Original StudyColorectal Cancer Survival: An Analysis ofPatients With Metastatic Disease Synchronousand Metachronous With the Primary TumorRajiv Kumar,1Timothy J. Price,2,3Carol Beeke,4Kunal Jain,1Gargi Patel,1Rob Padbury,4Graeme P. Young,5David Roder,6Amanda Townsend,2Sarwan Bishnoi,2Christos S. Karapetis1,5AbstractUsing the population-based South Australian Clinical Registry for Metastatic Colorectal Cancer, we analyzeddifferencesinsurvival betweenpatientswithmetachronousandsynchronouspresentationof metastaticcolorectal cancer. Patientswithmetachronouspresentationhavealongeroverall survival thanthosewithsynchronous presentation, independent of treatment received. These results highlight the prognosticsignicance of metachronous vs. synchronous presentation.Background: Whether metastaticcolorectal cancer (mCRC) that presentssynchronouslywiththeprimarylesionbehavesdifferentlyfrommCRCthat appearsmetachronouslytotheprimarydiseaseisnot clear. PatientsandMethods: The South Australian Clinical Registry for mCRC collects data for patients diagnosed after February 2006.Data from 2502 patients, available on October 22, 2012, were analyzed according to stage at initial diagnosis (SAID) tocompareoutcomesbetweenmetachronoustumors(MTs)(stagesI,II,III)andsynchronoustumors(STs)(stageIV).Overall survival (OS) was calculated from the date of mCRC diagnosis. Results: Patients with ST had more liver-onlymetastases, and patients with MT had more lung-only, non-lung and non-liver, and non-lung metastases. The mediantime to recurrence differed signicantly according to SAID: stage I, 49.3 mo (n 29), stage II, 25.2 mo (n 346) andstage III, 18.4 mo (n 497). The median OS was longer for patients with MT than for those with ST (19.0 vs.14.9 mo,P .003). For patients who received any treatment for mCRC, the OS was longer for patients with MT than for thosewithST(19.2vs.15.3mo,P .005).InpatientswhoreceivedonlychemotherapyformCRC,themedianOSwaslonger for patients with MT than for those with ST (15.2 vs. 9.9 mo, P < .0001). No difference in OS between the MTand ST groups for patients who did not receive treatment for mCRC (1.6 vs. 2.6 mo; P .95). Conclusion: PatientswithMThavealonger OSthanthosewithST, independent of treatment. Classicationof patientsaccordingtowhether they have metachronous or synchronous presentation of mCRC is prognostic. These results may add furthersupport for population screening with the aim to reduce de novo metastatic disease.Clinical Colorectal Cancer, Vol. 13, No. 2, 87-93 2014 Elsevier Inc. All rights reserved.Keywords: Epidemiological, Patterns of metastases, Patterns of treatment, Registry, SurvivalIntroductionMetastaticcolorectal cancer(mCRC)isthefourthmost com-moncause of cancer-relateddeathworldwide, withthe highestratesestimatedinAustraliaandNewZealand,at33.0deathsper100,000persons.1The cancer stage at initial diagnosis (SAID)correlates with prognosis, with 5-year overall survival (OS) of93.2%, 84.7%, 72.2%, 83.4%, 61.4%, 44.3%, and8.1%forstages I, IIA, IIB, IIIA, IIIB, IIIC, and IVcolorectal cancer(CRC), respectively.2Reported survival outcomes calculated fromthe date of initial diagnosis donot give insight intoanyeffect1Department of Medical Oncology, Flinders Centre for Innovation in Cancer, FlindersMedical Centre, Bedford Park, Australia2Department of Medical Oncology, The Queen Elizabeth Hospital Woodville,Australia3The University of Adelaide, Adelaide, Australia4Department of Surgery, FlindersMedical Centre, Bedford Park, Australia5Flinders Centre for InnovationinCancer, Flinders University, Bedford Park,Australia6SansomInstitute for Health Research, University of South Australia,AustraliaSubmitted: Sep 15, 2013; Accepted: Nov 8, 2013; Epub: Nov 13, 2013Address for correspondence: Christos S. Karapetis, Department of Medical Oncology,Flinders MedicalCentre, Bedford Park, SA 5042, AustraliaE-mail contact: C.Karapetis@inders.edu.au1533-0028/$ -see frontmatter 2014 Elsevier Inc. Allrights reserved.http://dx.doi.org/10.1016/j.clcc.2013.11.008 Clinical Colorectal Cancer June 2014-87resultingfromCRCscreeningprograms3,4formetachronoustu-mors (MTs), in other words, recurrent stage I, II, and III,comparedwithsynchronoustumors(STs), inotherwords, met-astaticdiseaseispresentatinitial diagnosis.Asidefrompotentialearlydiagnosisandstagemigration,differ-encesinthe biology basedon SAIDmay alsoimpact outcome.Inearly-stageCRC, stageIIandIIItumorsappeartohavedifferentbiology. Aside from lymph node status, stage II tumors are larger atdiagnosis, independent of T-stage, compared with stage III tumors,particularlyright-sidedcoloncancer(CC)withhighmicrosatelliteinstability (MSI).5MSI due to somatic mutations inmismatchrepair genes occur in 15% to 20% of CRCs, affecting 17% of stageII and12%of stage III CRCs.6HighMSI instage II CRCispredictive of a better prognosis, with no additional benet from 5-uorouracil therapy,7whereasstageIIICRCsstillderiveabenetfromadjuvant chemotherapy.8HighMSItumorsaremoreprox-imal, poorlydifferentiated, mucinous, andshowmarkedlympho-cytic inltration.9Furthermore, therearedifferencesintheefcacyof treatmentsaccording to SAID that may reect thisbiological variation. Adju-vant chemotherapy for stage III CRCimproves progression-freesurvival and OS10; however, its role in stage II CRCremainscontroversial,11and the survival benet is limited to high-riskgroups.12Also, drugs such as irinotecan,13,14bevacizumab,15,16and cetuximab17,18provide an OS benet onlyfor stageIV CRC.These differences intreatment efcacy speak to the underlyingdifferences in tumor biology for the different SAIDs.With the establishment of population-based CRCscreeningprograms, we expect tosee more patients withearlier SAID.3,4Giventheapparentbiological differences, wemayseeadifferencein survival between patients with MT and patients with ST that willbe of prognostic signicance. To evaluate this further, we used thedata fromthe South Australian Clinical Registry (SACR) formCRC.16Our primary analysis lookedat OSbetweenpatientswithMTandpatientswithST. Secondaryanalysesreviewedanyinteractions between initial SAIDand OS, time to recurrence(TTR), and patterns of metastases.Patients and MethodsThe SACR for mCRC is a statewide population-based database,established in February 2006, that collects information on patient,tumor, andtreatmentcharacteristics, asdescribedbyNeoetal.16For this analysis, datawerecollectedbetweenFebruary1, 2006,and October 22, 2012.Atotal of 2502patients were groupedbySAIDtocompareoutcomes betweenMTandSTgroups. All analyses were per-formedusingGraphPadPrismversion6.0(GraphPadSoftware,La Jolla, CA). Disease-specic survival analysis was undertakenusingconventional Kaplan-Meierproduct-limitestimates(differ-ences insurvival were testedusing the log-ranktest). OSwascalculatedfromthe date of diagnosis of mCRCtothe date ofdeath or the date of censoring of live cases on October 22, 2012,whichevercamerst.TTRwascalculatedfromthedateofdiag-nosistothedateofrecurrenceordateofcensoringoflivecases,whichever came rst. All survival outcomeswereanalyzedusingintervalsofmonths.ResultsPatient DemographicsDatafrom2502patientswereavailableforanalysisonOctober22,2012.PatientdemographicswerestratiedaccordingtoSAID(Table1). ThemajorityofpatientshadST(64.3%), whereastheremainder had MT (1.2%, 13.8%, and 19.9% with stages I, II, andIIICRC, respectively). Themedianageof patientswas70years,balanced across the SAID. There was a male predominance (57%),balanced across the SAID. CC was the primary site in the majorityof patients (68%). The dominant tumor grade was moderatelydifferentiated (58%), with stage II/III CRC having more moderatelydifferentiated tumors than stage I/IV CRC (P < .0001). Testing forthe KRAS gene was performedinfrequently at the time of thisanalysis (7%), but it was balanced across the SAID. Liver resectionwasperformedin35%of patientswithliver-onlymetastases. Forpatients with liver-only disease, those with MT were more likely tohave had liver resection than those with ST (56%, 61%, 59%, and26% with stagesI, II,III, andIV CRC, respectively; P