Mr Hassan Malik - Bowel Cancer UK

Aintree University HospitalLiverpool, UKMultidisciplinary approach in metastaticcolorectal cancer. Hope for a cure?Hassan Z Malik MD FRCSConsultant Hepatobiliary Surgeon

Referral zoneReferral population3.7 millionSupraregionalandinternationalquaternaryreferrals

Hepatobiliary Surgery UnitGreater than 1800 resections to date2012: > 200 complex HB procedures

Colorectal Liver Metastases• The liver is the major site of spread for colorectalcancer• Patients without treatmenthave poor survival• Liver resection forcolorectal liver metastases(CRLM) may significantlyimprove survival

• The use of parachutes to preventmajor trauma due to gravitationalchallenge after jumping out of anaircraft has not been proven in anyrandomised Systematic controlled review would trial NOT• recommend But there are the a use very of small parachutes numberwhen of anecdotal jumping reports from an of people aeroplanesurviving falls from planes flying atconsiderable heights• And the use of parachutes is notwithout the risk of their own inherentcomplications

Onco-surg approach for metastaticColorectal cancerWhere is the evidence of benefit?

Overall survival for patients with mCRC treatedat MD Anderson and Mayo clinics, by year ofdiagnosisOverall survival (%)• 2470 patients from two highly specialized centers were included100806040201990–19911992–19941995–19971998–20002001–20032004–2006Is this ONLY dueto betterchemotherapy ?00 12 24 36 48 60Time (months)Over the past decade, OS has improved substantially in patients with mCRCKopetz S, et al. J Clin Oncol 2009;27:3677–83

English HES data project:Liver resection for colorectal metastases• Using national data in the UK 1998 - 2004• Matched staged colorectal cancer diagnosis with codes for liverresection• Patients followed up from diagnosis until death• Assumption 1. Indication for liver resection was mCRC• Assumption 2. All death was due to CRCMorris EJA et al. Brit J Surg 2010; 97: 1110-8

Survival probabilityFive-year survival of English colorectalcancer patients10.90.80.70.60.50.40.30.20.1All stage 4 resected n=3116All patientsAll stage 3All Stage 400 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5YearsPatients with resected liver metastases All patients without resected metastases Dukes C Dukes DMorris EJA et al. Brit J Surg 2010; 97: 1110-8

Survival (%)Survival after chemotherapyplus surgery for metastases100806048%BSC5-FU--- FOLFIRI/FOLFOX6--- FOLFOX6/FOLFIRI--- Resectable liver metastases--- Resectable after chemotherapy402033%30%23%0 1 2 3 4 5 6 7 8 9 10Time (years)Colon Cancer Collaborative Group, BMJ 2000; Tournigand, JCO 2004; Adam, Ann Surg 2004

Bringing more patients to resection:induction chemotherapyWhat is the differencebetween this patient and ...this patient?NOTHING! They are the same patientpre- and post-chemotherapy

Resection rateSecondary liver resection rates ofmetastases and tumour response90%Resectability defined80%Resectability not defined70%60%50%40%30%20%10%0%30% 40% 50% 60% 70% 80% 90%Response rateJones et al 2013

Response rate (%)Significant improvement in response ratesin Phase III trials in 1st line mCRC70%FOLFIRI +Erbitux57% vs 40%FOLFOXIRI60% vs 34%Ox-CT +Erbitux59% vs 50%50%KRAS wtKRAS wtIFL + bev43% vs 35%FOLFIRI40–56%FOLFOX45–54%Capecitabine19–25%IFL31–39%FLOX46%0%BSC5FU15%FluoropyrimidineIrinotecanOxaliplatinFalcone A, et al. J Clin Oncol 2007;25:1670–1676; Hoff PM, et al. J Clin Oncol 2001;19:2282–2292;Hurwitz H, et al. N Engl J Med 2004;350:2335–2342; Goldberg RM, et al. J Clin Oncol 2004;22:23–30;Tournigand C, et al. J Clin Oncol 2004;22:229–237; Van Cutsem E, et al. J Clin Oncol 2001;19:4097–4106, J Clin Oncol 2011;29:2011–2019

Onco-surg approach for metastaticColorectal cancerRole of the Tumour Board

R0 resection (%)Response (%)807060504030201006050403020100Response rates and R0 liver resection ratesin initially unresectable kras WT LLDp

CRYSTAL: Resection rates according to country16%14%12%10%8%6%4%2%0%Country3.8%2.9%15.6%Worked13.0%10.1%within9.4%MDTs6.9%6.2%3.7%3.7%No MDT working2.3%1.4% 1.7%1.9%2.0%10.0%1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16No. Pts 106 103 89 85 80 73 64 58 58 54 54 49 32 32 27 10Resection s 4 3 9 2 3 1 6 1 4 7 1 1 5 2 1 1

Comparison of process and liver resection rates inErbitux trials in liver limited kras WT studiesStudyCRYSTALWhorecruited?Entry bygeneraloncologist% RRErbitux armTreatmentwith ErbituxRR 70%Who determinedliverresectability?Liver resectionrate ErbituxarmDecision onliver resectionby generaloncologist13%OPUSEntry bygeneraloncologistTreatmentwith ErbituxRR 75%Decision onliver resectionby generaloncologist16%CELIMEntry byMDT withLiverSurgeonTreatmentwith ErbituxRR 70%Decision onliver resectionby MDT withLiver Surgeon34%POCHEREntry byMDT withLiverSurgeonTreatmentwith ErbituxRR 78%Decision onliver resectionby MDT withLiver Surgeon60%Liver surgeons MUST work with medical oncologists fromthe outset if these outcomes are to be reproduced

Tumour Board• The NHS Cancer Plan (2000) gave a commitment thatall patients with cancer have the right to have theircare and treatment discussed at a multidisciplinaryteam meeting.• The Cancer Reform Strategy (2007) emphasises thatMDT working, as specified by NICE guidance, willremain the core model for cancer service delivery inthe future.

Current Tumour Board managementof advanced CRC• Through local CRC MDT, HPB sMDT and thoracicsMDT• Across the UK “HPB” MDTs are• Incorporated into UGI MDT• Combined Liver / Pancreas MDT• Separated Liver / Pancreas MDT

Limitations of current Tumour Boards• Delayed referral into sMDT• Limited / inadequate information into the sMDT• No input from colorectal surgeon / thoracic surgeon /clinical oncologist• Often no clinicians present have direct knowledge ofthe patient• Delays and sometimes inadequate information toclinical team managing patient

Liverpool ApproachAdvanced colorectal cancer tumor boardIn Liverpool we have a dedicated Hepatobiliary sMDT.This has been separated into 2:Advanced CRC sMDTPrimary liver tumour sMDT

Onco-surg approach for metastaticColorectal cancerRole of the Advanced Colorectal CancerTumour Board

Liver SurgeonMedicalOncologistTumour boardCross sectionalRadiologistColorectalSurgeonPathologistSpecialistnursePatientClinicalOncologistPET RadiologistAnaesthesiologistThoracicSurgeonMDTCoordinatorInterventionalRadiologist

Key relationshipThe medical oncologist needs the surgeon…• Advising on potential resectability• Advising on timing of surgery• Improving long-term survivalThe surgeon needs the medical oncologist…• Making unresectable patients resectable• Controlling the disease before surgery• Preventing recurrence after surgery ?

What are the key questions in themanagement of CRC liver metastases?• Defining resectability?• Timing of surgery after chemotherapy ininitially inoperable cases?• Which chemotherapy regimen?• Duration of chemotherapy?– Rapid tumor shrinkage preferred– Avoiding a ‘complete response’

Expert review from ICACT 2009: Optimizing1st-line treatment for mCRCCareful analysis of each patient and their tumor characteristicsAim: Maximumtumor shrinkagewithout delayingsurgeryYESIs there the potential for cure?NOChoice of initialtherapy is key dueto the impact onsubsequentoptionsKRAS testingKRAS testingKRAS wild-typeKRAS mutantKRAS wild-typeKRAS mutantCetuximab + Bevacizumabirinotecan- or + CToxaliplatin-based CTCetuximab orbevacizumab + CTBevacizumab+ CTConsider: 5-FU vs oral fluoropyrimidine; continuous vs intermittent CT;neuroprotective measures when using oxaliplatinAdam R, Haller D, Poston G, Raoul JL, Spano JP, Tabernero J, Van Cutsem E. Ann Oncol 2010 (Epub ahead of print)

Patient groups innon-resectable mCRCGroup 1Patients withmetastases thatmight becomeresectableGroup 2Patients withnon-resectablemetastases, hightumor burden, ortumor-relatedsymptomsGroup 3Patients withnon-resectablemetastases,asymptomatic andless aggressivediseaseIntensive therapyLess intensive therapyPotential for cureSchmoll H-J, Sargent D. Lancet 2007;370:105–107

The impact of multidisciplinarymanagement% surviving100502010 chemotherapyMedian survival >30 months5 year survival 15 %2010 overall (Surgery + Chemo)Median survival >40 months5 year survival 30 %2020>50%?020000 1 2 3 4 5Years after diagnosis of colorectal metastases30%15%Poston et al. J Clin Oncol 2008; 26: 4828-33, Kopetz et al. J Clin Oncol 2009;27:3677–833%1000%in10 yrs

Our golden rules

Liver only +/- resectableextrahepatic diseaseFitness assessment asper local protocolInitial SMDTassessmentResectable diseaseBorderline resectableNever likely to beresectablePrimovist MRI and PETCTPrimovist MRI, PET CTand K-ras statusKras test: chemotherapy+/- Erbitux (liver only)Formal re-assessmentat hepatobiliary SMDTChemotherapy +/-biologicFormal re-assessment athepatobiliary SMDTSURGERYPost chemo re staging(CT / MRI)Formal re-assessment athepatobiliary SMDT‘Accidental’hepatectomy?Alberto Sobrero

Onco-surg approach for metastaticColorectal cancer

Order of investigationsOverall survivals for resected and non-resected(with or without PET-CT) Colorectal Liver MetatasesCT10080B: Upfront palliativeA: Occult extrahepatic disease detected by PET-CTC: Curative resectionsMDTSurvival (%)6040£7885.22 perQALY gainedPET& MRI20sMDT00 10 20 30 40 50 60Time (Months)Surgery

Every patient has access to NICErecommended treatment or clinical trialWild TypeLiver MetastasesFolFiri + CetBorderline / NeedsDownsizing beforeresectableOLIVIA trialLiverMDTNever liable to beresectableBest StandardTherapy foradvanced diseaseFOXFIRETrialSurgery / RFWild TypeNew EPOCOperableK rasTestMutant TypePARAGON IItrialPeri-operative chemotherapy ifpatient not willing to recruit toclinical trail

Onco-surg approach for metastaticColorectal cancerDefining resectability ?

Percentage of patients receiving a liver resection within three years of resection of theircolorectal primaryVariation in hepatic resection for colorectalcancer metastases across cancer networks4.54.0Liverpool3.53.0Missing patients?2.52.01.51.00.50.0Network

Variation between specialist and nonspecialistassessmentJones et al BJS 2012

Relative risks for prognostic factorsassessed and post-surgical survival54 prospective studies of >100 hepatectomies for CRLM 1999-2010Prognostic Factor Number of studies mRR (95% CI)Grade (poorly differentiatedprimary)7 1.88 (1.32-2.67)Node-positive primary 20 1.59 (1.46-1.73)CEA level > 100 9 1.92 (1.14-3.22)>1 liver metastases 36 1.57 (1.39-1.78)Liver tumour >3 cm indiameter20 1.52 (1.28-1.80)Extra-hepatic disease 13 1.88 (1.50-2.37)Positive resection margin 20 2.02 (1.65-2.48)mRR, meta relative risk; CEA, carcinoembryonic antigenSo all are RELATIVE contraindications, NONE are absolute contraindicationsKanas G et al. Clin Epidemiol 2012

Making more patients resectable2000MetachronouspresentationConfined to 1 lobeLess than 4 metastasesNo metastases largerthan 5 cm1 cm negative resectionmargin2010Adequate liver remnantConfined to the liverResectable with adequatemarginsWhat you take out What you leave behind10% patients eligible forresectionPreservation of functionalliver anatomy20% patients eligible forresection at presentation

Reality?• Resectable metastases• Borderline• Not resectable

In reality!Technical aspects(Remaining functional tissue,vascular structures)•?•Non-resectable, palliative therapyExtrahepatic disease(Resectable/non-resectable)Experience(Surgeon, center)Tumor biology/prognostic factor(No. of met’s, DFS)scores: size, tumor markers,primary stageRisk/benefit(Surgeon, patient)

Future?• A paradigm shift in the management of these patients?• Move towards an advanced colorectal cancer tumour board• Management tailored to the individual patientPrimarysurgeryLiver surgeryLung surgeryTargetedchemotherapy(TACE)AblationtechniquesBiologicalsTargetedRadiotherapySystemicchemotherapy

Conclusion• Liver resection is the gold standard for patients withresectable disease• New technologies and new chemotherapy regimensincluding biologicals are bringing more patients toresection• Tumour board is essential for optimal management• All patients with liver only disease should haveimaging assessed at the regional liver centre