The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Long-term regional chemotherapy for patients with epithelial malignant peritoneal mesothelioma results in improved survival.

PURPOSE: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 300 new cases per year in the USA. Its natural history is described as local progression within the peritoneal space in the absence of liver metastases or systemic disease. METHODS: Cytoreductive surgery (CRS) is a series of peritonectomy procedures and visceral resections with a goal of complete removal of all visible disease from the abdomen and pelvis. Over 20 years, three protocols investigating increasing efficacy of additional chemotherapy treatments added to CRS have been initiated. Initially, hyperthermic perioperative chemotherapy (HIPEC) with doxorubicin and cisplatin was used in the operating room. Then, early postoperative intraperitoneal chemotherapy (EPIC) with paclitaxel was added for the first 5 days after CRS. The third protocol employed HIPEC, then EPIC, and then long-term intraperitoneal (IP) paclitaxel or IP pemetrexed plus intravenous (IV) cisplatin as a adjuvant normothermic intraperitoneal chemotherapy (NIPEC). RESULT: The 5-year survival of 42 patients treated with CRS and HIPEC was 44%, for 58 patients treated with EPIC and HIPEC was 52% and 29 patients who received HIPEC, EPIC, and NIPEC was 75% (p = 0.0374). Prognostic variables of age, gender, treatment administered, peritoneal cancer index (PCI) and completeness of cytoreduction were significant by univariate analysis and treatments administered and completeness of cytoreduction significant by multivariate analysis. CONCLUSIONS: Long-term regional chemotherapy was associated with improved survival in patients with MPM. In this rare disease, additional phase 2 investigations are suggested.

Management of an inguinal hernia in patients with pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei is a disease that results from a perforated mucinous neoplasm of the appendix so that mucinous ascites and mucin-producing tumor cells are widely disseminated in a characteristic pattern throughout the abdomen and pelvis. The intraabdominal mucus can accumulate in the inguinal canal and by physical examination be indistinguishable from the usual inguinal hernia. METHODS: A database of patients with pseudomyxoma peritonei was used to identify patients who had an inguinal hernia prior to or at the time of cytoreductive surgery (CRS) and perioperative hyperthermic chemotherapy (HIPEC). At the time of CRS, care was taken in all patients to remove the peritoneal lining of the inguinal canal. Patients who had the inguinal hernia repaired prior to definitive treatment with CRS and HIPEC had all tissue and mesh associated with prior herniorrhaphy resected. RESULTS: In 178 pseudomyxoma peritonei patients, 17 had a new onset or previously repaired inguinal hernia that required extraction of mucus and mucinous tumor from the hernia site. No repair of the open inguinal canal was attempted at the time of CRS. No recurrent inguinal hernias were recorded and no patients required an inguinal incision at a later time to resect progressive disease within the inguinal canal. CONCLUSIONS: Inguinal hernias caused by mucinous ascites and tumor were definitively treated by cytoreductive surgery plus HIPEC. Extraction of tumor and peritoneum from the inguinal canal facilitates fibrous closure of the hernia defect so that hernia recurrence was not observed.

Symptoms, signs and radiologic findings in patients having reoperative surgery for malignant peritoneal mesothelioma.

BACKGROUND: A reasonable estimate is that 50% of patients treated with cytoreductive surgery (CRS) and perioperative chemotherapy for malignant peritoneal mesothelioma will recur. Recognition of this recurrence and knowledgeable selection for additional surgical intervention is important in improving survival of patients who progress. MATERIAL AND METHODS: Patients treated for malignant peritoneal mesothelioma with CRS and perioperative chemotherapy were placed in follow-up for assessment of symptoms and signs and radiologic abnormalities by CT. The data were prospectively maintained and retrospectively reviewed. RESULTS: From a database of 130 patients with malignant peritoneal mesothelioma, 38 patients who had 50 reoperations with disease recurrence that was histologically confirmed were studied. The median time to first recurrence was 14 months with a range of 3-102. Considering 50 reoperative events the most common symptoms or signs were abdominal pain (40%) and abdominal distention (34%). The most common radiologic finding was a tumor mass (56%). Patients with an abdominal or pelvic mass had a reduced prognosis (p = 0.006) and patients with an absence of radiologic abnormalities had an improved survival (p = 0.047). CONCLUSIONS: In patients having reoperative surgery, symptoms, signs and radiologic abnormalities associated with recurrent (progressive) malignant peritoneal mesothelioma are abdominal pain, abdominal distention, and a tumor mass. An abdominal or pelvic mass was associated with a reduced prognosis and an absence of radiologic abnormalities with an improved prognosis.

A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent.

Recently, Peritoneal Surface Oncology Group International (PSOGI) developed a novel comprehensive treatment consisting of cytoreductive surgery (CRS) and perioperative chemotherapy (POC) for the treatment of peritoneal metastases (PM) from gastric cancer with curative intent. This article reviews the results of this treatment and verifies its indication. In this strategy, peritoneal cancer index (PCI) is determined by laparoscopy, and a peritoneal port is placed. Neoadjuvant bidirectional intraperitoneal/systemic chemotherapy (NIPS) is performed for 3 cycles, and then laparotomy is performed. Cytoreductive surgery with peritonectomy procedures and hyperthermic intraperitoneal chemoperfusion (HIPEC) are performed. Multivariate analyses showed that completeness of cytoreduction, pathologic response to NIPS and PCI level and cytologic status after NIPS, as independent prognostic factors. PCI less than cut-off level after NIPS, negative cytology after NIPS, and positive response to NIPS were identified as the indications for comprehensive treatment. Patients who hold these criteria should be considered as the candidates for CRS and HIPEC.

Effect of intraperitoneal chemotherapy and peritoneal lavage in positive peritoneal cytology in gastric cancer. Systematic review and meta-analysis.

INTRODUCTION: The most common cause of tumour progression in advanced gastric cancer is peritoneal carcinosis (PC). The necessity to increase the survival in advanced diseases suggested to deliver the chemotherapy directly in the peritoneal cavity also in Cy+/PC- and to experiment the effect of massive peritoneal lavage to wash out the tumour cells. The aim of this study is to investigate the gain in term of survival and peritoneal recurrence rate of the intraperitoneal chemotherapy and/or peritoneal lavage in patients with Cy+/PC-. MATERIAL AND METHODS: A systematic review with meta-analysis of trials about the effect of intraperitoneal chemotherapy (IPC) and/or peritoneal lavage (PL) on positive cytology in gastric cancer without carcinosis. RESULTS: Three trials have been included (164 patients: 76 received surgery alone, 51 surgery + IPC and 37 surgery + IPC + PL). Two- and five-years survival is increased by IPC (RR = 1.62, RR = 3.10). 2 and 5 years survival is further increased by IPC + PL (RR = 2.33, RR = 6.19). Peritoneal recurrence is reduced by IPC (OR = 0.45) and by IPC + PL (OR = 0.13). CONCLUSIONS: Two- and five-years overall survival in patients with free cancer cells without carcinosis is incremented by intraperitoneal chemotherapy. Peritoneal lavage further increases these survival rates and also it further decreases the peritoneal recurrence rate.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Methodology, Drugs and Bidirectional Chemotherapy.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) combined have been recognized as standard of care for treatment of a subset of patients with peritoneal carcinomatosis (PC). The aim of CRS is to eliminate all macroscopic disease through a series of visceral resections followed by targeting any residual microscopic disease with intraperitoneal chemotherapy, exposing the peritoneal surfaces to a high concentration of chemotherapy with a lower systemic toxicity. Different regimes of intraperitoneal chemotherapy include HIPEC, early postoperative intraperitoneal chemotherapy (EPIC) and bidirectional chemotherapy. The efficacy and modality of treatment with intraperitoneal chemotherapy is dependent on multiple factors including the chosen cytotoxic agent and its pharmacokinetics and pharmacodynamics. There is no standardized methodology for intraperitoneal chemotherapy administration. This review will discuss the pharmacological principles of the various intraperitoneal chemotherapy techniques.

Complete versus incomplete cytoreduction in peritoneal carcinosis from gastric cancer, with consideration to PCI cut-off. Systematic review and meta-analysis.

INTRODUCTION: The completeness of cytoreduction has been considerated as fundamental in increasing the life expectancy in patients with peritoneal carcinosis (PC) in gastric cancer. However no definitive data about the real effect of complete cytoreduction (CC) have still been published. Moreover the PCI cut-off to attempt CC with a reasonable risk-benefit ratio still lacks. MATERIAL AND METHODS: A systematic review with meta-analysis of trials of complete vs incomplete cytoreduction in patients with peritoneal carcinosis from GC was performed. RESULTS: Nine trials have been included (748 patients: 417 with CC0-CC1 and 324 with CC2-CC3 cytoreduction). 1, 2, 3 and 5 years survival is favorable to CC0-CC1 (Risk Ratio: 2.41, 8.18, 8.66, and 7.96 respectively). CC0 vs. CC1 survival benefit at 1 and 3 years: RR 2.28 and 6.36 respectively, favoring CC0. 1, 2, 3 and 5 years survival changes significantly above and below a PCI of 12. CONCLUSIONS: 1, 2, 3 and 5-year overall survival is increased by CC0-CC1 cytoreduction in patients with PC from gastric origin. Moreover CC0 increases the 1 and 3 years survival when compared to CC1 cytoreduction.

Multicentre study of the learning curve and surgical performance of cytoreductive surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei.

BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

Pharmacokinetics of the perioperative use of cancer chemotherapy in peritoneal surface malignancy patients.

Background. The peritoneal surface is an acknowledged locoregional failure site of abdominal malignancies. Previous treatment attempts with medical therapy alone did not result in long-term survival. During the last two decades, new treatment protocols combining cytoreductive surgery with perioperative intraperitoneal and intravenous cancer chemotherapy have demonstrated very encouraging clinical results. This paper aims to clarify the pharmacologic base underlying these treatment regimens. Materials and Methods. A review of the current pharmacologic data regarding these perioperative chemotherapy protocols was undertaken. Conclusions. There is a clear pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal and intravenous cancer chemotherapy in peritoneal surface malignancy patients.

Importance of gender in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival. PATIENTS AND METHODS: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival. RESULTS: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment. CONCLUSIONS: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Doxorubicin is a drug consistently used by our group in this clinical setting. The surgical and clinical factors that modify the pharmacokinetics of HIPEC may be important for the design of future perioperative chemotherapy regimens. MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using CRS prior to treatment with HIPEC with doxorubicin as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after a single intraperitoneal bolus administration with doxorubicin was determined. RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal doxorubicin showed a 78 times greater exposure to peritoneal surfaces as compared to plasma. At 90 min 12% of the drug remained in the chemotherapy solution and 88% was retained in the body. The extent of visceral resection and peritonectomy increased the clearance of doxorubicin from the peritoneal space. A major resection of visceral peritoneal surface, a contracted peritoneal space, and an incomplete cytoreduction reduced drug clearance. CONCLUSIONS: Surgical and clinical factors may require modifications of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced doxorubicin clearance. Total diffusion surface is an important determinant of doxorubicin pharmacokinetics.

A new standard of care for the management of peritoneal surface malignancy.

Cancer dissemination to peritoneal surfaces was, in the past, a lethal condition with a limited survival. Clinical and pharmacologic research have shown that options for both treatment and prevention are now reality. The diseases most commonly treated include peritoneal dissemination from appendiceal malignancy, colorectal malignancy, and peritoneal mesothelioma. Selection factors are important to minimize the number of treated patients who will experience short-term benefit. Treatments involve cytoreductive surgery and perioperative chemotherapy. The intraperitoneal chemotherapy in the operating room is used with heat. Although this combined approach has been criticized, the informed oncologist will seek to identify those patients that may benefit from this more optimistic concept of peritoneal dissemination of cancer.

Multi-institutional experience of diffuse intra-abdominal multicystic peritoneal mesothelioma.

BACKGROUND: This study was undertaken to measure survival of patients with multicystic peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy through a multi-institutional collaboration. METHODS: A multi-institutional data registry, established by the Peritoneal Surface Oncology Group, was used to identify patients with peritoneal mesothelioma and the subgroup with multicystic tumours, treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Outcomes for this subgroup are reported. The primary endpoint was overall survival. A secondary endpoint was the incidence of treatment-related complications. RESULTS: Of 405 patients with peritoneal mesothelioma, 26 (6·4 per cent) had multicystic tumours. There were 20 women and six men with a mean(s.d.) age of 42(12) years. The median peritoneal carcinomatosis index (PCI) was 14 (range 6-39). There was no perioperative mortality. Six patients developed grade III or IV complications. After a median follow-up of 54 (range 5-129) months, all 26 patients were still alive. CONCLUSION: Multicystic peritoneal mesothelioma appears to be a distinct subtype of peritoneal mesothelioma, where long-term survival may be achieved through cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Revised guidelines for second-look surgery in patients with colon and rectal cancer

Proper indications for a second surgical intervention in patients with colorectal cancer have always been a controversial subject. Surgeons find benefit in a second-look operation where a limited extent of cancer is discovered and resected with negative margins. However, a negative exploratory laparotomy or an intervention that is unable to achieve an R0 resection provides little or no benefit. Unfortunately, this type of intervention may place the patient in a worse condition, leading to morbidity or mortality. This manuscript attempts to define clinical parameters of primary colorectal cancer that are associated with a pattern of recurrence and that can be definitively addressed by second-look surgery. Also, new surgical technologies that may assist in achieving a potentially curative resection of local-regional recurrence are described. Cytoreductive surgery with peritonectomy and perioperative intraperitoneal chemotherapy with hyperthermia is presented as a new treatment option for reoperative surgery. A new management plan utilized in patients at high risk for local-regional recurrence may result in a high likelihood of conversion of a second-look cancer-positive patient to a long-term survivor (AU)

A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin.

PURPOSE: A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality. METHODS: Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid. CONCLUSIONS: Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.

Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy.

Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy.