Furosemide versus mannitol in patients who received cisplatin-based chemotherapy using short hydration: study protocol for a randomized controlled trial

Background: Cisplatin (CDDP) is a key drug for various thoracic malignancies. To avoid renal toxicity of CDDP, mannitol is routinely used, but it reportedly causes phlebitis. Furosemide is another widely-used option for diuresis, but to date, it has not been assessed in comparison with mannitol. We therefore undertake a randomized phase II comparative study of furosemide and mannitol in CDDP-based chemotherapy using short hydration. Methods: This study is designed as a two-arm, prospective, randomized, single-center, open-label phase II study. The primary endpoint is set as the proportion of patients who experienced any grade renal dysfunction, defined as elevation in creatinine using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, during the first cycle. Secondary endpoints are: the proportion of patients who experienced ≥ grade 2 renal dysfunction during the first cycle, any grade and ≥ grade 2 renal dysfunction after the completion of forth cycle, and the proportion of patients who had phlebitis. A total of 105 patients will be enrolled in this trial. Discussion: The results of this study will suggest that furosemide can be better choice than mannitol regarding convenience and in reduction of phlebitis. Trial registration: University Hospital Medical Information Network Clinical Trials Registry, ID: UMIN000031910(http://www.umin.ac.jp/ctr/index.htm). Registered on 1 April 2018.


Background
Cisplatin (CDDP) is a key drug for various types of thoracic malignancies, but renal toxicity occurs in about 30% of the patients who receive it [1]. To avoid renal toxicity of CDDP, adequate hydration and diuresis are important [2,3]. Currently, mannitol is the only drug recommended in National Comprehensive Cancer Network Chemotherapy Order Templates (NCCN Templates®). Although several studies have compared the renal toxicity of mannitol with another drug, furosemide, their studies did not have sufficient power to detect significant difference [4,5]. One benefit of furosemide is that it can be infused intravenously. Moreover, patients receiving mannitol often experience phlebitis. We therefore undertake a randomized phase II comparative study of furosemide and mannitol in CDDP-based chemotherapy using short hydration.

Study objectives
We assess the renal toxicity of furosemide compared with mannitol in CDDP-based chemotherapy (≥ 60 mg/m2) using short hydration in chemotherapy-naive patients with thoracic malignancy.

Study setting
This study is designed as a two-arm, prospective, randomized, single-center, open-label phase II study. The protocol scheme is shown in Figure 1. Study duration will be 3 years and 10 months.

Registration and Randomization
After registration, patients will be randomized in 1:1 ratio, using minimization method that balances the treatment arms considering sex (male vs. female).

Data collection
Data is collected prospectively for all patients including history, physical examination, laboratory data, all adverse events (Figure 2). Data is collected via datasheets on paper and kept securely. All handling cases are managed by subject identification code or anonymized registration number. The correspondence table of the anonymizing code and names and the consent form containing the names are kept strictly in the separate lockable document storage at Wakayama Medical University Hospital(WMUH).

Interim analysis and monitoring
We plan no interim analysis. In-house monitoring will be performed every 1 year by each data to evaluate and improve study progress and quality.

Treatment
Patients receive CDDP-based chemotherapy (≥ 60 mg/m2). After common antiemetic premedication (aprepitant, palonosetron and dexamethasone) and one other cytotoxic agent, an hour-long infusion of cisplatin dissolved in a 500 mL of normal saline solution is administered between the pre-hydration (potassium chloride and magnesium sulfate dissolved in 500 mL of normal saline solution) and post-hydration (500 mL of maintenance solution). In arm A, patients receive 300 mL of 20% mannitol by intravenous drip infusion just before CDDP, over 30 min. In arm B, patients receive 20 mg of furosemide intravenously an hour before CDDP. CDDP-based chemotherapy is repeated every 3 or 4 weeks for up to four cycles except where there is disease progression, unacceptable 6 toxicity, or patients' refusal. The chemotherapy regimen is shown in Figure 3.

Follow-Up and Assessment
Routine blood tests are evaluated on Day 1 of every cycle and on Day 8 of the first cycle.
Phlebitis is assessed by a nurse and another staff physician. All adverse events are defined according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The study protocol adheres to the SPIRIT statement (Additional file 1).

Statistical Analysis
The primary population for efficacy analysis are the intention-to-treat (ITT) population, defined as all randomized patients. The primary endpoint is the proportion of patients who experienced any grade renal dysfunction. It will be evaluated using risk difference (arm Barm A) with 80% Confidence intervals (CIs) (one sided). An upper confidence limit below 10% suggest that arm B is non-inferior to arm A. Secondary endpoints are summarized using frequency and percentage with exact 95% CIs using Clopper & Pearson's method for each arm.

Discussion
Diuresis is necessary to avoid renal toxicity by CDDP. Although mannitol is the only drug recommended in NCCN Templates®, furosemide may be a useful option according to previous small studies. These studies were conducted in a prospective manner, but statistical concerns exist. If the current study reaches primary endpoint, it will suggest that furosemide can be better choice than mannitol regarding convenience and in reduction of phlebitis. This study has several limitations. First, It is designed nonblinded. Another limitation is single institutional feature. Despite its limitations, we believe that result of this 7 trial will add useful information to support the utility of furosemide.