Effect of Sodium Thiosulfate on Nephrotoxicity of Cisplatin Intraperitoneal Heat-perfusion Chemotherapy

Study Overview
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Brief Summary
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Ovarian cancer is the most lethal malignancy of the female genital tract. Cytoreductive surgery combined with chemotherapy is the primary treatment for ovarian cancer, and radical tumor resection is an important means to improve the prognosis. However, even after complete tumor resection, 75% of patients with ovarian cancer still recur within 3 years after the initial treatment and eventually die from recurrence. In ovarian cancer, the lesions are located primarily in the peritoneal cavity. High-grade evidence demonstrates that the use of intraperitoneal hyperthermic chemotherapy (HIPEC) with cisplatin after cytoreductive surgery significantly improves the outcome in some patients with ovarian cancer. Currently, this is the only non-pharmacologic treatment that reduces both the risk of recurrence and death from ovarian cancer with a multi treatment. However, HIPEC with cisplatin can lead to acute kidney injury, and a serious complication that can seriously affect the short and long-term prognosis of patients. Sodium thiosulfate has previously been reported to reduce the incidence of acute kidney injury after HIPEC with cisplatin, but this finding has not been confirmed in a high-level study. Therefore, we propose a multi-center, prospective, open-label, randomized, controlled trial including 110 patients with ovarian cancer who received HIPEC with cisplatin, to evaluate whether sodium thiosulfate combined with hydration (55 patients in the trial group) can reduce the incidence of acute kidney injury after HIPEC with cisplatin compared with hydration alone (55 patients in the control group), and to provide high-level evidence for the rationale of using sodium thiosulfate for nephrotoxicity relief in cisplatin HIPEC.

Official Title
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Effect of Sodium Thiosulfate on Nephrotoxicity of Cisplatin Intraperitoneal Heat-perfusion Chemotherapy: a Multi-center Prospective Randomized Controlled Trial.

Conditions
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Epithelial Ovarian Cancer, Acute Kidney Injury Due to Circulatory Failure

Intervention / Treatment
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* Drug: Sodium Sulfate
* Other: Hydration
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:（The following conditions must be met at the same time） Patients treated with HIPEC with cisplatin. Estimated survival > 12 weeks Age from 18 to 70 years Bone marrow reserve was well functioning. Leukocytosis ≥ 3.0×10^9/L, neutrophilic granulocyte ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 10^9/L, and hemoglobin ≥ 80 g/L. Organs work well. AST ≤ 2.5 × ULN, ALT ≤ 2.5 × upper limit of normal(ULN), total serum bilirubin ≤ 1.5 × ULN, and creatinine ≤ 1.5 × ULN ECOG score 0-1 Patients voluntarily sign an informed consent form Exclusion Criteria:（None of which was eligible）. Extensive abdominal adhesions HIPEC with Cisplatin for other medical conditions in the last 5 years. Receiving other drugs that cause kidney damage. Simultaneous use of amifotin for other diseases. Any situation of disease instability or potentially impact safety and adherence of patient. Chronic or acute nephropathy of any degree or other serious medical complications.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients were randomly assigned to treatment group or control group by block randomisation in a 1:1 ratio. Treatment group: Receive HIPEC using sodium thiouracil and hydration Control group: Receive HIPEC only using hydration.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIPEC with sodium thiosulfate and hydration<br>Sodium sulfate 9 g/m^2 combined with 0.9% natrium chloride 150 ml were instilled in 20 min as the time when HIPEC with cisplatin was beginning. After that, sodium sulfate 12 g/m^2 combined with 0.9% natrium chloride 1000 ml was pumped for 6 h . hydration: On the day of surgery, the day of HIPEC, and 24 hours after HIPEC, daily intravenous rehydration should be performed using natrium chloride, glucose chloride or potassium chloride. The amount of fluid to be replenished should not be less than 3000 milliliters. | Drug: Sodium Sulfate<br>* Sodium thiosulfate has previously been reported to reduce the incidence of acute kidney injury after HIPEC with cisplatin, but this finding has not been confirmed in a high-level study.<br>Other: Hydration<br>* On the day of surgery, the day of HIPEC, and 24 hours after HIPEC, daily intravenous rehydration should be performed using natrium chloride, glucose chloride or potassium chloride. The amount of fluid to be replenished should not be less than 3000 milliliters.<br>Drug: Cisplatin<br>* Infuse cisplatin (75mg/m^2) at 43℃ through the two drainage tubes placed in the upper abdomen, using the two drainage tubes placed in the lower abdomen as the effluent tubes, with an infusion time of 60-90 minutes and an infusion rate of 500-600 mL/min. The first HIPEC should be performed within 24-48 hours after cytoreductive surgery. The second HIPEC should be performed 24 hours after the completion of the first HIPEC. Intravenous sedatives such as dexmedetomidine or propofol at 2-6 ml/h should be administered during HIPEC treatment with continuous intravenous infusion by a pump，or intramuscular injection of 50 mg of pethidine.<br>|
| Active Comparator: HIPEC with hydration only<br>hydration:On the day of surgery, the day of HIPEC, and 24 hours after HIPEC, daily intravenous rehydration should be performed using natrium chloride, glucose chloride or potassium chloride. The amount of fluid to be replenished should not be less than 3000 milliliters. | Other: Hydration<br>* On the day of surgery, the day of HIPEC, and 24 hours after HIPEC, daily intravenous rehydration should be performed using natrium chloride, glucose chloride or potassium chloride. The amount of fluid to be replenished should not be less than 3000 milliliters.<br>Drug: Cisplatin<br>* Infuse cisplatin (75mg/m^2) at 43℃ through the two drainage tubes placed in the upper abdomen, using the two drainage tubes placed in the lower abdomen as the effluent tubes, with an infusion time of 60-90 minutes and an infusion rate of 500-600 mL/min. The first HIPEC should be performed within 24-48 hours after cytoreductive surgery. The second HIPEC should be performed 24 hours after the completion of the first HIPEC. Intravenous sedatives such as dexmedetomidine or propofol at 2-6 ml/h should be administered during HIPEC treatment with continuous intravenous infusion by a pump，or intramuscular injection of 50 mg of pethidine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculate the incidence of acute kidney injury after HIPEC based on creatinine levels and 24-hour urine output according to KDIGO criteria. | To determine whether the use of sodium sulfate combined with hydration reduces the incidence of acute kidney injury (KDIGO criteria grade 1-3) effectively in the intention to treat population compared with hydration alone in patients receiving HIPEC with cisplatin (75mg/m^2,43 °C,90 minutes) according to creatinine levels and 24-hour urine. | Within one week after patients receive cisplatin-based HIPEC. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculate the incidence of chronic kidney injury after HIPEC based on creatinine levels according to KDIGO criteria. | To determine whether the use of sodium sulfate combined with hydration reduces the incidence of chronic kidney injury effectively in the intention to treat population compared with hydration alone in patients receiving HIPEC with cisplatin (75mg/m^2,43 °C,90 minutes) according to creatinine levels. | Through study completion, an average of 2 year | 
| Number of patients with sodium sulfate-related adverse events assessed by CTCAE v5.0. | To investigate adverse events associated with sodium sulfate. The Adverse events were evaluated and graded according to CTCAE5.0 | 72 hours after sodium sulfate administration. | 
| Time from randomization to relapse or death（DFS）. | Time from randomization to relapse or death. The diagnosis of disease recurrence includes CA125 more than two times the minimum value, as specified by the Gynecologic Cancer International Collaborative Group (GCIG), or according to the RECIST v1.1 criteria. Any one of the above two criteria is met first, then the tumor is recurrent. | From date of randomisation to date of first recorded progression or death from any cause, whichever came first, assessed up to 5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epithelial Ovarian Cancer, Acute Kidney Injury, Hyperthermic Intraperitoneal Chemotherapy, Sodium thiosulfate