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

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.

Management of epithelial cancer of the ovary, fallopian tube, primary peritoneum. Long text of the joint French clinical practice guidelines issued by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY, endorsed by INCa. (Part 2: systemic, intraperitoneal treatment, elderly patients, fertility preservation, follow-up).

Adjuvant chemotherapy by carboplatin and paclitaxel is recommended for all high-grade ovarian and tubal cancers (FIGO stages I-IIA) (grade A). After primary surgery is complete, 6 cycles of intravenous chemotherapy (grade A) are recommended, or a discussion with the patient about intraperitoneal chemotherapy, according to her risk-benefit ratio. After complete interval surgery for FIGO stage III, hyperthermic intraperitoneal chemotherapy (HIPEC) can be proposed, in accordance with the modalities of the OV-HIPEC trial (grade B). In cases of postoperative tumor residue or in FIGO stage IV tumors, chemotherapy associated with bevacizumab is recommended (grade A).

Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Long text of the Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa. Part 1: Diagnostic exploration and staging, surgery, perioperative care, and pathology.

An MRI is recommended for an ovarian mass that is indeterminate on ultrasound. The ROMA score (combining CA125 and HE4) can also be calculated (grade A). In presumed early-stage ovarian or tubal cancers, the following procedures should be performed: an omentectomy (at a minimum, infracolic), an appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C), and pelvic and para-aortic lymphadenectomies (grade B) for all histologic types, except the expansile mucinous subtypes, for which lymphadenectomies can be omitted (grade C). Minimally invasive surgery is recommended for early-stage ovarian cancer, when there is no risk of tumor rupture (grade B). For FIGO stages III or IV ovarian, tubal, and primary peritoneal cancers, a contrast-enhanced computed tomography (CT) scan of the thorax/abdomen/pelvis is recommended (grade B), as well as laparoscopic exploration to take multiple biopsies (grade A) and a carcinomatosis score (Fagotti score at a minimum) (grade C) to assess the possibility of complete surgery (i.e., leaving no macroscopic tumor residue). Complete surgery by a midline laparotomy is recommended for advanced ovarian, tubal, or primary peritoneal cancer (grade B). For advanced cancers, para-aortic and pelvic lymphadenectomies are recommended when metastatic adenopathy is clinically or radiologically suspected (grade B). When adenopathy is not suspected and when complete peritoneal surgery is performed as the initial surgery for advanced cancer, the lymphadenectomies can be omitted because they do not modify either the medical treatment or overall survival (grade B). Primary surgery (before other treatment) is recommended whenever it appears possible to leave no tumor residue (grade B).

Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Short text of the French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa.

An MRI is recommended for an ovarian mass that is indeterminate on ultrasound. The ROMA score (combining CA125 and HE4) can also be calculated (Grade A). In presumed early-stage ovarian or tubal cancers, the following procedures should be performed: an omentectomy (at a minimum, infracolic), an appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C), and pelvic and para-aortic lymphadenectomies (Grade B) for all histologic types, except the expansile mucinous subtypes, for which lymphadenectomies can be omitted (grade C). Minimally invasive surgery is recommended for early-stage ovarian cancer, when there is no risk of tumor rupture (grade B). Adjuvant chemotherapy by carboplatin and paclitaxel is recommended for all high-grade ovarian and tubal cancers (FIGO stages I-IIA) (grade A). For FIGO stage III or IV ovarian, tubal, and primary peritoneal cancers, a contrast-enhanced computed tomography (CT) scan of the thorax/abdomen/pelvis is recommended (Grade B), as well as laparoscopic exploration to take multiple biopsies (grade A) and a carcinomatosis score (Fagotti score at a minimum) (grade C) to assess the possibility of complete surgery (i.e., leaving no macroscopic tumor residue). Complete surgery by a midline laparotomy is recommended for advanced ovarian, tubal, or primary peritoneal cancers (grade B). For advanced cancers, para-aortic and pelvic lymphadenectomies are recommended when metastatic adenopathy is clinically or radiologically suspected (grade B). When adenopathy is not suspected and when complete peritoneal surgery is performed as the initial surgery for advanced cancer, the lymphadenectomies can be omitted because they do not modify either the medical treatment or overall survival (grade B). Primary surgery (before other treatment) is recommended whenever it appears possible to leave no tumor residue (grade B). After primary surgery is complete, 6 cycles of intravenous chemotherapy (grade A) are recommended, or a discussion with the patient about intraperitoneal chemotherapy, according to her risk-benefit ratio. After complete interval surgery for FIGO stage III disease, hyperthermic intraperitoneal chemotherapy (HIPEC) can be proposed, in accordance with the modalities of the OV-HIPEC trial (grade B). In cases of postoperative tumor residue or in FIGO stage IV tumors, chemotherapy associated with bevacizumab is recommended (grade A).

[Part II drafted from the short text of the French guidelines entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa. (Systemic and intraperitoneal treatment, elderly, fertility preservation, follow-up)]. / Partie 2 rédigée à partir de la synthèse de la recommandation nationale de bonnes pratiques cliniques intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY et labélisée par l'INCa. (Traitement systémique et intrapéritonéal, personnes âgées, préservation de la fertilité et suivi).

Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A). For BRCA mutated patient, Olaparib is recommended (grade B).

[Malignant epithelial ovarian cancer: Role of intra peritoneal chemotherapy and hyperthermic intra peritoneal chemotherapy (HIPEC): Article drafted from the French Guidelines in oncology entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa]. / Tumeurs épithéliales malignes de l'ovaire : place de la chimiothérapie intrapéritonéale et de la chimiothérapie hyperthermique intrapéritonéale (CHIP). Article rédigé sur la base de la recommandation nationale de bonnes pratiques cliniques en cancérologie intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY sous l'égide du CNGOF et labellisée par l'INCa.

Intraperitoneal drug delivery in first-line treatment of advanced ovarian cancer have been widely studied. After a complete primary surgery or with residual disease<1cm, intraperitoneal chemotherapy significantly improves disease-free and overall survival (NP1), but with more local and systemic toxicities. Whenever this therapeutic option is under consideration, the ratio efficacy/toxicity must be carefully discussed. Intraperitoneal chemotherapy has to be considered after complete or optimal primary surgery in ovarian, tubal or primitive peritoneal carcinomatosis FIGO IIIC. This treatment must be performed by trained teams and after an assessment of the ratio efficacy/toxicity. In one randomized study, hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatinum at interval surgery demonstrated an improvement in recurrence free and overall survival compared to surgery alone, in patients initially not resectable and with residual tumor less than 1cm (complete or optimal surgery) (NP1). HIPEC has to be considered after a complete or optimal interval surgery (residu<10mm) in patients with ovarian, tubal or primitive carcinomatosis FIGO IIIC, initially not resectable (Grade B).

[Part I drafted from the short text of the French Guidelines entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa. (Diagnosis management, surgery, perioperative care, and pathological analysis)]. / Partie 1 rédigée sur la base de la recommandation nationale de bonnes pratiques cliniques en cancérologie intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY et labélisée par l'INCa. (Explorations diagnostiques et bilan d'extension, chirurgie, soins périopératoires et anatomopathologie).

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B).

Occupational exposure to platinum drugs during intraperitoneal chemotherapy. Biomonitoring and surface contamination.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been introduced over the last decade for the treatment of peritoneal carcinomatosis. In this procedure, heated cytotoxic drugs are administered directly into the abdominal cavity, ensuring cancer cells to be exposed while reducing systemic toxicity. More recently, pressurized intraperitoneal aerosol chemotherapy (PIPAC), where the chemotherapeutic drug is injected into the peritoneal cavity as an aerosol under pressure, has been proposed to patients in palliative situation, as a new approach. The amount of drug used is up to 10 fold lower than in HIPEC. The use of cytotoxic drugs poses an occupational risk for the operating room personnel. This study investigated the potential exposure of the medical staff by biomonitoring and surface contamination measurements, during a HIPEC procedure and a PIPAC procedure. METHOD: Wipe samples were collected from various locations in operating rooms including gloves, hands, devices and floor. Urines samples were collected from 10 volunteers of the medical staff and from a control group. The platinum analysis was performed by inductively coupled plasma mass spectrometry. RESULTS: Significant contaminations were observed on the floor, gloves, shoes and devices. However, urinary platinum was below the limit of quantification (<10 ng/L) for more than 50% of samples from the healthcare workers performing HIPEC and PIPAC. Concentrations did not differ significantly from those reported for the control group. CONCLUSION: There appears to be little risk of exposure to platinum drugs during HIPEC and PIPAC providing the adequate safety measures are implemented.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei of appendicular and extra-appendicular origin.

BACKGROUND: The prognostic value of the primary neoplasm responsible for pseudomyxoma peritonei (PMP) remains poorly studied. The aim of this study was to determine the prognosis for patients with extra-appendicular PMP (EA-PMP) treated optimally with complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: All patients treated for PMP with CCRS and HIPEC between 1994 and 2016 were selected retrospectively from a French multicentre database. Patients with EA-PMP had pathologically confirmed non-neoplastic appendices and were matched in a 1 : 4 ratio with patients treated for appendicular PMP (A-PMP), based on a propensity score. RESULTS: Some 726 patients were identified, of which 61 (EA-PMP group) were matched with 244 patients (A-PMP group). The origins of primary tumours in the EA-PMP group included the ovary (45 patients), colon (4), urachus (4), small bowel (1), pancreas (1) and unknown (6). The median peritoneal carcinomatosis index was comparable in EA-PMP and A-PMP groups (15·5 versus 18 respectively; P = 0·315). In-hospital mortality (3 versus 2·9 per cent; P = 1·000) and major morbidity 26 versus 25·0 per cent; P = 0·869) were also similar between the two groups. Median follow-up was 66·9 months. The 5-year overall survival rate was 87·8 (95 per cent c.i. 83·2 to 92·5) per cent in the A-PMP group and 87 (77 to 96) per cent in the EA-PMP group. The 5-year disease-free survival rate was 66·0 (58·7 to 73·4) per cent and 70 (53 to 83) per cent respectively. CONCLUSION: Overall and disease-free survival following treatment with CCRS and HIPEC is similar in patients with pseudomyxoma peritonei of appendicular or extra-appendicular origin.

A new internet tool to report peritoneal malignancy extent. PeRitOneal MalIgnancy Stage Evaluation (PROMISE) application.

Based on the importance of assessing the true extent of peritoneal disease, PeRitOneal MalIgnancy Stage Evaluation (PROMISE) internet application (www.e-promise.org) has been developed to facilitate tabulation and automatically calculate surgically validated peritoneal cancer index (PCI), and other surgically validated scores as Gilly score, simplified peritoneal cancer index (SPCI), Fagotti and Fagotti-modified scores. This application offers computer-assistance to produce simple, quick but precise and standardized pre, intra and postoperative reports of the extent of peritoneal metastases and may help specialized and non-specialized institutions in their current practice but also facilitate research and multicentre studies on peritoneal surface malignancies.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer.

Ovarian cancer remains the fourth leading cause of cancer death in women in France. It is all too often diagnosed at an advanced stage with peritoneal carcinomatosis (PC), but remains confined to the peritoneal cavity throughout much of its natural history. Because of cellular selection pressure over time, most tumor recurrences eventually develop resistance to systemic platinum. Options for salvage therapy include alternative systemic chemotherapies and further cytoreductive surgery (CRS), but the prognosis remains poor. Over the past two decades, a new therapeutic approach to PC has been developed that combines CRS with hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment strategy has already been shown to be effective in non-gynecologic carcinomatosis in numerous reports. There is a strong rationale for the use of HIPEC for PC of ovarian origin. On the one hand, three prospective randomized trials have demonstrated the superiority of intraperitoneal chemotherapy (without hyperthermia) in selected patients compared to systemic chemotherapy. Moreover, retrospective studies and case-control studies of HIPEC have reported encouraging survival data, especially when used to treat chemoresistant recurrence. However, HIPEC has specific morbidity and mortality; this calls for very careful selection of eligible patients by a multidisciplinary team in specialized centers. HIPEC needs to be evaluated by means of randomized trials for ovarian cancer at different developmental stages: as first line therapy, as consolidation, and for chemoresistant recurrence. Several European phase III studies are currently ongoing.

Quality of life after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy: a prospective study of 216 patients.

INTRODUCTION: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) have demonstrated promising results in the treatment of peritoneal carcinomatosis (PC). The purpose of this study was to assess the impact of this combined procedure on quality of life (QoL). MATERIALS AND METHODS: A prospective single centre study of 216 consecutive patients treated with CRS and HIPEC was conducted using the Gastro-Intestinal Quality of Life Index questionnaire (GIQLI), completed preoperatively and at 1, 3, 6 and 12 months. RESULTS: Questionnaire compliance was 81%, 90%, 89%, 89% and 74% at baseline, 1, 3, 6 and 12 months respectively. QoL was significantly decreased up to 6 months and returned to baseline at 12 months. In multivariate analysis, factors decreasing QoL were origin of PC at 3 months, presence of stoma at 6 months and length of surgery over 270 min and disease recurrence at 12 months. CONCLUSIONS: Despite morbidity associated with CRS and HIPEC, QoL returned to baseline at one year after surgery. This treatment strategy should be considered for the treatment of peritoneal carcinomatosis.

Postoperative outcomes of laparoscopic vs open cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for treatment of peritoneal surface malignancies.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered the only curative treatment for many peritoneal surface malignancies. The purpose of this study was to evaluate feasibility and safety of CRS combined with HIPEC by laparoscopy for patients with limited peritoneal disease and to compare postoperative outcomes with those for an open procedure. METHODS: Between January 2011 and November 2012, all patients with low-grade pseudomyxoma peritonei (PMP) or multicystic mesothelioma (MM) and limited peritoneal disease (Peritoneal Cancer Index [PCI] less than 10) underwent CRS and HIPEC by a laparoscopic approach. The study cohort was matched with a historical cohort of patients with the same characteristics (completeness of cytoreduction, HIPEC agent, PCI ± 11 and age ± 20 years) treated with CRS and HIPEC by laparotomy. RESULTS: Eight patients (five low-grade PMP and three MM) treated by a laparoscopic approach were compared to eight patients treated by laparotomy. All patients underwent complete cytoreductive surgery with HIPEC, and no conversion to laparotomy was needed. The median surgical length was 210 min (150-300) vs 240 (210-360), with a median hospital stay of 12 days (9-18) vs 19 (13-33). One patient had a postoperative complication (intraperitoneal haematoma treated by radiological drainage) vs four in the laparotomy group. CONCLUSION: Laparoscopic CRS combined with HIPEC is feasible and safe for curative treatment of strictly selected patients with peritoneal surface malignancy and might reduce postoperative complications and length of hospital stay.

Intraperitoneal vascular endothelial growth factor burden in peritoneal surface malignancies treated with curative intent: the first step before intraperitoneal anti-vascular endothelial growth factor treatment?

INTRODUCTION: Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors in solid tumours and plays an important role in ascites development in peritoneal surface malignancies (PSM). The main goal of this study was to determine the evolution and factors influencing intraperitoneal (IP) VEGF burden during cytoreductive surgery (CRS) with curative intent. PATIENTS AND METHODS: Ninety-seven consecutive patients with PSM were treated with CRS at a single centre with curative intent. Patient data were collected prospectively between February 2012 and October 2012. An enzyme-linked immunosorbent assay technique was used to assess VEGF levels in intravenous (IV) systemic blood samples before incision and after abdominal closure, and in IP samples during abdominal cavity exploration, after completion of CRS, after hyperthermic IP chemotherapy, and at 1 and 24h after abdominal closure. RESULTS: The IP VEGF burden increased significantly after CRS, and then decreased progressively (p<0.005). In multivariate analysis, neoadjuvant IV bevacizumab significantly decreased the preoperative IP VEGF burden, tumour load according to Peritoneal Cancer Index value increased significantly the preoperative IP VEGF burden and a low preoperative IP VEGF burden was associated with significantly increased postoperative complications. Neoadjuvant IV bevacizumab is the only factor that influences the preoperative IV VEGF concentration. CONCLUSION: For patients with PSM who were treated with curative intent, the IP VEGF burden increased after CRS, and was reduced prior to surgery by the administration of neoadjuvant IV bevacizumab.