2.  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.
 Itsonset and progression is associated with
deterioration in quality of life (QoL) and a poor
prognosis.

3. 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.

4.  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.

5.  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.

6.  Differentiation
between neoplastic and
nonneoplastic causes of ascites can be challenging.
 indistinguishable by physical examination and
radiographic appearance
 Unlessassociated with overt evidence of peritoneal
carcinomatosis

8.  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

9. Proposed pathophysiology involved in malignant ascites development

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

12.  Ultrasoundor CT likely required to demonstrate
small volumes of free peritoneal fluid
 Diagnostic
paracentesis to determine type of ascites
with newly diagnosed cases
 Identifyingetiology is essential to determining
interventions required

13.  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.

14.  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.

15.  Other tests which can be done
 To differentiate between malignant versus
nonmalignant ascites,
 sialic acid levels,
improvement in the sensitivity and
 HCG-β levels,
specificity for the diagnosis of
 VEGF levels, malignant ascites, but not
recommended for routine clinical
 telomerase activity, use.
 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

16.  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.

17.  Thepresence of malignant ascites has a strong
negative prognostic import,
 different for different malignancies.
 Oneretrospective 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.

18.  otherprognostic 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.

19. Dietary
 Dietary salt restriction (2 g salt or 88 mmol Na+/d)
should be initiated
 Routine water restriction is not necessary.
 Ifdilutional hyponatremia (serum Na+ <120 mmol/L)
occurs, fluid restriction to 1,000-1,500 mL/d usual

20. DIURETICS
 There is a lack of randomized trials to assess the
efficacy of diuretics in malignant ascites.
 Uncontrolledtrials show an average response
rate of 44% when diuretics are used.

21.  Spironolactone100-400mg/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.

22.  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.

23.  Paracentesiscan 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.

24.  Hypovolemia after large volume paracentesis,
 hypotension
 electrolyte imbalance,
 visceral or vascular injury
 Infection and rarely,
 Pulmonary embolization.
 Hypoalbuminemia with repeated paracentesis.

25.  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.

26.  TheLaveen shunt ,The Denver
Shunt
 Both shunts direct ascitic fluid into
the vena cava through a one-way
valve.
 Palliatesymptoms in 70% of
patients.
 Complications include
 shunt occlusion,
 bleeding,
 fever - True fever associated with
shunting is transient
 infection,
 cardiopulmonary compromise,
 hepatic encephalopathy and
 DIC.

27. Contraindications to peritoneovenous shunt
 fulminant hepatic failure
 DIC
 Ascites 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

28.  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

29.  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

30.  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
 Studieshave demonstrated benefits with cytoreductive
surgeries of intraperitoneal tumours followed by
intraperitoneal administration of chemotherapies

31.  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.

32.  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.

33. Metalloproteinase inhibitors- Batimastat
 hasbeen 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.
 Themajor adverse effect in the first 24 hours was
nausea and vomiting.

34. 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

35.  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.

36.  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

37.  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.

38.  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.