Peritoneal Surface Malignancies Research Articles

Concerning CT features used to select patients for treatment of peritoneal metastases, a pictoral essay

Background: During the Fifth International Workshop on Peritoneal Surface Malignancy in Milan in 2008, a consensus was reached that contrast-enhanced CT (ceCT) was the principal imaging modality for patients being evaluated for treatment of peritoneal metastases. This fact being accepted, the radiologic criteria for that may exclude patients from a high value cytoreductive surgery (CRS) plus hyperthermic perioperative chemotherapy (HIPEC) have not been reliably determined.Methods: From a consensus of surgeons and radiologists, radiologic images were selected and their determinant radiologic characteristics described. The anatomic pathology causing the abnormal images were identified and characterised. The cytoreductive surgical procedures that may, in selected patients, result in a complete resection of the pathology identified were presented.Results: Radiographs of 15 CT images that cause concern when a patient is being evaluated for CRS were listed. The anatomic pathology these images define and possible surgical resections they require were reviewed. The surgical implications of the absence or presence of a single, or of multiple concerning CT features was extracted from the surgical and radiologic literature.Conclusions: There is a definite need to identify new pre-operative imaging parameters to define optimal indication of CRS with HIPEC. The presence of a single concerning radiologic feature is associated with the possibility of an adverse outcome or technically more complex resections associated with increased morbidity and mortality. If two or more of the concerning radiologic features are described from the CT, suboptimal cytoreduction will usually occur.

Interval between cytoreductions as a marker of tumor biology in selecting patients for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for recurrence of peritoneal surface malignancies is safe and effective. Patient selection and factors associated with a favorable outcome are still evolving. A prospectively maintained institutional database consisting of 1314 CRS/HIPEC procedures performed between February 1993 and December 2015 was reviewed. Clinicopathologic data from 103 patients and 112 (8.5%) repeat CRS/HIPEC procedures were retrospectively analyzed. Primary tumors were appendiceal for 60 patients (58.3%), mesothelioma for 14 (13.6%), colorectal for 9 (8.7%), ovarian for 8 (7.8%). R0/R1 resection was achieved in 46 (46.5%) patients. The time interval between the initial and the repeat CRS/HIPEC was <1 year for 21 (20.4%), 1-2 years for 40 (38.8%), and >2 years for 42 patients (40.8%). Overall median survival was 4.3 years and correlated with the time interval (1.3 years for <1 years, 3.7 years for 1-2 years, and 7 years for >2 years; P < 0.001). In multivariate analysis, the R status (P = 0.005) and a time interval of more than 2 years (P = 0.0002) were strongly associated with survival with each additional month between the surgeries conferring a 2.6% reduction in the risk of death. The current series validates time interval between cytoreductions as a major surrogate of tumor biology in selection of patients with recurrent peritoneal surface malignancies for repeat CRS/HIPEC. Complete repeat cytoreduction more than 2 years from the initial surgery is associated with a favorable outcome.

Extra-peritoneal hysteroannessiectomy with eventual concomitant en bloc rectal resection and cytoreductive surgery in epithelial ovarian cancer (and other peritoneal surface malignancies): technical details

Surgery allows the correct evaluation of the peritoneal dissemination of the epithelial ovarian cancer (EOC) and the removal of as much tumor as possible to maximize adjuvant chemotherapy. Neoadjuvant chemotherapy (NACT) and interval debulking surgery have been proposed as a reasonable alternative to primary complete cytoreductive surgery (CRS) in patients not fit for an initial extensive debulking surgery. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has been offered as a promising therapeutic procedure to increase survival by treating the microscopic component of the neoplastic disease. Matherial and Method. 419 eligible patients with stage III-IV EOC were subjected to CRS, previous NACT in 343 patients, 20 of which with CRS combined with extraperitoneal hysterectomy (EH) + HIPEC. Purposes of our four years retrospective observational study are the revision of the surgical approaches to the EOC, a detailed report of the pelvic peritonectomy in association to hysteroannessiectomy (+/- consensual rectal resection) and the prospective review of the results. Conclusions. This study shows that EH + HIPEC is feasible. The detailed description of the technique here depicted could help to standardize this type of peritonectomy.

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.

Pharmacological principles of intraperitoneal and bidirectional chemotherapy.

Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.

Overview of the optimal perioperative intraperitoneal chemotherapy regimens used in current clinical practice.

Peritoneal surface malignancy (PSM) is a common manifestation of digestive and gynecologic malignancies alike. At present, patients with isolated PSM are treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The combination of CRS and intraperitoneal (IP) chemotherapy should now be considered standard of care for PSM from appendiceal epithelial cancers, colorectal cancer and peritoneal mesothelioma. Although there is a near universal standardization regarding the CRS, we are still lacking a much-needed standardization among the various IP chemotherapy treatment modalities used today in clinical practice. Pharmacologic evidence should be generated to answer important questions raised by the myriad of variables associated with IP chemotherapy.

Current Management of Peritoneal Carcinomatosis From Colorectal Cancer: The Role of Cytoreductive Surgery and Hyperthermic Peritoneal Chemoperfusion.

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a disease with a poor prognosis, often thought to be a terminal illness with no hope except for palliative treatment. New therapeutic modalities combining cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown favorable outcomes and may provide a significant survival benefit in a selected group of patients. The main rational for CRS is to remove all visible tumor burden to allow for the chemotherapeutic agent (HIPEC) to eradicate any microscopic residual disease. The Amsterdam statement formulated at the 9th International Congress on Peritoneal Surface Malignancies supports the use of CRS with HIPEC as a standard of care for selected patients with small-to-moderate volume PC from CRC. Selecting appropriate patients who would benefit from CRS/ HIPEC is paramount to derive the maximum oncological outcomes while minimizing the risks of postoperative complications and mortality. In this paper, we will review the role for CRS/HIPEC in the management of PC from CRC.

A Prognostic Model for Predicting Overall Survival in Patients with Peritoneal Surface Malignancy of an Appendiceal Origin Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Our aim was to develop a prognostic model for predicting overall survival following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma and peritoneal metastasis. A retrospective analysis of a prospectively maintained database for all patients treated for appendiceal adenocarcinoma with peritoneal metastasis from 1989 to 2012 was conducted. Overall, 734 (50.7%) males and 715 (49.3%) females, with a mean age at presentation of 48.6years, were included. Prognostic variables identified in a univariate Cox analysis included sex, tumor recurrence, tumor histology, Peritoneal Carcinomatosis Index, age at diagnosis, lesion size, completeness of cytoreduction (CC) score, distant metastasis, lymph node status, and use of HIPEC. A multivariate Cox analysis identified distant metastasis, CC score, tumor histology, HIPEC use, and sex as independently predictive of survival. A prognostic index was derived and four risk groups were categorized (≤1, 2-4, 5-10, and ≥10). Median survival for the four risk groups differed significantly: 240months for patients with a prognostic score ≤1 versus 235, 78.4, and 19.4months for the cohort of patients with a prognostic score of 2-4, 5-10 and ≥10, respectively (p=0.000). An internal validation of our prognostic model was carried out on a series of 379 randomly selected patients from our data, which provided corresponding estimates. Our prognostic model demonstrated a significant difference in overall survival for patients stratified by our derived prognostic scores. External validation of this model in other cohorts of patients is needed.

The RENAPE observational registry: rationale and framework of the rare peritoneal tumors French patient registry

BackgroundRare peritoneal cancers represent complex clinical situations requiring a specific and multidisciplinary management. Because of their rarity, lack of awareness and knowledge often leads to diagnostic delays and misdiagnosis. And patients are not systematically referred to expert centers as they should be. Clinicians and researchers also face unique challenges with these rare cancers, because it is hard to conduct adequately powered, controlled trials in such small patient population. This is how an observational patient registry constitutes a key instrument for the development of epidemiological and clinical research in the field of these rare cancers. It is the appropriate tool to pool scarce data for epidemiological research and to assess the impact of diagnostic and therapeutic strategies. We aimed to provide the outlines and the framework of the RENAPE observational registry and share our experience in the establishment of a national patient registry.ResultsThe RENAPE observational registry has been launched in 2010 thanks to institutional supports. It concerns only patients with a histological diagnosis confirming a peritoneal surface malignancy. A web secured clinical database has been implemented based on data management procedures according to the principles of international recommendations and regulatory statements. A virtual tumor bank is linked in order to the conduct translational studies. Specialized working groups have been established to continuously upgrade and evolve the common clinical and histological data elements following the last classifications and clinical practices. They contribute also to standardize clinical assessment and homogenize practices.ConclusionsThe RENAPE Registry may improve awareness and understanding of the rare peritoneal tumors into the incidence, prevalence, recurrence, survival and mortality rates, as well as treatment practices thereby enabling therapeutic intervention to be evaluated and ultimately optimized.Trial registrationClinicalTrials.gov Identifier: NCT02834169

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce. In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo. Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10-15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min. The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.

Evaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) and its peri-operative management for peritoneal surface malignancies – single institute Indian experience

Evaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) and its peri-operative management for peritoneal surface malignancies – single institute Indian experience

Phase II Randomized Trial of Negative-Pressure Wound Therapy to Decrease Surgical Site Infection in Patients Undergoing Laparotomy for Gastrointestinal, Pancreatic, and Peritoneal Surface Malignancies

Surgical site infections (SSIs) remain a major source of morbidity and cost after resection of intra-abdominal malignancies. Negative-pressure wound therapy (NPWT) has been reported to significantly reduce SSIs when applied to the closed laparotomy incision. This article reports the results of a randomized clinical trial examining the effect of NPWT on SSI rates in surgical oncology patients with increased risk for infectious complications. From 2012 to 2016, two hundred and sixty-five patients who underwent open resection of intra-abdominal neoplasms were stratified into 3 groups: gastrointestinal (n= 57), pancreas (n= 73), or peritoneal surface (n= 135) malignancy. They were randomized to receive NPWT or standard surgical dressing (SSD) applied to the incision from postoperative days 1 through 4. Primary outcomes of combined incisional (superficial and deep) SSI rates were assessed up to 30 days after surgery. There were no significant differences in superficial SSIs (12.8% vs 12.9%; p > 0.99) or deep SSI (3.0% vs 3.0%; p > 0.99) rates between the SSD and NPWT groups, respectively. When stratified by type of surgery, there were still no differences in combined incisional SSI rates for gastrointestinal (25% vs 24%; p > 0.99), pancreas (22% vs 22%; p > 0.99), and peritoneal surface malignancy (9% vs 9%; p > 0.99) patients. When performing univariate and multivariate logistic regression analysis of demographic and operative factors for the development of combined incisional SSI, the only independent predictors were preoperative albumin (p=0.0031) and type of operation (p= 0.018). Use of NPWT did not significantly reduce incisional SSI rates in patients having openresection of gastrointestinal, pancreatic, or peritoneal surface malignancies. Basedon these results, at this time NPWT cannot be recommended as a therapeutic intervention to decrease infectious complications in these patient populations.

BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

IntroductionMalignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma. MethodsTaking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples. ResultsWe detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex. ConclusionsAs in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers. Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care. Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics. Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.

10th International Congress on Peritoneal Surface Malignancies

Abstract Book of the 10th International Congress on Peritoneal Surface Malignancies.Washington, DC, November 17-19, 2016

Repeat cytoreductive surgery with or without perioperative intraperitoneal chemotherapy for peritoneal surface malignancy

BackgroundA significant proportion of patients with peritoneal surface malignancy (PSM) experienced recurrence after initial cytoreductive surgery (CRS). Thus the aims of this study were to determine short-term outcomes and long-term survivals associated with repeat CRS. MethodsThis was a retrospective study of prospectively collected data of consecutive patients with PSM who underwent CRS by one surgical team at St George Hospital in Sydney, Australia between Jan 1996 and May 2016. ResultsThere was no significant difference in hospital mortality (p=0.343) and major morbidity rate (p=0.454). Patients who underwent repeat surgery had a significantly higher 5-year overall survival (OS) rate (p<0.001) and a longer median disease free interval (DFS) (p<0.001). Repeat CRS was also found to be a significant prognostic factor for OS (p<0.001) and DFS (p<0.001). ConclusionsRepeat CRS with or without perioperative intraperitoneal chemotherapy could provide long-term survival benefits to patients with PSM with acceptable mortality and morbidity rates. Summary1. Repeat CRS with or without PIC provides long-term survival benefits to patients with PSM. 2. Repeat CRS with or without PIC is feasible and can be performed without acceptable mortality and morbidity rates.

Peritoneal surface malignancies computerized staging system

Peritoneal surface malignancies computerized staging system

117. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal surface malignancies in the elderly

117. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal surface malignancies in the elderly

Biobank-based research on digestive peritoneal carcinomatosis (the BIG-RENAPE Biobank)

Access to good quality biological samples is a prerequisite for highlevel translational research. The BIG-RENAPE Biobank has been established by the French hyperthermic intraperitoneal chemotherapy centers involved in the management of peritoneal surface malignancies. The Biobank is a core facility aiming to support researchers who conduct studies with sample collections, both within and outside the Big- RENAPE Network. The Biobank is certified according to NFS 96-900 and has been launched in February 2016 as a service of processing, storage and transfer of high quality biological (plasma, serum, buffy coat) and tissue (formalin-fixed-paraffin-embedded) samples from patients with digestive peritoneal carcinomatosis. Biospecimens are collected at each stage of diagnostic and therapeutic care. The patient and his derivates are anonymized and registered in a web database reporting disease status, treatments, surgical procedures, pathological diagnosis, quality of life’s assessment and long term follow-up. All participants have given their informed consent before any sample. The Biobank was approved by the local Ethical Committee, based on the assessed compliance to French regulatory rules. The Biobank is located in the Centre Hospitalier Lyon (SudBioTech), which is known to be an expert center in the management of the peritoneal carcinomatosis. Research projects that require material stored in the Biobank are submitted by specific form and evaluated by the BIG-RENAPE Scientific Committee. A material transfer agreement is agreed with the recipient before samples are allowed to be sent from the Biobank.

Role of Imaging in Peritoneal Surface Malignancies.

Imaging plays a vital role in the evaluation of peritoneal malignancies. The presence of peritoneal metastases (PM) alters tumor staging, with direct implications in treatment choice and prognosis. Cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC) as a combined modality treatment have led to prolonged survival and even cure in selected patients with PM. Better outcomes are seen in patients with limited disease spread. Therefore, early diagnosis of peritoneal tumor seeding is essential. Despite significant advancement of technology, assessment of the origin of PM is often difficult, due partly to the complex peritoneal anatomy and partly due to the complex overlap of imaging features. Multidetector CT (MDCT) is the main stay due to its wide availbility, rapid evaluation, robust technique and good resolution. Imaging plays a vital role in selecting patients for the combined modality treatment. MRI is not as popular as CT due to limited availability, time required for the study and lack of experience with interpreting the results. PET-CT is useful in ruling out extra peritoneal disease and it is the CT component that is more reliable for predicting the disease extent. This article reviews the current use of various imaging modalities in various stages of treatment of patients with PM especially those undergoing CRS and HIPEC.