Eur J Surg Oncol. 1996;22(3):237–239.

Mackey JR, Venner PM. Can J Oncol. 1996;6(2):474–480.

TREATMENT

Dietary

Dietary salt restriction (2 g salt or 88 mmol Na+/d) should be initiated

Routine water restriction is not necessary. If dilutional hyponatremia (serum Na+ <120 mmol/L)

occurs, fluid restriction to 1,000-1,500 mL/d usual

DIURETICS

There is a lack of randomized trials to assess the efficacy of diuretics in malignant ascites.

Uncontrolled trials show an average response rate of 44% when diuretics are used.

MEDICAL TREATMENT

Spironolactone 100-400mg/day Furosemide 40-120mg/day

Responses have been identified in those with increased renin values, massive liver metastases as well as elevated SAAG.

The goal of diuretic therapy should be a daily weight loss of ≤1.0 kg in patients with edema ~0.5 kg in those without edema until ascites is adequately

controlled.

PARACENTESIS Paracentesis can result in rapid symptom

control in 90% of patients. no agreement on the optimal rate of fluid

removal large volume paracentesis (up to 5 L ) can

be performed without complication like renal impairment and hypotension which are well documented in the nonmalignant liver disease population.

McNamara P. Palliat Med. 2000;14(1):62–64.Stephenson J, Gilbert J. Palliat Med.2002;16(3):213.

Paracentesis can be done safely in the presence of coagulopathy.

• Runyon BA. Hepatology. 1998;27(1):264–272.

There is no evidence for benefit with the use of albumin infusions for patients with malignant ascites after large volume paracentesis.

• Salerno F, et al. J Hepatol. 1987;5(1):102.

COMPLICATIONS OF PARACENTESIS

Hypovolemia after large volume paracentesis,

hypotension electrolyte imbalance, visceral or vascular injury Infection and rarely, Pulmonary embolization. Hypoalbuminemia with repeated

paracentesis.

In an effort to minimize these complications and to provide greater patient comfort, indwelling percutaneous catheters, such as the Pleurx catheter (Denver Biomedical, Denver, Colorado), were developed to provide long-term access for repeated external drainage.

These catheters can be managed at home with drainage performed as needed for comfort.

PERITONEOVENOUS SHUNTING

The Laveen shunt ,The Denver Shunt Both shunts direct ascitic fluid into

the vena cava through a one-way valve.

Palliate symptoms in 70% of patients.

Complications include shunt occlusion, bleeding, fever - True fever associated with

shunting is transient infection, cardiopulmonary compromise, hepatic encephalopathy and DIC.

Contraindications to peritoneovenous shuntfulminant hepatic failureDICAscites with +ve cytology haemorrhagic ascites increased risk for shunt block

chylous ascites, loculated ascites , cardiac, pulmonary, or renal insufficiency, life expectancy less than a month.

Shunt block occurs more often in the patients with positive cytology

The shunt tends to function longer in the patient with cytologically negative fluid

Parsons and associates demonstrated no survival or quality-of-life advantage when peritoneovenous shunting was compared with repeated paracentesis.

Parsons SL et al. Eur J Surg Oncol. 1996;22(3):237–239.

Shunts may not be an optimal option in patients with gastrointestinal malignancies, as the response rates for symptom control are inferior to those with ovarian and breast cancer

• Adam RA, J Am Coll Surg. 2004;198(6):999–1011

high cytotoxic concentrations of active agents will reach the abdominal cavity with minimum systemic absorption and systemic toxicity

clinical trials involving patients of ovarian carcinoma have shown that intraperitoneal chemotherapy can be superior to systemic chemotherapy with regard to PFS and median OS.

Studies showed that the combination of a systemic and an intraperitoneal chemotherapy was more effective than an exclusively intravenous treatment.

Deborah K. et al. N Engl J Med 2006; 354:34-43

INTRAPERITONEAL CHEMOTHERAPY

Better tolerated intraperitoneal drugs include cisplatin, carboplatin, mitomycin C, 5fluorouracil, and bleomycin.

With the exception of ovarian cancer, the effectiveness of intraperitoneal administration of these drugs is unclear due to lack of large randomized clinical studies

Studies have demonstrated benefits with cytoreductive surgeries of intraperitoneal tumours followed by intraperitoneal administration of chemotherapies

Yan et al. have reported favorable survival in selected patients with colon cancer, appendiceal cancer, and mesothelioma undergoing radical tumor debulking and peritonectomy followed by intraperitoneal chemotherapy.

Yan TD, Stuart OA, Yoo D, et al. J Transl Med 2006;4:17.

Others have reported the intraoperative use of hyperthermic intraperitoneal chemotherapy delivered via continuous infusion using a roller pump and a heating element immediately after cytoreductive surgery.

Experimental data have demonstrated that hyperthermia can enhance the cytotoxicity of intraperitoneal chemotherapy.

Although encouraging, this aggressive combined approach should be reserved for selected patients with malignant ascites.

OK-432 : A preparation from the Su-strain of

Streptococcus pyogenes.

Intraperitoneal OK-432 reported ascites reduction in approximately 60% of patients.

Mechanism of action is not clear.

Mean survival for patients receiving this therapy was 10.2 months compared to 3.1 months for a control group.

OTHER NEW EXPERIMENTAL DRUGS

Metalloproteinase inhibitors- Batimastat

has been studied in early phase clinical trials of patients with malignant ascites.

Ascites prevention and reduction have been reported, but larger trials are needed to define the actual clinical benefit of these inhibitors.

The major adverse effect in the first 24 hours was nausea and vomiting.

Anti-VEGF therapy

The use of inhibitors of the tyrosine kinase activity of VEGF has been shown to inhibit formation of ascites in cell lines and animal models.

Unfortunately there have been are no human studies at this time with this modality

Direct intraperitoneal administration of cytokines including interferon-α,interleukin-2, and tumor necrosis factor has been reported with variable effectiveness in small pilot studies.

Stuart GC, Nation JG, Snider DD, et al.  Cancer 1993;71:2027.   Lissoni P, Barni S, Tancini G, et al. Support Care

Cancer 1995;3:78.  Rath U, Kaufmann M, Schmid H, et al. Eur J

Cancer 1991;27:121.

NEW IMMUNOLOGIC APPROACHES: NEW

TARGETS cellular adhesion molecules are

overexpressed in several malignancies

One cellular adhesion protein called epithelial cell adhesion molecule (EpCAM)

EpCAM is a significant tumor antigen because its overexpression has been observed in a majority of carcinomas including ovarian cancer, breast cancer, prostate cancer, and nonsmall cell lung cancer

The inhibition of this antigen has been associated with a decrease in the proliferation, migration, and invasion of cancer cells

Catumaxomab is a trifunctional antibody with one binding arm to the epithelial cell adhesion molecule (EpCAM) of carcinoma cells, with the second binding arm to CD3-receptors of T cells and with its Fc portion to the Fc receptor of accessory cells such as macrophages and natural killer cells.

Trifunctional antibodies have a much higher capacity for tumor kill than previous monoclonal antibody lines.

CATUMAXOMAB

When compared with paracentesis alone, paracentesis followed by catumaxomab therapy was associated with significant prolongation of paracentesis-free survival, improvement in the quality of life, there are also signs of a prolongation of overall survival.

The benefits of catumaxomab were seen across a broad range of epithelial ovarian and nonovarian cancers.

Catumaxomab was generally well tolerated in the pivotal phase II/III trial.

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