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| Agents for control of ascites |
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Cancer accounts for approximately 10% of all cases of ascites, which occurs particularly in ovarian, endometrial, breast, colon, gastric and pancreatic carcinomas. It has been shown that around 10 to 15% of all patients with gastrointestinal cancer develop ascites at some stage of their disease. Generally, the presence of malignant ascites is associated with poor prognosis, regardless of the cause. The mean survival in patients with malignant ascites is usually less than 4 months.
Ascites may result in unpleasant symptoms including anorexia, respiratory distress and immobility. Therefore therapy has concentrated on symptom control. Approaches have included sodium restricted diets, diuretics, serial paracentesis, peritoneal shunting and chemotherapy (systemic and intraperitoneal).
Diuretics
There is no general consensus for the use of diuretics and no reliable way for predicting response. Overall, 44% of cases reported in the literature, involving patients with varied diseases, has shown that diuretics are effective in relieving ascites. Initial dose of spironolactone 150mg/day can be given, increasing the dose every few days until response is achieved. If this proves insufficient, a thiazide or loop diurectic can be added (hydrochlorothiazide 50-100mg/day or furosemide 40-160mg/day po in divided doses).
Intraperitoneal chemotherapy
Drugs given directly to the peritoneal cavity are absorbed via the portal circulation and undergo first pass metabolism in the liver. Hence, dose intensity is increased within the peritoneal cavity and systemic toxicity reduced. Complications associated with intraperitoneal chemotherapy include infection or perforation due to catheter insertion, direct toxic effects of the drugs leading to fever and abdominal pain. Examples of drugs given intraperitoneally include cisplatin, fluorouracil, mitomycin C, etoposide, mitoxantrone, topotecan and bleomycin. Overall, ascites was controlled in 47% of cases. Intraperitoneal radio-isotopes has also been used and reported to produce response rate of around 50%.
Newer agents
(a)
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Vascular endothelial growth factor (VEGF) inhibition
VEGF is a multifunctional cytokine and increases vascular permeability via its action of the vascular endothelium, hence promoting ascites. In vivo studies involving human ovarian cancer, showed inhibition of formation and reaccumulation of ascites with anti-VEGF monoclonal antibody. |
| (b) |
Matrix metalloproteinase (MMP) inhibitors
Matrix metalloproteinases are involved in the degradation of extracellular matrix proteins important to the process of angiogenesis. Hence, inhibition of the enzymes would lead to loss of metastatic potential of tumour cells.
Phase I/II studies using matrix metalloproteinases inhibitors eg batimastat in patients with ascites showed some improvement in clinical features. Intraperitoneal batimastat was given as single dose, 600 to 1050mg/m 2, to 9 patients with malignant ascites from various primary tumours. Positive response defined as reduction in weight or abdominal girth or reduction in frequency of paracentesis was observed in 5 patients. However, some patients still required further paracentesis after batimastat injection. Further studies are warranted to fully assess the effectiveness of MMP. |
In summary, malignant ascites is a frequent cause of morbidity and currently there are no evidence-based guidelines available for the prevention or reduction of ascites. Properly constructed trials are necessary in order to assess the benefits of newer agents. Currently, reduced number of paracentesis required is often used clinically to assess response. Consensus regarding the standard definition of response would allow true comparison between different agents and approaches in the control of ascites.
Viviannce Shih
Pharmacist
Onco Pharmacy
National Cancer Centre, Singapore
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