Safety and feasibility of hyperthermic intraperitoneal chemotherapy during interval cytoreductive surgery in patients with advanced high‐grade serous ovarian, fallopian tube, peritoneal cancer in an Australian context

To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high‐grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context.


INTRODUCTION
Ovarian cancer is the ninth most commonly diagnosed cancer in Australian women, with 1720 diagnoses and 1042 deaths in 2021. 1 Compared to other gynaecological cancers, ovarian cancer has the highest mortality rate. 1 The most common subtype is high-grade serous carcinoma. 2Patients with stages III and IV disease at the time of diagnosis account for 80% of cases. 2 Globally, five-year survival remains low at approximately 20% for late-stage (IIIa-IV) disease. 3,4Complete cytoreduction has been shown to increase overall survival and surgical radicality is intended to produce this result. 3perthermic intraperitoneal chemotherapy (HIPEC), in conjunction with interval cytoreductive surgery (CRS), has been used in late-stage mesothelioma, gastrointestinal cancers, and is being incorporated into the management of patients with advanced ovarian cancer. 5,6A 2018 multicentre open-label phase-III trial found that the addition of HIPEC to interval CRS improved overall survival by a median of 11.8 months among patients who received neoadjuvant chemotherapy for stage III ovarian cancer. 7Similarly, a 2022 single blinded randomised controlled trial from Korea reported that the addition of HIPEC to interval CRS provided improvements in both progression-free survival (PFS) and overall survival in patients with stage III/IV ovarian cancer. 8A systematic review of the overall use of CRS and HIPEC in ovarian cancer and associated peritoneal carcinomatosis found improvements in median PFS and mean fiveyear survival. 3As there has been limited implementation of HIPEC and CRS in an Australian context, this study provides evidence for the safety and feasibility of this practice in the management of advanced ovarian cancer within Australia.

MATERIALS AND METHODS
This study was conducted within the Peritoneal Malignancy Service of a metropolitan hospital in Brisbane Australia.This hospital is one of three gynaecology-oncology services in Queensland and is part of a larger network of hospitals that provide health care across Queensland.
Approval for the study was obtained from the Mater Misericordiae Ltd Human Research Ethics Committee (EC00332) and all patients provided written consent to be involved.

RESULTS
During the period December 2018 to July 2022, a total of 25 of 335 women with ovarian cancer underwent CRS and HIPEC for advanced ovarian, fallopian tube and peritoneal cancer after one to four cycles of neoadjuvant chemotherapy.A published open coliseum technique was used for HIPEC with cisplatin (100 mg/m 2 ) perfusion at 40-42°C for 90 min based on the OVHIPEC-1 trial protocol. 7,9The intra-operative and post-operative morbidity is comparable to the van Driel et al. 7 study.The results indicate that the implementation of HIPEC and CRS in our cohort was safe and feasible.

Patient demographics and clinical data
Demographic, pathological and clinical characteristics for the group are shown in Table 1.The median age was 61 years (42-72 years) and the median pre-operative body mass index was 23.3 kg/m 2 (18.1-33.9kg/m 2 ).The ASGC-RA for the population was primarily urban, with 16 women from major cities (64%), with the remainder living in inner-regional or outer-regional Australia.
The comorbidities of the group are listed in Table 1, where the greatest number of concurrent comorbidities was three, in three cases (12%).Nineteen patients had an ASA score III (76%).All patients received neoadjuvant chemotherapy and the majority of women received three cycles prior to surgery.

Patient pathological and operative data
Table 2 shows pathological, pre-operative, intra-operative and acute post-operative data.Ninety-six percent of cases had highgrade serous carcinoma, with one case of high-grade endometroid adenocarcinoma (4%) on histopathology.Eighteen cases were FIGO stage-IIIC (72%), with 84% of cases diagnosed histologically and 16% of cases diagnosed cytologically.Seven patients (28%) had confirmed germline and somatic BRCA mutations.The chemotherapy response score was two or three for greater than 50% of cases.
A CC-score of 0-1 was achieved for 100% of subjects.The median pre-operative PCI was 12 (5-17) and the median intraoperative PCI was 13 (6-26).The mean operating time (knife to skin) was 437 min, the mean blood loss was 734 ± 219 mL and the mean units of PRBC transfused was 3 ± 1 units.The mean haemoglobin level was 116 ± 4 g/L pre-operatively which fell to 64 ± 13 g/L at day three post-operation.
Six patients had acute CTCAE Grade 3 morbidity postoperatively (severe complications that were not immediately life threatening).These consisted of three cases (12%) of pleural effusions drained in the ICU, one case (4%) of acute kidney injury (AKI) that had a greater than three-fold increase in creatinine (55-173 μmol/L), one case (4%) of deep vein thrombosis (DVT), and one case (4%) of bladder injury which was treated intra-operatively.

There were no cases of pulmonary embolism (PE).
1][12] Patients exhibiting renal dysfunction had a median of four days (0-5 days) until resolution, with one case (4%) of AKI never returning to their baseline creatinine level.
All patients received inotropes.The mean duration until inotropes were ceased was 1.7 ± 0.5 days, with 13 of 25 cases (52%) requiring >1 day of inotropes, and the majority occurring in the first half of the cohort.The median days spent in the ICU postoperatively was four days (2-10 days) and the median duration of hospital stay was 11 days (5-20 days).
There were no returns to theatre post-operatively.Surgical data and intra-operative complications are displayed in Table 3.

Post-operative morbidity and mortality
There were no mortalities within 30 days or six months of interval CRS and HIPEC and morbidity was low with only two patients (8%) requiring post-operative opioid analgesia at six weeks.The average duration until follow-up adjuvant chemotherapy was 33 ± 5 days, with one patient (4%) in regional Australia requiring 67 days to travel for chemotherapy due to flooding and restricted transport options throughout Queensland.Eight women (32%) presented to hospital in the six-week follow-up post-operatively, six (24%) with constipation and two (8%) with a urinary tract infection (UTI).Of these, three patients (12%) were admitted for constipation, treated with laxatives or enemas, none of which required total parenteral nutrition and one patient (4%) for a UTI (CTCAE Grade III).All complications are listed in Table 4.

DISCUSSION
This Peritoneal Malignancy Service is the only unit that offers interval CRS and HIPEC as standard of care within Queensland for ovarian cancer and represents the number of cases of ovarian cancer treated with interval CRS and HIPEC in Australia.
This unique offering of both public and private services ensures equitable access to HIPEC for all eligible women with ovarian cancer regardless of medical coverage.
As assessing feasibility and safety was the aim of this study, patients were selected with low-risk comorbidities, resulting in only two cases (8%) with an ASA score of IV.
Our cohort includes a high proportion (36%) of rural patients, which is congruent with the usual referral distribution between metropolitan, regional, and rural areas at this peritoneal malignancy service.Markman and colleagues showed a clear survival benefit to outpatient intraperitoneal chemotherapy. 13It is only accessible in specialist centres, thereby requiring significant travel and long stays away from home for rural patients, limiting its use in these populations.One of the key benefits of HIPEC is intraoperative access to intraperitoneal chemotherapy, negating the need for ongoing travel, accommodation, and disruptions to patients and their families.Through the improved accessibility to intraperitoneal chemotherapy, interval CRS and HIPEC can aid in addressing healthcare equity.
A 2018 study described how PCI was correlated with completeness of cytoreduction and post-operative morbidity, with poor post-operative prognosis being associated with PCI scores of greater than ten in advanced ovarian cancer. 14Our patients all had advanced ovarian cancer and had a median pre-operative PCI SD refers to standard deviation applicable to statistical analysis [1].‡AKI was defined as an increase in creatinine by 100% or more from previously known baseline level on day 0 or thereafter post-operatively as per RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease) and AKIN (Acute Kidney Injury Network) criteria [9].§Suspected risk of AKI was defined as raised creatinine that was 50-99% from previously known baseline level on day 0 per RIFLE and AKIN guidelines [9].

Peri-operative outcomes
CC-scores of 0-1 were achieved in all cases and the average operative time (437 ± 23 min) did not largely differ from an Australian study by Farrell et al. 19 (~492 min).Their cohort of patients had similar demographics and disease staging and 98% of CRS resulted in CC-scores of 0-1. 19ngth of stay and duration of ICU admission reflect the complexity of CRS and morbidity.In several studies the admission time post-CRS and HIPEC in patients with advanced ovarian cancer was recorded as significantly higher than what was observed in our study. 19,20Di Giorgio carried out a retrospective review in 2016 of 511 patients with ovarian cancer who received CRS with HIPEC, finding that patients spent a mean of 21 (8-93) days in hospital post-operatively. 20Similarly, Farrell and colleagues found that patients were admitted for a mean of 29.3 (7-82) days post-operatively. 19These studies compare poorly with the OVHIPEC-1 trial, where patients had a median Anterior resection with/without rectal anastomosis Mesenteric nodule ablation/resection 2 8 Right colectomy 1 4

12
Uterine vein bleed 1 4 Right adrenal gland bleed 1 4 Mesenteric injury/repair 1 4 Venous oozing at right vaginal angle 1 4 Pancreatic tail bleed 1 4 †One case of bladder injury required intra-operative treatment and a post-operative cystoscopy and formal trial of void (Common Terminology Criteria for Adverse Events (CTCAE) Grade III).
‡Pleural effusions were drained in the intensive care unit postoperatively (CTCAE Grade III).admission length ten days. 7As the median duration of admission in our cohort was 11 days, our results comparable to the Netherlands Cancer Institute. 7U stay was found to be similar to that reported by Farrell et al., with a median of four vs 4.5 days. 19Interestingly, the van Driel study reported a shorter ICU length of stay of one day. 7ssible contributing factors to the observed ICU length of stay in our cohort include the swing bed concept operated by our ICU, which doubles as a high dependency unit (HDU) with no separate stepdown facility.Interval CRS and HIPEC is routinely performed on Fridays.This means that there is reduced weekend ward staffing to support stepdown care of complex patients, resulting in increased ICU and HDU length of stay.Some reductions in ICU length of stay may be possible if interval CRS and HIPEC were performed earlier in the week and when there is stepdown capability outside of the ICU.Additionally, the length of ICU stay among patients may vary from the Netherlands experience due to surgical differences between the two units.Consistent with the Netherlands cohort of 2018, our patients did not require any returns to the operating theatre.This compares favourably with the experience of Farrell et al., where four of 41 patients (9.8%) required return to theatre. 7,19eeding and transfusions are reflections of the extent of CRS and the state of disease among our patients.Within our cohort the mean blood loss was 734 ± 219 mL.This level of blood loss equated to a haemoglobin drop from 116 ± 4 g/L to 64 ± 13 g/L.
There was no discussion about blood loss in the paper by van Driel et al. or Farrell et al. 7,19 In a study of 880 patients undergoing interval CRS and HIPEC by Fisher et al., 21 intra-operative PRBC transfusions of >5 units was found to worsen long-term patient mortality and morbidity.Our mean transfusion rate was 3 ± 1 units.The transfusions in our cohort compare favourably with Farrell et al., where the average transfusion rate was 7.3 units and Di Giorgio et al., where the average transfusion rate exceeded four units. 19,20e usage and duration of inotropes can be a similar metric in considering intra-operative safety of interval CRS and HIPEC.
All patients within our cohort received inotropic intervention for at least one day post-surgery.Although the summative effects of HIPEC and surgical radicality may require inotropic intervention in some patients, further assessment should be made regarding the necessity of inotropes in patients undergoing interval CRS and HIPEC. 22This differs from CRS on its own, where the need for inotropes post-operatively is uncommon without the physiological effects of HIPEC. 22The mean duration of post-operative inotropes was 1.7 ± 0.5 days, where the duration patients remained on inotropes decreased as more patients underwent the procedure.Similar trends were found in reductions in blood loss and PRBC transfusion rate.These trends are likely due to progressive adoption of multi-modal goal-directed haemodynamic monitoring and therapy intra-operatively over the first five cases. 234][25] Among our cohort, AKIs are difficult to directly attribute to HIPEC or intra-operative complications and this is an area to be considered in future studies.The sole case of DVT in our study is difficult to attribute to any direct cause, other than the hypercoagulable state of patients prior to CRS.Although DVTs can potentially be provoked by CRS or HIPEC respectively, this should be a consideration for ongoing evaluation of safety.[25]

Post-operative morbidity and mortality
Medium-term outcomes are important in the assessment of the feasibility of interval CRS and HIPEC.Constipation was the main complication reported (24%), of which only three patients (12%) had short-stay readmissions.The effect of constipation on morbidity is considered minor.Similarly, UTIs were the next most common representation (8%), with one patient (4%) admitted for three days.The remainder of follow-up presentations were for minor morbidities and did not require readmission, with the exception of myelosuppression needing short-term review in one patient (4%).This is indicative of overall low morbidity associated with interval CRS and HIPEC up to six weeks post-operatively.An additional positive post-operative finding was that only 8% of patients required opioid analgesia up to six weeks, indicative of low post-operative morbidity.
In conclusion this study demonstrated the feasibility and safety of interval CRS and HIPEC in the Australian setting and these procedures are clearly both safe and feasible.Future work will address the PFS and overall survival in our patients.
Limitations include the small number of patient and that it is a single centre study.This study serves to provide an Australian perspective on the use of CRS and HIPEC in advanced ovarian cancer in the setting of neoadjuvant chemotherapy.This paper adds to the evolving body of literature regarding CRS and HIPEC in ovarian cancer.
Data were collected for 25 women who consecutively underwent interval CRS and HIPEC for an ovarian malignancy of ovarian, fallopian tube, and peritoneal origin from December 2018 to July 2022.Patient suitability for CRS and HIPEC was individually assessed through multi-disciplinary evaluation, considering chemotherapy response score, peritoneal cancer index (PCI) via laparoscopic assessment and comorbidities.Clinical and surgical data were collected for all patients at preoperative, intra-operative and post-operative timepoints.Data were collected for demographics, American Society of Anaethetists (ASA) score, carbohydrate antigen 125 (Ca125) level, baseline creatinine and albumin level, Federation of Gynaecology and Obstetrics (FIGO) tumour staging, Australian Statistical Geography Standard -Remoteness Area (ASGC-RA), comorbidities, number of cycles of neoadjuvant chemotherapy received, source of diagnosis, tumour histology, BRCA (BReast CAncer) status.Intra-operative data included operation time, procedures performed, complications, blood loss, units of packed red blood cells (PRBC) transfused and completeness of cytoreduction score (CC-score).Post-operative data included day three haemoglobin, albumin and creatinine levels, days until normalisation of renal function and cessation of inotropes, days in the intensive care unit (ICU) and until discharge, opioid analgesia requirements, complications, and days until recommencement of adjuvant chemotherapy.Acute (within six weeks) and long-term (>6 weeks post-op) complications were recorded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.Categorical variable data are presented as percentages, with continuous variable data presented as medians or means with SD.
Koole et al. in 2022,18 found BRCA1/2 proteins having increased susceptibility to HIPEC due to impairment of these proteins during hyperthermia.Our cohort had seven (28%) germline BRCA positive patients; somatic BRCA status was not consistently recorded in our group.Additional studies are required to assess the interplay between the BRCA gene and sensitivity to HIPEC in advanced ovarian cancers.

TABLE 2
Pathological and peri-operative characteristics of patients with advanced ovarian cancer who underwent cytoreduction surgery with hyperthermic intraperitoneal chemotherapy

TABLE 2 (
Continued) 17d not impact prognosis or rate of complete cytoreductions in patients undergoing CRS and HIPEC.15Although68% of our patients had ascites at the time of diagnosis, it is unlikely this affected patient outcomes in our cohort.Accurate histopathological diagnosis is crucial in determiningresistance to platinum agents and aids in the correct prescription of CRS and HIPEC in advanced ovarian cancer.16Tissuehistologysupersedes cytological diagnosis and was achieved in 84% of cases.Our cohort had one case (4%) of endometroid adenocarcinoma and 24 cases (96%) of high-grade serous carcinoma.It is well described that BRCA status significantly affects prognosis.17

TABLE 3
Intra-operative procedures and complications in advanced ovarian cancer patients who underwent cytoreduction surgery (CRS) with hyperthermic intraperitoneal chemotherapy