Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer in an Australian institution: lessons from 20 years' experience.

OBJECTIVES: We report the 20-year experience of the largest Australian unit performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer and reflect on learning opportunities. METHODS: A retrospective review of all cases of CRS for ovarian cancer at St George Peritonectomy Unit from Jan 1998 to Jan 2018 was performed. Prospectively collected data include age, stage, histology, disease extent (PCI), completeness of cytoreduction (CC score), HIPEC regime, 30-day surgical morbidity, disease recurrence, and death. Survival was computed using Kaplan-Meier method and analysed using log-rank tests and Cox-proportional hazards models. RESULTS: Forty-one women with advanced ovarian cancer (11 primary stage III/IV, 30 recurrent) underwent CRS, 29 (71%) with HIPEC. Most (68%) had high-volume disease (PCI > 15). In 98%, CC0/CC1 (residual < 2.5 mm) was achieved. Fourteen (34%) had grade 3/4 complications, 1 patient (2%) died within 30 days and 2 patients (5%) died within 90 days. Progression-free and median overall survival was 30.0 and 67.0 months for primary cancer, and 6.7 and 18.1 months for recurrent cancer. Survival was associated with platinum-sensitivity, PCI ≤ 15, and CC score 0, but not HIPEC. CONCLUSION: This study reports outcomes for patients with advanced ovarian cancer patients treated in an Australian centre offering CRS and HIPEC. Whilst survival and morbidity outcomes were good for primary disease, they were poorer than predicted from the literature for cases of recurrent disease. The incorporation of evidence-based predictors of survival and multidisciplinary input are essential to achieve the best survival outcomes.

A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Oxaliplatin versus Mitomycin C for HIPEC in colorectal cancer peritoneal carcinomatosis.

OBJECTIVE: Compare long-term outcomes in colorectal cancer (CRC) patients with peritoneal carcinomatosis (PC) treated with peritonectomy/HIPEC using oxaliplatin versus MMC. BACKGROUND: Peritonectomy and heated intraperitoneal chemotherapy (HIPEC) greatly improves patient survival in CRC PC. This procedure is not uniform across centres and the optimal choice of HIPEC chemotherapeutic is unclear. Oxaliplatin and Mitomycin C (MMC) are the most commonly used agents and comparative studies have reported varying results. METHOD: 201 patients were retrospectively selected from the St George Hospital database, all of which had undergone peritonectomy/HIPEC for CRC PC. Oxaliplatin and MMC were used in 106 and 96 patients, respectively. Each patient's baseline characteristics, operative details, choice of chemotherapeutic agent and survival were noted. RESULTS: The two groups did not differ significantly at baseline. Patients receiving oxaliplatin had significantly greater unadjusted median survival compared to MMC (56.0 ± 8.1 vs. 29.0 ± 3.4 months) which translated into a hazards ratio of 0.59 (95% CI 0.37-0.91, p = 0.017). Subgroup analysis further confirmed an advantage with oxaliplatin in females, moderate-well differentiated tumours, tumours without signet ring pathology and PCI 10-15. CONCLUSION: Our study suggests oxaliplatin offers a survival advantage over MMC when used for HIPEC in CRC PC. Further studies to understand its efficacy, complications and ideal preparation are required. A Phase III randomised control trial comparing oxaliplatin and MMC would enhance decision-making.

High risk features of primary colorectal carcinomas which subsequently undergo peritonectomy.

OBJECTIVE: Determine what portion of colorectal cancer (CRC) patients with peritoneal metastases (PM) undergoing peritonectomy would have been identified/treated if second-look surgery protocol existed for high-risk primary tumours. BACKGROUND: The prognosis of CRC PM greatly improves following peritonectomy/HIPEC. Survival remains dependent upon stage of PM and there is some knowledge of high-risk factors for its development. Subsequently, there is interest in routine second-look laparotomy to follow-up high-risk CRC patients so to 'prevent' PM. METHODS: Patients were retrospectively selected from the St George database, all of whom had had PM recurrence after primary CRC resection thus underwent peritonectomy/HIPEC. Each patient's primary tumour pathology was obtained with incidence of high-risk stage (T4), macroscopic (peritoneal involvement, ovarian metastases, perforated primary) and microscopic (mucinous, signet ring) features noted. RESULTS: 125 patients were included. At primary diagnosis, 34.4%, 46.4% and 19.2% were of T3, T4a and T4b stage. Primary tumour macroscopic features included 41.1%, 12.6% and 23.7% with synchronous peritoneal involvement, perforated primary and ovarian metastases. Primary tumour microscopic features included 8.1%, 44.0% and 5.6% with signet ring, mucinous and both pathologies. Individually T4 status, macroscopic and microscopic features would have identified 65.6%, 56.8% and 46.5% of patients. Any high-risk factor would have identified 85.6%. CONCLUSION: Our study suggests that T4 stage, high-risk macroscopic and high-risk microscopic features at time of primary diagnosis identifies the majority of CRC patients who later develop PM. This provides support for a selective second-look protocol in such patients to enable early identification and, potentially, 'prevention' of CRC PM.

Laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) for refractory malignant ascites in patients unsuitable for cytoreductive surgery.

INTRODUCTION: Malignant ascites (MA) is the abnormal accumulation of fluid in the peritoneal cavity of patients with intraperitoneal dissemination of their disease and is associated with a short life expectancy. The most common clinical feature is a progressive increase of abdominal distention resulting in pain, discomfort, anorexia and dyspnoea. Currently, no treatment is established standard of care due to limited efficacy or considerable toxicity. The objective was to examine the efficacy of laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) in the palliation of refractory MA in patients who were unsuitable for cytoreductive surgery. METHODS: From May 2009 to June 2015, 12 patients with MA due to their peritoneal malignancy were treated with laparoscopic HIPEC. The time between operation and repeat paracentesis, in-hospital data, and the proportion of patients that did not require repeat paracentesis was analyzed. RESULTS: One patient (8%) was admitted to ICU for 1 day. The mean operating time and hospital stay was 149.3 min (range 79-185) and 4.6 days (range 2-11) respectively. Neither high-grade morbidity nor mortality was observed. The median OS was 57 days. In our experience, a complete and definitive disappearance of MA was observed in 83% of patients. Two patients (17%) developed recurrent MA 124 days and 283 days post-HIPEC. CONCLUSION: Laparoscopic HIPEC is a beneficial treatment for the management and palliation of refractory MA and results in an excellent clinical and radiological resolution in patients with a complete resolution observed in selected patients.

Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer: A systematic review and meta-analysis.

PURPOSE: Emerging evidence suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) shows a survival benefit over CRS alone for patients with epithelial ovarian carcinoma (EOC). This systematic review and meta-analysis will assess the safety and efficacy of HIPEC with CRS for EOC. DESIGN: Searches of five databases from inception to 17/02/15 was performed. Clinical outcomes were synthesised, with full tabulation of results. RESULTS: A total of 9 comparative studies and 28 studies examining HIPEC + CRS for primary and/or recurrent EOC were included. Meta-analysis of the comparative studies showed HIPEC + CRS + chemotherapy had significantly better 1-year survival compared with CRS + chemotherapy alone (OR: 3.76, 95% CI 1.81-7.82). The benefit of HIPEC + CRS continued for 2-, 3-, 4-, 5- and 8-year survival compared to CRS alone (OR: 2.76, 95% CI 1.71-4.26; OR: 5.04, 95% CI 3.24-7.85; OR: 3.51, 95% CI 2.00-6.17; OR: 3.46 95% CI 2.19-5.48; OR: 2.42, 95% 1.38-4.24, respectively). Morbidity and mortality rates were similar. Pooled analysis of all studies showed that among patients with primary EOC, the median, 1-, 3-, and 5-year overall survival rates are 46.1 months, 88.2%, 62.7% and 51%. For recurrent EOC, the median, 1-, 3-, and 5-year overall survival rates are 34.9 months, 88.6%, 64.8% and 46.3%. A step-wise positive correlation between completeness of cytoreduction and survival was found. CONCLUSION: The addition of HIPEC to CRS and chemotherapy improves overall survival rates for both primary and recurrent EOC.

Repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent diffuse malignant peritoneal mesothelioma.

INTRODUCTION: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS: This is a retrospective study of prospectively collected data of 44 consecutive patients with DMPM who underwent CRS and HIPEC by the same surgical team at St George Hospital in Sydney, Australia. A total of 58 operations were performed. Clinical data were divided according to the number of operation and HIPEC the patient had undergone (Group 1 = initial CRS and HIPEC; Group 2 = 2nd CRS and HIPEC; Group 3 included 3rd CRS and HIPEC; Group 4 = 4th CRS and HIPEC). A significant difference was defined as p < 0.05. RESULTS: There were no significant differences in mortality and morbidity results among the four groups. The median survival for those who only had one operation was 22 months (95% confidence interval (CI) = 0-47.2), whereas the median survival for those who had a second operation was 62 months (95% CI = 22.9-101.1). However, such a difference did not translate into a statistical significance (p = 0.141). CONCLUSION: We report an encouraging median survival of 62 months in patients who had recurrence of disease and had repeat CRS and HIPEC with similar morbidity and mortality with the initial operation. Due to the learning curve of this technique, patients with recurrent mesothelioma should be referred to specialised tertiary care centres for evaluation. Selected patients may experience prolonged survival after repeat CRS and HIPEC.

Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.