Peter H Cashin

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis: Prognosis and treatment of recurrences in a cohort study

BACKGROUND Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal carcinomatosis (PC) is gaining acceptance, but controversy remains. The primary aims were to analyse the outcome and prognostic variables of colorectal PC patients treated with CRS and IPC, and to report on the outcome of additional surgical treatments of subsequent recurrences. METHODS Patients referred for treatment of colorectal PC between 1996 and 2010 were included in a cohort. The following data was collected: clinicopathological parameters, survival, recurrences, perioperative chemotherapy and type of IPC (hyperthermic intraperitoneal chemotherapy, HIPEC; or sequential postoperative intraperitoneal chemotherapy, SPIC). Multivariable analyses were conducted on potential prognostic factors for overall survival (OS). RESULTS In the 151-patient cohort, the median OS was 34 months (range: 2-77) for CRS and HIPEC with five-year survival predicted at 40% (five-year disease-free survival 32%). For CRS and SPIC, the OS was 25 months (range: 2-188) with five-year survival at 18%. Open-and-close patients survived 6 months (range: 0-14) with no five-year survival (HIPEC vs. SPIC p = 0.047, SPIC vs. open-and-close p < 0.001). Adjuvant systemic chemotherapy was a noteworthy independent prognostic factor in the multivariable analysis. OS for patients undergoing additional surgical treatment of recurrences was 25 months vs. 10 months with best supportive care or palliative chemotherapy (p = 0.01). CONCLUSION Substantial long-term survival is possible in patients with colorectal PC. HIPEC was associated with better OS than SPIC and adjuvant systemic chemotherapy may improve the outcome in patients. Good OS is achievable in selected patients undergoing additional surgical treatment of isolated liver or peritoneal recurrences after prior complete CRS.

Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case–control study

BACKGROUND Cytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer. PATIENTS AND METHODS A matched case-control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared. RESULTS Median overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group. CONCLUSION HIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.BACKGROUND Cytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer. PATIENTS AND METHODS A matched case-control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared. RESULTS Median overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group. CONCLUSION HIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.

Patient Selection for Cytoreductive Surgery in Colorectal Peritoneal Carcinomatosis using Serum Tumour Markers – an Observational Cohort Study

Objective:There were 2 objectives: first, to investigate how many patients were excluded from surgery on the basis of the radiological extent of the peritoneal carcinomatosis (PC) or the clinical examination; and second, to develop a score based primarily on serum tumor markers (STMs) that could predict short cancer-specific survival (<12 months). Background:Patient selection and prediction of prognosis is crucial for successful treatment of colorectal PC. Methods:All patients with colorectal PC referred for cytoreductive surgery and intraperitoneal chemotherapy (2005–2008) at Uppsala University hospital were included. Patients were divided into 2 groups—nonsurgery and surgery. Clinicopathological and laboratory parameters were collected in the surgery group. A Corep (COloREctal-Pc) score was developed using hazard ratios from histology, hematological status, serial serum tumor markers (STMs), and STM changes over time. Sensitivity, specificity, positive predicted value (PPV), and negative predicted value (NPV) were calculated in a second validating dataset (n = 24) with a survival cutoff of less than 12 months. Results:A total of 107 patients were included in the study, 42 in the nonsurgery group and 65 in the surgery group. In the nonsurgery group, 2 patients were excluded solely on the basis of the radiological extent of PC and 7 patients on clinical examination. The Corep score ranged from 0 to 18. A score of 6 or more showed a validated sensitivity of 80%, specificity 100%, PPV 1.0, and NPV 0.93. Conclusions:Radiological extent of PC was not a main deciding factor for treatment decisions and had less impact than the clinical examination. The Corep score identified patients with short cancer-specific survival that may not be suitable for treatment.

Cytoreductive Surgery and Hyperthermic Intra-Peritoneal Chemotherapy Treatment of Colorectal Peritoneal Metastases : Cohort Analysis of High Volume Disease and Cure Rate

Cytoreductive surgery (CRS) and hyperthermic intra‐peritoneal chemotherapy (HIPEC) treatment of colorectal peritoneal metastases (PM) is an established treatment alternative. The study aim was, first, to investigate the outcome of high‐volume disease defined by the peritoneal cancer index (PCI) 20; second, to report the long‐term disease‐free survival of patients with >5 years observation.

Activity ex vivo of cytotoxic drugs in patient samples of peritoneal carcinomatosis with special focus on colorectal cancer

BackgroundThe optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with cytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis (PC) is poorly defined. We investigated drug sensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity within the subset of PC from colorectal cancer (CRC).MethodsPC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or appendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan, docetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset.ResultsMesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and PMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug sensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not obviously correlate to time-to-progression (TTP) in individual patients.ConclusionsDrug-sensitivity varies considerably between PC diagnoses and individual patients arguing for individualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of treatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and concentration perspective. In the CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was inconclusive due to the heterogeneous nature of the data.

Preliminary Finding: Detection of Circulating Cancer Cells in Blood from a Patient with Peritoneal Carcinomatosis Treated with Cytoreductive Surgery and Intraperitoneal Chemotherapy

Background: Patients with Peritoneal Carcinomatosis (PC) from colorectal cancer have a poor prognosis. Aggressive treatments by Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) offer a cure in selected patients with PC. However, in the great majority of patients the disease will recur in liver or lung. The underlying cause for recurrence could be the existence of Circulating Cancer Cells (CTCs) in PC patients prior to or at the time of CRS and HIPEC. There is a need for new cell-surface marker independent techniques to detect and isolate CTCs. We decided to try one such new technique, developed by Liquid Biopsy, and made available to us as a pre-production model. This method isolates both EpCAM positive and EpCAM negative CTCs potentially detecting a wider, more representative, sample of cells than samples restricted to certain known cell surface markers (Lab Chip, 2011, 11, 375). Methods: This report focuses on a PC patient treated by CRS and HIPEC. The patient presented with PC from caecal cancer. Prior to CRS and HIPEC, the patient was treated with neoadjuvant chemotherapy. CTCs were isolated from peripheral blood preoperatively, at one week and one month after CRS and HIPEC using the novel marker independent method (Liquid Biopsy, patent pending). Conventional soluble serum tumour markers were also taken and analysed at the same time as the CTCs. Findings: The preoperative level of CTCs was 25 cells/5 ml bloods. One-week post CRS and HIPEC, CTCs level was 21 cells/5 ml blood and one-month after CRS and HIPEC no CTC cells could be detected in 5 ml blood. Serum tumour marker analysis of preoperative CEA showed 5.8 (ref 600 (ref <6.9 KE/L). One week post CRS and HIPEC, CEA was normalised (1.6) and CA72-4 was significantly reduced to 31.1. Interpretation: It appears that CTCs can be detected successfully in peritoneal carcinomatosis opening up the possibility to study the molecular characteristics of these CTCs. CTC numbers are also seen to drop to undetectable levels following radical surgery. Thus the occurrence and characteristics of CTCs in blood have the potential to assist decision making when considering treating patients with postoperative adjuvant systemic chemotherapy.

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.