Normothermic Intraperitoneal Chemotherapy Research Articles

Effect of postoperative normothermic intraperitoneal chemotherapy on the prognosis of MPM patients receiving CRS+HIPEC: A single-center case-control study

BackgroundThe comprehensive treatment strategy, mainly cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), combined with systemic and intraperitoneal chemotherapy, is the standard treatment for malignant peritoneal mesothelioma (MPM), which can significantly prolong the survival of patients. The aim of this study is to investigate the clinical significance of postoperative normothermic intraperitoneal chemotherapy (NIPEC) in MPM patients. MethodsData of 152 MPM patients who underwent CRS + HIPEC and postoperative intravenous chemotherapy were retrospectively analyzed. Patients were divided into the Non-NIPEC group and the NIPEC group according to whether they received NIPEC after surgery. The baseline characteristics of the two groups were compared, and the survival outcome was analyzed in subgroups according to completeness of cytoreduction (CC) score. Multivariate survival analysis was used to determine the independent prognostic factors. ResultsIn CC 0–1 and CC 2–3 subgroups, there was no significant difference in baseline characteristics between Non-NIPEC and NIPEC groups. Survival analysis showed that for CC 0–1 patients, there was no significant difference in overall survival (OS) between Non-NIPEC and NIPEC groups (P = 0.503). However, for CC 2–3 patients, the median OS of the NIPEC group was significantly longer than that of the Non-NIPEC group (24.5 vs. 10.3 months, P = 0.005). Pathological type, preoperative thrombosis and postoperative NIPEC (HR = 0.423, 95%CI: 0.228–0.786, P = 0.006) were independent prognostic factors for CC 2–3 patients. ConclusionsFor MPM patients receiving CRS + HIPEC, postoperative intraperitoneal combined with intravenous chemotherapy may improve the survival of CC 2–3 patients, but CC 0–1 patients do not seem to derive the same benefit.

Long-term intraperitoneal access with description of a new access catheter.

Intraperitoneal chemotherapy can be administered as a single dose associated with hyperthermia (HIPEC) or in successive doses under normothermic conditions, such as early postoperative intraperitoneal chemotherapy (EPIC) or normothermic intraperitoneal chemotherapy (NIPEC or NIPEC-LT). Repetitive administration of intraperitoneal chemotherapy over a prolonged period may be associated with catheter-related complications, which are the primary cause of treatment interruption. This study aims to introduce and evaluate an innovative catheter system designed to mitigate these issues. Using a porcine experimental model, we tested a new catheter for long-term intraperitoneal access. Sixteen animals underwent catheter implantation followed by normothermic recirculation of peritoneal dialysis solution. Catheter functionality and any complications were monitored throughout successive treatment cycles. The new catheter system demonstrated optimal recirculation and maintained its functionality throughout successive treatments, without complications. Catheter replacement with a guidewire was successful, ensuring continued efficacy. The innovative catheter system shows promise in reducing complications and improving compliance in successive intraperitoneal chemotherapy doses, justifying further clinical trials to confirm its efficacy in patients.

Intraperitoneal chemotherapy for colorectal cancer peritoneal metastasis

Peritoneal metastasis is one of the common site of colorectal cancer metastasis and associated with a poor prognosis. The core strategy for colorectal cancer peritoneal metastasis primarily revolves around a comprehensive treatment approach with cytoreductive surgery and systemic chemotherapy as the mainstay, supplemented by intraperitoneal chemotherapy. As an important supplement to treatment, intraperitoneal chemotherapy has broad application prospects. The main modalities are hyperthermic intraperitoneal chemotherapy (HIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), early postoperative intraperitoneal chemotherapy (EPIC), sequential postoperative intraperitoneal chemotherapy (SPIC), normothermic intraperitoneal chemotherapy (NIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). To promote the standardized application of intraperitoneal chemotherapy, further research on the mechanisms underlying peritoneal metastasis of colorectal cancer, selection of effective intraperitoneal chemotherapy agents, determination of optimal timing and administration protocols, exploration of the feasibility of sequential intraperitoneal chemotherapy and conduction of valuable basic and clinical research are currently needed. This paper will review the development and origins of intraperitoneal chemotherapy, treatment modalities, as well as the current application status and prospects of various treatment approaches in the context of peritoneal metastasis of colorectal cancer.

Intraoperative Normothermic Intraperitoneal Chemotherapy Following Optimal Cytoreduction in Advanced Ca Ovary: A Feasibility Study

Introduction: Extrapolating the results from the studies using HIPEC, EPIC and normothermic intraperitoneal chemotherapy, we proposed that normothermic chemotherapy instilled after optimal cytoreduction will improve survival in patients who underwent optimal cytoreduction. We undertook this feasibility study with the aim of studying the effectiveness of intraoperative normothermic intraperitoneal chemotherapy in patients with advanced-stage epithelial carcinoma ovary. Methods: This was a single institutional feasibility study. The primary objective was progression-free survival (PFS) following the instillation of normothermic chemotherapy following optimal cytoreduction in cases of advanced ovarian cancer after neoadjuvant chemotherapy. The secondary objective was to study tolerability and toxicity. The study received institutional ethical committee clearance. Results: A total of 24 patients were included in the pilot study over two years. The short-term analysis was made by comparing 45 patients who underwent interval cytoreductive surgery (ICS) with CC 0 and 1 during the same period. The most common side effect was prolonged post-operative ileus which was seen in six patients. The median PFS among patients who received IP chemotherapy was significantly better in comparison to patients who received ICS alone (34.0 vs. 13.0 months, p=0.018). Conclusion: Uniform state-of-the-art management of advanced epithelial ovarian cancer may not be accessible to all due to global resource limitations. Although the evidence is weak due to the small sample size and short follow-up of patients, the findings are encouraging. This feasibility study has provided substantial evidence to work further with this approach in our institute and plan an randomised controlled trial to gain more evidence.

Investigation of the effectiveness of hyperthermic intraperitoneal chemotherapy in experimental colorectal peritoneal metastasis model.

In our study, we aimed to (1) create a peritoneal metastasis (PM) model in nude mice, administer intraperitoneal chemotherapy using the peritoneal infusion pump we developed in this model, and (2) compare the efficacy of intraperitoneal chemotherapy using various drugs at different temperatures. The peritoneal metastasis model was established in nude mice using the CC531 colon carcinoma cell line. Models with peritoneal metastasis (PM) were randomized into four groups of seven animals each: Group 1, control group (n=7); Group 2, normothermic intraperitoneal chemotherapy (NIPEC) with mitomycin C(MMC) (n=7); Group 3, hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (n=7), and Group 4, NIPEC with 5-fluorouracil (5-FU). Tumor development was achieved in all animals. While the tumor burden decreased significantly in the treatment Group 3 (p=0.034), no significant difference was found in the other groups. In the PM mouse model, hyperthermic intraperitoneal administration of MMC had the highest tumoricidal effect. Our PM model provided a good opportunity to examine the efficacy of HIPEC and intraperitoneal infusion pump (IPIP). In future studies, we plan to evaluate efficacies of different drugs in the PM models we have created.

Phase II clinical trial of sequential treatment with systemic chemotherapy and intraperitoneal paclitaxel for gastric and gastroesophageal junction peritoneal carcinomatosis - STOPGAP trial

BackgroundStudies from Asia indicate that normothermic intraperitoneal chemotherapy (NIPEC) may confer survival benefit in patients with gastric peritoneal carcinomatosis (PC). However, data regarding this approach is lacking in western population. The current STOPGAP trial is intended to assess 1-year progression-free survival benefit of sequential systemic chemotherapy and paclitaxel NIPEC in patients with gastric/ gastroesophageal junction (GEJ) adenocarcinoma PC.MethodsThis is a prospective, single center, single arm, phase II investigator-initiated clinical trial. Patients with histologically proven gastric/GEJ (Siewert 3) adenocarcinoma with positive peritoneal cytology or PC will be eligible to participate after three months of standard of care systemic chemotherapy and with no evidence of visceral metastasis on restaging scans. The primary treatment is iterative paclitaxel NIPEC with systemic paclitaxel and 5-fluorouracil, which will be administered on days1 and 8 and repeated every three weeks for 4 cycles. Patients will undergo diagnostic laparoscopy both before and after NIPEC to assess peritoneal cancer index (PCI). Patients with PCI less than or equal to 10 in whom complete cytoreduction (CRS) is feasible may opt to undergo CRS with heated intraperitoneal chemotherapy (HIPEC). The primary endpoint is 1-year progression free survival and secondary endpoints are overall survival and patient reported quality of life outcomes measured by EuroQol- 5 dimensions-5 level (EuroQol-5D-5L) questionnaire.DiscussionIf the sequential approach of systemic chemotherapy followed by paclitaxel NIPEC proves beneficial, then this approach could be used in larger, muti-institutional randomized clinical trial of gastric PC.Trial RegistrationThe trial was registered on 21/02/2021, under clinical trials.gov; Identifier: NCT04762953.

Diagnostic and Therapeutic Pathway in Diffuse Malignant Peritoneal Mesothelioma.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare form of mesothelioma that carries a very poor prognosis. The 5-year overall survival is about 20% (±5.9). Survival is optimal for patients suitable for cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), with a median OS ranging from 34 to 92 months. However, selecting patients for surgery remains a complex task and requires a careful preoperative workup, rational analysis of prognostic profiles, and risk prediction models. Systemic chemotherapy could be offered: (1) in the adjuvant setting for high-risk patients; (2) for patients not eligible for CRS; and (3) for those with recurrent disease. It mainly includes the combination of Platin compound with Pemetrexed or immunotherapy. The biology of DMPM is still largely unknown. However, progress has been made on some fronts, such as telomere maintenance mechanisms, deregulation of apoptosis, tyrosine kinase pathways, and mutation of BRCA1-associated protein 1 (BAP1). Future perspectives should include translational research to improve our understanding of the disease biology to identify druggable targets. We should also clear the role of immune checkpoint inhibitors and investigate new locoregional technologies, such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) or normothermic intraperitoneal chemotherapy (NIPEC).

Optimizing regional chemotherapy for epithelial ovarian cancer.

The response with intravenous chemotherapy using cisplatin and paclitaxel in patients with advanced ovarian cancer is often substantial. However, this regression of the malignancy is not durable, and a majority of patients succumb to this disease process. It is possible that alternative types of chemotherapy and alternative routes of chemotherapy administration can improve the results of treatment and perhaps, reduce the morbidity and mortality that patients experience. Regional chemotherapy treatments previously presented in the ovarian cancer literature were reviewed and critically analyzed. New methods for chemotherapy delivery for both advanced primary and recurrent ovarian cancer were reviewed. This included hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and normothermic intraperitoneal chemotherapy (NIPEC) long-term. An important addition to perioperative chemotherapy delivery is the simultaneous use of heat with intraperitoneal drug delivery after a complete cytoreductive surgery. Drugs to be considered for HIPEC are cisplatin, gemcitabine, and melphalan. For EPIC, chemotherapy agents to consider include paclitaxel, pemetrexed, gemcitabine, and liposomal doxorubicin. For NIPEC, paclitaxel is the drug of choice usually combined with a systemic agent as bidirectional chemotherapy. Also, pemetrexed, gemcitabine, and liposomal doxorubicin are drugs to be considered for NIPEC in phase I/II trials. Innovative regimens of regional chemotherapy may improve the outcome of patients with advanced ovarian cancer. These chemotherapy treatments must be integrated with complete cytoreductive surgery and the availability of peritoneal access for repeated delivery of chemotherapy solutions.

Review of Regional Therapies for Gastric Cancer with Peritoneal Metastases.

Simple SummaryGastric cancer is usually diagnosed at late stages and is associated with poor five-year survival rates. Metastasis to the peritoneal cavity is common and leads to even worse outcomes. Currently, the mainstay of treatment for metastatic gastric cancer is systemic chemotherapy or supportive care. These recommendations remain despite evidence that suggests systemic therapy has poor penetration into the abdominal cavity, limiting efficacy against peritoneal disease. Newer treatments have been developed to address this problem, specifically regional therapies aimed at delivering chemotherapy directly into the peritoneal cavity to eradicate tumor cells. These novel therapies include hyperthermic intraperitoneal chemotherapy, normothermic intraperitoneal chemotherapy, and pressurized intraperitoneal aerosolized chemotherapy. Regional therapies may also be combined with surgery to remove both macroscopic and microscopic disease. Although more clinical trials are needed to evaluate its efficacy, early studies have shown promising outcomes with intraperitoneal chemotherapy.Gastric cancer carries a poor prognosis and is a leading cause of cancer-related mortality worldwide. Patients with gastric cancer who develop peritoneal metastases have an even more dismal prognosis, with median survival time measured in months. Since studies have demonstrated that systemic chemotherapy has poor penetration into the peritoneum, multimodal treatment with intraperitoneal chemotherapy has been proposed for the treatment of peritoneal metastases and has become the foundation for newer therapeutic techniques and clinical trials. These include heated intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS), which involves the application of heated chemotherapy into the abdomen with or without tumor debulking surgery; normothermic intraperitoneal chemotherapy (NIPEC), in which non-heated chemotherapy can be delivered into the abdomen via a peritoneal port allowing for repeat dosing; and pressurized intraperitoneal aerosolized chemotherapy (PIPAC), a newer technique of pressurized and aerosolized chemotherapy delivered into the abdomen during laparoscopy. Early results with intraperitoneal chemotherapy have shown promise in increasing disease-free and overall survival in select patients. Additionally, there may be a palliative effect of these regional therapies. In this review, we explore and summarize these different intraperitoneal chemotherapy treatment regimens for gastric cancer with peritoneal metastases.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Advanced Serous Epithelial Ovarian Cancer: A 14-Year French Retrospective Single-Center Study of 124 Patients.

Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases. A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed. From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%. CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates.

Safety and tolerability of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in ovarian cancer: clinical results from a phase I trial

Objectives: To demonstrate safety and tolerability of HIPEC in ovarian cancer. Methods: A phase I, single-institution feasibility study was designed to evaluate the safety and feasibility of HIPEC at time of optimal cytoreductive surgery (CRS) in ovarian cancer patients, followed by optional normothermic intraperitoneal chemotherapy, at City of Hope National Comprehensive Cancer Center (Duarte, CA). Primary endpoint of the trial was to evaluate the safety and feasibility of HIPEC at time of optimal cytoreductive surgery (CRS). Progression-free survival was a secondary end-point. Exploratory endpoints included the assessment of molecular markers in tumors. Eligibility criteria included epithelial ovarian cancer (stage III or IV), primary or recurrent, ECOG 0-1, and appropriate surgical candidates. 35 patients were enrolled between 2015 and 2019, who underwent optimal CRS (gross residual disease less than 1 cm), and received HIPEC intra-operatively with cisplatin at 75 mg/m2 for 60 minutes immediately following optimal CRS. Patients were stratified as either 1) primary disease (n=19), defined as having received HIPEC at time of interval CRS following neoadjuvant chemotherapy for primary EOC; 2) recurrent disease (n=16), defined as having received HIPEC at time of interval or upfront CRS for recurrent (salvage) EOC. Adjuvant chemotherapy was given at the discretion of the treating oncologist following HIPEC. Results: Median age was 58 years (36-74 years), with a mean BMI of 26. Primary (interval) patients represented 54% of patients, with pretreatment clinical stages III (53%) and IV (47%). Recurrent (salvage) patients represented 45.7%, with platinum-sensitive (75%) and platinum-resistant (25%). The most common histological subtype was high grade serous (69%). All primary (interval) patients underwent neoadjuvant chemotherapy (3-4 cycles) prior to interval CRS and HIPEC. The majority of recurrent patients (81%) did not receive neo-adjuvant chemotherapy. Thirty-three patients underwent closed technique and two underwent laparoscopic technique. Total mean operating time was 8.4 hours (4.6-15.3). Mean length of stay was 10 days (3-30). All patients underwent optimal cytoreduction (69% with complete R0 resection). Peritoneal carcinomatosis index (PCI) ranged 2 to 30 (median of 8). Patients with PCI /= 8 whose PFS was 12.6 (p=0.04). Time to initiation of adjuvant chemotherapy in recurrent patients was 8.4 weeks. 22.9% of the ovarian cancer cohort was gBRCA mutated. Median PFS for primary patients was 12.6 months (95% CI 6.4; NR); with median follow up of 22.1 months (95% CI 12.6, 31.5). Median PFS for recurrent patients was 18.8 months (95% CI 7.2; 28.7), with median follow up of 36.3 months (95% CI 21.1, 51.5). There were no grade 4 or 5 AEs. Anemia was the most common Grade 3 AE (43%), followed by liver dysfunction and electrolyte abnormalities. The most common AE of any grades were abdominal pain (86%), anemia (77%), and nausea (66%). Two patients (6%) had grade 3 acute kidney injury and one patient had grade 3 chronic kidney disease. Sodium thiosulfate was introduced to the trial in January 2018, following which there were no grade 1-4 acute or chronic kidney injuries. Download : Download high-res image (61KB) Download : Download full-size image Conclusions: HIPEC in ovarian cancer was well tolerated, without any grade 4 or 5 AEs. Renal toxicities were mitigated with sodium thiosulfate. Patients with a low PCI ( /= 8.

Cytoreductive Surgery Plus HIPEC With and Without NIPEC for Malignant Peritoneal Mesothelioma: A Propensity-Matched Analysis.

Malignant peritoneal mesothelioma is a rare and often fatal disease. Dissemination is confined to the abdominal and pelvic peritoneal spaces in a great majority of patients. Standardized cytoreductive surgery and perioperative chemotherapy was used in all patients. Long-term normothermic intraperitoneal chemotherapy (NIPEC) was added to the treatment of our most recent group of patients. Survival with and without NIPEC was compared using a propensity-matched analysis. In a uniform group of 74 patients, the clinical- and treatment-related features that had an impact on survival were age (hazard ratio [HR] 1.99, 95% confidence interval [CI] 0.929-4.238, p=0.0766), completeness of cytoreduction (HR 2.356, 95% CI 1.113-4.989, p=0.0251), and treatments administered (HR 3.497, 95% CI 1.199-10.20, p=0.0219). In the Cox proportional hazards multivariant model, sex and age were borderline significant. Treatments administered were significant (HR 3.549, 95% CI 1.157-10.888, p=0.0268). Using five features to match 29 patients in the control group (no NIPEC) to 29 patients in the experimental group (with NIPEC), the propensity-matched survival was significantly different (p=0.0263). The addition of NIPEC was associated with long-term survival in this cohort of patients. A multi-institutional randomized trial may be the next step.

Intraperitoneal gemcitabine chemotherapy is safe for patients with resected pancreatic cancer: final clinical and pharmacologic data from a phase II protocol and recommended future directions.

Worldwide, the surgical management of pancreas cancer using the Whipple procedure results in long-term survival in approximately 20% of patients when there is a R0 resection. Local recurrence within the resection site and peritoneal metastases are a prominent part of this treatment failure. Gemcitabine was used for a regional chemotherapy treatment strategy. Doses and schedules of chemotherapy routinely used for systemic treatment were administered as hyperthermic intraperitoneal chemotherapy (HIPEC) in the operating room. Then patients went on to receive 6 months of long-term normothermic intraperitoneal chemotherapy (NIPEC) with gemcitabine. Data was gathered to determine a pharmacologic rationale and safety of this monotherapy with gemcitabine. The use of intraperitoneal gemcitabine was well supported by pharmacologic data. The peritoneal surface exposure as measured by pharmacokinetic studies showed the area under the curve (AUC) of intraperitoneal concentration times time divided by plasma concentration times time to be 95-507. Regarding the safety of HIPEC gemcitabine in 12 patients, a single class III adverse event that resolved by radiologic intervention occurred. In patients with resected pancreas cancer treated with HIPEC gemcitabine the morbidity and mortality rate was not increased over historical data of resection alone. Also, six cycles of NIPEC gemcitabine were well tolerated in eight of eight eligible patients with seven patients completing 6 months of long-term intraperitoneal treatment. Local recurrence and peritoneal metastases were absent. Median survival was 29 months and five patients survived longer than 2 years. These early data suggest that intraperitoneal gemcitabine given under hyperthermic conditions in the operating theater and long-term through an intraperitoneal port is safe. Also, in this pilot study long-term local control with intraperitoneal gemcitabine occurred. Intraperitoneal gemcitabine may improve local-regional control of resected pancreas cancer. This may lead to more successful multimodality strategies.

Key points of perioperative whole-process management for patients with advanced gastric cancer

Perioperative whole-process management (WPM) for patients with advanced gastric cancer (AGC) mainly focuses on some clinical issues which are easily neglected or underappreciated. WPM is helpful in making a scientific and rational therapeutic plan, and avoiding inadequate communication in multi-disciplinary participation, so that the diagnosis, treatment and rehabilitation for AGC patients can be integrated organically. Based on the current clinical practice for AGC patients, eight key issues in WPM should be emphasized.(1) Preoperative clinical staging. An accurate preoperative staging by endoscopy and imaging technique is helpful in setting up a rational therapeutic plan, and is also a prerequisite to start WPM. (2) Indications and value of diagnostic laparoscopy. Laparoscopic exploration is beneficial to find intraperitoneal micro-metastases so as to avoid unnecessary laparotomy. For cases of AGC infiltrating serosal layer or suspected of peritoneal metastasis, preoperative laparoscopic exploration should be routinely performed. (3) Neoadjuvant therapy. Multiple RCT studies have shown that neoadjuvant chemotherapy can benefit a majority of patients with AGC, improving prognosis and prolonging their overall survival. Therefore, neoadjuvant therapy should be considered first for stage III and IVA AGC patients. (4) Prediction of efficacy in neoadjuvant chemotherapy. Endoscopy, MDCT scan, PET-CT and liquid biopsy have certain predictive value individually, which can be used together or separately to improve the accuracy of prediction. (5) Effective prevention of postoperative peritoneal metastasis. Extensive intraoperative peritoneal lavage (EIPL), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and normothermic intraperitoneal chemotherapy (NIPEC) have been shown to be of various efficacy in preventing peritoneal metastases. (6) Prediction of postoperative prognosis of AGC patients. The key pathological indicators are tumor regression grade (TRG) and ypTNM staging, especially if there is lymph node metastasis. Usually for AGC patients who received neoajuvant chemotherapy with TRG 0 or ypN0, their prognosis was comparable to that of patients with cTNM stage I.(7) Postoperative adjuvant chemotherapy. Postoperative adjuvant therapy is always an important part of the WPM management of AGC patients. Several recent RCT studies have shown that duplet chemotherapy can significantly reduce the risk of death after D2 radical gastrectomy compared to singlet chemotherapy, especially for stage III patients. (8) Perioperative nutritional support. Due to different degrees of malnutrition in AGC patients, enhanced nutritional treatment in the perioperative period can not only reduce surgical complications, but also enable patients to complete necessary course of chemotherapy, and ultimately further improve their survival rate.

Unusually favorable outcome of 6 consecutive patients with diffuse malignant peritoneal mesothelioma treated with repeated doses of intraperitoneal paclitaxel. A case series

BackgroundDiffuse malignant peritoneal mesothelioma (DMPM) is a disease in transition. Two decades ago this cancer had a median survival of 1 year. Recent reports in selected patients show a 5-year survival of 70% and median survival not reached at 10 years. MethodsConsecutive patients with a biopsy-confirmed diagnosis of DMPM, epithelial type, were treated by a consistent treatment plan. Cytoreductive surgery using peritonectomy procedures was always the first intervention. In the operating theater after all resections were complete but prior to intestinal reconstruction, hyperthermic intraperitoneal chemotherapy (HIPEC) using 2 cytotoxic agents was given. An intraperitoneal port was placed for normothermic intraperitoneal chemotherapy (NIPEC). Prospective data regarding pharmacokinetics, survival and adverse events were accumulated. ResultsSix consecutive patients were treated. Three to 6 one-week long cycles of normothermic intraperitoneal paclitaxel were administered through an intraperitoneal port. No systemic chemotherapy was given. Pharmacokinetic studies were performed on 5 patients. Four patients are free of disease at 8, 13, 18, and 19 years and two patients died of disease 15 years after definitive treatment. Three of 6 patients had a grade III/IV adverse event related to intraperitoneal chemotherapy administration through a port. ConclusionsThe small number of patients treated with repeated doses of intraperitoneal paclitaxel cause these data to be interpreted with caution. However, the long-term benefit and favorable pharmacology of these patients suggests the need for further study. Adverse events from this intraperitoneal port were recorded in half of the patients.

Update on the management of malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPM) is a rare disease whose natural history is confined to the peritoneal space. Systemic chemotherapy has little impact on survival of patients with MPM. A surgical procedure with a goal of resection of all visible evidence of disease, called cytoreductive surgery (CRS) has been utilized in MPM patients. Also, regional chemotherapy with hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic intraperitoneal chemotherapy long-term (NIPEC-LT) have been effectively utilized in MPM patients. In the absence of CRS and HIPEC the median survival of MPM patients is approximately 1 year. The aggressive surgical approach plus regional chemotherapy has increased the median survival to more than 5 years. With NIPEC-LT added on, 70% 5-year survival has been reported. Knowledgeable patient selection for treatment is mandatory. The use of CRS, HIPEC and NIPEC-LT has greatly benefited patients with MPM. Global application of these treatments is indicated.

Normothermic intraperitoneal chemotherapy long term (NIPEC-LT) in the management of peritoneal surface malignancy, an overview.

Peritoneal metastases from gynecologic and gastrointestinal cancer is of increasing interest to surgical and medical oncologists because of newly recognized benefits of treatment. In contrast to prior outcomes, prolonged disease-free survival and cure have been reported. To date, the benefits are to use complete surgical removal of the peritoneal metastases combined with hyperthermic intraperitoneal chemotherapy (HIPEC) delivered in the operating room. To supplement the local-regional control, normothermic intraperitoneal chemotherapy used long term (NIPEC-LT) and delivered by an intraperitoneal port has been explored. In three high grade malignancies with the preponderance of cytoreductive surgery (CRS) and HIPEC treatment failures within the peritoneal space, NIPEC-LT has been favorably reported in the oncology literature. In ovarian cancer and malignant peritoneal mesothelioma the NIPEC-LT is used an adjuvant treatment in an attempt to preserve a surgical complete response of CRS. In gastric cancer, NIPEC-LT is given as a neoadjuvant treatment with responders going on to radical surgical resection. Responses are monitored by laparoscopy. This overview highlights benefits of NIPEC-LT in three diseases where benefits from CRS and HIPEC have been recognized but that local-regional failures persist. Improved results with NIPEC-LT have been reviewed for ovarian cancer, gastric cancer, and peritoneal mesothelioma.

Strategies to improve local control of resected pancreas adenocarcinoma

BackgroundOnly approximately one in ten pancreas cancer patients is a candidate for potentially curative resection of this disease. Even this small fraction of patients has a poor prognosis following pancreatico-duodenectomy. The disease has an anatomic location that makes it difficult for the surgeon to maintain adequate margins of resection and prevent tumor spillage at the time of resection. Also, the disease is biologically aggressive and even with a complete visible resection of the disease, micrometastases are likely to remain behind. MethodsA survey of the sites for surgical treatment failure of resected pancreas cancer was performed. Also, the multiple modalities used in an attempt to improve the results of cancer resection are scrutinized. ResultsThe surgical treatment failures are regional in nature and occur at the resection site and on peritoneal surfaces, within the liver, and within the regional lymph nodes. These anatomic sites account for nearly 100% of the initial sites of disease progression. Current hypothesis suggests that micrometastases released from the cancer specimen by the trauma of surgery account for the high incidence of resection site progression and peritoneal metastases. Although surgical trauma may contribute to micrometastases within the liver and lymph nodes, these are most likely present though not detected by preoperative radiologic studies. Adjuvant treatments such as neoadjuvant chemotherapy or combination systemic chemotherapy have not been associated with improved survival. Extended resections such as total pancreatectomy or extended lymphadenectomy have not been associated with benefit. However, resection with a negative margin of excision along with the removal of at least 12 lymph nodes in and around the pancreaticoduodenectomy specimen is associated with superior outcomes. A regional chemotherapy treatment that consists of hyperthermic intraperitoneal chemotherapy (HIPEC) with gemcitabine and long-term normothermic intraperitoneal chemotherapy (NIPEC-LT) gemcitabine for 6 months postoperatively is suggested as a new treatment that has demonstrated decreases in local-regional failure and promises to more adequately target micrometastases in the peritoneal space, in the liver and lymph nodes. ConclusionsPancreas cancer surgery should attempt to achieve negative margins of resection with the removal of at least 12 lymph nodes. Hyperthermic intraperitoneal gemcitabine can adequately eradicate malignant cells dislodged from the cancer specimen into the bed of the resection at high density and on distant peritoneal surfaces as peritoneal metastases. Long-term intraperitoneal gemcitabine may act on micrometastases in the liver through absorption into the portal vein blood and the lymph nodes as a result of gemcitabine absorption by subperitoneal lymphatic channels. The use of HIPEC and NIPEC-LT gemcitabine may improve local control of resected pancreas cancer.

Assessment of Ovarian Cancer Tumors Treated with Intraperitoneal Cisplatin Therapy by Nanoscopic X-ray Fluorescence Imaging.

Ovarian cancer is amongst the most common types of cancer in women, with a relatively low overall cure rate of approximately 30%. This is therefore an important incentive to urge for further research in order to maximize the chances of survival for these patients. Intraperitoneal chemotherapy with Cisplatin is an effective treatement for ovarian cancer; however, many questions still remain concerning the ideal treatment protocol and tumor resistance towards the drug, which should be resolved for optimal application of this therapy. For the first time in-vivo grown tumors treated with both hyper- and normothermic intraperitoneal chemotherapy have been studied using nano-XRF spectroscopy to examine the platinum (Pt) distribution within the analyzed tissues. These measurements prove Pt resides predominantly outsides the cancer cells in the stroma of the tissue. These findings indicate the resistance mechanism of the cancer cells prevents Cisplatin from diffusing through their cell membranes. This is an important addition to the existing knowledge on the resistance mechanism providing insights which might help to overcome this effect. In our aim to find the optimal treatment protocol, no significant differences were found between the two examined procedures. A more extensive data set will be needed to draw definite conclusions.

Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Carcinomatosis: Is HIPEC the Only Answer?

Gastric cancer with peritoneal carcinomatosis is notorious for its dismal prognosis. While the pa- thophysiology of peritoneal dissemination is still controversial, the rapid downhill course is uni- versal. Patients usually suffer abdominal distension, intestinal obstruction and various complica- tions before they succumb after a median of 3 - 6 months. Although not adopted in most interna- tional treatment guidelines, intraperitoneal chemotherapy has growing evidence compared with conventional systemic chemotherapy for the treatment of peritoneal carcinomatosis. Cytoreduc- tive surgery with hyperthermic intraperitoneal chemotherapy is well-established for clinical ben- efit but is technically demanding with substantial treatment-related morbidities and mortality. On the other hand, normothermic intraperitoneal chemotherapy in the form of bidirectional neoad- juvant treatment is promising with various newer chemotherapeutic agents. Regardless of the treatment technique applied, the essential element of success is meticulous patient selection and availability of expertise. Future direction is along the line of personalized treatment with the ap- plication of translational science.