Specific genomic aberrations in primary colorectal cancer are associated with liver metastases

Background: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods: Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25). A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM). Results: Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations. Conclusion: Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management.MediamaticsElectrical Engineering, Mathematics and Computer Scienc

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 degrees C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival

Morbidity Associated with Colostomy Reversal After Cytoreductive Surgery and HIPEC

ABSTRACT Background. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the survival in selected colorectal cancer patients with peritoneal metastases. In these patients, the risk of a low anastomosis is sometimes diminished through the creation of a colostomy. Currently, the morbidity and mortality associated with the reversal of the colostomy in this population is unknown. Methods. Our study involved two prospectively collected databases including all patients who underwent CRS-HI-PEC. We identified all consecutive patients who had a colostomy and requested a reversal. The associations between four clinical and ten treatment-related factors with the outcome of the reversal procedure were determined by univariate analysis. Results. 21 of 336 patients (6.3 %) with a stoma with a mean age of 50.8 (standard deviation 10.2) years underwent a reversal procedure. One patient was classified as American Society of Anesthesiologists (ASA) grade III, 6 as ASA grade II, and the remaining as ASA grade I. Median time elapsed between HIPEC and reversal was 394 days (range 133-1194 days). No life-threatening complications or mortality were observed after reversal. The reversal-related morbidity was 67 %. Infectious complications were observed in 7 patients (33 %). Infectious complications after HIPEC were negatively correlated with the ultimate restoration of bowel continuity (P = 0.05). Bowel continuity was successfully restored in 71 % of the patients. Conclusions. Although the restoration of bowel continuity after CRS-HIPEC was successful in most patients, a relatively high complication rate was observed. Patients with infectious complications after HIPEC have a diminished chance of successful restoration of bowel continuity. Colorectal carcinoma is the third most common cancer worldwide, accounting for approximately 1 million newly diagnosed patients per year and over 600,000 deaths due to this disease. 1 Approximately 10-25 % of colorectal cancer patients develop peritoneal metastases, of whom 25 % present with the peritoneum as the sole site of distant metastases. 2-4 The peritoneum is a thin membrane that covers the abdominal wall and internal organs. 5 Peritoneal metastases are believed to be the result of tumor cell shedding into the peritoneal cavity, either spontaneously or as a result of spill during surgical procedures, ultimately resulting in the development of tumor deposits on the peritoneal surface

Challenging the dogma of colorectal peritoneal metastases as an untreatable condition: Results of a population-based study

To determine the impact of the implementation of novel systemic regimens and locoregional treatment modalities on survival at population level in colorectal cancer (CRC) patients presenting with peritoneal metastases (PMs). All consecutive CRC patients with synchronous PM ( <3 months) between 1995 and 2014 were extracted from the Eindhoven area of the Netherlands Cancer Registry. Trends in treatment and overall survival were assessed in four time periods. Multivariable regression analysis was used to analyse the impact of systemic and locoregional treatment modalities on survival. A total of 37,036 patients were diagnosed with primary CRC between 1995 and 2014. Synchronous PM was diagnosed in 1,661 patients, of whom 55% had also metastases at other sites (n = 917) and 77% received anticancer therapy (n = 1,273). Treatment with systemic therapy increased from 23% in 1995-1999 to 56% in 2010-2014 (p < 0.0001). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was applied since 2005 and increased from 10% in 2005-2009 to 23% in 2010-2014. Surgery for lymphatic or haematogenous metastases increased from 2% to 10% in these periods. Median overall survival of the complete cohort improved from 6.0 months in 1995-2000 to 12.5 months in 2010-2014 (p < 0.0001), with a doubling of survival for both PM alone and PM with other involved sites. The influence of year of diagnosis on survival (hazard ratio, 2010-2014 versus 1995-1999; 0.5, 95% confidence interval: 0.43-0.62; p < 0.0001) disappeared after including systemic therapy and locoregional treatment modalities in subsequent multivariable models. CRC patients presenting with PM are increasingly offered a multidisciplinary treatment approach, resulting in an increased overall survival for the entire cohor

Implementation of a Standardized HIPEC Protocol Improves Outcome for Peritoneal Malignancy

Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented. The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP). Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p <0.001), more resections (mean 3.8 vs. 3.4, p <0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p <0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p <0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group. This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity

Specific genomic aberrations in primary colorectal cancer are associated with liver metastases

Abstract Background Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25). A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM). Results Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations. Conclusion Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management.</p

Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study

Background: In the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS). Methods: Between 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS. Results: A total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40-5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47-0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67-0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06-1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high frequency referring hospitals (12.6 months, HR 0.82 [0.73-0.91]) and reduced in low frequency referring hospitals (8.1 months, HR 1.12 [1.01-1.24]). Conclusion: Treatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC. (C) 2017 Elsevier Ltd. All rights reserved