当前位置：文档库 › CEA+CT

CEA+CT

Effect of 3to 5Years of Scheduled CEA and CT Follow-up to Detect Recurrence of Colorectal Cancer The FACS Randomized Clinical Trial

John N.Primrose,MD,FRCS;Rafael Perera,DPhil;Alastair Gray,BA,PhD;Peter Rose,MD,FRCGP;Alice Fuller,BSc;Andrea Corkhill,BN;Steve George,MD,FRCP;David Mant,FRCGP,FRCP,FMedSci;for the FACS Trial Investigators

Author Audio Interview at https://www.wendangku.net/doc/eb2644433.html,

Supplemental content at https://www.wendangku.net/doc/eb2644433.html,

Author Affiliations:University of Southampton,Southampton,

England (Primrose,Corkhill,George);University of Oxford,Oxford,England (Perera,Gray,Rose,Fuller,Mant).Group Information:The FACS Trial Investigators are listed at the end of this article.

Corresponding Author:John N.Primrose,MD,FRCS,University Surgery,Mailpoint 816,C Level SAB,Southampton General Hospital,Tremona Road,Southampton SO166YD,England (j.n.primrose @https://www.wendangku.net/doc/eb2644433.html,).

Research

Original Investigation

263

C olorectal cancer is a major cause of morbidity and mortal-

ity.It is the third most common cancer worldwide,with

1.24millioncasesreportedtotheInternationalAgencyfor ResearchonCancerin2008.1Traditionally,patientswhohavehad curative treatment for colorectal cancer undergo regular hospi-tal follow-up for at least5years to detect recurrence.Although locoregional relapse is traditionally associated with poor progno-sis,specialistcentersarereportingimprovedcureratesforselected patients with combined-mode treatment.2Success in treating metastatic recurrence has also been increasing.Approximately 40%of patients survive5years after complete resection of liver metastases3and comparable results have been reported for lung metastases.4The likelihood of survival is increased if metastatic disease is treated before it becomes symptomatic.5

Seven published clinical trials have compared different fol-low-up regimens.6-12Two systematic reviews suggest an over-all survival benefit associated with more intensive follow-up.13,14However,trial quality was modest,the esti-mated effect on disease-specific survival was not statistically significant,and the mechanism by which the substantial sur-vival benefits reported were achieved is unclear.Two reviews13,14concluded that the existing evidence base needed to be strengthened by high-quality trials addressing the effec-tiveness of the individual components of follow-up.

The2individual components of follow-up recognized to be widely available and affordable and to have the potential to de-tect isolated metastatic recurrence at an early and surgically treatable stage are computed tomography(CT)imaging of the chest,abdomen,and pelvis and regular blood carcinoembry-onic antigen(CEA)measurement.The FACS(Follow-up After Co-lorectal Surgery)trial was commissioned by the UK National In-stitute for Health Research Health Technology Assessment program to assess the effect of these2modes with the inten-tion of providing a sound evidence base to inform clinical prac-tice.The original intention was to conduct a trial of sufficient size to assess survival advantage but when this proved infea-sible,detection of recurrence that was treatable surgically with curative intent was chosen as the main outcome measure.Pre-trial modeling suggested that unless follow-up increased the number of such recurrences detected,an important survival ad-vantage of follow-up would not be achieved.

Methods

Trial Design

The FACS trial was a factorial2×2pragmatic randomized clini-cal trial conducted in39centers in the United Kingdom;par-ticipants were randomized independently to CT imaging ev-ery6to12months or minimum follow-up and to CEA testing every3to6months or minimum follow-up.

Participants

To enroll in the trial,all participants had to have undergone cu-rative treatment for primary colorectal cancer with no residual disease,microscopically clear margins,and Dukes stage A to C (TNM stage1-3).Patients were disease-free based on colonic imaging with no evidence of metastatic disease(confirmed by CT or magnetic resonance imaging liver scan and chest CT scan) and with a postoperative blood CEA level of10μg/L or less fol-lowing surgery or completion of adjuvant therapy as indicated.

Patients were excluded if they had concurrent serious ill-ness or dominantly inherited colon cancer,were unable to pro-vide written informed consent,or were involved in a primary treatment trial with conflicting follow-up requirements.Poten-tial participants younger than50years or more than6months from completion of primary or adjuvant treatment were in-cluded only if agreed on by the chief surgical investigator.

All participants gave written informed consent to partici-pate in the trial.Ethical approval for the trial was granted by the National Health Service(NHS)South-West Research Eth-ics Committee.

Study Setting

Participants were recruited at39NHS hospitals in the United Kingdom with access to high-volume regional services geared to offer surgical treatment for recurrence.

Interventions

Follow-up was scheduled to occur for5years after trial entry. The factorial design,with independent allocation to the CEA and CT interventions,meant that patients received1of4types of follow-up:

1.CEA follow-up:measurement of blood CEA every3months

for2years,then every6months for3years,with a single chest,abdomen,and pelvis CT scan at12to18months if re-quested at study entry by hospital clinician

2.CT follow-up:CT of the chest,abdomen,and pelvis every

6months for2years,then annually for3years

3.CEA and CT follow-up:both blood CEA measurement and

CT imaging as above

4.Minimum follow-up:no scheduled follow-up except a single

CT scan of the chest,abdomen,and pelvis at12to18months if requested at study entry by the hospital clinician

All patients had undergone colonoscopy at trial entry to ensure there was no residual intraluminal disease and were of-fered an end-of-trial colonoscopy at5years;in the2CT groups, an additional colonoscopy was undertaken at2years.

Blood collection kits were sent directly to patients,who then attended their own general practice for phlebotomy.Blood was sent to the biochemistry laboratory at the John Radcliffe Hos-pital,Oxford;the CEA analysis was performed using a Siemens Centaur XP analyzer.If a patient’s blood CEA level was7μg/L or more above the level at trial entry,the test was repeated as soon as possible;if the second test result was also greater than this threshold,the patient’s general practice physician was asked to refer the patient urgently to the local hospital.

Outcomes

The primary outcome was surgical treatment of recurrence with curative intent after a minimum of3years of follow-up. Secondary outcomes were mortality(total deaths and deaths due to colorectal cancer),time to detection of recurrence,and survival after treatment of recurrence with curative intent.

Information on participant deaths was collected at the Of-fice for National Statistics central registry(all patients were reg-

Research Original Investigation CEA and CT to Detect Colorectal Cancer Recurrence

264JAMA January15,2014Volume311,https://www.wendangku.net/doc/eb2644433.html,

istered to have the trials unit notified in the event of the patient’s death);cause of death was abstracted from death certificates. Data on treatment of recurrence and treatment intent were re-corded on case report forms by local National Cancer Research Network staff who had access to the full clinical records.

Randomization and Blinding

Randomizationto1of4groups(Figure1)ona1:1:1:1ratiowasper-formed centrally at the Oxford Clinical Trials Unit using a mini-mization algorithm to balance patient characteristics within each centerbasedon3variables:adjuvantchemotherapy,sex,andage group.Study nurses contacted the Oxford Clinical Trials Unit by telephone to enter a patient in the trial,reporting the relevant pa-tient characteristics;they were then told the trial group to which the patient had been allocated.

Because this was a pragmatic open trial,it was not possible to conceal the allocation group from either participants or clini-cians.However,the research staff who abstracted outcome data from clinical notes were employed by the local National Cancer Research Network teams independent of the investigators.The analysis program was undertaken first using dummy variables for the allocation groups and the code was not broken until the precise procedures for analysis were agreed on.

Sample Size

From the run-in phase of the trial,it was predicted that2%of pa-tientsintheminimalfollow-upgroupwouldhaveundergonesur-gery for recurrence with curative intent by3years of follow-up. It was therefore estimated that a sample size of590participants wouldneedtobeallocatedtoeachfactorialgrouptoachieve80% power with a2-sidedα=.05to detect a minimum3%absolute ef-fect of intensive monitoring with CT or CEA.Modeling suggested that a3%difference in treatment with curative intent translated intooverallsurvivalwasthesmallestdifferencethatwouldprove costeffective.Tocomparetheminimuminterventiongroupwith each of the CEA,CT,and CEA+CT groups separately,this sample size would provide51%,70%,and84%power to detect absolute differencesof3%,4%,and5%,respectively.Wethereforedecided to stop recruitment when the sample size reached a minimum of1180participants.

Statistical Analysis

Theprimaryanalysiswasanintention-to-treatcomparisonofthe proportion of patients experiencing recurrence who were treated surgically with curative intent(1)comparing all patients random-ized to the3intensive follow-up groups(CEA only,CT only,and CEA+CT)with the minimum follow-up group and(2)comparing all patients randomized to the2factorial groups(CEA vs no CEA and CT vs no CT).When feasible,crude data are presented with statisticalcomparisonmadebetweenrandomizationgroupsbased onχ2tests for binary or categorical data,the t test or analysis of variance as appropriate for comparing group means,and the Kruskal-Wallis test for comparing medians.

Time to recurrence was analyzed by the Kaplan-Meier methodtotakeaccountofbothtimecensoringandthedifference in the number of recurrences detected in each group(ie,a crude comparisonoftimetorecurrencemaybemisleadingbecausethis approachdoesnottakeintoaccountrecurrencesnotyetdetected inless-effectivefollow-upgroups).Theplotsoftimetorecurrence were compared by the log-rank Mantel-Cox statistic.Adjusted odds ratios for the main outcome were calculated by binary lo-gisticregression,enteringallthebaselinecharacteristicsreported in Table1into the model.For the comparison of factorial groups (CEA vs minimum follow-up and CT vs minimum follow-up),an interaction term(CEA factor×CT factor)was also entered.We set astatisticalsignificancethresholdofα=.05basedon2-sidedtests. The analyses were conducted using IBM SPSS version20.

Protocol Adherence and Amendments AdherencetoprotocolwasascertainedthroughNHShospitaland laboratory records.A secondary per-protocol analysis was con-ducted excluding patients who received any unscheduled inves-tigationorhadmissedmorethan1scheduledexamination.There were2significant amendments to the original protocol during

Figure1.Participant Flow

It was not feasible to collect information on the number of potentially eligible pa-tients excluded from the trial.For the primary intention-to-treat analysis,mortality data were available through the NHS central registry for all participants;the poten-tial completeness of ascertainment of recurrence is reported in Table2.For the per-protocol analysis,details of the deviations from the follow-up intervention re-sulting in exclusion are given in eTable1in the Supplement.

CEA and CT to Detect Colorectal Cancer Recurrence Original Investigation Research

the trial.The initial protocol did not specify the single CT at12 to18months in the minimum follow-up and CEA groups;66pa-tients had been randomized to the minimum follow-up group before this change took effect in May2005.Surgical treatment with curative intent rather than overall survival was specified as the main outcome in2007when it became clear that we could not recruit the number of participants necessary to estimate an effect on overall survival with adequate statistical power.

Results

Characteristics of Participants

Allocation of the1202eligible participants recruited between January2003and August2009to each randomization group is shown in Figure1.The follow-up intervention lasted5years or, for patients recruited after August2007,until August31,2012. Characteristics at trial entry are shown in Table1.The mean age of participants was69years,736(61.2%)were male,350(29.1%) had significant comorbidity;487(40.5%)had received adjuvant chemotherapy and139(11.6%)preoperative radiotherapy(for rectal cancer)before randomization.The randomization method was successful in achieving a good balance between random-ization groups and factorial comparison groups.Cumulative overall survival by stage and randomization group are shown in eFigures1and2,respectively,in the Supplement.Detection of Recurrence

During the period of observation for recurrence(mean,4.4[SD, 0.8]years),cancer recurrence was detected in199partici-pants(16.6%;95%CI,14.5%-18.7%);41(3.4%)had locore-gional recurrence only and101(8.4%)had metastatic disease limited to the lung and/or liver(Table2).The Kaplan-Meier plots in Figure2show that the3intensive interventions tended to detect recurrence earlier,although these differences in ear-lier detection were not statistically significant.There were no recurrences treatable with curative intent detected in the mini-mum follow-up group after year2.Two-thirds of recurrences (n=130[65.3%;95%CI,58.7%-71.9%])were detected by a sched-uled follow-up investigation;the remainder were interval cases, presenting symptomatically or incidentally during investiga-tion of concurrent illness.Three luminal recurrences were de-tected by the2-year colonoscopy in the groups monitored by CT imaging.Additionally,3cancers were detected by the5-year colonoscopy but these were new cancers and not recurrent dis-ease.The way in which the recurrences were treated is de-tailed in eTable1in the Supplement.

Curative Treatment and Survival

The proportion of participants with recurrence surgically treated with curative intent was5.9%(71/1202;95%CI,4.6%-7.2%)overall,with little difference between participants ac-cording to Dukes staging(stage A,5.1%[13/254];stage B,6.1%

Abbreviations:CEA,carcinoembryonic antigen;CT,computed tomography; IQR,interquartile range.

a Site not specified precisely for32participants(2.7%).

b Dukes stage not recorded for41participants(3.4%).Dukes stage is a measure of the extent of the tumor.Dukes stage A indicates the cancer is only in the

innermost lining of the colon or rectum or slightly growing into the muscle layer;Dukes stage B indicates the cancer has grown through the muscle layer of the colon or rectum;and Dukes stage C indicates the cancer has spread to at least1lymph node in the area close to the bowel.

c Smoking status not recorde

d for40participants(3.3%).

Research Original Investigation CEA and CT to Detect Colorectal Cancer Recurrence

266JAMA January15,2014Volume311,https://www.wendangku.net/doc/eb2644433.html,

[34/553];stage C,6.2%[22/354]).Table 3shows that surgical treatment of recurrence with curative intent was higher in each of the 3more intensive follow-up groups compared with the minimum follow-up group (absolute difference ranged from 4.3%to 5.7%;overall P =.02).The adjusted odds ratios were 3.0(95%CI,1.2-7.3)for CEA only and 3.6(95%CI,1.5-8.7)for CT only.The odds ratio for the combined CEA+CT group was similar to that for CT or CEA alone,providing no evidence that any additive effect is achieved by using both together.The fac-torial comparison showed an absolute difference between the intervention and comparison groups of 1.4%(95%CI,?1.2%to 4.1%)for CEA and 2.8%(95%CI,0.2%-5.5%)for CT.

Of the 71participants treated surgically with curative intent,30alsoreceivedchemotherapy(7withradiotherapy).Ofthesepa-tients,47(69%;95%CI,56.9%-79.5%)were still alive at the time offollow-up(median,4.4yearsafterdiagnosisofrecurrence).The absolute difference in the proportion of patients treated and sur-viving compared with the minimum follow-up group was 3.3%(95%CI,0.5%-6.2%)for CEA,2.0%(95%CI,?0.6%to 4.6%)for CT,and 3.6%(95%CI,0.7%-6.5%)for CEA+CT (overall P =.09).The differences in the factorial comparison were 2.4%(95%CI,0.3%-4.7%)for CEA and 1.2%(95%CI,1.0%-3.4%)for CT.

The number of deaths was higher but not significantly dif-ferent in the more intensive follow-up groups compared with

Figure 2.Time to Diagnosis of Recurrence by Randomization Group

CEA plus CT

Minimum follow-up

CT only CEA only 0

No. at risk 01234

P a t i e n t s W i t h D e t e c t e d R e c u r r e n c e , C u m u l a t i v e %

Follow-up, y

All recurrences

Minimum follow-up

301

261

235

224

172

119

301

261

235

224

172

119

CEA only 300270249232172122300270249232172122CT only 299263236226173115299263236226173115CEA plus CT 30226524623017712330226524623017712315

R e c u r r e n c e T r e a t e d W i t h C u r a

t i v e I n t e n t , C u m u l a t i v e %

Follow-up, y 10

Recurrences treated with curative intent

Mantel-Cox log-rank P =.18

Mantel-Cox log-rank P =.03

Y-axis scale shown in blue indicates range from 0%to 15%.

Abbreviations:CEA,carcinoembryonic antigen;CT,computed tomography.

Reported P values are based on the Pearson χ2test for binary comparisons,1-way analysis of variance or independent t tests in comparing means.b

Participants who died during follow-up without evidence of recurrence

(n =46),withdrew consent or moved from National Health Service to private care (n =24),developed another primary cancer (n =36),or for whom case report forms seeking information on recurrence had not been completed for the entire period at risk (n =78).

CEA and CT to Detect Colorectal Cancer Recurrence Original Investigation Research

https://www.wendangku.net/doc/eb2644433.html,

JAMA January 15,2014Volume 311,Number 3

267

the minimum follow-up group (18.2%[164/901]vs 15.9%[48/301];difference,2.3%;95%CI,?2.6%to 7.1%),as was the num-ber of disease-specific colorectal cancer deaths (10.4%[94/901]vs 9.3%[28/301];difference,1.1%;95%CI,?2.7%to 5.0%).The Kaplan-Meier survival curves by randomization group and Dukes stage are shown in eFigures 1and 2in the Supplement.

Adherence to Protocol

The extent of adherence to the follow-up protocol is shown in eTable 2in the Supplement.Patient adherence was very good,with only 5.8%(35/602)in the CEA group missing more than 1scheduled CEA test and 5.0%(30/601)in the CT group missing more than 1CT scan.Although clinician adherence appears to be lower(10.6%ofparticipants[127/1202]receivedunscheduledCEA

bloodtests,10.6%[127/1202]unscheduledCTscans,and9.7%[117/1202]unscheduled colonoscopies),the protocol required inves-tigation of any patients presenting with symptoms between scheduled follow-up tests.Substantially more unscheduled tests were performed in patients not receiving regular CT scans,with 16.5%(99/601)vs4.7%(28/601)receiving 1or more unscheduled CEAtests,17.6%(106/601)vs3.5%(21/601)receiving1ormoreun-scheduled CT tests,and 15.6%(94/601)vs3.8%(23/601)receiving 1or more unscheduled colonoscopies.

Per-Protocol Analysis

Theresultsofaper-protocolanalysisareshownin Table4,exclud-ing the 308patients (25.6%)who missed more than 1scheduled visitorunderwentanyunscheduledinvestigation.Theresultsare

Abbreviations:CEA,carcinoembryonic antigen;CT,computed tomography.a

The adjusted odds ratios and associated 95%CIs were estimated using logistic regression,including all the baseline variables listed in Table 1in the model.For the factorial group comparison,the odds ratio is also adjusted for interaction with the other randomization factor (eg,the CEA×CT interaction).The

standard P values given for comparison of proportions are based on the χ2test for heterogeneity (which tests whether the overall distribution in proportions could have occurred by chance).The Wald P values test whether the odds of detecting recurrence in each of the intensive follow-up groups are significantly different from that in the minimum follow-up

group.

Abbreviations:CEA,carcinoembryonic antigen;CT,computed tomography.a

The adjusted odds ratios and associated 95%CIs were estimated using logistic regression including all the baseline variables listed in Table 1in the model.For the factorial group comparison,the odds ratio is also adjusted for interaction with the other randomization factor (eg,the CEA×CT interaction).The

standard P values based on the χ2test for heterogeneity (which tests whether the overall distribution in proportions could have occurred by chance).The Wald P values test whether the odds of detecting recurrence in each of the intensive follow-up groups are significantly different from that in the minimum follow-up group.

Research Original Investigation CEA and CT to Detect Colorectal Cancer Recurrence

268

JAMA January 15,2014Volume 311,Number 3

https://www.wendangku.net/doc/eb2644433.html,

consistentwiththeintention-to-treatanalysisbuteffectestimates are higher:the absolute differences in rate of detection of treat-ablerecurrenceinthemoreintensivefollow-upgroupscompared with the minimum follow-up group were5.8%to8.0%.

Discussion

The2follow-up tests assessed in this trial were CEA and CT imaging.Meta-analyses have suggested that these are the only modes with significant potential to detect curatively treatable metastaticrecurrenceinpatientswithcolorectalcancer.13,14Clini-calandultrasoundexaminationlacksensitivitywhereasmagnetic resonanceimagingcanrealisticallybeappliedonlytotheliverand lacksstrongevidenceofeffectivenessindetectingrecurrence.13,14 Computed tomography–positron emission tomography was not anavailabletechnologywhenthistrialwasinitiatedand,because of cost and logistics,would be preferred to standard CT for rou-tine follow-up only if evidence suggested much superior perfor-mance.Endoscopic imaging(colonoscopy)was provided to pa-tients in all study groups because it is a standard evidence-based element of follow-up care that can detect metachronous polyps or cancer(and,rarely,intraluminal recurrence).15

Ourresultsshowthatintensivefollow-upbyeitherscheduled CEA or CT increased the likelihood of detecting a recurrence that can be treated with curative intent.The absolute difference in the proportion of participants treated with curative intent was ap-proximately5%in the intention-to-treat analysis and8%in the per-protocol analysis,suggesting that between12and20patients needtobefolloweduptoidentify1potentiallycurablerecurrence. More than two-thirds of the patients treated surgically with cu-rative intent were still alive at a median follow-up of just over4 yearspostrecurrence,suggestingthat5-yearsurvivalmaybemore than the40%previously reported.3,4

Although the proportion of recurrences treated with cura-tive intent(and the success of such treatment)is higher com-pared with earlier reports,the absolute number of treatable recurrences detected is lower.14This is not explicable by differ-ences in stage-specific case-mix(detection of recurrences treat-able with curative intent was similar irrespective of stage),nor is there any evidence that participants in the FACS trial were at low risk of recurrence within stage(84.5%of stage C participants hadreceivedadjuvantchemotherapy).Stage-specificoverallsur-vival of participants in this study(eFigure2in the Supplement) is comparable with that reported in trials of adjuvant chemo-therapy,such as MOSAIC.16A more likely explanation for the lower detection of treatable recurrence is the rigor of the inves-tigative procedures undertaken to ensure that no residual can-cer was present at trial entry.It suggests that the high rate of early recurrence reported from routine cancer statistics in England and Scandinavia17reflects residual disease that would have been detected with more thorough imaging.It probably also explains the greater benefit of intensive follow-up reported in previous trials—follow-up detected residual disease,not recurrence.A key finding of this study is therefore the need to fully stage colorec-tal cancer before embarking on follow-up.

The comparison between intervention groups suggests that monitoring with CEA combined with a single CT scan at12to 18months is not significantly different from undertaking regu-lar CT scanning.Because CEA testing can be done in primary care,it is likely to be more cost-effective than regular CT imaging.However,imaging is still necessary to confirm recur-rence,and in the combined CEA+CT group,two-thirds of re-currences were first detected by CT.The diagnostic perfor-mance of CEA as a monitoring test depends on the frequency of testing and the algorithm used to interpret the result.The algorithm applied in the FACS trial(refer for imaging if blood CEA level is7μg/L above baseline)achieves good specificity but at the cost of modest sensitivity.18An ongoing study is in-vestigating whether a higher sensitivity can be achieved at an acceptable level of specificity by applying a diagnostic algo-rithm that takes account of change over time and has been ap-plied successfully in interpreting cancer antigen125levels when screening for ovarian cancer.19

Wehadplannedtoreportourresultsafterallparticipantshad completed5years of follow-up because early analysis increases the risk of lead-time bias.However,there have been no cases of recurrence treatable with curative intent after2years of follow-up in the minimum follow-up group,making lead-time bias un-likely in our main comparison.Nevertheless,subject to continu-ing informed consent from those in the minimum follow-up group,we plan to continue follow-up as planned to increase the precisionofourresults,particularlyinrelationtodisease-specific mortality and posttreatment survival.

The decision on whether the absolute benefit of follow-up is sufficient to justify its opportunity cost will differ between health economies.The benefits of follow-up appear to be inde-pendent of diagnostic stage(because although there are fewer recurrences with better-stage tumors,they are more likely to be curable),suggesting that stage-specific follow-up strategies may not be necessary.However,thorough staging investigation at the end of primary treatment to detect residual disease is still im-portant because a large number of“recurrences”reported in rou-tine series are probably residual disease that should be de-tected and treated before embarking on follow-up.Because of the detailed investigation performed before trial entry to ex-clude residual disease,our results also provide data on the tim-ingofrecurrencethatcanstrengthentheevidencebaseforchoos-ing the optimal frequency of testing.Duplication of monitoring testsdoesnotappearto addvalue;participantsintheCEAgroups had a single CT at12to18months,when3recurrences were de-tected,but otherwise there was no suggestion of benefit from monitoring with both CEA and CT.

The size of the trial provides limited precision in estimating survival.With an observed15.9%mortality rate in the minimum follow-up group,we had only31%power(with2-sidedα=.05)to detect a5%effect on survival.Although the observed2%aggre-gate survival advantage of the minimum follow-up group vs the moreintensivefollow-upgroupsisunlikelytobeduetobias(cen-tral death registration in the United Kingdom means there was no loss to follow-up),it could be due to chance.An observed ab-solute6%increase in surgery with curative intent predicts a2% to3%survivaladvantagewithintensivefollow-up.Theconfidence intervals around both the total mortality and colorectal cancer–specific mortality rates indicate that our results are still consis-tent with this outcome.

CEA and CT to Detect Colorectal Cancer Recurrence Original Investigation Research

Conclusions

Among patients who had undergone curative surgery for primary colorectal cancer,intensive imaging and CEA screening each provided an improved rate of recurrence treated with curative intent compared with minimal follow-up;there was no advantage to combining both strategies.If there is a survival advantage to any strategy,it is likely to be small.

ARTICLE INFORMATION

Author Contributions:Dr Perera and Ms Fuller had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design:Primrose,Gray,Rose, Corkhill,George,Mant.

Acquisition of data:Primrose,Fuller,Mant. Analysis and interpretation of data:Primrose, Perera,Gray,Rose,Fuller,George,Mant.

Drafting of the manuscript:Primrose,Gray,George, Mant.

Critical revision of the manuscript for important intellectual content:All authors.

Statistical analysis:Primrose,Perera,Fuller,Mant. Obtained funding:Primrose,Gray,Rose,George, Mant.

Administrative,technical,and material support: Fuller,Corkhill.

Study supervision:Primrose,George,Mant.

Conflict of Interest Disclosures:All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.Dr Rose reports board membership with GP Update Ltd.No other disclosures were reported.

FACS Trial Investigators:University of Southampton:Sian Pugh(surgical registrar),Louisa Little,Andrea Corkhill(clinical trial managers),Scott Regan,Jane Mellor(clinical trial coordinators); University of Oxford:Indika Pathiraja(clinical research fellow),Helen Campbell(research fellow in health economics);Oxford University Hospitals Trust:Tim James(head biomedical scientist),Helen Bungay(clinical radiologist).Participating NHS hospitals:Birmingham Heartlands Hospital(Gamal Barsoum);Castle Hill Hospital,Hull(John Hartley); Charing Cross Hospital(Peter Dawson); Cumberland Infirmary(Jonathan Nicoll);Darent Valley Hospital(Mike Parker);Derriford Hospital, Plymouth(Mark Coleman);Grantham and District Hospital(Dilip Mathur);Harrogate District Hospital (Jon Harrison);Hillingdon Hospital(Yasser Mohsen);Hinchingbrooke Hospital(Litee Tan); King’s Mill Hospital(Mukul Dube);Leeds St James (Simon Ambrose);Leeds General Infirmary(Paul Finan);Leighton General Hospital(Arif Khan); Maidstone Hospital(Mark Hill);Croydon University Hospital(formerly Mayday Hospital)(Muti Abulafi); Newham University Hospital(Roger Le Fur);Oxford Radcliffe Hospitals(Neil Mortensen);Queen Alexandra/Portsmouth(Daniel O’Leary);Queen Elizabeth Hospital,Birmingham(Neil Steven); Queens Hospital Burton-on-Trent(Stelios Vakis); Queens Medical Centre,Nottingham(John Scholefield);Royal Cornwall Hospital(Ponnandai Arumugam);Royal Derby Hospital(Jonathan Lund); Royal Shrewsbury(Trevor Hunt);Russels Hall Hospital(David Ferry);Scarborough Hospital(Ian Renwick);Southampton General Hospital(Paul Nichols);St Mark’s Hospital,Harrow(John Northover,Arun Gupta);St Peter’s Hospital, Chertsey(Philip Bearn);St Richard’s Hospital, Chichester(Neil Cripps);Taunton and Somerset (Mary Tighe);Torbay Hospital(Rupert Pullan);

Manor Hospital,Walsall(Jonathan Stewart);

Warrington Hospital(Barry Taylor);West Middlesex

Hospital(Subramanian Ramesh);Wexham Park

Hospital(Harpreet Wasan);Worcester Royal

Hospital(Stephen Lake);Wycombe General

Hospital(Andrew Weaver).Data Monitoring and

Ethics Committee:Jack Hardcastle,Nottingham

University;Michael Campbell,Sheffield University;

David Whynes,Nottingham University.

Funding/Support:The project was funded by the

UK National Institute for Health Research Health

Technology Assessment(NIHR HTA)program

(project No.99/10/99).

Role of the Sponsors:The NIHR HTA had no role in

the design and conduct of the study;collection,

management,analysis,and interpretation of the

data;preparation,review,or approval of the

manuscript;or decision to submit the manuscript

for publication.

Disclaimer:The views and opinions expressed

therein are those of the authors and do not

necessarily reflect those of the HTA program,the

NIHR,the NHS,or the Department of Health.

Additional Contributions:We acknowledge the

invaluable contributions of the local NIHR cancer

research networks,NHS trusts,and patients who

agreed to participate in this trial.

REFERENCES

1.Cancer Research UK.Cancer statistics–colorectal

cancer.https://www.wendangku.net/doc/eb2644433.html,/cancer

-info/cancerstats/world/colorectal-cancer-world/.

Accessed May3,2013.

2.Colibaseanu DT,Mathis KL,Abdelsattar ZM,

Larson DW,Haddock MG,Dozois EJ.Is curative

resection and long-term survival possible for locally

re-recurrent colorectal cancer in the pelvis?Dis

Colon Rectum.2013;56(1):14-19.

3.Kanas GP,Taylor A,Primrose JN,et al.Survival

after liver resection in metastatic colorectal cancer:

review and meta-analysis of prognostic factors.Clin

Epidemiol.2012;4:283-301.

4.Gonzalez M,Poncet A,Combescure C,Robert J,

Ris HB,Gervaz P.Risk factors for survival after lung

metastasectomy in colorectal cancer patients:a

systematic review and meta-analysis.Ann Surg

Oncol.2013;20(2):572-579.

5.Nordic Gastrointestinal Tumor Adjuvant Therapy

Group.Expectancy or primary chemotherapy in

patients with advanced asymptomatic colorectal

cancer:a randomized trial.J Clin Oncol.

1992;10(6):904-911.

6.Schoemaker D,Black R,Giles L,Toouli J.Yearly

colonoscopy,liver CT,and chest radiography do not

influence5-year survival of colorectal cancer

patients.Gastroenterology.1998;114(1):7-14.

7.Secco GB,Fardelli R,Gianquinto D,et al.Efficacy

and cost of risk-adapted follow-up in patients after

colorectal cancer surgery:a prospective,

randomized and controlled trial.Eur J Surg Oncol.

2002;28(4):418-423.

8.Rodríguez-Moranta F,SalóJ,Arcusa A,et al.

Postoperative surveillance in patients with

colorectal cancer who have undergone curative

resection:a prospective,multicenter,randomized,

controlled trial.J Clin Oncol.2006;24(3):386-393.

9.Pietra N,Sarli L,Costi R,Ouchemi C,Grattarola

M,Peracchia A.Role of follow-up in management of

local recurrences of colorectal cancer:a

prospective,randomized study.Dis Colon Rectum.

1998;41(9):1127-1133.

10.Ohlsson B,Breland U,Ekberg H,Graffner H,

Tranberg KG.Follow-up after curative surgery for

colorectal carcinoma:randomized comparison with

no follow-up.Dis Colon Rectum.1995;38(6):

619-626.

11.Kjeldsen BJ,Kronborg O,Fenger C,J?rgensen

OD.A prospective randomized study of follow-up

after radical surgery for colorectal cancer.Br J Surg.

1997;84(5):666-669.

12.M?kel?JT,Laitinen SO,Kairaluoma MI.

Five-year follow-up after radical surgery for

colorectal cancer:results of a prospective

randomized trial.Arch Surg.1995;130(10):1062-

1067.

13.Renehan AG,Egger M,Saunders MP,O’Dwyer

ST.Impact on survival of intensive follow up after

curative resection for colorectal cancer:systematic

review and meta-analysis of randomised trials.BMJ.

2002;324(7341):813.

14.Jeffery M,Hickey BE,Hider PN.Follow-up

strategies for patients treated for non-metastatic

colorectal cancer.Cochrane Database Syst Rev.

2007;(1):CD002200.

15.Rex DK,Kahi CJ,Levin B,et al.Guidelines for

colonoscopy surveillance after cancer resection:a

consensus update by the American Cancer Society

and US Multi-Society Task Force on Colorectal

Cancer.CA Cancer J Clin.2006;56(3):160-167.

16.AndréT,Boni C,Navarro M,et al.Improved

overall survival with oxaliplatin,fluorouracil,and

leucovorin as adjuvant treatment in stage II or III

colon cancer in the MOSAIC trial.J Clin Oncol.

2009;27(19):3109-3116.

17.Morris EJ,Sandin F,Lambert PC,et al.A

population-based comparison of the survival of

patients with colorectal cancer in England,Norway

and Sweden between1996and2004.Gut.

2011;60(8):1087-1093.

18.Tan E,Gouvas N,Nicholls RJ,Ziprin P,Xynos E,

Tekkis PP.Diagnostic precision of carcinoembryonic

antigen in the detection of recurrence of colorectal

cancer.Surg Oncol.2009;18(1):15-24.

19.Drescher CW,Shah C,Thorpe J,et al.

Longitudinal screening algorithm that incorporates

change over time in CA125levels identifies ovarian

cancer earlier than a single-threshold rule.J Clin

Oncol.2013;31(3):387-392.

Research Original Investigation CEA and CT to Detect Colorectal Cancer Recurrence

270JAMA January15,2014Volume311,https://www.wendangku.net/doc/eb2644433.html,