Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) confers a survival benefit in epithelial ovarian cancer (EOC) and in preclinical models. However, the molecular changes induced by HIPEC have not been corroborated in humans. PATIENTS AND METHODS: A feasibility trial evaluated clinical and safety outcomes of HIPEC with cisplatin during optimal cytoreductive surgery (CRS) in patients with EOC diagnosed with stage III, IV, or recurrent EOC. Pre- and post-HIPEC biopsies were comprehensively profiled with genomic and transcriptomic sequencing to identify mutational and RNAseq signatures correlating with response; the tumor microenvironment was profiled to identify potential immune biomarkers; and transcriptional signatures of tumors and normal samples before and after HIPEC were compared to investigate HIPEC-induced acute transcriptional changes. RESULTS: Thirty-five patients had HIPEC at the time of optimal CRS; all patients had optimal CRS. The median progression-free survival (PFS) was 24.7 months for primary patients and 22.4 for recurrent patients. There were no grade 4 or 5 adverse events. Anemia was the most common grade 3 adverse event (43%). Hierarchical cluster analyses identified distinct transcriptomic signatures of good versus poor responders to HIPEC correlating with a PFS of 29.9 versus 7.3 months, respectively. Among good responders, significant HIPEC-induced molecular changes included immune pathway upregulation and DNA repair pathway downregulation. Within cancer islands, % programmed cell death protein 1 expression in CD8+ T cells significantly increased after HIPEC. An exceptional responder (PFS 58 months) demonstrated the highest programmed cell death protein 1 increase. Heat shock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. CONCLUSION: Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.

"Optimal" cytoreduction for advanced epithelial ovarian cancer: a commentary.

OBJECTIVE: To derive the most appropriate threshold to classify primary cytoreductive operations as "optimal" and address the clinical significance of this issue. METHODS: Criteria used to classify primary cytoreductive outcomes are reviewed. Survival outcomes are analyzed to address relative influences of the completeness of cytoreduction and "biological aggressiveness", as manifested by the extent of intra-abdominal metastases. RESULTS: Most cohorts analyzing relative influences of metastatic tumor burden and the dimension of residual disease on survival report completeness of cytoreduction to influence the prognosis more significantly than tumor burden, with necessity to perform various procedures having minimal or no influence. Equivalent survival is reported for completely cytoreduced patients with stage III disease whether substages IIIa/b (smaller tumor burden) are excluded or included. However, some stage IIIc series report more favorable median and 5-year survivals for small fractions of completely cytoreduced patients than series with a large visibly disease-free fraction. Increasing fractions of complete cytoreduction are reported in recent cohorts, without increase in morbidity. CONCLUSIONS: Complete primary cytoreduction improves the prognosis for survival significantly more than a small dimension of residual disease. Although prospective randomized trials addressing surgical issues have not been undertaken and numerous variables may reflect "biological aggressiveness" by influencing the prognosis, available data justify elimination of macroscopic disease to be the most appropriate objective of primary cytoreductive surgery. Stratification of survival by dimensions of residual disease in an investigational setting should include a visibly disease-free subgroup and if used, the term "optimal" should be applied to patients undergoing complete cytoreduction.

Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer.

OBJECTIVE: To determine if the need to perform splenectomy due to metastatic disease in the context of complete primary cytoreduction for ovarian cancer diminishes the prognosis for survival. METHODS: Between 1990 and 2004, 356 stage IIIC epithelial ovarian cancer patients underwent resection of all visible disease before systemic platinum-based combination chemotherapy. Forty-nine (13.8%) required a splenectomy due to metastatic disease. Survival was analyzed (log rank) on the basis of whether splenectomy was necessary. The frequency of performing other procedures, operative time, blood loss, transfusion rate, and hospitalization, was compared (Chi-square test; discrete and binomial data, t test; continuous data) on the basis of whether a splenectomy was required. RESULTS: Survival was not influenced (log rank) by the requirement of splenectomy (required; median 56.4 months, estimated 5-year survival of 48% vs. not required; median 76.8 months, estimated 5-year survival of 58% P = 0.4). The splenectomy subgroup more commonly required en-bloc resection of reproductive organs with rectosigmoid (89.8% vs. 55.7%, P < 0.001), diaphragm stripping (63.3% vs. 33.6%, <0.001)), full-thickness diaphragm resection (28.6% vs. 9.4%, P < 0.001), and resection of grossly positive retroperitoneal nodes (67.3% vs. 46.3%, P = 0.006). The splenectomy group had a longer operative time (238 min vs. 192 min, P = 0.004), estimated blood loss (1663 ml vs. 1167 ml, P = 0.001), transfusion rate (5.3 units prbc vs. 3.2 units prbc, P = 0.002), and hospitalization (16.1 vs. 12.2 days P = 0.001). CONCLUSIONS: The need for splenectomy to achieve complete cytoreduction is a reflection of advanced disease but is not a manifestation of tumor biology precluding long-term survival.

Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study.

OBJECTIVE: The purpose of this study was to determine the relative influences of the extent of disease present before surgery and completeness of cytoreduction on survival for patients with advanced ovarian cancer. METHODS: Patients (408) with stage IIIC epithelial ovarian cancer had cytoreductive surgery before systemic platinum-based combination chemotherapy. A ranking system (0-3) was devised to prospectively quantify the extent of disease involving: (1) right upper quadrant (diaphragm/hepatic, and adjacent peritoneal surfaces), (2) left upper quadrant (omentum/gastro-colic ligament, spleen, stomach, transverse colon, splenic flexure of colon), (3) pelvis (reproductive organs, recto-sigmoid, pelvic peritoneum), (4) retroperitoneum (pelvic/aortic nodes), and (5) central abdomen (small bowel, ascending/descending colon, mesentery, anterior abdominal wall, pericolic gutters). Survival was analyzed (log rank and Cox regression) on the basis of the rankings at these anatomic regions, the sum of intraabdominal rankings, and the cytoreductive outcome. RESULTS: Overall median and estimated 5-year survivals were 58.2 months and 49%. On univariate analysis, the central abdominal (P = 0.008) and left upper quadrant (P = 0.03) rankings, the sum of rankings (P = 0.01), and the cytoreductive outcome (P 1 cm residual, RR 2.98; P = 0.001). CONCLUSIONS: Cytoreduction to a visibly disease-free outcome has a more significant influence on survival than the extent of metastatic disease present before surgery. Operative efforts should not be abbreviated on the hypothesis that extensive disease at specific anatomic regions precludes long-term survival.

Reduction of blood loss during extensive pelvic procedures by aortic clamping--a preliminary report.

OBJECTIVE: The aim was to determine the effect of intraoperative aortic clamping during extensive pelvic procedures on blood loss, operative time, and morbidity. METHODS AND MATERIALS: Thirteen women with ovarian cancer, 1 with cervical cancer, and 1 with an extensive pelvic sarcoma had their aortas completely occluded with a vascular clamp before the pelvic phases of their operations. Heparin and protamine reversal were used. RESULTS: Patients requiring en bloc excision of the internal reproductive organs, pelvic peritoneum, and recto-sigmoid colon in the context of a cytoreductive operation had a median estimated total blood loss of 650 ml (range 200 to 3500), a median of 2 units (range 0 to 8) of blood transfused, and a median total operative time of 155 min (range 90 to 280). There were no complications due to the aortic clamping. CONCLUSION: Most procedures were completed with a less than anticipated blood loss and operative time. Clamping of the aorta may potentially diminish blood loss, operative time, and the incidence of transfusion-related morbidity associated with extensive pelvic operations. Intraoperative aortic clamping merits further investigation.