Evaluation of the Efficacy of Diuretics for Symptomatic Malignant Ascites Episodes in Advanced Stage of Cancer (DIASC)

Study Overview
=================
Brief Summary
-----------------
While some authors recommend diuretics as the first treatment to initiate for symptoms caused by malignant ascites (MA), their prescription is variable. No randomized, controlled study has assessed their benefit in this context. According to literature, diuretics may bring relief in about 40% of cases, regardless of primary tumor. The purpose of our study is to assess the effectiveness of diuretic treatment according to Serum Ascites Albumin Gradient (SAAG) measured before treatment. Judgment criteria is the time elapsed between recurrent MA that requires paracentesis. The investigators will also examine whether SAAG and serum levels of renin and aldosterone can predict symptom response to diuretics.

Detailed Description
-----------------
Patients eligible for the trial and having signed their consent to participate will be randomized to arm A or B. Treatment order is randomly attributed to patients at the 1st paracentesis, after the reception of the laboratory results necessary to evaluate SAAG value. Randomization is stratified 1:1 according to SAAG values (≥ or < to 11g/L) and Systemic treatment (yes or not) Patients randomized to arm A will be observed until the next episode requiring paracentesis (due to clinical symptoms : abdominal pain or heaviness, dyspnoea, orthopnoea, nausea/vomiting, anorexia, early satiety, gastro-oesophageal reflux, lower limb and genital oedema), at which time they will receive arm B (diuretics), in absence of contra-indication to diuretic treatment. Patients randomized to arm B will receive diuretics until the next episode requiring paracentesis, at which time they will receive arm A (observation). Patients will have a physical assessment within 24 hours prior to the start of treatment, once every two weeks for patients randomized in arm A and each week for patients randomized in arm B, at cross-over and at the end of the study. Patient will also have a biological assessment within 24 hours prior to the start of treatment, twice a week for patients randomized in arm B, at cross-over and at the end of the study. Finally, they will address a quality of life questionnaire (QLQ-C15-PAL) prior to the start of treatment, at cross-over and at the end of the study.

Official Title
-----------------
A Randomized Cross-over Trial Evaluating the Efficacy of Diuretics for Symptomatic Malignant Ascites Episodes in Advanced Palliative Stage of Cancer

Conditions
-----------------
Cancer

Intervention / Treatment
-----------------
* Drug: Spironolactone (+/- Furosemide)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with advanced stage cancer First episode of malignant ascites Grade 2 or 3 ascites Clinically symptomatic ascites requiring paracentesis due to : abdominal pain or heaviness, dyspnoea, orthopnoea, nausea/vomiting, anorexia, early satiety, gastro-oesophageal reflux, lower limb and genital oedema Age ≥ 18 years Performance status ≤ 3 Life expectancy ≥ 1 month Absence of contra-indication to diuretic treatment Patient regularly followed up by a palliative care or supportive care team Signed and dated informed consent Exclusion Criteria: Hepatic disorders : cirrhosis, hepatitis, hepatocellular insufficiency, hepatic encephalopathy Non malignant ascites Hydroelectrolytic disorders: hyponatremia (< 130 mmol/L) or hyperkaliemia (> 5 mmol/L) or severe hypokaliemia (< 3 mmol/L) Functional acute renal insufficiency Urinary disorders : Obstruction in the urinary tract, Oliguria/anuria Chronic renal failure Patient unable to swallow Sulfamides allergy Hypersensitivity to spironolactone or to any of the excipients Hypersensitivity to furosemide or to any of the excipients Pregnant or breastfeeding women Patient under guardianship

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: A : observation<br>Clinical monitoring and best supportive care. | |
| Active Comparator: B : diuretics<br>Diuretics (spironolactone +/- Furosemide) are administered the day after the paracentesis and until the next episode requiring paracentesis. | Drug: Spironolactone (+/- Furosemide)<br>* Administration of spironolactone alone 100 mg/day each morning, increased in increments of 100 mg / week to a maximum of 400 mg / day in the absence of efficiency. In case of ineffectiveness or hyperkalemia: addition of Furosemide 40 mg / day increased in increments of 40 mg / week to a maximum of 160 mg / day in the absence of efficiency.<br>* Other names: Aldactone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time between symptomatic malignant ascites episodes requiring paracentesis |  | Patients will be followed until their third malignant ascites episode, an expected average of 30 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance | Adverse events and serious adverse events related to diuretic treatment according to NCI-CTCAE v4.0 | Up to 30 days after the last administration of the product | 
| Quality of life based on the EORTC (European Organization for Research and Treatment of Cancer) QLQ-C15-PAL |  | At baseline (prior to the start of treatment) | 
| Quality of life based on the EORTC (European Organization for Research and Treatment of Cancer) QLQ-C15-PAL |  | At cross-over (approximately 15 days after inclusion) | 
| Quality of life based on the EORTC (European Organization for Research and Treatment of Cancer) QLQ-C15-PAL |  | At the end of the study (up to 6 months). | 
| Description of the patterns of prescription of diuretics | Growth pattern doses of diuretics, decrement pattern doses of diuretics, maintenance doses of diuretics, maximum doses reached of diuretics. | During randomization in arm B (that is to say during approximately 15 days between the first and the second or between the second and the third milgnant ascites episode). | 
| Predictive factors of response to diuretics : Serum Ascites Albumin Gradient (SAAG) |  | Within 24 hours prior to the start of treatment | 
| Predictive factors of response to diuretics : renin aldosterone plasmatic level |  | Within 24 hours prior to the start of treatment | 
| Predictive factors of response to diuretics : SAAG |  | Twice a week for patients randomized in arm B | 
| Predictive factors of response to diuretics : renin aldosterone plasmatic level |  | Twice a week for patients randomized in arm B | 
| Predictive factors of response to diuretics : SAAG |  | At cross-over (approximately 15 days after inclusion) | 
| Predictive factors of response to diuretics : renin aldosterone plasmatic level |  | At cross-over (approximately 15 days after inclusion) | 
| Predictive factors of response to diuretics : SAAG |  | At the end of the study (up to 6 months). | 
| Predictive factors of response to diuretics : renin aldosterone plasmatic level |  | At the end of the study (up to 6 months). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diuretic, Malignant ascites