human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 Introduction The treatment of peritoneal carcinomatosis is based on cytoreduction followed by hyperthermic intraperitoneal chemotherapy and combined with adjuvant chemotherapy . In 2003 , a r and omized trial was finished comparing systemic chemotherapy alone with cytoreduction followed by hyperthermic intraperitoneal chemotherapy and systemic chemotherapy . This trial showed a positive result favoring the studied treatment . This trial has now been up date d to a minimal follow-up of 6 years to show long-term results . Patients and Methods For all patients still alive , the follow-up was up date d until 2007 . In the original study , four patients were excluded — two because of no eligible histology/pathology and two because of major protocol violations . After r and omization , four patients in the HIPEC arm and six in the control arm were not treated using the intended therapy , one patient because of withdrawal , one because of a life-threatening other malignant disease and the others because of progressive disease before initiation of the treatment . During the follow-up , one patient was crossed over from the control arm and underwent cytoreduction and HIPEC for recurrent disease , after the assigned treatment was completed . The data from these patients were censored at the moment of the cross-over . Progression-free and disease-specific survival were analyzed using the Kaplan Meyer test and compared using the log rank method . The long-term results were studied in more detail to evaluate efficacy and toxicity . Results At the time of this up date , the median follow-up was almost 8 years ( range 72–115 months ) . In the st and ard arm , 4 patients were still alive , 2 with and 2 without disease ; in the “ HIPEC ’ arm , 5 patients were still alive , 2 with and 3 without disease . The median progression-free survival was 7.7 months in the control arm and 12.6 months in the HIPEC arm ( P = 0.020 ) . The median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm ( P = 0.028 ) . The 5-year survival was 45 % for those patients in whom a R1 resection was achieved . Conclusion With 90 % of all events having taken place up to this time , this r and omized trial shows that cytoreduction followed by HIPEC does significantly add survival time to patients affected by peritoneal carcinomatosis of colorectal origin . For a selected group , there is a possibility of long-term survival Abstract Cytoreductive surgery ( CRS ) and hyperthermic intraperitoneal chemotherapy ( HIPEC ) is an extensive procedure with considerable morbidity . Since only few hospitals perform CRS + HIPEC , this might lead to confounded outcomes between hospitals when audited . This study aims to compare outcomes between peritoneally metastasized ( PM ) colon cancer patients treated with CRS + HIPEC and patients undergoing conventional colon surgery .  Furthermore , the impact of CRS + HIPEC on the risk of postoperative complications will be assessed , probably leading to better insight into how to report on postoperative outcomes in this distinct group of patients undergoing extensive colon surgery . All patients with primary colon cancer who underwent segmental colon resection in a tertiary referral hospital between 2011 and 2014 were included in this prospect i ve cohort study . Outcome after surgery was compared between patients who underwent additional CRS + HIPEC treatment or conventional surgery . Consequently , 371 patients underwent surgery , of which 43 ( 12 % ) underwent CRS + HIPEC . These patients were younger and healthier than patients undergoing conventional surgery .  Tumor characteristics were less favorable and surgery was more extensive in CRS + HIPEC patients . The morbidity rate was also higher in CRS + HIPEC patients ( 70 % vs 41 % ; P < 0.001 ) . CRS + HIPEC was an independent predictor of postoperative complications ( odds ratio 6.4 ) , but was not associated with more severe postoperative complications or higher treatment-related mortality . Although patients with colonic PM undergoing CRS + HIPEC treatment were younger and healthier , the postoperative outcome was worse . This is most probably due to less favorable tumor characteristics and more extensive surgery . Nevertheless , CRS + HIPEC treatment was not associated with severe complications or increased treatment-related mortality . These results stress the need for adequate case-mix correction in colorectal surgery audits Background Dealing with heterogeneity in meta-analyses is often tricky , and there is only limited advice for authors on what to do . We investigated how authors addressed different degrees of heterogeneity , in particular whether they used a fixed effect model , which assumes that all the included studies are estimating the same true effect , or a r and om effects model where this is not assumed . Methods We sample d r and omly 60 Cochrane review s from 2008 , which presented a result in its first meta- analysis with substantial heterogeneity ( I2 greater than 50 % , i.e. more than 50 % of the variation is due to heterogeneity rather than chance ) . We extracted information on choice of statistical model , how the authors had h and led the heterogeneity , and assessed the method ological quality of the review s in relation to this . Results The distribution of heterogeneity was rather uniform in the whole I2 interval , 50 - 100 % . A fixed effect model was used in 33 review s ( 55 % ) , but there was no correlation between I2 and choice of model ( P = 0.79 ) . We considered that 20 review s ( 33 % ) , 16 of which had used a fixed effect model , had major problems . The most common problems were : use of a fixed effect model and lack of rationale for choice of that model , lack of comment on even severe heterogeneity and of reservations and explanations of its likely causes . The problematic review s had significantly fewer included trials than other review s ( 4.3 vs. 8.0 , P = 0.024 ) . The problems became less pronounced with time , as those review s that were most recently up date d more often used a r and om effects model . Conclusion One-third of Cochrane review s with substantial heterogeneity had major problems in relation to their h and ling of heterogeneity . More attention is needed to this issue , as the problems we identified can be essential for the conclusions of the review Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves Background Colorectal peritoneal carcinomatosis ( PC ) is a frequent and very lethal event . However , cure may be possible with maximal cytoreductive surgery associated with early postoperative intraperitoneal chemotherapy ( EPIC ) . Methods Between 1996 and 2000 , we conducted a two-center prospect i ve r and omized trial comparing EPIC plus systemic chemotherapy with systemic chemotherapy alone , both after  complete cytoreductive surgery of colorectal PC . Only 35 patients could be included among the 90 who were theoretically required , mainly because of patient dissatisfaction with the inclusion criteria . For this reason , the trial was stopped prematurely . Results Analysis of these 35 patients showed that complete resection of PC result ed in a 2-year survival rate of 60%—far above the classic 10 % survival rate among patients with colorectal PC treated with systemic  chemotherapy  and symptomatic surgery . In this small series , EPIC did not demonstrate any advantage for survival . Conclusions This supports the use of complete cytoreductive surgery in selected patients and calls for a prospect i ve r and omized trial comparing adjuvant systemic chemotherapy with intraperitoneal chemohyperthermia after complete resection Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy . We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy ( HIPEC ) in these patients . 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C ( MMC ) , followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin .  Surgical complications occurred in 11 patients ( 38 % ) . One patient died directly related to the treatment , result ing in a mortality rate of 3 % . MMC toxicity existed mainly of leucocytopenia ( in 15 patients ; 52 % ) . After a median follow-up of 38 months ( range 26 - 52 months ) we found a 2- and 3-year survival rate ( Kaplan-Meier ) of 45 and 23 % , respectively . Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer . First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy , therefore a r and omised phase III study is now being conducted Regional recurrence of malignant tumors in the peritoneal cavity usually signifies a poor prognosis for the host and often results in gastrointestinal complications requiring surgical intervention . One hundred patients with nongynecological malignancies found with peritoneal carcinomatosis were followed prospect ively . The most common primary tumors were colorectal ( N = 45 ) and pancreatic ( N = 20 ) carcinoma . When associated with pancreatic carcinoma , 65 % of patients had liver metastases and 60 % had ascites . The presence of 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 Introduction The treatment of peritoneal carcinomatosis is based on cytoreduction followed by hyperthermic intraperitoneal chemotherapy and combined with adjuvant chemotherapy . In 2003 , a r and omized trial was finished comparing systemic chemotherapy alone with cytoreduction followed by hyperthermic intraperitoneal chemotherapy and systemic chemotherapy . This trial showed a positive result favoring the studied treatment . This trial has now been up date d to a minimal follow-up of 6 years to show long-term results . Patients and Methods For all patients still alive , the follow-up was up date d until 2007 . In the original study , four patients were excluded — two because of no eligible histology/pathology and two because of major protocol violations . After r and omization , four patients in the HIPEC arm and six in the control arm were not treated using the intended therapy , one patient because of withdrawal , one because of a life-threatening other malignant disease and the others because of progressive disease before initiation of the treatment . During the follow-up , one patient was crossed over from the control arm and underwent cytoreduction and HIPEC for recurrent disease , after the assigned treatment was completed . The data from these patients were censored at the moment of the cross-over . Progression-free and disease-specific survival were analyzed using the Kaplan Meyer test and compared using the log rank method . The long-term results were studied in more detail to evaluate efficacy and toxicity . Results At the time of this up date , the median follow-up was almost 8 years ( range 72–115 months ) . In the st and ard arm , 4 patients were still alive , 2 with and 2 without disease ; in the “ HIPEC ’ arm , 5 patients were still alive , 2 with and 3 without disease . The median progression-free survival was 7.7 months in the control arm and 12.6 months in the HIPEC arm ( P = 0.020 ) . The median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm ( P = 0.028 ) . The 5-year survival was 45 % for those patients in whom a R1 resection was achieved . Conclusion With 90 % of all events having taken place up to this time , this r and omized trial shows that cytoreduction followed by HIPEC does significantly add survival time to patients affected by peritoneal carcinomatosis of colorectal origin . For a selected group , there is a possibility of long-term survival Abstract Cytoreductive surgery ( CRS ) and hyperthermic intraperitoneal chemotherapy ( HIPEC ) is an extensive procedure with considerable morbidity . Since only few hospitals perform CRS + HIPEC , this might lead to confounded outcomes between hospitals when audited . This study aims to compare outcomes between peritoneally metastasized ( PM ) colon cancer patients treated with CRS + HIPEC and patients undergoing conventional colon surgery .  Furthermore , the impact of CRS + HIPEC on the risk of postoperative complications will be assessed , probably leading to better insight into how to report on postoperative outcomes in this distinct group of patients undergoing extensive colon surgery . All patients with primary colon cancer who underwent segmental colon resection in a tertiary referral hospital between 2011 and 2014 were included in this prospect i ve cohort study . Outcome after surgery was compared between patients who underwent additional CRS + HIPEC treatment or conventional surgery . Consequently , 371 patients underwent surgery , of which 43 ( 12 % ) underwent CRS + HIPEC . These patients were younger and healthier than patients undergoing conventional surgery .  Tumor characteristics were less favorable and surgery was more extensive in CRS + HIPEC patients . The morbidity rate was also higher in CRS + HIPEC patients ( 70 % vs 41 % ; P < 0.001 ) . CRS + HIPEC was an independent predictor of postoperative complications ( odds ratio 6.4 ) , but was not associated with more severe postoperative complications or higher treatment-related mortality . Although patients with colonic PM undergoing CRS + HIPEC treatment were younger and healthier , the postoperative outcome was worse . This is most probably due to less favorable tumor characteristics and more extensive surgery . Nevertheless , CRS + HIPEC treatment was not associated with severe complications or increased treatment-related mortality . These results stress the need for adequate case-mix correction in colorectal surgery audits Background Dealing with heterogeneity in meta-analyses is often tricky , and there is only limited advice for authors on what to do . We investigated how authors addressed different degrees of heterogeneity , in particular whether they used a fixed effect model , which assumes that all the included studies are estimating the same true effect , or a r and om effects model where this is not assumed . Methods We sample d r and omly 60 Cochrane review s from 2008 , which presented a result in its first meta- analysis with substantial heterogeneity ( I2 greater than 50 % , i.e. more than 50 % of the variation is due to heterogeneity rather than chance ) . We extracted information on choice of statistical model , how the authors had h and led the heterogeneity , and assessed the method ological quality of the review s in relation to this . Results The distribution of heterogeneity was rather uniform in the whole I2 interval , 50 - 100 % . A fixed effect model was used in 33 review s ( 55 % ) , but there was no correlation between I2 and choice of model ( P = 0.79 ) . We considered that 20 review s ( 33 % ) , 16 of which had used a fixed effect model , had major problems . The most common problems were : use of a fixed effect model and lack of rationale for choice of that model , lack of comment on even severe heterogeneity and of reservations and explanations of its likely causes . The problematic review s had significantly fewer included trials than other review s ( 4.3 vs. 8.0 , P = 0.024 ) . The problems became less pronounced with time , as those review s that were most recently up date d more often used a r and om effects model . Conclusion One-third of Cochrane review s with substantial heterogeneity had major problems in relation to their h and ling of heterogeneity . More attention is needed to this issue , as the problems we identified can be essential for the conclusions of the review Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves Background Colorectal peritoneal carcinomatosis ( PC ) is a frequent and very lethal event . However , cure may be possible with maximal cytoreductive surgery associated with early postoperative intraperitoneal chemotherapy ( EPIC ) . Methods Between 1996 and 2000 , we conducted a two-center prospect i ve r and omized trial comparing EPIC plus systemic chemotherapy with systemic chemotherapy alone , both after  complete cytoreductive surgery of colorectal PC . Only 35 patients could be included among the 90 who were theoretically required , mainly because of patient dissatisfaction with the inclusion criteria . For this reason , the trial was stopped prematurely . Results Analysis of these 35 patients showed that complete resection of PC result ed in a 2-year survival rate of 60%—far above the classic 10 % survival rate among patients with colorectal PC treated with systemic  chemotherapy  and symptomatic surgery . In this small series , EPIC did not demonstrate any advantage for survival . Conclusions This supports the use of complete cytoreductive surgery in selected patients and calls for a prospect i ve r and omized trial comparing adjuvant systemic chemotherapy with intraperitoneal chemohyperthermia after complete resection Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy . We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy ( HIPEC ) in these patients . 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C ( MMC ) , followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin .  Surgical complications occurred in 11 patients ( 38 % ) . One patient died directly related to the treatment , result ing in a mortality rate of 3 % . MMC toxicity existed mainly of leucocytopenia ( in 15 patients ; 52 % ) . After a median follow-up of 38 months ( range 26 - 52 months ) we found a 2- and 3-year survival rate ( Kaplan-Meier ) of 45 and 23 % , respectively . Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer . First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy , therefore a r and omised phase III study is now being conducted Regional recurrence of malignant tumors in the peritoneal cavity usually signifies a poor prognosis for the host and often results in gastrointestinal complications requiring surgical intervention . One hundred patients with nongynecological malignancies found with peritoneal carcinomatosis were followed prospect ively . The most common primary tumors were colorectal ( N = 45 ) and pancreatic ( N = 20 ) carcinoma . When associated with pancreatic carcinoma , 65 % of patients had liver metastases and 60 % had ascites . The presence of 
    Output:
    