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Background: This study aimed to identify the cumulative incidence and risk factors of metachronous peritoneal metastasis (M-PM) from colorectal cancer in patients who had intended curative treatment., Methods: Patients with colorectal cancer were identified using the Danish Colorectal Cancer Group database for 2006-2015. The Danish Pathology Registry and the Danish National Patient Registry were used to identify M-PM to 2017. Risk factors were estimated by multivariable absolute risk regression, treating death and other cancers as competing risks. Overall risk and risk differences (RDs) were estimated at 1, 3 and 5 years., Results: In 22 586 patients with colorectal cancer, the overall risk of M-PM was reported to be 0·9 (95 per cent c.i. 0·8 to 1·0) per cent at 1 year, 1·9 (1·8 to 2·1) per cent at 3 years and 2·2 (2·0 to 2·4) per cent at 5 years. Advanced tumour category ((y)pT4 versus (y)pT1) increased the RD of both M-PM (2·9 (95 per cent c.i. 2·1 to 3·7) at 1 year and 6·0 (4·9 to 7·2) at 3 years) and lymph node involvement ((y)pN2 versus (y)pN0) (2·5 (1·8 to 3·2) at year and 4·3 (3·2 to 5·3) at 3 years). No further increase in risk was observed at 5 years. In a subanalysis, tumour-involved resection margin (R1 versus R0) was associated with M-PM with a RD of 3·9 (1·6 to 6·2) at 1 year and 5·9 (2·6 to 9·3) at 3 years., Conclusion: The overall risk of M-PM in patients with colorectal cancer is low, but is increased in advanced T and N status. Follow-up of at least 3 years after colorectal cancer surgery may be necessary, given the potential curative treatment of early diagnosed M-PM., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

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., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Patients presenting with peritoneal metastases (PM) of colorectal cancer (CRC) can be curatively treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Angiogenesis is under control of multiple molecules of which HIF1a, SDF1, CXCR4, and VEGF are key players. We investigated these angiogenesis-related markers and their prognostic value in patients with PM arising from CRC treated with CRS and HIPEC., Patients and Methods: Clinicopathological data and tissue specimens were collected in 2 tertiary referral centers from 52 patients who underwent treatment for isolated PM of CRC. Whole tissue specimens were subsequently analyzed for protein expression of HIF1a, SDF1, CXCR4, and VEGF by immunohistochemistry. Microvessel density (MVD) was analyzed by CD31 immunohistochemistry. The relationship between overall survival (OS) and protein expression as well as other clinicopathological characteristics was analyzed., Results: Univariate analysis showed that high peritoneal cancer index (PCI), resection with residual disease and high expression of VEGF were negatively correlated with OS after treatment with CRS and HIPEC (P < 0.01, P < 0.01, and P = 0.02, respectively). However, no association was found between the other markers and OS (P > 0.05). Multivariate analysis showed an independent association between OS and PCI, resection outcome and VEGF expression (multivariate HR: 6.1, 7.8 and 3.8, respectively, P ≤ 0.05)., Conclusions: An independent association was found between high VEGF expression levels and worse OS after CRS and HIPEC. The addition of VEGF expression to the routine clinicopathological workup could help to identify patients at risk for early treatment failure. Furthermore, VEGF may be a potential target for adjuvant treatment in these patients.

Background: CytoReductive Surgery and Hyperthermic IntraPEritoneal Chemotherapy (CRS-HIPEC) is now the preferred treatment of many peritoneal surface malignancies. In this retrospective study we aimed to analyze how several performance indicators changed during the first 100 CRS-HIPEC procedures in hospitals which recently introduced this treatment, and compare those with an experienced institution., Methods: The first consecutive 100 CRS-HIPEC procedures of three institutions were compared to those of the pioneer hospital. The training provided by the pioneer hospital consisted of hands-on training during the first ten procedures; hereafter guidance was available on consult basis. Operation characteristics, morbidity and completeness of cytoreduction were evaluated by case sequence. Locally-estimated-scatter-plot smoothing was used to evaluate the learning curve., Results: From four institutions 372 cases were included. A macroscopic complete cytoreduction was reached in 66% of the cases in the pioneer hospital and in 86% in the new hospitals (p < 0.001). Complete cytoreduction rates were higher at start off in the new institutions compared with the experienced institution and increased significantly in the first 100 procedures. The new hospitals started with lower morbidity than the experienced hospital, which did not significantly decrease during the study period., Conclusion: New institutions that were trained and mentored by an experienced CRS-HIPEC hospital performed better from the beginning with regard to complete cytoreduction and morbidity rate with than the experienced center. An improvement in complete cytoreduction rate during the first 100 procedures was observed in the new institutions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Colorectal cancer peritoneal metastasis (CPM) confers an exceptionally poor prognosis, and traditional treatment involving systemic chemotherapy (SC) is largely ineffective. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly advocated for selected patients with CPM; however, opinions are divided because of the perceived lack of evidence, high morbidity, mortality, and associated costs for this approach. As there is no clear consensus, the aim of this study was to compare outcomes following CRS+HIPEC vs SC alone for CPM using meta-analytical methodology, focusing on survival outcomes. Secondary outcomes assessed included morbidity, mortality, quality of life (QOL), and health economics (HE)., Methods: An electronic literature search was conducted to identify studies comparing survival following CRS+HIPEC vs SC for CPM. The odds ratio (OR) was calculated using the Mantel-Haenszel method with corresponding 95% confidence intervals (CI) and P-values. Heterogeneity was examined using the Q-statistic and quantified with I(2). The fixed-effect model (FEM) was used in the absence of significant heterogeneity. For included studies, 2- and 5-year survival was compared for CRS+HIPEC vs SC alone., Results: Four studies (three case-control, one RCT) provided comparative survival data for patients undergoing CRS+HIPEC (n=187) vs SC (n=155) for CPM. Pooled analysis demonstrated superior 2-year (OR 2.78; 95% CI 1.72-4.51; P=0.001) and 5-year (OR 4.07; 95% CI 2.17-7.64; P=0.001) survival with CRS+HIPEC compared with SC. Mortality ranged from 0 to 8%. No data were available for the assessment of QOL or HE., Conclusions: Although limited by between-study heterogeneity, the data support the assertion that in carefully selected patients, multimodal treatment of CPM with CRS+HIPEC has a highly positive prognostic impact on medium- and long-term survival compared with SC alone. There is a paucity of comparative data available on morbidity, QOL, and HE.

Aim: To compare outcome of women with ovarian metastasis who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to outcome of women without ovarian metastasis who underwent CRS-HIPEC., Methods: A prospective CRS-HIPEC database was searched to identify women with surgically treated colorectal carcinoma between 2000 and 2012. Patients with ovarian metastasis were identified and patients with peritoneal carcinomatosis but without ovarian metastasis were included as control cases., Results: 75 patients with macroscopic ovarian metastasis underwent CRS-HIPEC with curative intent, while 50 female patients without ovarian metastasis were identified who underwent CRS-HIPEC. Patients with ovarian metastasis more often had a primary appendiceal tumour and had a more extensive intra-abdominal tumour load compared to patients without ovarian metastases. Median follow-up time was 45 months (95% confidence interval (CI): 37-53 months). Overall survival (OS) did not differ significantly between the two groups with a median OS in the ovarian metastasis group of 40 months (95% CI 26-54) compared to 64 months (95% CI 17-111, P = 0.478) in the non-ovarian metastasis group. Recurrence patterns did not differ significantly between groups (p = 0.183)., Conclusions: Patients with ovarian metastasis of colorectal and appendiceal origin who underwent CRS-HIPEC had similar outcome compared to patients without ovarian metastasis. Given the findings of high coincidence of peritoneal metastases with ovarian metastases and ovarian metastases not being an independent factor for survival after CRS-HIPEC, this procedure should be recommended for patients with peritoneal metastases and ovarian metastases of colorectal and appendiceal carcinoma., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC., Patients and Methods: A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence., Results: Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns., Conclusions: In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.

Background: The incidence of ovarian metastases at the time of peritoneal carcinomatosis, and the influence of such metastases on survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), are unknown., Methods: This retrospective analysis included 194 women subjected to CRS and HIPEC since 2001. The incidence of ovarian metastases, disease-free survival and disease-specific survival were analysed., Results: The histological diagnosis was colorectal cancer carcinomatosis in 108 patients, peritoneal mucinous carcinomatosis (PMCA) in 23 and disseminated peritoneal adenomucinosis (DPAM) in 63. Ninety-nine patients underwent oophorectomy during the HIPEC procedure. Ovarian metastases were confirmed in at least 52 per cent of the patients. There was a significant difference in disease-free survival between women with or without ovarian metastases in both PMCA and DPAM groups (P = 0·044 and P = 0·010 respectively). No significant differences in survival were found in the group with colorectal cancer carcinomatosis., Conclusion: When peritoneal carcinomatosis of colorectal or appendiceal origin is confirmed, at least 52 per cent of ovaries will have synchronous metastases. Disease-free survival after a HIPEC procedure for PMCA or DPAM is significantly lower in women with ovarian metastases. Oophorectomy during CRS for peritoneal carcinomatosis should be strongly considered.

Background: Delayed gastric emptying (DGE) is a main complication with unknown origin after a cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy (CRS-HIPEC). The aim of this study was to investigate if preservation of the right gastro-epiploic artery (GEA) during standard omentectomy would have a positive effect on gastric emptying after CRS-HIPEC., Methods: Forty-two patients subjected to a CRS-HIPEC were randomized into two groups perioperatively before performing an omentectomy: in Group I (N = 21) omentectomy was performed with preservation of the GEA; in Group II (N = 21) omentectomy was performed with resection of the GEA. The primary endpoint was the number of days to full oral intake of solid food. Secondary endpoints were number of days to intended occlusion of gastrostomy catheter and total hospital admission time., Results: No significant differences were discovered between both groups in any of the study endpoints after CRS-HIPEC. No significant differences were observed in patient or operation characteristics between the randomized groups., Conclusions: No association was demonstrated between preservation of the gastro-epiploic artery during omentectomy and gastric emptying after CRS-HIPEC. The extensive intestinal manipulation or the heated intra-peritoneal chemotherapy during surgery are more plausible causes of this phenomenon. This clinical trial was registered in the Netherlands at the Central Committee on Research involving Human Subjects (CCMO) under registration number P06.0301L., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: The late revelation of ovarian cancer ensures it as the leading cause of death among gynecologic cancers. Cytoreductive surgery (CRS) and intravenous (i.v.) chemotherapy have been the cornerstone for a long time to treat this disease. More recently, the modality of intraperitoneal administration of chemotherapy under hyperthermic conditions (HIPEC) has been added. This review surveys the results of HIPEC added to CRS in ovarian cancer., Methods: A multi-database search was conducted focusing on mortality, morbidity and overall and disease-free (DF) survival rates., Results: 16 studies were identified reporting the results of CRS followed by HIPEC of 546 patients with advanced ovarian cancer. Postoperative mortality was reported for 14 out of 481 patients in total (2.9%). The major morbidity rate varied between 3.4 and 50.0%. In all but one study (533 patients), 185 events were reported (34.5%) and 21 re-interventions after 476 operations (4.4%). Survival data ranged from 10.0 to 57.1 months for the DF survival and from 19.0 to 76.1 months for the overall survival. Optimal cytoreduction and recurrent disease were associated with a better outcome in selected cases., Conclusions: Adding HIPEC to the current treatment modalities for ovarian cancer seems to be feasible. Improved survival rates have been reported at the cost of acceptable mortality rates. Nevertheless, there was a selection bias, the morbidity should not be underestimated and it is unclear yet which patient will benefit most from this treatment. Randomized controlled trials will provide an answer to this question.

Aims: Selecting patients for cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy (HIPEC) remains challenging. We compared the predictive power of three intra-operative assessment tools of peritoneal involvement of colorectal cancer., Methods: Ninety-two procedures (1999-2005) were prospectively scored using the Simplified Peritoneal Cancer Index (SPCI) and 7 Region Count. The Peritoneal Cancer Index (PCI) was retrospectively scored using the SPCI tool, operative notes and pathological reports. Endpoints were completeness of cytoreduction and overall survival. Logistic regression and Receiver Operating Characteristic (ROC) curves were applied to compare the predictive value of the three scoring systems on completeness of cytoreduction., Results: After a median follow-up of 31 months, the median overall survival was 25.6 months. It decreased to 7.3 months, when cytoreduction was incomplete (p=0.001). An increased PCI, SPCI or number of regions were all associated with a decrease in probability of complete cytoreduction (p<0.05). With complete cytoreduction as outcome, the ROC areas for the PCI, SPCI and 7 Region Count were 0.92, 0.94 and 0.90, respectively (p=0.14). Using a cut-off value of 16 in the PCI system (p=0.03), 13 in the SPCI system (p=0.04) and 6 regions in the 7 Region Count (p=0.0002) the probability of complete cytoreduction decreased significantly., Conclusion: The PCI, SPCI and 7 Region Count are useful and equally effective prognostic tools predicting completeness of cytoreduction and associated improved survival. The 7 Region Count may be preferred due to its practical simplicity.

Background: Pseudomyxoma peritonei (PMP) is a rare disease with an estimated incidence of 1 per million per year, and is thought to originate usually from an appendiceal mucinous epithelial neoplasm. However it is not known exactly how often these neoplasms lead to PMP. The aim of this study is to investigate the incidence of both lesions and their relation., Methods: The nationwide pathology database of the Netherlands (PALGA) was searched for the incidence of all appendectomies, the incidence of primary epithelial appendiceal lesions and the incidence and pathology history of patients with PMP. All regarded the 10-year period of 1995-2005., Results: In the 10-year period 167,744 appendectomies were performed in the Netherlands. An appendiceal lesion was found in 1482 appendiceal specimens (0.9%). Nine percent of these patients developed PMP. Coincidentally, an additional epithelial colonic neoplasm was found in 13% of patients with an appendiceal epithelial lesion. A mucinous epithelial neoplasm was identified in 0.3% (73% benign, 27% malignant) of appendiceal specimens and 20% of these patients developed PMP. For mucocele and non-mucinous neoplasm the association with PMP was only 2% and 3%, respectively. From the nationwide database 267 patients (62 men and 205 women) with PMP were identified, which demonstrates an incidence of PMP in the Netherlands approaching 2 per million per year. The primary site was identified in 68% and dominated by the appendix (82%)., Conclusions: Primary epithelial lesions of the appendix are rare. One third of these lesions are mucinous epithelial neoplasms and especially these tumours may progress into PMP. The incidence of PMP seems to be higher than thought before. Furthermore there is a considerable risk of an additional colonic epithelial neoplasm in patients with an epithelial neoplasm at appendectomy.

Background: Cytoreductive surgery with intraperitoneal chemotherapy has emerged as a new standard approach for peritoneal surface disease. This study investigated the learning curve of this combined modality treatment at a single institute., Methods: Variables analysed over three consecutive treatment periods (1996-1998, 1999-2002 and 2003-2006) included number of abdominal regions affected, Simplified Peritoneal Cancer Index (SPCI) score, result of cytoreduction, morbidity, duration of hospital stay and survival., Results: A total of 323 procedures were performed between January 1996 and June 2006, 184 for peritoneal carcinomatosis of colorectal cancer origin and 139 for pseudomyxoma peritonei (PMP), including second procedures in 11 patients with PMP. The mean SPCI score decreased significantly over the study period (P < 0.001), but the number of regions affected did not. The rate of complete cytoreductions increased from 35.6 to 65.1 per cent (P = 0.012). The postoperative morbidity rate decreased from 71.2 to 34.1 per cent (P < 0.001). The median duration of hospital stay decreased from 24 to 17 days. The peak of the learning curve, graded by the percentage of complete cytoreductions, was reached after approximately 130 procedures., Conclusion: The learning curve of combined modality treatment for peritoneal surface disease is long, and reflects patient selection and treatment expertise., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

Pseudomyxoma peritonei (PMP) is a rare condition, which is known for its high mortality when not treated properly. The first step to improve prognosis of these patients is to recognize this clinical syndrome preferably in an early stage. Knowledge of pathogenesis and common diagnostic tools is essential in this regard. Treatment strategy for PMP should pursue complete cytoreduction and prevention of recurrence or progression. Combined modality treatment, consisting of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, seems very efficient in this regard. This approach is currently carried out in many centers throughout the world with promising results and seems to win ground as the standard treatment approach.

Three patients, men aged 47 and 30 and a woman aged 48 years, presented with appendicitis-like symptoms, progressive abdominal distension, and an ovarian pelvic mass, respectively. All three were diagnosed with pseudomyxoma peritonei. Treatment consisted of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). After a mean follow-up of 64 months (range: 19-89) after initial treatment, the second patient had died of disease progression but the other two were alive and free of disease. Pseudomyxoma peritonei is a rare disease, characterised by progressive intraperitoneal accumulation of mucinous ascites, produced by a mucinous tumour mass on the peritoneal surfaces. The primary tumour is usually a mucinous adenoma of the appendix. Treatment by cytoreductive surgery and HIPEC can result in a 5-year survival rate of more than 80%, depending on the histopathology and the completeness of the cytoreduction. Recognising pseudomyxoma peritonei in an early stage, when complete cytoreduction is still achievable, may result in a considerable improvement in survival.

Aims: To report on treatment related toxicity and mortality in patients with pseudomyxoma peritonei (PMP) treated by cytoreduction in combination with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and to identify prognostic factors., Methods: A review was performed of 103 procedures of cytoreduction and intraoperative HIPEC for PMP between 1996 and 2004. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) classification. A surgical complication was defined as any post-operative event that needed re-intervention. Pre and peroperative factors were studied on their relationship to toxicity and mortality., Results: The median hospital stay was 21 days (4-149) with a treatment related toxicity of 54% and a 30 days mortality of 3%. In univariate analysis, toxicity was associated with abdominal tumour load (p<0.01), completeness of cytoreduction (p<0.01), and age (p=0.05). Surgical complications, mainly small bowel perforations/suture leaks, were the main cause of toxicity. A favourable pathology decreased mortality., Conclusions: Cytoreduction in combination with intraoperative HIPEC in PMP patients is a treatment with a relatively high toxicity, but a considerable long-term survival in selected patients. Toxicity is mainly surgery related. Concentration of cases to acquire sufficient experience and better selection on age, pathology, and extent of disease is essential to reduce treatment related toxicity and mortality.

Aim: A survival benefit has been observed for colorectal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). However, this treatment modality is associated with a considerable morbidity and mortality and in a significant number of patients survival is not improved. We studied whether poor survivors could be identified on preoperative computed tomography (CT), in order to avoid unnecessary surgery., Patients and Methods: Films of abdominopelvic CT scans from 25 such patients treated by cytoreductive surgery and HIPEC were retrospectively analysed by two radiologists separately. A simplified peritoneal cancer index (SPCI) was used to determine the extent of peritoneal involvement. Correlation between the on preoperative CT based SPCI-scores as well as number of involved abdominopelvic areas (N) and survival was examined with the log-rank test. The relation between each affected region and survival was evaluated with Cox regression analysis., Results: The preoperative SPCI- and N-scores of one of the radiologists had no statistically significant prognostic value, while for the second radiologist SPCI > or = 7 and N > or = 4 were associated with particularly poor outcome. Additionally, the presence of ileocaecal region involvement and, depending on the radiologist, the occurrence of tumour deposits in the left subdiaphragmatic area on CT appeared to be unfavourable prognostic signs., Conclusions: The prognostic value of preoperative conventional CT appeared to be radiologist dependent and may, therefore, be of limited value in selecting colorectal cancer patients with peritoneal carcinomatosis who will not benefit from extensive cytoreductive surgery followed by HIPEC.

Background: Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by intraperitoneal accumulation of mucus produced by neoplastic cells of mostly appendiceal origin. The aim of this study was to analyze primary and secondary involvement and treatment-related complications of the urinary tract in PMP., Methods: A retrospective study of 92 patients with PMP, treated by cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) at The Netherlands Cancer Institute between 1996 and 2004., Results: Seven patients presented with involvement of the urinary tract. Major urologic complications occurred in five patients, of which two had secondary involvement of the urinary tract. Major urologic complications consisted predominantly of surgical complications related to the bladder. All patients with secondary involvement and/or urologic complications had undergone previous pelvic surgery., Conclusions: The urinary tract is rarely involved in patients with PMP. Secondary involvement is mostly observed and may be a result of seeding of PMP of pelvic origin after prior pelvic surgery. There is a low urologic complication risk of treatment with cytoreduction and HIPEC. The combination of secondary involvement and previous pelvic surgery is an omen of treatment-related urologic complications, necessitating (surgical) re-interventions and further management in close collaboration with urologists., ((c) 2005 Wiley-Liss, Inc.)

Aims: To report the results of standard therapy for peritoneal carcinomatosis of colorectal origin, which consists of conventional surgery and systemic chemotherapy., Method: In a prospective study 50 patients with proven peritoneal carcinomatosis of colorectal origin were treated with conventional surgery combined with 5-fluorouracil and leucovorin, or irinotecan in patients treated by 5-fluorouracil within 12 months prior to entry. Survival and progression-free survival were studied and prognostic factors were analysed., Results: The median survival time was 12.6 months. The median time to progression was 7.6 months. Location of primary tumour and result of conventional surgery and systemic chemotherapy were prognostic factors related to survival., Conclusion: The survival time of patients with peritoneal carcinomatosis of colorectal origin seems to be increased in patients treated by conventional surgery and systemic chemotherapy when compared to minimal treatment.

Background: Peritoneal carcinomatosis in the absence of distant metastasis occurs in approximately 8 per cent of patients with colorectal cancer. Cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a new treatment option. Patient selection is crucial to outcome., Methods: Cytoreduction followed by HIPEC was performed in 102 patients with peritoneal carcinomatosis. The following factors were studied for association with survival: perforation and obstruction of the primary lesion, location of the primary lesion, obstruction associated with carcinomatosis, presentation, tumour differentiation and histological type. Extent of disease and completeness of cytoreduction were also studied. Hazard ratios (HRs) were used to study these factors., Results: Location of the primary tumour in rectum (HR 3.14 (95 per cent confidence interval (c.i.) 1.11 to 8.91); P = 0.069), poor differentiation (HR 1.73 (95 per cent c.i. 1.04 to 2.88); P = 0.031) and signet cell histological type (HR 2.24 (95 per cent c.i. 1.21 to 4.16); P = 0.008) were associated with shorter survival. Important factors predicting survival were the number of affected regions (HR 1.38 (95 per cent c.i. 1.20 to 1.59); P < 0.001), the simplified peritoneal cancer score (HR 1.19 (95 per cent c.i. 1.12 to 1.26); P < 0.001) and completeness of cytoreduction (HR 8.54 (95 per cent c.i. 4.01 to 18.18); P < 0.001). No other factor correlated with survival., Conclusion: The survival of patients with peritoneal carcinomatosis of colorectal origin is dominated by the extent of disease and the amount of residual tumour after cytoreduction., (Copyright 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Aim: The aim of this study was to determine the value of medical history and physical examination, tumour marker testing, and CT-scanning in the follow-up of patients treated for peritoneal carcinomatosis of colorectal origin., Methods: Between November 1995 and June 2003, 107 patients were treated by cytoreduction and hyperthermic intra-peritoneal chemotherapy. The treatment was considered effective if residual tumour after cytoreduction was no thicker than 2.5 mm. The follow-up consisted of history, physical examination, serum CEA and CA 19.9 testing three-monthly, and CT-scanning of the abdomen six-monthly. Location of the recurrence was categorized into intra-abdominal, hepatic, thoracic, and both intra-abdominal and systemic. The investigation that led to the detection of a recurrence was ranked according to its invasiveness and costs. The simplest investigation that could have led to the detection was marked., Results: A recurrence developed in 63 patients of the 74 patients effective initial treatment during the study period. Physical examination revealed the recurrence in 38 patients, at least one of the markers was raised above normal value in 39 patients and in 37 patients the CT-scan showed the recurrence. History and physical examination could have triggered the finding of a recurrence in 38 patients, tumour markers in 21 patients and CT-scanning in only three of the 74 recurrences., Conclusion: Physical examination and tumour marker testing detect most recurrences. CT-scanning is not an effective tool in the follow-up, and should be reserved for on-demand use.

Aim: Pseudomyxoma peritonei (PMP) is a rare disease characterized by the abundance of mucus in the abdomen without extra-peritoneal growth., Methods: Our patients with PMP have been treated with cytoreduction and hyperthermic intraperitoneal chemotherapy since 1996. The clinical and histopathological features of PMP and the relation of these features with disease-free interval and survival were assessed., Results: Sixty-two patients with PMP (24 M/38 F) were studied. Adenomatous mucosal changes were present in 31 patients. In females, the ovaries were normal in 5 patients and pseudomyxoma ovarii was present in 20 patients. Patients with minimal atypia and with 1% focal proliferation or less (n=38) had a better survival (p=0.0008) than those with more focal proliferation (n=14)., Conclusion: In most patients with PMP the appendix is affected; in females the ovaries are usually also involved. Focal proliferation appears to be a prognostic factor.

The favorable pharmacokinetics of MMC, used during intraperitoneal chemotherapy, has been reported in several studies [11-19]. A major safety issue in studies using intraperitoneal chemotherapy perfusion is the resulting systemic drug exposure. The AUCplasma is determined by the dose, the clearance, and the fraction absorbed from the peritoneal cavity. The reported mean plasma peak concentrations are about one-third of the systemic exposure following a therapeutic dose of MMC given by intravenous administration [30]. The best method to quantify the exposure to MMC are the time concentration profiles (AUC). Because MMC can still be found in plasma the day after intraperitoneal administration, the AUC0-90 is an underestimate of the real AUC; extrapolation to infinity gives the most reliable AUCplasma value. In our series the AUCplasma is about half the AUCplasma when given a therapeutic dose MMC intravenously [30]. What is the best dose in intraperitoneal chemotherapy perfusion? The ideal amount of MMC should include a high AUCperfusate, a high AUCplasma and an acceptable systemic toxicity. In our series grade III/IV leucopenia was observed in 28% patients. We find this rather high percentage acceptable as the problem has proved to be transient, and we have experienced no toxic deaths in recent years. In a phase I study it was estimated that a dose of 25 mg/m2 would result in approximately 10% of grade III/IV leucopenia [20]. Our data indicate that dosing based on body surface area is rational and reliable. The variation between individuals is low. Dosing based on a fixed concentration per liter perfusion fluid is probably more liable to have unforeseen variations, given the fact that we deal with linear pharmacokinetics of MMC [20]. As represented in Fig. 3, the dose of MMC can best be administered in three divided doses, resulting in the more equal exposure of peritoneal structures to MMC during the perfusion. It must be emphasized that our findings only hold true for the perfusion system as used in The Netherlands Cancer Institute. This involves a semi-open abdomen, basic perfusate volume of 3 L, perfusion rate of 1 L/min, abdominal temperature of 40 degrees C, 90 minutes of perfusion, and three drug additions (50% at t = 0, 25% at t = 30 and t = 60 minutes). The differences in perfusion techniques make comparisons of published pharmacokinetics data difficult. Cautions comparison suggest that most groups are dosing far below the maximal tolerated dose. We assume that there is a dose-effect relation for MMC. This means that obtaining a maximal safe dose is important to get maximal results. It seems that better dosing of intraperitoneal MMC can still improve results. The pharmacokinetics of intraperitoneal MMC can, however, be influenced by many details. Open or closed perfusion for instance may make some essential differences. It is therefore important that each treatment group performs its own pharmacokinetics studies on intraperitoneal MMC to achieve the optimal dose method for their chemotherapy perfusion setting. In conclusion, the major advantage of intraperitoneal chemotherapy is the regional dose intensity provided. Following intraperitoneal MMC administration, the affected peritoneal surface is exposed to high concentrations while the systemic toxicity is limited. Comparative analyses on MMC pharmacokinetics are difficult to perform because the diversity of treatment techniques. We recommend administration of MMC, divided in three drug additions, based on BSA.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C has been applied following cytoreductive surgery for various peritoneal surface malignancies. The aim of this study was to evaluate heat penetration in the abdomen during 10 HIPEC procedures., Materials and Methods: Temperature measurements were taken at 5 levels through the abdominal wall. Core temperature and room temperature were also measured. The relationships between the temperature gradient and room or core temperature were studied., Results: At the start of perfusion, the temperature was estimated on average to be 40.6 degrees C at the first level, then it decreased by 1.7 degrees C (SD 1.0 degree C, p = 0.0001) in the first mm. In outward direction, it decreases by a further 1.5 degrees C per cm (SD 0.3 degree C/cm, p < 0.0001). The core temperature influenced the temperature gradient; the room temperature was not found to be a significant factor. At the end of perfusion, the temperature is estimated on average to be 40.1 degrees C at the first level, then it decreased by 0.8 degree C (SD 0.7 degree C, p = 0.011) in the first mm. In an outward direction, it decreased by a further 1.7 degrees C per cm (SD 0.4 degree C/cm, p = 0.0001). No evidence of an association between the temperature gradient and the room temperature or the core temperature was observed., Conclusion: Hyperthermia used during HIPEC procedures has a limited penetration depth. The slope in temperature seems to be related to the core temperature.

Background: Tumor markers are useful for diagnosis and follow-up. We studied the prognostic value of baseline and serial carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) measurements in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: Sixty-three patients with pseudomyxoma peritonei were treated with cytoreductive surgery and HIPEC. The tumor markers CEA and CA19.9 were collected before therapy and at 3-month intervals during follow-up., Results: Preoperative CEA and CA19.9 levels were increased in, respectively, 75% and 58% of the patients. Baseline tumor marker values were related to the extent of tumor. Immediately after HIPEC, both tumor markers decreased markedly (P <.0001). CA19.9 was shown to be a more useful tumor marker than CEA for follow-up. During follow-up, a high absolute CA19.9 level (P =.0005) was predictive for imminent recurrence. Patients who never attained a normal CA19.9 level showed a higher recurrence rate at 1 year (53%; SE, 15%), in comparison to patients who did so (6%; SE 4%). The median lead time of increased CA19.9 to recurrence was 9 months., Conclusions: The measurement of the tumor marker CA19.9 is useful in evaluating therapy in patients with pseudomyxoma peritonei treated with cytoreductive surgery and HIPEC. CA19.9 is a prognostic factor for predicting recurrent disease.