• colorectal cancer
• hyperthermic intraperitoneal chemotherapy (HIPEC)
• peritoneal metastasis model

• HIPEC ((hyperthermic intraperitoneal chemotherapy)
• Hyperthermia
• anti-tumor immunity
• cancer stem-like cells
• macrophage
• ovarian cancer

Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Small animal models are valuable research tools allowing for rapid, reproducible, and inexpensive study and optimization of different forms of IPC. Here, we present a mouse model of ovarian cancer-derived PM and demonstrate its suitability for various modes of IPC, including pressurized intraperitoneal chemotherapy (PIPAC) using a micro-nozzle for aerosolized drug delivery.

Intraperitoneal chemotherapy (IPC) is a locoregional treatment option in patients with peritoneal metastases (PM). Here, we present an ovarian cancer (OC)-derived PM mouse model for the study of different forms of IPC. Xenograft cell proliferation (luciferase-transfected OVCAR3 and SKOV3 clones) and growth kinetics were assessed using PET scan, bioluminescence imaging (BLI), and histological tumor analysis. Liquid IPC was achieved by intraperitoneal injection with/without capnoperitoneum (6–7 mmHg). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was mimicked using an intratracheal drug aerosol administration system (micro-nozzle), which, as demonstrated by ex vivo granulometric analysis using laser diffraction spectrometry, produced a polydisperse, bimodal aerosol with a volume-weighted median diameter of (26.49 ± 2.76) µm. Distribution of Tc-99m-labeled doxorubicin in mice was characterized using SPECT and was dependent on the delivery mode and most homogeneous when the micro-nozzle was used. A total of 2 mg doxorubicin per kg body weight was determined to be the optimally effective and tolerable dose to achieve at least 50% tumor reduction. Repeated PIPAC (four times at seven-day-intervals) with doxorubicin in SKOV3-luc tumor-bearing mice resulted in halted tumor proliferation and tumor load reduced after the second round of PIPAC versus controls and the number of tumor nodules was significantly reduced (27.7 ± 9.5 vs. 57.3 ± 9.5; p = 0.0003). Thus, we established the first mouse model of OC PM for the study of IPC using a human xenograft with SKOV3 cells and an experimental IPC setup with a miniaturized nozzle. Repeated IPC was feasible and demonstrated time-dependent anti-tumor activity.

• aerosol
• chemotherapy
• intraperitoneal
• metastasis
• mouse model
• ovarian cancer
• peritoneal
• pressurized

• cisplatin
• fibrin
• intracavitary
• malignant pleural mesothelioma
• phase I study

We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer.

From October 2015 to May 2018, 65 patients with stages IIIC–IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m²) for 90 minutes, only in cases of optimal cytoreduction.

Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0–915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC.

According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits.

• Drug Therapy
• Hyperthermic Intraperitoneal Chemotherapy
• Ovarian Neoplasms
• Paclitaxel
• Surgery

Establishing a feasible intraperitoneal (i.p.) xenograft model in nude mice is a good strategy to evaluate the antitumor effect of drugs in vivo. However, the manipulation of human cancer cells in establishing a stable peritoneal carcinomatosis model in nude mice is problematic. In the present study, the ovarian and colorectal peritoneal tumor models were successfully established in nude mice by co-injection of human tumor cells and extracellular matrix gel. In ovarian tumor models, the mean number tumor nodes was significantly higher in the experimental group (intraperitoneal tumor cell co-injection with ECM gel) compared with the PBS control group on the 30th day (21.0±3.0 vs. 3.6±2.5; P<0.05). The same results were observed in the colorectal peritoneal tumor models on the 28th day. The colorectal peritoneal tumor model was further used to evaluate the chemotherapy effect of irinotecan (CPT-11). The mean weight of peritoneal tumor nodes in CPT-11 treatment group was significantly less than that of the control group (0.81±0.16 vs. 2.18±0.21 g; P<0.05). The results confirmed the value of these i.p. xenograft models in nude mice as efficient and feasible tools for preclinical evaluation.

• extracellular matrix gel
• intraperitoneal xenograft model
• irinotecan
• tumor

• Peritoneal carcinomatosis
• cytoreductive surgery
• hipec

• Colorectal cancer
• Gastric cancer
• Intraperitoneal chemotherapy
• Peritoneal carcinomatosis
• Pharmacokinetics

AIM: To reduce postoperative complications and to make possible an optimal cytoreduction, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery has been applied with encouraging results.

METHODS: Between December 2009 and February 2012, patients with stage IIIC-IV epithelial ovarian cancer (EOC) underwent diagnostic laparoscopy, to assess the feasibility of optimal debulking surgery. The modified Fagotti score was applied to assess the feasibility of resection with zero residual tumor. Patients who were not candidate for upfront debulking surgery were submitted to NACT, then reassessed according to the RECIST 1.1 criteria and submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) if they showed clinical response or stable disease. The remaining cycles of adjuvant systemic chemotherapy (ASCT) were administered postoperatively, to complete 6 cycles of systemic chemotherapy.

RESULTS: Nine patients were included. Clinical response to NACT was complete in 3 patients and partial in 5 patients; one patient had stable disease. All patients underwent CRS resulting in CC0 disease prior to HIPEC. Average operative time was 510 min. Average intensive care unit stay was 2 d. Average postoperative hospital stay was 25 d. No postoperative mortality was observed. One patient experienced pelvic abscess. One patient refused ASCT. The remaining 8 patients started ASCT. Average time to chemotherapy was 36 d. All patients are alive, with an average follow up of 11 mo. Eight patients are disease-free at follow up.

CONCLUSION: HIPEC after CRS for advanced EOC is feasible with acceptable morbidity and mortality. NACT may increase the chance for achieving complete cytoreduction. Phase 3 studies are needed to determine the effects of HIPEC on survival.

• Peritoneal carcinomatosis
• Ovarian cancer
• Cytoreductive surgery
• Intraperitoneal chemotherapy
• Hyperthermic intraperitoneal chemotherapy
• Hyperthermia

Epithelial ovarian cancer (EOC) represents approximately 90% of primary malignant ovarian tumors, the sixth most common cancer in women and the second most common gynecologic cancer. Approximately 80%-85% of all ovarian carcinomas in Western society are serous and up to 95% of patients are in advanced stages (FIGO stage III-IV) at diagnosis. Treatment of ovarian cancer is mainly based on three key approaches: surgical removal of neoplasia; chemotherapy to kill cancer cells; direct chemotherapy on peritoneal surfaces. The application of hyperthermic chemotherapy to the peritoneal cavity (HIPEC) after radical surgery may also be an attractive option. We analyzed the natural history of EOC in the literature and identified various time-points where sensitivity to chemotherapy, freedom from disease and overall survival are different. We propose eight time-points in EOC history with homogeneous oncological findings. The effectiveness of HIPEC in EOC treatment should be evaluated based on these eight time-points and we believe that retrospective and prospective studies of HIPEC should be evaluated according to these time-points.

• Ovarian cancer
• Hyperthermic intraperitoneal chemotherapy
• Chemo-sensitivity
• Time-points
• Survival

Ovarian cancer has as its predominant pattern of dissemination metastases to the peritoneal surfaces and disease spread within the abdomen and pelvis that most commonly causes the patients demise. To combat peritoneal metastases, cytoreductive surgery with peritoneal and visceral resections is combined with intraperitoneal and systemic chemotherapy. Chemotherapy given in the operating room after the complete visible removal of ovarian cancer is hyperthermic intraperitoneal chemotherapy. The results of the combined treatment are determined by the extent of prior surgery, the extent of disease as established by the peritoneal cancer index, and the quality of the cytoreduction as measured by the completeness of cytoreduction score. Recent clinical information on patients with recurrent ovarian cancer suggest a median overall survival of up to 60 mo. These data are greatly improved over the one year survival observed in the past.

• Peritoneal metastases
• Carcinomatosis
• Cytoreductive surgery
• Hyperthermic intraperitoneal chemotherapy
• Intraperitoneal chemotherapy
• Cisplatin
• Doxorubicin
• Ifosfamide
• Mitomycin C
• Intraperitoneal port

• Advanced
• Cancer
• Carcinosis
• Colorectal
• Cytoreductive surgery
• Gastric
• Hipec
• Intraperitoneal chemotherapy
• Ovarian
• Peritoneal

• Carcinoma/mortality
• Carcinoma/secondary
• Carcinoma/therapy
• Female
• Gastrointestinal Neoplasms/mortality
• Gastrointestinal Neoplasms/pathology
• Gastrointestinal Neoplasms/therapy
• Genital Neoplasms, Female/mortality
• Genital Neoplasms, Female/pathology
• Genital Neoplasms, Female/therapy
• Humans
• Male
• Peritoneal Neoplasms/mortality
• Peritoneal Neoplasms/secondary
• Peritoneal Neoplasms/therapy
• Treatment Outcome

• Cytoreductive surgery
• HIPEC
• Morbidity
• Ovarian cancer

• cytoreductive surgery
• hyperthermic
• intraoperative
• intraperitoneal chemotherapy
• ovarian carcinoma

Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis.

Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM.

Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity.

This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

• Antineoplastic Agents/administration & dosage
• Carcinoma, Ovarian Epithelial
• Combined Modality Therapy
• Female
• Humans
• Hyperthermia, Induced
• Infusions, Parenteral
• Neoplasms, Glandular and Epithelial/surgery
• Ovarian Neoplasms/surgery
• Standard of Care

• Antineoplastic Agents/administration & dosage
• Carcinoma/epidemiology
• Carcinoma/mortality
• Carcinoma/secondary
• Carcinoma/therapy
• Combined Modality Therapy
• Female
• Humans
• Hyperthermia, Induced/methods
• Infusions, Parenteral
• Intraoperative Care/methods
• Ovarian Neoplasms/mortality
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/therapy
• Ovariectomy/methods
• Peritoneal Neoplasms/epidemiology
• Peritoneal Neoplasms/mortality
• Peritoneal Neoplasms/secondary
• Peritoneal Neoplasms/therapy
• Postoperative Complications/epidemiology
• Postoperative Complications/mortality
• Treatment Outcome