Impact of ovarian metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancy originating from appendiceal and colorectal cancer.

AIM: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. METHOD: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. RESULTS: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty-two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low-grade appendiceal tumour or CPM. In women with high-grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. CONCLUSION: Women with ovarian metastases from low-grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long-term survival and cure is feasible in patients amenable to complete tumour removal.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1000 patients with perforated appendiceal epithelial tumours.

PURPOSE: To report early and long term outcomes following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in 1000 patients with perforated appendiceal epithelial tumours, predominantly with pseudomyxoma peritonei (PMP). METHODS: Retrospective analysis of a prospective database of 1000 consecutive patients undergoing CRS and HIPEC for perforated appendiceal tumours between 1994 and 2014 in a UK National Peritoneal Malignancy unit. RESULTS: Overall 1000/1444 (69.2%) patients treated for peritoneal malignancy had appendiceal primary tumours. Of these 738/1000 (73.8%) underwent complete cytoreductive surgery (CCRS), 242 (24.2%) had maximal tumour debulking (MTD) and 20 (2%) had laparotomy and biopsies only. Treatment related 30-day mortality was 0.8% in CCRS and 1.7% in MTD group with major postoperative morbidity rates of 15.2% (CCRS) and 14.5% (MTD). Five- and 10-year overall survival was 87.4% and 70.3% in the 738 patients who had CCRS compared with 39.2% and 8.1% respectively in the MTD group. On multivariate analysis, significant predictors of reduced overall survival were male gender (p = 0.022), elevated CEA (p = 0.001), elevated CA125 (p = 0.001) and high tumour grade or adenocarcinoma (p = 0.001). CONCLUSIONS: Perforated epithelial appendiceal tumours are rare, though may be increasing in incidence and can present unexpectedly at elective or emergency abdominal surgery, often with PMP. CRS and HIPEC results in good long term outcomes in most patients.

The results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1200 patients with peritoneal malignancy.

AIM: The study determined the outcome of 1200 consecutive patients treated for peritoneal malignancy in one surgical unit over a 20-year period. METHOD: A retrospective analysis was conducted of a custom designed prospective database of patients undergoing surgery for peritoneal malignancy since 1994. Patient demographics, tumour type, extent of surgery and outcome were recorded. RESULTS: Between 1994 and January 2014 (when the 1200th case had undergone surgery) 2956 patients were referred with a diagnosis of peritoneal malignancy. Pseudomyxoma peritonei of appendiceal origin was the pathology in 956/1200 (79.7%) patients. Other aetiologies included colorectal peritoneal metastases [89/1200 (7.4%)], abdominal mesothelioma [65/1200 (5.4%)] and miscellaneous [90/1200 (7.5%)]. Overall 863/1200 (71.9%) had complete cytoreduction, 294 (24.5%) had maximal tumour debulking and 43 (3.6%) had laparotomy only. The proportion undergoing complete cytoreduction per quartile of 300 patients was 60.7%, 65.0%, 77.0% and 80.3%. Laparotomy and biopsy fell from 6.4% in the first quartile to 2.7%, 1.7% and 1.3% in subsequent quartiles. The 30-day mortality in the four quartiles was 3.0%, 1.0%, 0.7% and 0.7%. The 5-year survival was 84% in the 636 patients with appendix tumours who had complete cytoreduction, 76% in the 38 with abdominal mesothelioma and 44% in the 60 with colorectal peritoneal metastases. CONCLUSION: A centralized approach facilitated high volume experience in a single centre with an increase in the completeness of surgical excision rates and a reduction in mortality and morbidity over time.

Elevated tumour markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumour removal.

AIM: Elevation of the preoperative tumour markers in pseudomyxoma peritonei (PMP) is common and is a risk factor for recurrence. There has, however, been no documentation of the effect of complete tumour removal on tumour markers levels after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of the study was to compare the tumour markers 7 days after surgery in patients with elevated preoperative levels. METHOD: This was an observational prospective study of patients with PMP of appendiceal origin treated in one of the UK National Referral Centres for this condition. Thirty patients [median age = 61 (range: 31-74) years; six men] with an elevated preoperative level of carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA-125) and/or carbohydrate antigen 19-9 (CA19-9) underwent repeated estimation, 7 days after CRS and HIPEC for PMP. RESULTS: The median preoperative CEA level of 12 µg/l fell to 0.75 µg/l postoperatively (P < 0.0001), CA-125 fell from 45 to 31 kU/l (P = 0.183) and CA19-9 fell from 134 to 37 kU/l (P = 0.003). The CEA was raised in 22 (73%) of 30 patients preoperatively and in two (7%) of 30 patients 7 days after surgery (P < 0.0001). The corresponding data for CA-125 were 18 (60%) and 13 (43%) (P = 0.196) and for CA19-9 they were 24 (80%) and 16 (53%) (P = 0.028). CONCLUSION: This is the first documentation of a reduction or normalization of CEA 7 days after CRS, but not for CA19-9 or CA-125. This may indicate completeness of surgical resection and could aid selection for adjuvant therapy and predict prognosis. Long-term follow-up is, however, necessary to determine the significance of this observation.

Risk of definitive stoma after surgery for peritoneal malignancy in 958 patients: comparative study between complete cytoreductive surgery and maximal tumor debulking.

INTRODUCTION: Complete cytoreductive surgery (CRS) can achieve cure or long-term survival in selected patients with peritoneal malignancy. In selected patients, due to extensive disease, complete tumour removal is impossible and optimal strategy may be maximal tumour debulking (MTD). We analysed the stoma related outcome in a series of patients undergoing surgery in a National Peritoneal Malignancy Referral Centre. METHODS: All patients who underwent CRS, with or without, intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) between 1994 and 2012 were included. Data was collected prospectively in an institutional database and analysed retrospectively. RESULTS: CRS was performed in 958 patients (female: 595, male: 363) of whom 781 (81.5%) had a primary appendix tumour, 63 (6.6%) had a colorectal primary, 47 (4.9%) peritoneal mesothelioma, 38 (4%) an ovarian tumour and 29 patients (3%) other tumours. Complete CRS was achieved in 72% (693/958). Overall 352/958 (37%) had a stoma, which was permanent in 165/958 (17.2%). The median time interval from CRS to reversal of stoma was 4.4 months (range: 1.4-13.8). Stomas were created in 113/265 (42.6%) at MTD (permanent: n = 105 (93%), temporary: n = 8 (7%)), and 239/693 (34.5%) at complete CRS (permanent: n = 60 (25%), temporary: n = 179 (75%)) (p = 0.020). All temporary stomas in the 168/693 (24.4%) of patients who had complete CRS were subsequently reversed. CONCLUSION: To achieve complete CRS for peritoneal malignancy a stoma is often required and in a proportion this will be permanent. Overall over one third had a stoma at surgery with almost half subsequently reversed.

Recurrence and outcome after complete tumour removal and hyperthermic intraperitoneal chemotherapy in 512 patients with pseudomyxoma peritonei from perforated appendiceal mucinous tumours.

BACKGROUND: Pseudomyxoma peritonei (PMP) usually originates from perforated mucinous appendiceal tumours and may present unexpectedly at surgery, or be suspected at cross sectional imaging. The optimal treatment involves macroscopic tumour removal by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The 10-year Kaplan-Meier predicted disease-free survival is 61%. Some patients with recurrence are amenable to further CRS and HIPEC. AIM: To evaluate the outcomes of re-do surgery in a large single centre series of reoperation for recurrence of peritoneal surface malignancy. METHOD: Retrospective analysis of prospective database of 752 patients undergoing CRS for perforated appendiceal tumours analysed. Routine follow up involved annual CT scans and serum tumour marker measurement. The survival and recurrence in the 512/752 (68.1%) who had complete cytoreduction between March 1994 and January 2012 was calculated by Kaplan-Meier univariate analysis. RESULTS: Overall 137/512 (26.4%) developed recurrence and of those 35/137 (25.5%) underwent repeat surgery. Complete tumour removal was again achieved in 20/35 (57.1%). There were no postoperative deaths and no significant difference in early postoperative complications and length of stay compared to primary CRS surgery. The 5-year survival in the 375 without recurrence, the 35 who had re-do surgery and the 102 who had recurrence with no surgery was 90.9%, 79.0% and 64.5% respectively. CONCLUSION: Approximately one in four patients develops recurrence after complete CRS and HIPEC for PMP of appendiceal origin. Selected patients can undergo salvage surgery with good outcomes.

Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients with colorectal peritoneal metastases compared with systemic chemotherapy alone.

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.

Pre-operative tumour marker status predicts recurrence and survival after complete cytoreduction and hyperthermic intraperitoneal chemotherapy for appendiceal Pseudomyxoma Peritonei: Analysis of 519 patients.

BACKGROUND: Cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the optimal treatment for Pseudomyxoma Peritonei (PMP). Despite treatment, disease often recurs and may not be amenable to further CRS. Clinical experience suggests a spectrum of disease which may correlate with tumour marker levels. The aim of this study was to analyse the influence of markers on recurrence and survival. METHODS: The details of all patients undergoing surgery for PMP of appendiceal origin at a national centre for peritoneal malignancy were recorded in a dedicated prospective database. The data on all patients who had CRS and HIPEC between March 1994 and January 2012 was analysed and recurrence and survival correlated with pre-operative levels of CEA, CA-125 and CA19-9. RESULTS: Overall, 519 (69%) of 752 consecutive patients, underwent complete CRS and HIPEC. The median (range) age was 56 (20-82) years with 342/519 (66%) females. The mean overall (OS) and disease free survival (DFS) in the 131/519 patients who had normal preoperative tumour markers was 168 (128-207) and 125 (114-136) months respectively, significantly higher when compared with the 109/519 (21%) who had all three tumour markers elevated (OS of 65 (42-88) and DFS of 55 (41-70) months respectively) (P = 0.002). CONCLUSIONS: Elevated tumour markers predict an increased risk of recurrence and reduced survival after complete CRS. This may reflect cell biology in low grade tumours and is an independent prognostic feature. Further analysis may help to select patients for post-operative chemotherapy, second look procedures or stratification of follow up.

The use of cardiac output monitoring to guide the administration of intravenous fluid during hyperthermic intraperitoneal chemotherapy.

AIM: The optimal strategy for intravenous (IV) fluid management during administration of hyperthermic intraperitoneal chemotherapy (HIPEC) is unclear. In this prospective study we describe the use of a LiDCOrapid™ (LiDCO, Cambridge, UK) cardiac output monitor to guide IV fluid management during cytoreductive surgery (CRS) with HIPEC. The aim of this study was to determine whether cardiac output monitoring will allow close maintenance of physiological parameters during the HIPEC phase. METHOD: Twenty-five patients who underwent CRS combined with HIPEC were included in the study. Intra-operative IV fluid boluses were titrated using parameters measured by the LiDCOrapid™ monitor. Stroke volume variation was maintained below 10% with fluid boluses and mean arterial pressure was maintained within 20% of the baseline figure with vasopressors. RESULTS: There was no significant change in heart rate and cardiac output. The systemic vascular resistance dropped from an average of 966 dyn.s/cm-5 to 797 dyn s/cm(5) at 60 min during the HIPEC phase (P = 0.62) despite an increase in the dose of phenylepherine. The average total volume of fluid given was 748 ml in the first 30 min and 630 ml in the second 30 min with an average urine output of 307 and 445 ml, respectively. The change in lactate levels was not statistically or clinically significant. CONCLUSION: LiDCOrapid™ is an effective noninvasive tool for guiding fluid management in this population. It allows the anaesthesiologist to maintain tight control of essential physiological parameters during a phase of the procedure in which there is a risk of renal injury.

Peritoneal metastases from colorectal cancer: patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment modality for patients with pseudomyxoma peritonei. The majority of patients with pseudomyxoma who have complete tumour removal and HIPEC are cured. Over the last decade CRS for peritoneal metastasis of colorectal origin has emerged as an effective treatment strategy in carefully selected patients. Although convincing evidence is limited, available data shows promising results. The key to a successful outcome is appropriate selection of patients. In patients with extensive peritoneal disease, where complete cytoreduction is not achieved, surgical treatment may not be beneficial and might impair quality of life. In this paper we discuss the challenges of selecting patients with colorectal peritoneal metastases who are likely to benefit from CRS with HIPEC.

Morphology of HRP-labelled cochlear nerve axons in the dorsal cochlear nucleus of the developing hamster.

To study the development of the central terminal arbors of the cochlear nerve fibers in the dorsal cochlear nucleus, horseradish peroxidase-labelled axons in young and adult hamsters were analyzed morphometrically. Brainstem slices with whole cochlear nuclei were maintained in a slice chamber and the cochlear nerve root was injected with a mixture of wheat germ agglutinin-horseradish peroxidase, horseradish peroxidase and poly-L-ornithine. The poly-L-ornithine was added to keep the injection site small; small injections resulted in only a few axons being labelled and permitted reconstruction of individual fibers. Axons underwent an initial period of ingrowth that was completed prior to the onset of hearing (postnatal day 16). After this time the morphology and area of influence of the axons remained unchanged but the nucleus continued to increase in size. Since no additional cochlear nerve axons grow into the nucleus during this period of nuclear growth, the existing axons necessarily become more widely spaced as development proceeds. These anatomical changes may contribute to the progressive narrowing of auditory cell tuning curves.