Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial Extended resections for colorectal cancer ‐ indications for supraradical lymphadenectomy Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--a study of CALGB 9581 and 89803. Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm Accuracy of radiological staging in identifying high‐risk colon cancer patients suitable for neoadjuvant chemotherapy: a multicentre experience Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. Anticipating the Clinical Use of Prognostic Gene Expression–Based Tests for Colon Cancer Stage II and III: Is Godot Finally Arriving? Nationwide quality assurance of rectal cancer treatment Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.
PURPOSE Three-year disease-free survival ( DFS ) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin ( LV5FU2 ) with the addition of oxaliplatin ( FOLFOX4 ) . Final results of the study , including 6-year overall survival ( OS ) and 5-year up date d DFS , are reported . PATIENTS AND METHODS A total of 2,246 patients were r and omly assigned to receive LV5FU2 or FOLFOX4 for 6 months . The primary end point was DFS . Secondary end points were OS and safety . Results Five-year DFS rates were 73.3 % and 67.4 % in the FOLFOX4 and LV5FU2 groups , respectively ( hazard ratio [ HR ] = 0.80 ; 95 % CI , 0.68 to 0.93 ; P = .003 ) . Six-year OS rates were 78.5 % and 76.0 % in the FOLFOX4 and LV5FU2 groups , respectively ( HR = 0.84 ; 95 % CI , 0.71 to 1.00 ; P = .046 ) ; corresponding 6-year OS rates for patients with stage III disease were 72.9 % and 68.7 % , respectively ( HR = 0.80 ; 95 % CI , 0.65 to 0.97 ; P = .023 ) . No difference in OS was seen in the stage II population . The incidence of second noncolorectal cancers was 5.5 % and 6.1 % in the FOLFOX4 and LV5FU2 groups , respectively . Among patients receiving oxaliplatin , the frequency of grade 3 peripheral sensory neuropathy was 1.3 % 12 months after treatment and 0.7 % at 48 months . CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease Summary Background Preoperative ( neoadjuvant ) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal , gastric , and rectal cancers , perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery . The FOxTROT trial aims to investigate the feasibility , safety , and efficacy of preoperative chemotherapy for colon cancer . Methods In the pilot stage of this r and omised controlled trial , 150 patients with radiologically staged locally advanced ( T3 with ≥5 mm invasion beyond the muscularis propria or T4 ) tumours from 35 UK centres were r and omly assigned ( 2:1 ) to preoperative ( three cycles of OxMdG [ oxaliplatin 85 mg/m2 , l-folinic acid 175 mg , fluorouracil 400 mg/m2 bolus , then 2400 mg/m2 by 46 h infusion ] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG ) or st and ard postoperative chemotherapy ( 12 cycles of OxMdG ) . Patients with KRAS wild-type tumours were r and omly assigned ( 1:1 ) to receive panitumumab ( 6 mg/kg ; every 2 weeks with the first 6 weeks of chemotherapy ) or not . Treatment allocation was through a central r and omisation service using a minimised r and omisation procedure including age , radiological T and N stage , site of tumour , and presence of defunctioning colostomy as stratification variables . Primary outcome measures of the pilot phase were feasibility , safety , and tolerance of preoperative therapy , and accuracy of radiological staging . Analysis was by intention to treat . This trial is registered , number IS RCT N 87163246 . Findings 96 % ( 95 of 99 ) of patients started and 89 % ( 85 of 95 ) completed  preoperative chemotherapy  with grade 3–4 gastrointestinal toxicity in 7 % ( seven of 94 ) of patients . All 99 tumours in the preoperative group were resected , with no significant differences in postoperative morbidity between the preoperative and control groups : 14 % ( 14 of 99 ) versus 12 % ( six of 51 ) had complications prolonging hospital stay ( p=0·81 ) . 98 % ( 50 of 51 ) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91 % ( 90 of 99 ) of patients following preoperative chemotherapy ( p=0·10 ) . Preoperative therapy result ed in significant downstaging of TNM5 compared with the postoperative group ( p=0·04 ) , including two pathological complete responses , apical node involvement ( 1 % [ one of 98 ] vs 20 % [ ten of 50 ] , p<0·0001 ) , resection margin involvement ( 4 % [ four of 99 ] vs 20 % [ ten of 50 ] , p=0·002 ) , and blinded central ly scored tumour regression grading : 31 % ( 29 of 94 ) vs 2 % ( one of 46 ) moderate or greater regression ( p=0·0001 ) . Interpretation Preoperative chemotherapy for radiologically staged , locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity . Proceeding to the phase 3 trial , to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome , is appropriate . Funding Cancer Research UK The laparoscopic approach to st and ard resections in colorectal cancer has proven that it may provide equal rates of R0 resections and adequate retrieval of lymph nodes as open procedures if performed by experienced h and s. There might be difficulties in more advanced tumors or those with lymphatic spread beyond typical drainage areas and more extensive operations might be required . An atypical pattern of lymphatic spread often is associated with other adverse factors such as multifocality of primary cancers and adverse tumorbiological factors such as grade . Such patient subgroups may be defined beforeh and and include particularly patients with underlying ulcerative colitis . Repetitively , extended lymph node dissection approaches have been advocated , however neither in r and omised trails nor in meta‐ analysis has a more favourable outcome of patients undergoing such extended lymphatic dissections been demonstrated . Sticking to the rules of classical dissection of lymphatic drainage basins with removal of adequate lymph node numbers is one corner stone for successful treatment of colorectal cancer . The other one refers to a detailed description of the procedure performed in order to make the surgical procedure trackable Background : Enhancer of zeste homologue 2 ( EZH2 ) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation . Methods : We studied EZH2 expression in 409 patients with colorectal cancer stages II and III . The patients were included in a r and omised study , and treated with surgery alone or surgery followed by adjuvant chemotherapy . Results : EZH2 expression was significantly related to increased tumour cell proliferation , as assessed by Ki-67 expression . In colon cancer , strong EZH2 expression ( P=0.041 ) and high proliferation ( ⩾40 % ; P=0.001 ) were both associated with better relapse-free survival ( RFS ) . In contrast , no such associations were found among rectal cancers . High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy ( P=0.001 ) , but not among those who were treated by surgery alone ( P=0.087 ) . In colon cancers stage III , a significant association between RFS and r and omisation group was found in patients with high proliferation ( P=0.046 ) , but not in patients with low proliferation ( P=0.26 ) . Multivariate analyses of colon cancers showed that stage III ( hazard ratio ( HR ) 4.00 ) and high histological grade ( HR 1.80 ) were independent predictors of reduced RFS , whereas high proliferation indicated improved RFS ( HR 0.55 ) . Conclusion : Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer , but not so in rectal cancer Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive ( Stage B2 ) or had regional nodal involvement ( Stage C ) were r and omly assigned to observation or to treatment for one year with levamisole combined with fluorouracil .  Patients with Stage C disease could also be r and omly assigned to treatment with levamisole alone . The median follow-up time at this writing is 3 years ( range , 2 to 5 1/2 ) . Among the patients with Stage C disease , therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent ( P less than 0.0001 ) . The overall death rate was reduced by 33 percent ( P approximately 0.006 ) . Treatment with levamisole alone had no detectable effect . The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions . Toxic effects of levamisole alone were infrequent , usually consisting of mild nausea with occasional dermatitis or leukopenia , and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone -- i.e . , nausea , vomiting , stomatitis , diarrhea , dermatitis , and leukopenia . These reactions were usually not severe and did not greatly impede patients ' compliance with their regimen . We conclude that adjuvant therapy with levamisole and fluorouracil should be st and ard treatment for Stage C colon carcinoma . Since most patients in our study were treated by community oncologists , this approach should be readily adaptable to conventional medical practice PURPOSE The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin ( FULV ) improved disease-free survival ( DFS ) in patients with stage II or III colon cancer . This analysis is the first publication of overall survival ( OS ) for the NSABP C-07 study . We up date d DFS and examined both end points in clinical ly relevant patient subsets . PATIENTS AND METHODS Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective . We investigated toxicity as a driver of divergent outcomes in these subsets . RESULTS In all , 2,409 eligible patients with follow-up were r and omly assigned to either FULV ( FU 500 mg/m(2 ) by intravenous [ IV ] bolus weekly for 6 weeks ; leucovorin 500 mg/m(2 ) IV weekly for 6 weeks of each 8-week cycle for three cycles ) or FLOX ( FULV plus oxaliplatin 85 mg/m(2 ) IV on days 1 , 15 , and 29 of each cycle ) . With 8 years median follow-up , OS was similar between treatment groups ( hazard ratio [ HR ] , 0.88 ; 95 % CI , 0.75 to 1.02 ; P = .08 ) . FLOX remained superior for DFS ( HR , 0.82 ; 95 % CI , 0.72 to 0.93 ; P = .002 ) . The effect of oxaliplatin on OS did not differ by stage of disease ( interaction P = .38 for OS ; interaction P = 0.37 for DFS ) but did vary by age for OS ( younger than age 70 v 70 + interaction P = .039 ) . There was a similar trend for DFS ( interaction P = .073 ) . Oxaliplatin significantly improved OS in patients younger than age 70 ( HR , 0.80 ; 95 % CI , 0.68 to 0.95 ; P = .013 ) , but no positive effect was evident in older patients . CONCLUSION Overall , the addition of oxaliplatin to FULV has not been proven to extend OS in this trial , but the DFS effect remained strong . Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70 BACKGROUND Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer . Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma . METHODS Patients from 330 centres in 34 countries were enrolled into this phase 3 , open-label r and omised trial . Patients with curatively resected stage III or high-risk stage II colon carcinoma were r and omly assigned ( 1:1:1 ) to receive FOLFOX4 ( oxaliplatin 85 mg/m(2 ) , leucovorin 200 mg/m(2 ) , and fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 1 ; leucovorin 200 mg/m(2 ) plus fluorouracil 400 mg/m(2 ) bolus plus 600 mg/m(2 ) 22-h continuous infusion on day 2 ) every 2 weeks for 12 cycles ; bevacizumab 5 mg/kg plus FOLFOX4 ( every 2 weeks for 12 cycles ) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks ( eight cycles over 24 weeks ) ; or bevacizumab 7·5 mg/kg plus XELOX ( oxaliplatin 130 mg/m(2 ) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2 ) twice daily on days 1 - 15 ) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks ( eight cycles over 24 weeks ) . Block r and omisation was done with a central interactive computerised system , stratified by geographic region and disease stage . Surgery with curative intent occurred 4 - 8 weeks before r and omisation . The primary endpoint was disease-free survival , analysed for all r and omised patients with stage III disease . This study is registered with Clinical Trials.gov , number NCT00112918 . FINDINGS Of the total intention-to-treat population ( n=3451 ) , 2867 patients had stage III disease , of whom 955 were r and omly assigned to receive FOLFOX4 , 960 to receive bevacizumab-FOLFOX4 , and 952 to receive bevacizumab-XELOX . After a median follow-up of 48 months ( range 0 - 66 months ) , 237 patients ( 25 % ) in the FOLFOX4 group , 280 ( 29 % ) in the bevacizumab-FOLFOX4 group , and 253 ( 27 % ) in the bevacizumab-XELOX group had relapsed , developed a new colon cancer , or died . The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·17 ( 95 % CI 0·98 - 1·39 ; p=0·07 ) , and for bevacizumab-XELOX versus FOLFOX4 was 1·07 ( 0·90 - 1·28 ; p=0·44 ) . After a minimum follow-up of 60 months , the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·27 ( 1·03 - 1·57 ; p=0·02 ) , and for bevacizumab-XELOX versus FOLFOX4 was 1·15 ( 0·93 - 1·42 ; p=0·21 ) . The 573 patients with high-risk stage II cancer were included in the safety analysis . The most common grade 3 - 5 adverse events were neutropenia  ( FOLFOX4 : 477 [ 42 % ] of 1126 patients , bevacizumab-FOLFOX4 : 416 [ 36 % ] of 1145 patients , and bevacizumab-XELOX : 74 [ 7 % ] of 1135 patients ) , diarrhoea ( 110 [ 10 % ] , 135 [ 12 % ] , and 181 [ 16 % ] , respectively ) , and hypertension ( 12 [ 1 % ] , 122 [ 11 % ] , and 116 [ 10 % ] , respectively ) . Serious adverse events were more common in the bevacizumab groups ( bevacizumab-FOLFOX4 : 297 [ 26 % ] ; bevacizumab-XELOX : 284 [ 25 % ] ) than in the FOLFOX4 group ( 226 [ 20 % ] ) . Treatment-related deaths were reported in one patient receiving FOLFOX4 , two receiving bevacizumab-FOLFOX4 , and five receiving bevacizumab-XELOX . INTERPRETATION Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer . Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients . On the basis of these and other data , we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer . FUNDING Genentech , Roche , and Chugai Due to uncertainties regarding clinical ly meaningful gains from adjuvant chemotherapy after colorectal cancer surgery , several Nordic Groups in the early 1990s initiated r and omised trials to prove or reject such gains . This report gives the joint analyses after a minimum 5-year follow-up . Between October 1991 and December 1997 , 2 224 patients under 76 years of age with colorectal cancer stages II and III were r and omised to surgery alone ( n = 1 121 ) or adjuvant chemotherapy ( n = 1 103 ) which varied between trials ( 5FU/levamisole for 12 months , n = 444 ; 5FU/leucovorin for 4 - 5 months according to either a modified Mayo Clinic schedule ( n = 262 ) or the Nordic schedule ( n = 397 ) . Some centres also r and omised patients treated with 5FU/leucovorin to+/-levamisole ) . A total of 812 patients had colon cancer stage II , 708 colon cancer stage III , 323 rectal cancer stage II and 368 rectal cancer stage III . All analyses were according to intention-to-treat . No statistically significant difference in overall survival , stratified for country or region , could be found in any group of patients according to stage or site . In colon cancer stage III , an absolute difference of 7 % ( p = 0.15 ) , favouring chemotherapy , was seen . The present analyses corroborate a small but clinical ly meaningful survival gain from adjuvant chemotherapy in colon cancer stage III , but not in the other presentations CONTEXT Leucovorin , fluorouracil , and oxaliplatin ( FOLFOX ) is the st and ard adjuvant therapy for resected stage III colon cancer . Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer . OBJECTIVE To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen ( mFOLFOX6 ) in patients with resected stage III wild-type KRAS colon cancer . DESIGN , SETTING , AND PARTICIPANTS A r and omized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10 , 2004 , and November 25 , 2009 . The primary r and omized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab . KRAS mutation status was central ly determined . The trial was halted after a planned interim analysis of 48 % of predicted events ( 246/515 ) occurring in 1863 ( of 2070 planned ) patients with tumors having wild-type KRAS . A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued . The 2070 patients with wild-type KRAS provided 90 % power to detect a hazard ratio ( HR ) of 1.33 ( 2-sided α = .05 ) , with planned interim efficacy analyses after 25 % , 50 % , and 75 % of expected relapses . MAIN OUTCOME MEASURES Disease-free survival in patients with wild-type KRAS mutations . Secondary end points included overall survival and toxicity . RESULTS Median ( range ) follow-up was 28 ( 0 - 68 ) months . The trial demonstrated no benefit when adding cetuximab . Three-year disease-free survival for mFOLFOX6 alone was 74.6 % vs 71.5 % with the addition of cetuximab ( HR , 1.21 ; 95 % CI , 0.98 - 1.49 ; P = .08 ) in patients with wild-type KRAS , and 67.1 % vs 65.0 % ( HR , 1.12 ; 95 % CI , 0.86 - 1.46 ; P = .38 ) in patients with mutated KRAS , with no significant benefit in any subgroups assessed . Among all patients , grade 3 or higher adverse events ( 72.5 % vs 52.3 % ; odds ratio [ OR ] , 2.4 ; 95 % CI , 2.1 - 2.8 ; P < .001 ) and failure to complete 12 cycles ( 33 % vs 23 % ; OR , 1.6 ; 95 % CI , 1.4 - 1.9 ; P < .001 ) were significantly higher with cetuximab . Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older . CONCLUSION Among patients with stage III resected colon cancer , the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00079274 PURPOSE Colorectal cancer ( CRC ) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss . These characteristics may classify CRC into subsets of distinct clinical behaviors . PATIENTS AND METHODS We studied two of these genomic defects-mismatch repair deficiency ( MMR-D ) and loss of heterozygosity  at chromosomal location 18q (18qLOH)-in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer . These trials included prospect i ve secondary analyses to determine the relationship between these markers and treatment outcome . A total of 1,852 patients were tested for MMR status and 955 ( excluding patients with MMR-D tumors ) for 18qLOH .  RESULTS Compared with stage III , more stage II tumors were MMR-D ( 21.3 % v 14.4 % ; P < .001 ) and were intact at 18q ( 24.2 % v 15.1 % ; P = .001 ) . For the combined cohort , patients with MMR-D tumors had better 5-year disease-free survival ( DFS ; 0.76 v 0.67 ; P < .001 ) and overall survival ( OS ; 0.81 v 0.78 ; P = .029 ) than those with MMR intact ( MMR-I ) tumors . Among patients with MMR-I tumors , the status of 18q did not affect outcome , with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 ( P = .18 ) for DFS and 0.81 versus 0.77 ( P = .18 ) for OS . CONCLUSION We conclude that MMR-D tumor status , but not the presence of 18qLOH , has prognostic value for stages II and III colon cancer Background . The recommendation of adjuvant chemotherapy for colon cancer with lymph node metastases , based on two studies from USA , was reluctantly accepted by Norwegian medical doctors . It was therefore decided to assess the role of adjuvant therapy with 5fluorouracil ( 5-FU ) combined with levamisole ( Lev ) in a confirmatory r and omised study . Material and methods . Four hundred and twenty five patients with operable colon and rectum cancer , Stage II and III ( Dukes ’ stage B and C ) , were from January 1993 to October 1996 , included in a r and omised multicentre trial in Norway . The age limits were 18–75 years . Therapy started with a loading course of bolus i.v . 5-FU ( 450 mg/m2 ) daily for 5 days and p.o . doses of Lev ( 50 mg x 3 ) for 3 days . From day 28 a weekly i.v . 5-FU dose ( 450 mg/m2 ) were administered for 48 weeks . From day 28 also p.o . doses of Lev ( 50 mg x 3 ) for 3 days were given every 14 days . In total 214 patients were r and omised to 5FU/Lev and 211 were included in the control group with surgery alone . Some did not comply with the inclusion and exclusion criteria , thus leaving 206 evaluable patients in each group . Results . There was no significant survival difference between the two groups at 5 years : Disease-free survival ( DFS ) was 73 % after chemotherapy , 68 % ( p=0.24 ) in the control group , and corresponding cancer specific survival ( CSS ) 75 % and 71 % , respectively ( p=0.69 ) . There was no difference between the two groups when analysed for colon and rectum separately . However , the subgroup of colon cancer with stage III exhibited a statistically significant difference both for DFS , 58 % vs. 37 % ( p=0.012 ) and CSS , 65 % vs. 47 % ( p=0.032 ) in favour of adjuvant chemotherapy . The benefit was further statistically significant for women but not for men . Toxicity was generally mild and acceptable with no drug related fatalities . Conclusions . Colon cancer patients with lymph node metastases benefit from adjuvant chemotherapy with 5-FU/Lev with acceptable toxicity . In a subgroup analysis females did better than males . Rectal cancer does not benefit from this regimen AIM Over recent years there has been a new focus on the quality of colon cancer surgery following the description and introduction of complete mesocolic excision ( CME ) . In the same period , laparoscopic surgery has been widely applied to the treatment of colon cancer . We aim ed to evaluate the introduction of both CME and laparoscopic-assisted surgery  at Aarhus University Hospital , Denmark between 2008 and 2011 . Secondly we aim ed to evaluate the impact on the quality of surgery of post-operative team meetings where pathologists demonstrated the plane of surgery on the specimens . METHOD A series of 209 consecutive and prospect ively collected colon cancer specimens were evaluated by assessing the plane of surgery and measuring the amount of tissue resected . Multivariate analyses were used to control for influencing factors . RESULTS The proportion of specimens resected in the mesocolic plane was high and increased significantly following the introduction of post-operative team meetings ( 52%-76 % , p = 0.02 ) . Laparoscopic surgery enhanced the distance between the tumour and the arterial tie by a mean of 27 mm ( p < 0.0001 ) and the distance between the nearest bowel wall and the arterial tie by 26 mm ( p < 0.0001 ) when compared to an open approach . Factors such as body mass index and age influenced the outcome for surgical quality . CONCLUSION Implementation of CME and laparoscopic-assisted surgery for colon cancer is a challenge and requires continuous training and feedback . Post-operative multidisciplinary team meetings may be a key element in this process BACKGROUND The Stockholm I and II r and omised trials demonstrated the value of preoperative radiotherapy in preventing local recurrence in rectal cancer . This , study investigated the potential for further improvement by introduction of the concept of total mesorectal excision ( TME ) to surgeons in Stockholm , Sweden . METHODS Workshops started in 1994 and included 11 television-based demonstrations and two histopathology sessions . The study population consisted of all patients who underwent abdominal operations for rectal cancer in Stockholm County during 1995 - 96 ( TME project ; n=447 ) . Outcomes at 2 years were compared with those from the Stockholm I ( n=790 ) and II ( n=542 ) trials as historical controls . FINDINGS For patients with curative abdominal resections , there were no differences between the Stockholm I ( n=686 ) , Stockholm II ( n=481 ) , and TME project ( n=381 ) groups in 30-day mortality ( 30 [ 4 % ] , six [ 1 % ] , and 12 [ 3 % ] ) , anastomotic leakage ( 27 [ 10 % ] , 18 [ 9 % ] , and 23 [ 9 % ] ) , or all complications ( 204 [ 30 % ] , 169 [ 35 % ] , and 134 [ 35 % ] ) . This similarity was achieved despite a decrease in the proportion of abdominoperineal procedures from 55 - 60 % to 27 % . Local recurrence occurred in significantly fewer of the TME group than of the Stockholm I and II groups ( 21 [ 6 % ] vs 103 [ 15 % ] and 66 [ 14 % ] , p<0.001 ) as did cancer-related death ( 35 [ 9 % ] vs 104 [ 15 % ] and 77 [ 16 % ] , p<0.002 ) . INTERPRETATION A surgical teaching initiative had a major effect on cancer outcomes . The proportion of abdominoperineal procedures and the local recurrence rate decreased by more than 50 % and there is already evidence of a decline in rectal-cancer mortality Aim A pilot study was undertaken to determine the accuracy of computed tomography ( CT ) staging in identifying patients with high‐risk colon cancers who would be considered as c and i date s for a neoadjuvant therapy trial ( FOxTROT ) and those at low risk ( T1/T2 ) who would be excluded PURPOSE R and omized studies have shown that irinotecan ( CPT-11 ) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil ( FU ) plus leucovorin ( LV ) in first-line therapy of metastatic colorectal cancer . When this study was initiated , FU plus LV was st and ard adjuvant treatment for stage III colon cancer . We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer . METHODS A total of 1,264 patients were r and omly assigned to receive either st and ard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV . The primary end points of the study were overall survival ( OS ) and disease-free survival ( DFS ) . RESULTS Treatment arms were well-balanced for patient characteristics and prognostic variables . There were no differences in either DFS or OS between the two treatment arms . Toxicity , including lethal toxicity , was significantly higher on the CPT-11 plus FU plus LV arm . CONCLUSION The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease , but did increase both lethal and nonlethal toxicity . This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment , and it reinforces the need for r and omized controlled adjuvant studies PURPOSE The primary objective of this r and omized , multicenter , phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin ( LV ) adjuvant regimen ( LV5FU2 ) would improve disease-free survival ( DFS ) in patients with stage III colon cancer . PATIENTS AND METHODS After curatively intentioned surgery , patients with stage II and III colon cancer were r and omly allocated surgery to receive LV5FU2 ( LV 200 mg/m(2 ) as a 2-hour infusion , followed by FU ; as a 400 mg/m(2 ) bolus and then a 600 mg/m(2 ) continuous infusion over 22 hours , days 1 and 2 , every 2 weeks for 12 cycles : de Gramont regimen ) with or without irinotecan ( 180 mg/m(2 ) as a 30- to 90-minute infusion , day 1 , every 2 weeks ) . In total , 260 ( 7.9 % ) of 3,278 patients received an alternative high-dose infusional FU/LV regimen ( Arbeitsgemeinschaft Internische Onkologie regimen ) with or without irinotecan . Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease , r and omly allocated in the LV5FU2 strata . After a median follow-up of 66.3 months , the 5-year DFS rate was 56.7 % with irinotecan/LV5FU2 and 54.3 % with LV5FU2 alone ( primary end point : log-rank P = .106 ) . Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone ( 5-year rate 73.6 % v 71.3 % , respectively ; log-rank P = .094 ) . The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia . CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone Purpose : According to current recommendations for adjuvant treatment , patients with colon cancer stage II are not routinely offered chemotherapy , unless considered to have a high risk of relapse based on specific clinicopathological parameters . Following these criteria , it is challenging to identify the subgroup of patients that will benefit the most from adjuvant treatment . Contrarily , patients with colon cancer stage III are routinely offered chemotherapy , but due to expected adverse effects and frailty , elderly patients are often excluded from st and ard protocol s. Colon cancer is a disease of the elderly and accordingly , there is a large subgroup of patients for which guidelines for adjuvant treatment remain less clear . In these two clinical setting s , improved risk stratification has great potential impact on patient care , anticipating that high-risk patients will benefit from chemotherapy . However , microsatellite instability is the only molecular prognostic marker recommended for clinical use . Experimental Design : In this perspective , we provide an up date d view on the status and clinical potential of the many proposed prognostic gene expression – based tests for colon cancer stage II and III . Results : The main limitation for clinical implementation is lack of prospect i ve validation . For patients with stage II , highly promising tests have been identified and clinical trials are ongoing . For elderly patients with stage III , the value of such tests has received less focus , but promising early results have been shown . Conclusion : Although awaiting results from prospect i ve trials , improved risk assessment for patients with stage II and III is likely to be achieved in the foreseeable future . Clin Cancer Res ; 19(24 ) ; 6669–77 . © 2013 AACR Objective The purpose of this prospect i ve study was to examine the influence of the efforts for nationwide quality assurance of  rectal cancer treatment . The study focuses on local recurrence and overall survival PURPOSE The National Surgical Adjuvant Breast and Bowel Project C-08 trial was design ed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 ( mFOLFOX6 ; ie , infusional/bolus fluorouracil , leucovorin , and oxaliplatin ) for the adjuvant treatment of patients with stages II to III colon cancer . METHODS Patients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab ( 5 mg/kg every 2 weeks for 52 weeks [ ie , experimental group ] ) . The primary end point was disease-free survival ( DFS ) . RESULTS Among 2,672 analyzed patients , demographic factors were well balanced by treatment . With a median follow-up of 35.6 months , the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS ( hazard ratio [ HR ] , 0.89 ; 95 % CI , 0.76 to 1.04 ; P = .15 ) . The point estimates for 3-year DFS for the overall population were 77.4 % and 75.5 % for the experimental and control arms , respectively . For patients with stages II and III diseases , these same estimates were 87.4 % and 84.7 % , respectively , for stage II and 74.2 % and 72.4 % , respectively , for stage III . Exploratory analyses found that the effect of  bevacizumab  on DFS was different before and after a 15-month l and mark ( time-by-treatment interaction P value < .0001 ) . Bevacizumab had a strong effect before the l and mark ( HR , 0.61 ; 95 % CI , 0.48 to 0.78 ; P < .001 ) but no significant effect after ( HR , 1.22 ; 95 % CI , 0.98 to 1.52 ; P = .076 ) . CONCLUSION Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer . However , a significant but transient effect during bevacizumab exposure was observed in the experimental arm . We postulate that this observation reflects a biologic effect during bevacizumab exposure . Given the lack of improvement in DFS , the use of bevacizumab can not be recommended for use in the adjuvant treatment of patients with colon cancer
In the early 1970s all colorectal cancer patients with metastases received intravenous 5-fl uorouracil ( 5FU ) chemotherapy which often continued despite tumor progression .
Some patients also received chemotherapy after radical resection as it was thought that the treatment at least could slow down the progress of the cancer .
This practice was terminated at our hospital in 1976 , supported by the paper of Moertel who question ed the role of 5FU , stating that it was a nontreatment and also emphasized its side effects [ 1 ] .
Despite his skepticism , Moertel continued his search for combinations which could infl uence the course of colorectal cancers .
In 1989 and 1990 , two seminal papers reported that 5FU combined with the antihelmintic drug levamisol for one year improved disease-free survival ( DFS ) and cancer-specifi c survival ( CSS ) [ 2,3 ] .
After the National Institute of Health Consensus Statement , this regimen rapidly was accepted in USA and most countries worldwide [ 4 ] .
However , in the Sc and inavian countries the new treatment was met with initial skepticism by the surgeons who had learned that 5FU had limited success in colorectal cancer .
In the current issue of Acta Oncologica , B ö ckelman et al. present an up date d review on the prognosis for colon cancer stage II and III [ 8 ] .
The review is one in a series of papers from an Acta Oncologica initiative to promote young scientists in the Nordic countries , ‘ young scientist ’ s workshop ’ held during the Acta Oncologica 50 year celebration in 2013 [ 9,10 ] .
This is important information refl ecting the current status of treatment of colon cancer , in contrast to a continuous improvement in treatment of rectal cancer including more extensive surgery termed total mesorectal excision , staging with MRI , multidisciplinary team and use of preoperative radiochemotherapy [ 12 – 14 ] .
Recently a similar focus on careful systematic surgery for colon cancer with central lymph node dissection ( D3 resection ) and total mesocolic excision has been accepted and is introduced in clinical practice [ 15 – 18 ] .
Colon cancer surgery is becoming more limited to gastrointestinal surgeons specially trained in colorectal surgery [ 19 ] .
Also the pathology assessment of the operation specimens has improved [ 20,21 ] .