Sodium thiosulfate protects from renal impairement following hyperthermic intraperitoneal chemotherapy (HIPEC) with Cisplatin

Abstract Background Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to provide benefits in the management of peritoneal metastasis. Cisplatin (CDDP) is one of the most frequently used drugs for peritoneal infusion. A major restriction is that CDDP causes renal toxicity and acute renal failure, sometimes leading to chronic renal failure. The aim of the present study was to assess the impact of sodium thiosulfate (ST) in preventing renal impairment (RI) following HIPEC with CDDP. Methods This prospective study assessed the RI rates for all patients who underwent HIPEC with CDDP during two successive periods: without ST (nST Period; from November 2016 to September 2017) and with ST (ST Period; from October 2017 to March 2018). During the ST Period, patients received an ST infusion at 9 mg/m2 prior to HIPEC and at 12 mg/m2 at the end of the procedure. RI was defined by postoperative serum creatinine >1.6 times elevation of baseline value. The impact of ST treatment was evaluated by comparison of the RI rates between the two periods. Results During ST Period, none of 38 patients (0%) developed RI versus 11/35 patients (31.4%) during the nST Period (p < .005); 2 of whom required definitive hemodialysis. Baseline characteristics, background circumstances, indications and laboratory parameters before HIPEC were comparable between the two groups, as well as CDDP dose use during HIPEC. Conclusion ST appears to be an effective drug for the prevention of the renal toxicity of CDDP used for HIPEC and should be used for all such procedures.


Introduction
Cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an unavoidable therapy in the management of a number of peritoneal carcinomatoses. Cisplatin is one of the most frequently used chemotherapies during HIPEC; it is used for several indications such as peritoneal mesothelioma and peritoneal metastasis of ovarian, endometrial, or gastric origin. HIPEC with cisplatin (CDDP) has proven interesting in long-term survival for these conditions [1][2][3][4][5].
The main side effect of CDDP is its acute and chronic nephrotoxicity, whether used systemically or intraperitoneally. First, CDDP induces early proximal renal tubular damage, leading to an acute or subacute tubular necrosis; subsequently acute renal failure can occur early during the first postoperative days following HIPEC with CDDP. Second, CDDP can induce a gradual and irreversible decrease in long-term glomerular filtration capacity, and therefore chronic renal failure. This toxicity is the main restriction to the use of intraperitoneal CDDP; acute renal failure rate after HIPEC with CDDP is reported to be up to 40.3% [6][7][8][9], and the rate of severe chronic renal failure (grade 3 or 4, i.e. glomerular filtration rate <30 ml/min) is estimated to be up to 8.5% [6][7][8][9][10][11]. These acute or chronic renal failures lead to long-term dialysis in up to 4.3% of patients, and may also compromise the subsequent administration of other anticancer agents for consolidation or in case of recurrence.
Sodium thiosulfate (ST) is a pharmacological agent that has been identified for many years to prevent and treat toxicities induced by the systemic use of platinum salts. The mechanism of action of ST is unclear, but its benefits in systemic CDDP chemotherapy are recognized [12]; in particular, ST is used as a protective and curative agent [13] for renal failure induced by a CDDP overdose [14]. This led to the hypothesis that ST may also be of benefit in the prevention of renal failure induced by HIPEC with CDDP [15,16]. In their randomized trial, Van Driel et al. reported no increased frequency of renal failure with the use of Sodium Thiosulfate following HIPEC with CDDP [5]. In France, as in some other countries, the use of this agent needs a specific and nominative request (ATU -Authorization for Temporary Use) to the national medicines agency (Agence nationale de s ecurit e du m edicament et des produits de sant e in France) and is not used.
The aim of this study was to assess the impact of ST in the prevention of renal impairment during HIPEC with CDDP from a prospective database.

Protocol
In this single-center study, all consecutive patients who underwent cytoreductive surgery with HIPEC with CDDP between November 2016 and April 2018 at the Lyon-Sud Hospital were included. From October 2017 and April 2018, all consecutive patients received ST following an individual specific and nominative request (ATU) to the ANSM (the ST period). They were compared to consecutive patients treated from November 2016 to September 2017 (the nST period).

Treatment
All patients were managed perioperatively with a standardized and equivalent protocol: immunonutrition for 7 days, discontinuation of nephrotoxic treatments, preoperative hydratation for 48 h, and bowel preparation. Patients received HIPEC with CDDP after a complete (CC-0) or subcomplete (CC-1) cytoreductive surgery [17]. The intraperitoneal infusion of CDDP was between 50 and 100 mg/m 2 , with a mesenteric temperature of 42 C, for a duration of 60-90 min regarding the protocol used [5,7,18]. Pre-and post-operative clinical and laboratory data were prospectively collected and recorded in an identified database. No patient was excluded. For administration of ST the protocol described by Van Driel et al. was used [5]: patients received a first intravenous bolus of 9 mg/m 2 initiated at the same time of the start of CDDP intraperitoneal perfusion, and delivered in 20 min; they then received a second infusion of 12 g/m 2 for 6 h, initiated at the end of the HIPEC (Figure 1).

Objectives
In order to evaluate the impact of ST in terms of nephroprotection, the primary objective was to compare the rate of postoperative acute renal impairement between patients treated over the two periods. The occurrence of acute renal failure was defined by a postoperative increase in serum creatinine to more than 1.6 times elevation of the basal value (World Health Organization grade I toxicity) during the first postoperative month [19][20][21]. The secondary objectives were to compare the chronic renal failure rate following the third postoperative month and the long-term dialysis rate between the two periods. Potential side effects of ST, metabolic acidosis and allergic reactions, were searched for and collected.

Data collection
Pre-operative data were collected for each patient: clinical data (baseline characteristics, etiology and indication) and laboratory data (baseline serum creatinine level, and glomerular filtration rate). The intraoperative data collected were: surgical data (extent of peritoneal carcinomatosis evaluated by the Peritoneal Carcinomatosis Index (PCI), dose of intraperitoneal CDDP used, duration of HIPEC, duration of procedure, and blood loss); anesthesiological data and medical management during procedure (intraoperative diuresis (ml and ml/kg/h), intravenous solute and amount infused (ml/kg/ h), potential transfusions of blood-derived products (U), hemodynamic instability, and the use of vasopressor amines during the procedure (mg)); post-operative data (daily serum creatinine level and glomerular filtration rate from day 0 to day þ10, serum creatinine level and glomerular filtration rate at 1 month, 3 months and 6 months, as well as other standard post-operative biological data: daily hemoglobin level, pH and lactic acid at þ12 h and þ36 h); surgical complications as well as other medical complications.

Statistical analysis
The Chi 2 test was used to evaluate the differences between the two periods. Qualitative variables were compared using the Chi 2 test. Quantitative variables were compared using the Wilcoxon test. Statistical significance was set at p < .05 for all analyses that were performed using SSPS 17.0 V R (SPSS Inc, Chicago, IL, USA).

Results
A total of 35 patients underwent HIPEC with CDDP during the nST period (without the use of ST) and 38 patients did so during the ST period (with the use of ST). The baseline characteristics of patients were not significantly different between the two study periods (Table 1), nor were the variables pertaining to intraoperative medical data, and the rates of surgical and medical complications ( Table 2).

Acute renal failure
Eleven of the 35 patients (31.4%) who underwent an HIPEC with CDDP without the use of ST (nST Period) developed postoperative acute renal failure, compared to none of the 38 patients who received ST (0%) (TS period; p < .05). In the nTS period, the mean time to occurrence of acute renal failure was 4 days according to the WHO definition. A rise in serum creatinine was observed compared to the basal values on post-operative day 1 (median 1.154 mg/dl) for patients who evolved toward acute postoperative renal failure and those who did not. This difference was significant on postoperative day 2 (median 1.349, p < .005) and day 3 (median 1.352, p < .005); this was below the threshold of 1.6 times elevation of the basal value according to the WHO definition ( Figure 2).

Chronic renal impairment
Nine of the 11 patients who presented post-operative acute renal failure in the nST group (25.7%) subsequently evolved to chronic grade-3 or higher renal failure (glomerular filtration rate GFR <30%), following the third postoperative month, including 2 patients with grade-4/5 renal impairment (GFR <15%) and 2 patients needing a long-term dialysis (5.7%; Table 3).

Side effects
No metabolic acidosis or allergic reaction was observed in any of the patients who received ST. There was no significant difference between the two groups for the pH level in the first 48 post-operative hours; mean pH was 7.29 (± 0.09) in the nST period versus 7.31 (± 0.07) in the ST period at þ 12 h (p ¼ .636), and 7.37 (± 0.14) versus 7.41 (± 0.92) at þ36 h (p ¼ .211). There was also no significant difference in post-operative lactic acid levels; mean arterial lactic acid concentration was 4.2 mmol/L (± 6.24) in the nTS period versus 4.6 mmol/L(± 2.06) in the ST period at þ 12 h (p ¼ .390), and 2.2 (± 0.80) versus 1.7 (± 0.69) at þ 36 h (p ¼ .133).

Discussion
In the present study, the use of ST during HIPEC with CDDP led to a lower of the rate of acute post-operative renal failure to zero. None of the potential side effects described or reported in the literature were observed. The results are Mean ± SD; n (%); ASA: American Society of Anesthesiologists.   [22]; despite intrathoracic CDDP was used at a high dose (225 mg/m 2 ), the use of ST reduced the renal toxicity of this procedure to 6%. This is higher than observed herein, but which could at least partly be explained by the higher doses of intracavitary CDDP used for the management of pleural mesothelioma. In addition, some teams already routinely use ST to prevent the nephrotoxicity induced by HIPEC with CDDP [5,15], and the rates of acute postoperative renal failure observed (<5%) are considerably lower than those described by some teams (up to more than 40%) [6,[8][9][10]23,24]. As a nonspecific agent, ST has been used for many years in variable and heterogeneous indications. In nephrology, its chelation of cations led to it being used for the treatment of calciphylaxis occurring in patients under dialysis [11]. Historically, it has been used for the treatment of ringworm or as an antifungal agent, and its use is also described in the management of cyanide poisoning [25]. It has antioxidant properties related to its reaction with oxidized glutathione and reactive oxygen species leading to the formation of glutathione, a natural antioxidant; it would therefore restore the functions of endothelial cells. In addition, ST also interacts with various enzymes by transsulfurization producing hydrogen sulfite, a vasodilator at the microcirculatory level. The plasma concentration of ST increases linearly with the injected dose. The half-life of the plasma distribution phase is approximately 23 min. Regarding its elimination, some of the injected ST is oxidized into sulfite and then into sulfate at the hepatic level. Only a small fraction of thiosulfate is incorporated into the endogenous sulfur compounds. ST is then mainly eliminated by the renal route, by glomerular filtration, and secretion. In healthy subjects, renal clearance is approximately 1.86 ml/min/kg and non-renal clearance is 2.25 ml/min/kg, for an elimination half-life of approximately 16-80 minutesr. The reported side effects of ST are rare. Metabolic acidosis and a QT prolongation in patients with chronic renal impairment or dialysis patients were reported; furthermore possible anaphylactic reactions have been described, but none of these adverse effects were found in the present study.
A pharmacological peculiarity of ST, that is rarely discussed, is that it has a cationic chelating activity which equates it with an anti-alkylating agent. These anti-alkylating properties also make it use in direct subcutaneous instillation to prevent or treat tissue destruction induced by accidental extravasation of CDDP during systemic chemotherapy [26]. From an oncological perspective, it therefore appears reasonable to question the use of a potentially anti-alkylant agent during the use of an alkylant chemotherapy such as CDDP. This has already been studied in a model of neuroblastoma, and it has been demonstrated that the use of ST does not compromise the antitumour effect of CDDP, both in vitro and in an animal model. This was confirmed in vitro and in murine models [27,28], and for endometrial and ovarian carcinomas [28]. Although these studies appear reassuring as to a potential decrease in the effectiveness of chemotherapy, there is still no prospective study describing the impact of ST on clinical outcomes, in particularly long-term survival. However, data reported from the Dutch trial led by Van Driel et al. [5], which assessed the impact of the addition of HIPEC with CDDP to interval cytoreductive surgery in the treatment of peritoneal metastases from ovarian origin do support the innocuousness of ST antitumoral activity of intraperitoneally  administered CDDP; as ST was systematically used in this trial in the HIPEC group.
The main limitation of the present study concerns the comparison of two successive periods. However, no element of pre-or intra-operative management differed from one group to the other, and the groups were completely comparable. The only way to provide a higher level of proof would be a randomized study, but this would be of little interest.
Given the important renal toxicity of HIPEC with HIPEC and its potential serious consequences in the long term such as dialysis, and considering the results herein and those reported elsewhere, it appears not reasonable at this time not to use the weapon that is Sodium Thiosulfate to prevent the nephrotoxicity induced by HIPEC with HIPEC.

Conclusion
The use of ST appears to be a reliable and effective means to prevent the occurrence of acute and chronic renal failures induced by HIPEC with CDDP, and should be used for HIPEC and should be used for all such procedures.