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.
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.
Primary endpoint is set as the proportion of patients who experience any grade renal dysfunction, defined as elevation in creatinine using the CTCAE version 4.0 (based on the upper limit of the normal range (ULN) for serum creatinine at each institute), during the first cycle. Secondary endpoints are: the proportion of patients who experience ≥ grade 2 renal dysfunction (based on the ULN for serum creatinine at each institute) during the first cycle, any grade and ≥ grade 2 renal dysfunction (based on the pretreatment baseline creatinine score in each patient) during the first cycle, any grade and ≥ grade 2 renal dysfunction (based on both criteria) after the completion of fourth cycle, and the proportion of patients who had phlebitis.
Using mannitol, two previous prospective studies conducted in an academic center reported that proportion of patients who experienced any grade renal dysfunction, defined as elevation in creatinine by CTCAE version 4.0, was 0−9% [6, 7]. Regarding furosemide, another retrospective study, conducted in a municipal hospital, reported that 52.1% of patients have experienced any grade renal dysfunction . Using this information, arm A (reference arm) proportion in the current study is 10.0%. Sample sizes of 51 patients in each arm achieve ≥ 80% power to detect a non-inferiority margin difference between the group proportions (arm B - arm A) of 10.0% using the one-sided binomial test with 0.2 alpha error. Assuming those patients will be censored, a total of 105 patients are required in the present study.
Patients are required to fulfill all the following criteria:
1) Histologically or cytologically confirmed thoracic malignancy
2) Aged between 20 and 74 years
3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
4) Adequate renal function (including both serum creatinine ≤ 1.2 mg/dL and a creatinine clearance of ≥ 60 mL/min using Cockcroft-Gault equation)
5) Normal cardiac function
6) Written informed consent
Patients are excluded if they meet any of all the following criteria:
1) Superior Vena Cava syndrome
2) Active mental illness
3) Pregnancy, breast feeding, or possibility of being pregnant
4) Other conditions rendering patients unsuitable for this study
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 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.
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 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).
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 B - arm 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.