Adjuvant intraperitoneal 5-fluorouracil and intravenous leucovorin after colorectal cancer surgery: a randomized phase II placebo-controlled study Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial Results of Systematic Second-Look Surgery in Patients at High Risk of Developing Colorectal Peritoneal Carcinomatosis Laparoscopic hyperthermic intraperitoneal chemotherapy as adjuvant modality following radical surgery for advanced rectal cancer a new look to an old problem. Evaluation of Best Supportive Care and Systemic Chemotherapy as Treatment Stratified according to the retrospective Peritoneal Surface Disease Severity Score (PSDSS) for Peritoneal Carcinomatosis of Colorectal Origin Combined intravenous and intraperitoneal chemotherapy with fluorouracil + leucovorin vs fluorouracil + levamisole for adjuvant therapy of resected colon carcinoma. Prognostic Value of CEA and CA 19-9 Tumor Markers Combined with Cytology from Peritoneal Fluid in Colorectal Cancer Staged laparoscopic adjuvant intraperitoneal chemohyperthermia after complete resection for locally advanced colorectal or gastric cancer: a preliminary experience Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. Feasibility of adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy in a short stay setting in patients with colorectal cancer at high risk of peritoneal carcinomatosis. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. Significance of Signet-Ring Cells in Patients with Colorectal Cancer Prospective randomized trial of intravenous v intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer. Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: A multicenter phase III trial.
Fifty patients were r and omized to receive adjuvant intraperitoneal 5-fluorouracil ( 5-FU , 500 mg/m2/day ) and intravenous leucovorin ( 60 mg/m2/day ) and 51 to receive placebo after curative surgery for colorectal cancer . Treatment started on the day after surgery and continued for 6 days . One case of stomatitis , one of leucopenia and one case of abnormal liver function tests were the only chemotherapy-related toxic effects . From the second day of treatment , pain during intraperitoneal infusions occurred more frequently in the 5-FU group , although statistical significance was only attained on day 2 ( P<0.05 ) . The groups did not differ substantially regarding any other adverse effects , the incidence of surgical complications , second laparotomies , time from surgery to discharge , or premature treatment terminations . The postoperative course after intraperitoneal 5-FU and intravenous leucovorin was thus not more complicated than that in patients treated with placebo . The tolerance was acceptable and chemotherapy-related toxicity was rare . Thus important prerequisites exist for more widespread use of the present regimen in order to evaluate its impact on survival . RésuméCent un patients ont été r and omisés après traitement chirurgical curatif d'un cancer colorectal ; 50 patients ont reçu un traitement adjuvant intrapéritional de 5-FU ( 500 mg/m2/jour ) et intraveineux de Leucovorine ( 60 mg/m2/jour ) et 51 patients ont reçu un  placebo .  Le traitement a été instauré le 1er jour postopératoire et poursuivi durant 6 jours . Les seuls troubles consécutifs à la chimiothérapie observés ont été : 1 cas de stomatite , 1 cas de leucopénie et 1 cas de perturbation des tests hépatiques . A partir du 2ème jour de traitement , des douleurs intraperitionales surviennent plus fréquemment après l'infusion de 5FU bien que la différence ne soit statistiquement significative que pour le 2ème jour ( P<0,05 ) . Les groupes ne différent pas de manière significative quant à d'autres effets secondaires : incidence de complications chirurgicales , taux de relaparotomies , durée des séjours hospitaliers , interruption prématurée du traitement . Les suites postopératoires après injection intrapéritionale de 5FU et intraveineuse de Leucovorine ne sont pas plus compliquées qu'après l'administration d'un placebo . La tolérance est acceptable et la toxicité due à la chimiothérapie est rare . Ainsi , les bases sont établies pour un emploi plus extensif de cette combinaison chimiothérapique dans le but d'établir l'impact sur le taux de survie 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 clinical ly 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 r and omized 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 ° 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 . Trial registration numberNCT02231086 ( Clinical trials.gov Objective : The aim of this prospect i ve study was to analyze the impact of second-look surgery in an attempt to treat peritoneal carcinomatosis ( PC ) at an early stage in a series of patients at high risk of developing PC from colorectal cancer . Background : The prognosis of colorectal PC has recently been improved with hyperthermic intraperitoneal chemotherapy ( HIPEC ) after complete cytoreductive surgery ( CCRS ) , and could be further improved if PC could be treated at an early stage . But , currently , the diagnosis of early PC is not accessible to imaging . Patients and Methods : From 1999 to 2006 , 29 patients without any sign of recurrence on imaging studies underwent second-look surgery 13 months after resection of the primary tumor . Patients were selected according to primary tumor-associated criteria : resected minimal synchronous macroscopic PC ( n = 16 ) , synchronous ovarian metastases ( n = 4 ) , perforated primary tumor ( n = 9 ) . Results : PC was found and treated with CCRS plus HIPEC in 16 of 29 ( 55 % ) cases , corresponding to 10 of 16 patients with initial PC , 3 of 4 patients with synchronous ovarian metastases and 3 of 9 patients with a perforated primary tumor . There was no postoperative mortality , and morbidity ( grade III/IV ) occurred in 14 % of cases . After a median follow-up of 27 months ( range , 6–96 ) , 8 of 16 patients treated with CCRS and HIPEC are free of disease , 4 relapsed in the peritoneum , and 4 developed isolated visceral metastases . Conclusion : Performing second-look surgery at 1 year in selected patients at high risk of developing PC allowed the early detection and treatment of PC in 55 % of cases . Our preliminary results have encouraged us to pursue this strategy and to evaluate it in a prospect i ve multicenter trial BACKGROUND / AIMS The benefits of adjuvant chemotherapy for colorectal cancer has been well accepted over the last decade . Published data so far has been focused in the direction of giving the right chemotherapy dose , schedule , and combinations , in order to increase the efficacy and decrease the toxicity . METHODOLOGY Eighty-seven patients with histological proved stage III rectal carcinoma were subjected to a combined adjuvant modality using laparoscopic heperthermic endoperitoneal chemotherapy ( HIPEC ) and systemic chemotherapy twenty days following the initial surgery . RESULTS Seventy patients who completed a one year follow-up had a disease free survival . Among forty patients who completed the two year follow-up , two patients developed local recurrence . CONCLUSIONS Cytoreduction followed by HIPEC improves survival in patients with rectal carcinoma and lymphnode positive and neurovascular involvement Background We evaluate the long-term survival of patients with peritoneal carcinomatosis ( PC ) treated with systemic chemotherapy regimens , and the impact of the of the retrospective peritoneal disease severity score ( PSDSS ) on outcomes . Methods One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987 - 2006 were identified from a prospect i ve institutional data base . These patients either received no chemotherapy , 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy . Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinical ly relevant factors . Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test . Results Median survival was 5 months ( 95 % CI , 3 - 7 months ) for patients who had no chemotherapy , 11 months ( 95 % CI , 6 - 9 months ) for patients treated with 5 FU/LV , and 12 months ( 95 % CI , 4 - 20 months ) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy .  Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy ( p = 0.026 ) . PSDSS staging was identified as an independent predictor for survival on multivariate analysis [ RR 2.8 ( 95%CI 1.5 - 5.4 ) ; p < 0.001 ] . Conclusion A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy . The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin Adjuvant chemotherapy with fluorouracil ( FU ) and levamisole or FU/leucovorin ( LV ) has been established as effective adjuvant treatment for patients with stage III colon cancer . Among several other promising treatment strategies in resected colon cancer , intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation . To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole , the present r and omized study was initiated . A total of 241 patients with resected stage III or high-risk stage II ( T4N0M0 ) colon cancer were r and omly assigned to ' st and ard therapy ' with FU and levamisole , given for a duration of 6 months , or to an investigational arm , consisting of LV 200 mg m(-2 ) plus FU 350 mg m(-2 ) , both administered intravenously ( days 1 - 4 ) and intraperitoneally ( days 1 and 3 ) every 4 weeks for a total of six courses . In patients with stage II disease , no significant difference was noted between the two arms after a median follow-up time of 4 years ( range 2.5 - 6 years ) . Among 196 eligible patients with stage III disease , however , a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival ( P = 0.0014 ) and a survival advantage ( P = 0.0005 ) , with an estimated 43 % reduction in mortality rate ( 95 % confidence interval 26 - 70 % ) in favour of the investigational arm . In agreement with its theoretical rationale , combined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement ( 9 vs 25 patients in the FU/levamisole arm ; P = 0.005 ) . Treatment-associated side-effects were infrequent and generally mild in both arms , although a lower rate of severe ( WHO grade 3 ) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy ( 3 % vs 12 % ; P = 0.01 ) . The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage III colon carcinoma Background Early diagnosis and management of peritoneal metastases from colorectal cancer patients are difficult clinical challenges . The aims of this study were to evaluate the clinical significance of  tumor markers and cytology  in peritoneal effusions ( PE ) and peritoneal irrigation fluid ( PI ) and to determine their value as prognostic indicators in this disease . Methods Two hundred thirty-four consecutive patients who underwent abdominal surgery for colorectal cancer from January 2006 to December 2007 were included , and tumor markers and cytology in PE and PI were analyzed prospect ively . Results The incidence of free cancer cells retrieved from peritoneal sample s was 7.9 % . Cytology was positive in 40.0 % by Papanicolaou and Giemsa staining , 73.3 % by hematoxylin and eosin staining of cell blocks , and 66.7 % by carcinoembryonic antigen ( CEA ) and calretinin immunohistochemistry . Multivariate analysis revealed that peritoneal CEA and cancer antigen ( CA ) 19–9 in PI were correlated with peritoneal metastasis and cytology . Level of peritoneal fluid CEA was statistically significantly correlated with recurrence and peritoneal metastatic recurrence in patients with negative peritoneal cytology . Cytology , peritoneal CEA , and peritoneal CA 19 - 9 showed correlations with cancer-free survival and overall survival . Conclusions These correlations demonstrate the importance of continuous follow-up of peritoneal metastasis if there is positive cytology or an increase in CEA and CA 19 - 9 in peritoneal fluid Background Cytoreductive surgery followed by intraperitoneal chemohyperthermia ( IPCH ) is a promising treatment for patients with peritoneal carcinomatosis , a disease with dismal prognosis . Methods We describe our preliminary experience with staged adjuvant laparoscopic IPCH after complete resection in patients with locally or regionally advanced colorectal or gastric cancer . Results Twenty-one patients underwent resection for colorectal ( N = 16 ) or gastric cancer ( N = 5 ) followed by staged laparoscopic IPCH . No conversion to laparotomy was required . No major operative incident occurred . Mean duration of hospital stay was 12 days ( range 9–23 days ) . No mortality occurred in the 30-day postoperative period . Four patients developed major complications ( 19 % ) . One patient ( 5 % ) was reoperated . Mean follow-up period was 15.5 months ( range 9–29 months ) . Three patients died , including two of cancer-related causes . No patient developed peritoneal carcinomatosis during the follow-up period . ConclusionS taged laparoscopic adjuvant IPCH after open or laparoscopic resection in selected patients with colorectal or gastric cancer is feasible and reasonably safe . However , additional data are required to determine the effect on long-term survival PURPOSE Symptoms and complications of metastatic colorectal cancer ( mCRC ) differ by metastatic sites . There is a paucity of prospect i ve survival data for patients with peritoneal carcinomatosis colorectal cancer ( pcCRC ) . We characterized outcomes of patients with pcCRC enrolled onto two prospect i ve r and omized trials of  chemotherapy and contrasted that with other manifestations of mCRC ( non-pcCRC ) . METHODS A total of 2,095 patients enrolled onto two prospect i ve r and omized trials were evaluated for  overall survival ( OS ) and progression-free survival ( PFS ) . A Cox proportional hazard model was used to assess the adjusted associations . RESULTS The characteristics of the pcCRC group ( n = 364 ) were similar to those of the non-pcCRC patients in median age ( 63 v 61 years , P = .23 ) , sex ( 57 % males v 61 % , P = .23 ) , and performance status ( Eastern Cooperative Oncology Group performance status 0 or 1 94 % v 96 % , P = .06 ) , but differed in frequency of liver ( 63 % v 82 % , P < .001 ) and lung metastases ( 27 % v 34 % , P = .01 ) . Median OS ( 12.7 v 17.6 months , hazard ratio [ HR ] = 1.3 ; 95 % CI , 1.2 to 1.5 ; P < .001 ) and PFS ( 5.8 v 7.2 months , HR = 1.2 ; 95 % CI , 1.1 to 1.3 ; P = .001 ) were shorter for pcCRC versus non-pcCRC . The unfavorable prognostic influence of pcCRC remained after adjusting for age , PS , liver metastases , and other factors ( OS : HR = 1.3 , P < .001 ; PFS : HR = 1.1 , P = .02 ) . Infusional fluorouracil , leucovorin , and oxaliplatin was superior to irinotecan , leucovorin , and fluorouracil as a first-line treatment among pcCRC ( HR for OS = 0.62 , P = .005 ) and non-pcCRC patients ( HR = 0.66 , P < .001 ) . CONCLUSION pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC . Future trials for mCRC should consider stratifying on the basis of pcCRC status INTRODUCTION Treatment of peritoneal carcinomatosis ( PC ) of colorectal cancer ( CRC ) origin is relatively ineffective and associated with morbidity . This raises the question whether we should focus on prevention of the development of PC . We determined the feasibility of adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy ( HIPEC ) in a short stay setting . METHODS A prospect i ve single centre pilot study was conducted between January 2011 and July 2012 . Ten patients at risk of developing PC of CRC origin were included .  Laparoscopic HIPEC using Mitomycin-C ( 90 min ; inflow temperature 42 - 43 ° C ) was performed within several weeks after primary resection of CRC and was considered feasible when postoperative hospital stay was three days or shorter in at least six patients , and if a maximum of one conversion and one re-admission within 30 days occurred . RESULTS HIPEC was performed after a median of 6 weeks ( range 3 - 9 weeks ) . Postoperatively , five patients were discharged at day one , four patients at day two and one patient at day three . Laparoscopic adhesiolysis result ed in small bowel injury in one patient , but no conversion to open surgery and no postoperative complications were observed . One patient was readmitted within 30 days due to a clostridium infection . The postoperative course was uneventful for the remaining patients . CONCLUSION Adjuvant laparoscopic HIPEC appeared to be feasible in a short stay setting based on this small pilot study . The necessity of adhesiolysis determines the complexity of the procedure and requires an operating team with experience in minimally invasive abdominal surgery PURPOSE To confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy ( HIPEC ) is superior to st and ard treatment in patients with peritoneal carcinomatosis of colorectal cancer origin . PATIENTS AND METHODS Between February 1998 and August 2001 , 105 patients were r and omly assigned to receive either st and ard treatment consisting of systemic chemotherapy ( fluorouracil-leucovorin ) with or without palliative surgery , or experimental therapy consisting of aggressive cytoreduction with HIPEC , followed by the same systemic chemotherapy regime . The primary end point was survival . RESULTS After a median follow-up period of 21.6 months , the median survival was 12.6 months in the st and ard therapy arm and 22.3 months in the experimental therapy arm ( log-rank test , P = .032 ) . The treatment-related mortality in the aggressive therapy group was 8 % . Most complications from HIPEC were related to bowel leakage . Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions ( log-rank test , P < .0001 ) . If the cytoreduction was macroscopically complete ( R-1 ) , the median survival was also significantly better than in patients with limited ( R-2a ) , or extensive residual disease ( R-2b ; log-rank test , P < .0001 ) . CONCLUSION Cytoreduction followed by HIPEC improves survival in patients with peritoneal carcinomatosis of colorectal origin . However , patients with involvement of six or more regions of the abdominal cavity , or grossly incomplete cytoreduction , had still a grave prognosis Purpose We performed a retrospective study to determine the pattern of metastases and overall outcome of patients with tumors exhibiting a component of signet-ring cells comprising < 50 percent of the tumor mass . Methods Medical records of 753 patients with primary colorectal cancer were retrospectively studied . Patients who had tumors with < 50 percent signet-ring cells were classified as having a component of signet-ring cells . The outcome of patients with a component of signet-ring cells was compared to all patients with mucinous adenocarcinoma ( defined as adenocarcinomas with ≥ 50 percent mucin ) to all patients with adenocarcinomas with a component of mucin ( defined as adenocarcinomas with < 50 percent mucin ) and to 100 r and omly selected patients with adenocarcinomas lacking mucin or signet-ring cells . Results Five percent of patients had a component of signet-ring cells , 3 percent had mucinous adenocarcinoma , 9 percent had a component of mucinous adenocarcinoma , and 83 percent had adenocarcinoma lacking mucinous or signet components . Patients with a component of signet-ring cells and mucinous adenocarcinomas metastasized predominantly to the peritoneum/ovaries ( 75 and 56 percent of metastatic cases , respectively ) and rarely to liver/lungs . The pattern of metastases of patients with adenocarcinoma without mucinous or signet components predominantly involved the liver/lungs and rarely the peritoneum/ovaries ( 12.5 percent ) . The pattern of metastases for patients with a component of mucinous adenocarcinoma was intermediate between mucinous adenocarcinoma and adenocarcinoma without mucin or signet-ring component . No differences in survival in Stage IV patients were seen among the four subgroups . Conclusions Patients with a component of signet-ring cells cancers , similar to mucinous adenocarcinoma , have a predisposition to metastasize to the peritoneum/ovaries No new chemotherapy agents have been developed in the recent past that present hope for improving survival in patients with colon or rectal cancer . This study was undertaken to investigate a new route of administering an old drug , 5-fluorouracil ( 5-FU ) . When 5-FU is delivered by the intraperitoneal ( IP ) route the tolerable dose of drug was markedly increased without an increase in adverse side effects . The natural history of surgically treated disease was changed by reducing the incidence of peritoneal carcinomatosis , but time to relapse and survival was not improved . Intraperitoneal 5-FU may be recommended for investigation in patients with perforated colon cancer , peritoneal implants , or as one part of a multimodality treatment protocol for colorectal cancer . If 5-FU is given to patients with gastrointestinal malignancy , the IP route should be strongly considered OBJECTIVE To evaluate the results of a prospect i ve multicenter r and omized study of adjuvant intraperitoneal 5-fluorouracil ( 5-FU ) administered during 6 days shortly after resection of stages II and III colon cancers . SUMMARY BACKGROUND DATA Systemic adjuvant chemotherapy improves the survival of patients with stage III colon cancer receiving treatment for 6 months . Intraperitoneal chemotherapy theoretically combines peritoneal and hepatic effects . METHODS After resection , 267 patients were r and omized into two groups . Patients in group 1 ( n = 133 ) underwent resection followed by intraperitoneal administration of 5-FU ( 0.6 g/m2/day ) for 6 days ( day 4 to day 10 ) . These patients also received intravenous 5-FU ( 1 g ) during surgery . Patients in group 2 underwent resection alone ( n = 134 ) . RESULTS In group 1 , 103 patients received the total dose , 18 received a partial dose as a result of technical or tolerance problems , and 12 did not receive the chemotherapy .  Rates of surgical death and complications were similar in both groups . Tolerance to treatment was excellent or fair in 97 % of the patients and poor in 3 % . After a median follow-up of 58 months , 5-year overall survival rates were 74 % in group 1 and 69 % in group 2 ; disease-free survival rates were 68 % and 62 % , respectively . Survival curves were superimposed until 3 years after treatment and began diverging thereafter . Among patients receiving the full treatment , the 5-year disease-free survival rate was improved in the treatment group in patients with stage II cancers but was unchanged in patients with stage III cancers . CONCLUSIONS Chemotherapy with intraperitoneal 5-FU administered during a short period after surgery was well tolerated but was not sufficient to reduce the risk of death significantly . However , it reduced the risk of recurrence in stage II cancers . These results suggest that it should be associated with systemic chemotherapy to reduce both local and distant recurrences
OBJECTIVE Early detection of peritoneal metastases ( PM ) of colorectal cancer ( CRC ) is difficult and treatment options at a clinical ly overt stage are limited .
Potentially , adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy ( HIPEC ) is of value .
The aim of this study was to present long term oncological outcomes of a pilot study on adjuvant HIPEC to reduce development of PMCRC , with systematic review of literature .