Adequate nephroprotection reduces renal complications after hyperthermic intrathoracic chemotherapy

Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern.


| INTRODUCTION
Hyperthermic intrathoracic chemotherapy (HITOC) offers an additional treatment option for malignant pleural tumors after surgical cytoreduction. Especially it is used to further improve local tumor control in malignant pleural mesothelioma (MPM) and thymic malignancies with pleural spread, who underwent multimodality therapy including surgical resection. 1 Some previous studies showed promising results with regard to recurrence-free survival and longterm. 2 Furthermore, HITOC proved to be safe with tolerably low rates of complications. [2][3][4] Nevertheless, certain aspects in the perioperative management of HITOC require special attention.
Particularly known is the dose-dependent renal toxicity of cisplatin, which is an integral part of the perfusion solution. 5 Moderate to severe nephrotoxicity was noted in 25% to 33% of patients receiving a single intravenous dose of cisplatin of 50 to 75 mg/m 2 body surface area (BSA). 6 Studies focusing on HITOC reported rates of postoperative renal dysfunction from 3.3% to 57%. 3,7,8 To avoid this serious complication, adequate hydration of the patient (and forced diuresis if necessary) is generally recommended. 9 In addition to this perioperative fluid management, however, drug therapy for renal cytoprotection is also available. In the recent literature, this cytoprotection most commonly consists of a combination of amifostine and sodium thiosulfate. 2,3,10 The pretreatment with amifostine is intended to reduce tubulotoxicity and sodium thiosulfate protects against renal damage by inactivating cisplatin through covalent binding. 5,11 There are only very few studies investigating the influence of this nephroprotective regime on postoperative renal function in patients undergoing HITOC. Therefore, the objective of this study was to investigate the rate of renal insufficiency and the postoperative course of serum creatinine after HITOC depending on the cisplatin concentration and the administration of cytoprotective agents.

| Study design
This retrospective, single-center study included all patients who received pleural tumor resection followed by HITOC from September 2008 to December 2018 (n = 84). Approval by our institutional ethics committee was given before data collection and informed consent was obtained from all patients. During the hospital stay data concerning the performed surgery and subsequent HITOC were enrolled within the patient records.
The minimum preoperative threshold of glomerular filtration rate (GFR) was more than 60 mL/minute/1.73 m 2 . Serum creatinine levels were routinely collected (preoperative, postoperative, first and second postoperative day, after 1 week and at the time of discharge) to assess renal function after major surgery. Based on risk of renal failure and acute kidney injury network classification, renal insufficiency grade 1 was defined as an increase in serum creatinine more than 0.3 mg/dL or doubling over 48 hours, a two to three-fold increase as stage 2 and a stage 3 consisted of a three-fold increase or serum creatinine more than 4 mg/dL. 12,13 Also the need for postoperative dialysis was registered.
The primary endpoint of the study was to determine postoperative renal insufficiency after surgical cytoreduction including HITOC. Secondary endpoints included the impact of the applied therapy (cisplatin dosage, application of cytoprotection, and surgical procedure) on postoperative serum creatinine levels.

| Surgical resection and HITOC
Depending on the location of the tumor, pleurectomy/decortication (P/D), extended P/D (eP/D) including resection of the pericardium and/or diaphragm and/or lung resection or extrapleural pneumonectomy (EPP) was carried out. A macroscopic complete resection and HITOC in one session was always aimed at. As perfusion system, the ThermoChemo HT1000 was used. Three to four liters of sodium chloride served as priming-volume until a stable circulation could be established. The dosage of the subsequently added chemotherapeutic agent was stepwise increased throughout the study. In the beginning, a dose of 100 to 150 mg/m 2 BSA was used. Later, cisplatin was increased to 175 mg/m 2 BSA and combined with 65 mg doxorubicin. About this time, additional cytoprotection was also introduced. If there were contraindications for the use of the maximum cisplatin dose (eg, reduced renal function), a lower dose was used. The perfusion was performed for 60 minutes at 42°C with a flow of approximately 1.5 L/minute. Sodium thiosulfate was administered directly afterward (4 g/m 2 BSA) and continuously over a period of 6 hours (12 g/m 2 BSA) after the HITOC at the intensive care unit.

| Statistical analysis
Data collection and statistical analyses were performed using IBM SPSS Statistics, Version 24 (IBM Corporation, Armonk, NY). Categorical data were summarized as absolute numbers and percentages and were compared between groups using the χ 2 test of independence or Fisher's exact test. Interval scaled data were presented as mean ± standard deviation or as median (IQR) and were compared using Student's t-test or the Mann-Whitney U-test depending on the underlying distribution of the variable. The distribution was analyzed using the Shapiro-Wilk test.
To examine the influence of cytoprotective therapy on postoperative creatinine levels, an analysis of covariance was performed with preoperative creatinine levels set as a covariate. P < .05 was considered statistically significant for all analyses. A logistic regression model was performed to assess the relationship between predictor variables to a binary response variable.

| Demographic data
The median age of the study population was 57 (IQR 16) years, and 33 (39.3%) of patients were female (Table 1)

| Surgical resection and HITOC
The most frequently performed surgery was eP/D in 46 patients (54.8%; Table 1). In only seven patients (8.3%) EPP was necessary. It was feasible to carry out surgical resection and HITOC in the same session in almost all cases (n = 82; 97.6%). In two patients a second session for HITOC was necessary, one and 19 days later due to an extended tumor resection with hemodynamic instability. Concerning the chemotherapeutic drugs used in HITOC, most patients (n = 48; 57.1%) were treated with cisplatin at a dosage of 175 mg/m 2 BSA, which was additionally combined with doxorubicin 65 mg, except in two cases. In 36 patients (42.9%), cisplatin was used alone in a dosage ranging between 100 to 150 mg/m 2 BSA. The mean inflow volume was 4202 ± 929 mL (P/D + eP/D: 4195 ± 908 mL; EPP: 4286 ± 1220 m). The average operation time including HITOC was 300 ± 90 minutes. Cytoprotective therapy was applied to 54 patients (64.3%).
The calculated intrathoracic cisplatin concentration (dosage × BSA/inflow volume) was significantly higher in patients receiving cisplatin in a dose of 175 mg/m 2 BSA (P = .049) and patients with cytoprotection (P = .016) ( Table 2). There were no significant differences in the occurrence of renal insufficiency with regard to  week after HITOC, but later developed a septic shock with renal failure making dialysis necessary. No chronic dialysis was needed.

| Postoperative creatinine levels
To assess renal function, serum creatinine levels were examined as renal function markers in the postoperative period depending on the applied therapy (Table 3) renal insufficiency remains a clinically relevant concern. Reported rates of renal dysfunction after HITOC differ from 3.3% to 57%, which may already indicate that relevantly different strategies are used to prevent this complication. 3,7,8 Especially high cisplatin doses are associated with postoperative renal complications. 5 In cisplatin-based chemotherapy regimens, hydration is generally introduced as a nephroprotective strategy. 9 Since excessive volume infusion can contribute to respiratory failure especially in patients undergoing lung surgery, additional diuresis, and fluid balance may be required. 17 In a rat model investigating   We also observed that the creatinine increase correlated with the extent of the surgical intervention. Patients who underwent EPP presented noticeably higher serum levels than patients who underwent P/D or eP/D. Actually, higher levels of serum creatinine were expected particularly after lung-sparing procedures due to resorption via the lung surface. 15  The significance is defined as bold P < .05. of complications but might provide a potential better local tumor control and overall survival. 5,7,10 The limitations of the study include the single-center design in selected patients and the retrospective nature. For the last 10 years, we routinely perform HITOC in patients who are scheduled for surgical cytoreduction. Therefore, we can not provide a control group without HITOC. Also, the dose of cisplatin was increased at the same time as cytoprotection was introduced, the effect of cytoprotection on postoperative creatinine and renal insufficiencies in our evaluation was probably attenuated. Furthermore, this was a heterogeneous group of patients with different tumor entities and therapeutical algorithms.

| CONCLUSIONS
In our opinion, cytoprotection is one of the most important tasks in the prevention of postoperative renal complications after HITOC.
Aside from perioperative fluid management, amifostine and sodium thiosulfate seem to be effective in protecting the renal function from cisplatin-induced nephrotoxicity. This is expressed in a milder increase in serum creatinine levels after HITOC. By implementing this cytoprotective treatment, higher intracavitary cisplatin doses can be administered without raising the rate of renal insufficiencies.
However, special caution is still required in patients with preoperatively elevated creatinine levels and/or known renal insufficiency.

CONFLICT OF INTEREST
The authors declare that there are no conflict of interest.