Hyperthermic intraperitoneal chemotherapy (HIPEC) is the delivery of heated chemotherapy (42 °C) into the intraperitoneal (IP) cavity immediately after optimal cytoreductive surgery (CRS). The OVHIPEC-1, randomized, phase III trial evaluated HIPEC with cisplatin 100 mg/m
2 in patients with epithelial ovarian cancer (EOC) and demonstrated an 11.8-month overall survival benefit for stage III patients undergoing interval cytoreduction and HIPEC.
1‐3 Cisplatin is considered the drug of choice in HIPEC for EOC due to its thermal enhancement at temperatures from 42 to 44 °C. It is renally excreted and, consequently, may result in significant renal toxicity.
4 Other accepted HIPEC regimens in EOC include paclitaxel, cisplatin, oxaliplatin, cisplatin with doxorubicin, as well as cisplatin with mitomycin-C.
5
The incidence of acute kidney injury (AKI) with cisplatin during HIPEC has been reported at 15–31% for cisplatin doses 50–100 mg/m
2.
6,7 Management of cisplatin-associated nephrotoxicity includes perioperative hyperhydration, mannitol, amifostine, and sodium thiosulfate (ST) administration.
6,7 ST is an agent used to treat calciphylaxis, kidney stones, and uremic vascular calcification.
8‐10 The mechanism of action of ST regarding nephroprotection is unclear, and some concerns exist that ST use may reduce the cytotoxic effect of chemotherapy due to its anti-alkylating properties.
11 ST was used as a pre-HIPEC bolus and as postoperative maintenance in all patients undergoing HIPEC in the OVHIPEC-1 trial, with few renal toxicities reported.
1 Nonetheless, the use of nephroprotectants in association with HIPEC with cisplatin is variable, and use of ST in the United States is limited.
7,12
Use of ST versus no ST (nST) has not been prospectively evaluated in ovarian cancer patients undergoing HIPEC with cisplatin. Rather, interim analyses showing higher-than-expected, renal, adverse effects has led to protocol amendment with inclusion of ST prophylaxis in some key HIPEC trials in ovarian cancer.
13,14 Additionally, no studies have investigated the molecular changes in peritoneal tissues exposed to cisplatin during HIPEC. Investigation of these changes may help to identify patients at higher risk of HIPEC-induced nephrotoxicity. We report clinical and molecular results of a retrospective, ancillary study of EOC and endometrial cancer (EC) patients who underwent HIPEC with cisplatin at 75 mg/m
2 with and without ST administration.
Methods
Study Population
A single-institution, clinical trial was approved by the City of Hope Institutional Review Board (NCT01970722) to evaluate feasibility and safety of HIPEC with cisplatin in EOC and EC patients. All research was carried out in accordance with ethical principles as defined by the Declaration of Helsinki.
15
Eligible patients had newly diagnosed or recurrent stage III/IV EOC, primary peritoneal, fallopian tube cancer, or EC. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and preexisting normal renal function. Patients were allowed to have received neoadjuvant chemotherapy before planned HIPEC. Complete or optimal gross resection of disease defined by R classification was required to be anticipated, as judged by participating surgeons.
16 Written, informed consent was obtained before patient inclusion, and baseline demographics were obtained at enrollment. Patients were followed prospectively for evaluation of response to treatment, disease status, progression-free survival (PFS), and length of follow-up. Enrollment proceeded until the target patient number was accrued without triggering safety stopping rules (grade ≥ 4 morbidity rate ≥ 40%; mortality rate ≥ 3.4%).
17 All subjects were recruited from patients undergoing treatment at City of Hope National Comprehensive Cancer Center (Duarte, CA). Supplementary Data 1 shows complete eligibility and exclusion criteria.
Trial Design
This prospective, feasibility, clinical trial investigated the safety and molecular changes associated with HIPEC with cisplatin in patients with gynecologic malignancies. Initial protocol treatment did not include ST administration. However, after an interim analysis of the first 21 patients demonstrated a high rate of renal toxicity, the protocol was amended. ST was then added to the protocol for the subsequent 19 patients recruited. This study examines the effects of the protocol change in the trial.
OVHIPEC-1 was referenced for the ST dosing protocol. For patients receiving ST, a bolus of 9 g/m
2 in 200 cc of sterile water was administered intravenously immediately before HIPEC. HIPEC with cisplatin was delivered at 75 mg/m
2 over 60 min at 41–43 °C immediately after optimal CRS by using closed or laparoscopic methods, determined by surgeon preference. The ThermoChemHT-2000 (ThermaSolutions, White Bear Lake, MN) hyperthermic pump system was used. After completion of all cytoreductive surgical procedures, two inflow tubes were placed in the pelvic cavity, and two outflow tubes were placed in the upper abdomen with IP thermometer probes attached. The abdomen was temporarily closed. Saline solution was used to confirm smooth circulation to and from the HIPEC pump. Once target temperature and adequate circulation were reached, chemotherapy was introduced in one dose and circulated for 60 min, while gently shaking the abdomen side-to-side to achieve even distribution. Following completion of HIPEC with cisplatin, a maintenance dose of ST of 12 g/m
2 in 1000 cc of sterile water was administered continuously over 6 h to patients in the ST group. In all instances, urinary output was closely monitored. Additional, intravenous, fluid boluses were administered to avoid urine output < 1 mL/kg perioperatively in both groups. Adverse events (AEs) were collected and graded according to CTCAE v.5.0.
18
Normal peritoneal samples were obtained at the start of surgery (pre-HIPEC) and immediately after HIPEC. Samples were primarily collected from the abdominal, pelvic, or diaphragmatic peritoneum. Other sample origins that included the omentum, appendix, and adipose tissue were considered. All normal samples were collected from locations distant from tumor. Samples were snap-frozen in liquid nitrogen and/or formalin-fixed, paraffin-embedded (FFPE) for histologic review, institutional tumor banking, and RNA extraction. Samples were stained with hematoxylin and eosin for assessment of cellularity and absence of tumor cells by a board-certified gynecologic pathologist.
Molecular Analysis
RNA from FFPE (miRNeasy RNA FFPE Kit, Qiagen) and snap-frozen tissues (miRNeasy RNA mini Kit, Qiagen) was extracted per standard manufacturer protocols. Concentration and purity were measured using NanoDrop One Spectrophotometer (Thermo Fisher Scientific) and Qubit 3.0 Fluorometer (Life Technologies). For whole transcriptome library construction, 500 ng of total RNA for each sample was used. See Supplementary Data 2 for detailed methods.
Endpoints
The primary endpoint of the trial was safety and survival outcomes, which was previously reported.
19 In this secondary outcome analysis, renal toxicities and clinical outcomes were evaluated in two groups undergoing HIPEC with cisplatin: ST versus nST. Renal toxicity was defined as development of grade ≥ 1 AKI, chronic kidney disease (CKD), or proteinuria. Additional analyses included PFS by ST and nST use in primary and recurrent EOC patients. Exploratory analyses included correlation of toxicities with transcriptomic signature changes by whole transcriptomic sequencing (WTS) following HIPEC.
Statistical Analysis
Baseline and postsurgical characteristics were compared between ST and nST patients by using the chi-square or Fisher’s exact test for categorical data, and the t-test (normally distributed) or Wilcoxon rank-sum (non-normally distributed) continuous variables. PFS was defined as the time in months from CRS and HIPEC to progression by CA-125 (Gynecologic Cancer Intergroup Criteria), imaging (CT or PET CT, per RECIST
20), or clinical symptoms or deterioration. Kaplan-Meier and log-rank tests compared the PFS of patients with and without ST administration. Statistical analyses of differential RNAseq expression analysis of post-HIPEC samples are described in Supplementary Data 2.
Discussion
Despite enthusiasm for HIPEC in EOC, routine use of HIPEC is marred by its toxicities and skepticism over its true clinical benefit. Despite a well-established incidence of nephrotoxicity from HIPEC with cisplatin, management and prevention of this toxicity vary widely. The Peritoneal Surface Oncology Group International (PSOGI) recently performed a consensus among international HIPEC experts to derive recommendations regarding the indications and delivery of HIPEC regimens.
5 While the evidence in favor of using nephroprotection in HIPEC with cisplatin was low, the consensus group recommended the routine use of nephroprotection in all patients undergoing HIPEC with cisplatin. Additionally, ST was considered the preferred drug for nephroprotection by most experts.
Despite preferred expert opinions, there have been limited studies investigating HIPEC-specific nephrotoxicities. To date, retrospective studies have compared the nephroprotective effects of ST versus no ST when given in conjunction with HIPEC with cisplatin.
23 While ST was used in all patients enrolled in OVHIPEC-1 without significant renal toxicities, ST use versus no ST use has not been evaluated in a prospective manner. We present an ancillary study that compares use of ST as a nephroprotectant versus no nephroprotectant use in patients undergoing HIPEC with cisplatin. While a theoretical concern exists that ST may abrogate cisplatin efficacy given its known anti-alkylating properties, we demonstrated no difference in PFS in patients with gynecologic malignancies who received ST (versus nST) for renal prophylaxis.
11
A major strength of our study is the evaluation of ST use versus no ST use on renal function as a primary outcome. Although some trials have shown the nephroprotective effect of ST, they have been largely retrospective or observational in design.
23,24 The OVHIPEC-1 study demonstrated improved survival outcomes in advanced stage ovarian cancer patients and included ST prophylaxis in the protocol, and no renal AEs were reported.
1 Baseline creatinine was similar between the ST and nST groups. Our trial demonstrated the safety, feasibility, and efficacy of HIPEC with cisplatin with ST in primary and recurrent EOC and EC patients for renal protection. No grade 4 or 5 AEs were reported, and the most common grade 3 AEs experienced (anemia; metabolic and electrolyte disturbances) were most often associated with CRS. Renal AEs and significant differences in postoperative Cr were only experienced by those who did not receive ST. These findings are consistent with OVHIPEC-1, where no significant renal toxicities were reported with the routine use of ST.
1 Median OR time was slightly shorter in patients with nephrotoxicity (6.4 vs. 7.5 h) compared with those without. Even with these increased operative times, the ST group did not have renal AEs. Our data reiterate support for the standard use of ST for nephroprotection in patients undergoing HIPEC with cisplatin.
While the median days to initiation of adjuvant chemotherapy was not statistically significant in our study, a trend favored the ST group in initiating adjuvant chemotherapy sooner than the nST group. There also was a trend toward improved median PFS amongst the ovarian cancer patients analyzed in the ST group compared with the nST group, although this may be due to imbalance of primary EOC predominance in the ST group compared with recurrent EOC predominance in the nST group. In the subcohorts of primary EOC and recurrent EOC, there was no difference in PFS between the nST and ST groups. We sought homogeneity for survival analysis and thus excluded patients with uterine cancer. The uterine cancer cohort was small (n = 6) and imbalanced toward recurrent disease.
We performed transcriptomic analyses in normal peritoneal samples to identify molecular signatures that correlate with HIPEC-induced renal toxicities. These novel analyses investigate what is occurring at a transcriptional level in patients who experience renal toxicity from HIPEC with cisplatin. Gene pathways related to immune modulation were significantly upregulated in patients who experienced renal failure, many of which are related to neutrophil, T-cell, and B-cell activation.
The upregulation of inflammatory cells, such as neutrophils and T cells, suggests an acute inflammatory response resulting in AKI. Indeed, immune and inflammatory mechanisms have been recognized as important mediators of cisplatin nephrotoxicity.
6 While immune mediated mechanisms of nephrotoxicity from intravenous cisplatin have been recognized, this is the first observation in IP cisplatin administration in humans, to our knowledge. Our inclusion of peritoneal transcriptomics in patients without nephrotoxicity demonstrate a strikingly differently patterned genetic heatmap compared with those with nephrotoxicity. Conversely, downregulated pathways were related to metabolism, pointing to a reduced metabolism phenotype in patients at risk for renal toxicities. Identifying potential biomarkers associated with nephrotoxicity may help to optimize HIPEC with cisplatin by identifying patients who are not ideal candidates for HIPEC or who may require additional supportive therapy to undergo HIPEC. Although kidney biopsies were not obtained in this study, there is evidence that cisplatin-related nephrotoxicity is induced by cytokine-mediated inflammation.
6 The microenvironment in the peritoneum may reflect a systemic proinflammatory state given that is where absorption of HIPEC with cisplatin is directly occurring.
Our study is limited by the lack of randomization, which led to the nST group preceding the ST group with resultant median follow up differences. ST administration was initiated after interim analysis revealing significant renal toxicities. This limited our ability to exclude possible confounders in our subject selection. This chronological recruitment for both groups accounts for the difference in median follow-up between the nST and ST groups (57.7 vs. 27.7 months), given that nST subjects were recruited first. An additional limitation includes a slight imbalance in disease characteristics between the nST and ST groups. The nST group had more recurrent cancer cases, whereas the ST group had more primary cases. Although it could be assumed that more heavily pretreated, recurrent EOC patients may have worse renal function, baseline Cr between the two groups was similar. Mean operating time and PCI were lower in the nST group. This could be associated with decreased surgical complexity and associated complications in the nST group, thus reducing the likelihood for acute renal failure in this group. BMIs were significantly different between the two groups (ST: 23.4 vs. nST: 28.5,
p = 0.04), but within the nST group, patients who had renal toxicity versus no renal toxicity had no significant difference in BMI. The median BMI for patients with and without observed renal AEs was 27.6 and 28.8, respectively (
p value from Wilcoxon rank-sum test was 0.6) within the nST group. Even though the patient group with renal AEs was small (
n = 7), the results do not lead us to believe that BMI was an important factor in the incidence of AEs among the nST patients. Patients in the ST group had more postoperative complications secondary to fluid overload. Given that the ST patients underwent HIPEC treatment chronologically later than their nST counterparts, perioperative volume management adjustments were made as recommendations emerged in the literature.
21,22 Cisplatin dosage in our study was different than the OVHIPEC-1 study; 75 versus 100 mg/m
2, respectively. However, while 100 mg/m
2 is the currently accepted dose for HIPEC with cisplatin in the first line setting for ovarian cancer,
25 other studies, including the Korean
13 and CARCINO-HIPEC
26 trials used 75 mg/m
2. Lastly, although our study population was primarily comprised of EOC patients, there was some heterogeneity with the inclusion of six patients (15%) with uterine cancer. However, given that our primary endpoint was renal AEs secondary to administration of HIPEC with cisplatin, it is unlikely that the variation in histology or disease site present any confounding factors.
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