1. The Christie NHS Foundation Trust Should patients with resected bile duct cancer receive an adjuvant treatment? Juan Valle Medical Oncologist The Christie / University of Manchester 2012 WCGIC Meeting, Barcelona 27 June 2012

2. The Christie NHS Foundation Trust Disclosures Honoraria and unrestricted educational grant funding Lilly Oncology

3. The Christie NHS Foundation Trust Outline Background Phase III data What do registry studies tell us? What do systematic reviews tell us? Forthcoming data Summary – status in 2012

4. The Christie NHS Foundation Trust Background “Biliary Tract Cancer (BTC)” Cholangiocarcinoma Intra-hepatic Hilar Extra-hepatic Gallbladder cancer Ampullary tumours 3% of all GI cancers globally 1 Second commonest primary hepatic tumour but more lethal than HCC 2 Mostly adenocarcinomas (95%), some mixed with HCC, +/- mucin production 1 Vauthey Sem Liver Dis 1994; 2 Taylor-Robinson Gut 2001, 3 Aljiffry et al. World J Gastroenterol 2009 From Aljiffry et al. 3

5. The Christie NHS Foundation Trust Surgery Surgery - challenges: Only modality of cure Most patients are inoperable  Late presentation  Difficult to image (diagnosis / surveillance)  Difficult to confirm histologically/ cytologically  Difficult to resect  Elderly patient population (65% over 65 yrs)  Associated co-morbidities  Unwell population: biliary obstruction/ infection

6. The Christie NHS Foundation Trust Survival In Biliary Tract Cancer Overall prognosis is poor (5-year survival 5-15%) 1,2 <35% of patients present with resectable disease and relapse rates are high Aims of adjuvant therapy: Locoregional control Prevent systemic relapse  Improve survival 1 Anderson et al. Oncologist 2004;9:43-57 2 deOliveira et al. Ann Surg 2007; 245:755-762

7. The Christie NHS Foundation Trust Different patterns of relapse MSKCC data (1990-2001) 156 resected patients (80 with GBCA and 76 with HCCA) Likelihood of recurrence similar: HCCA 68% vs, GBCA 66%. Patients with GBCA relapse earlier vs. CCA : median 11.5 vs. 20.3 months; p= 0.007 Diagnosis is an independent predictor of the site of disease recurrence (multivariate analysis Survival better with HCCA vs. GBCA: 29 vs. 20.6 months; p=0.037  How should these differences determine adjuvant strategy? Jarnagin et al, Cancer 2003;98:1689–700.

8. The Christie NHS Foundation Trust Importance of Margin and LN status in cholangiocarcinoma Johns Hopkins 564 patients (1973-2004) Multivariate analysis  negative margins (p<0.001)  tumour differentiation (p<0.001)  negative nodal status (p<0.001) For R0-resected patients,  lymph node status (p<0.001), but not tumour diameter, histology or differentiation, further predicted survival. R0 R1/2 Palliated LN- LN+ deOliveira et al. Ann Surg 2007; 245:755-762

9. The Christie NHS Foundation Trust (Only) one phase III study to date Curative resection (n=508) 1986 –1992 Stage II-IV (Japan) Pancreas (n=173) Bile duct (n=139) Gallbladder (n=140) Ampullary (n=56) MF* chemotherapy Observation RANDOMISATION No benefit: Pancreas BTC Ampullary Improved DFS and OS: Ca gallbladder In patients with Ca Gallbladder: Improved 5Y-DFS (20.3% vs. 11.6%, p=0.0210) per-protocol analysis Improved 5YS OS (26.0% vs. 14.4%, p=0.0367) per-protocol analysis Effect lost with ITT analysis (imbalance of ineligible (stage 1) patients Takada et al. Cancer 2002; 95:1685–95 * MMC 6mg/m2 IV peri-operatively then 5-FU 310mg/m2 IV infusion D1-5 (weeks 1&3) then 5-FU 100mg/m2/d PO week 5 - disease recurrence 1 o end-point: survival

10. The Christie NHS Foundation Trust What can we learn from registry studies? SEER (extra-hepatic cholangiocarcinoma [EH-CC]) Vern-Gross et al, IJROBP 2011;81:189–198 SEER (intra-hepatic cholangiocarcinoma [IH-CC]) Shinohara et al, IJROBP 208;72,1495–1501 SEER (gallbladder) Mojica et al, J Surg Oncol 2007;96:8-13 Wang et al, JCO 2008;26:2112-7 Wang JCO 2011;29:4627-32

11. The Christie NHS Foundation Trust Registry studies (SEER): EH-CC SEER database 1973 – 2003 EH-CC only Localised (T1-2) Regional (T3-4, N+) Excluded follow-up <3mo. N=1491 eligible patients Aged 66 (22-97 yrs) Mostly male (59%) Mostly regional disease (72%) More likely to receive RT if: high histology grade (G3:38%, G2:34%, G1:29%) regional (36% vs. localised 21%)

12. The Christie NHS Foundation Trust Registry studies (SEER): EH-CC Prognostic factors: Univariate/multivariate analyses: Age Grade Year of diagnosis (post 1990) Stage: localised 33 mo vs. regional 18 mo, p<0.001 Radiotherapy: Regional disease (fig 1.): no difference in survival (18 mo vs. 18 mo, p=0.8) Localised disease (fig 2.): initial positive effect (p<0.001) but negative effect on survival in long-term (p<0.001) “Adjuvant RT was not associated with an improvement in long-term survival in patients with resected EH-CCA” …”a potential detriment to long-term survival” (pre-1990 effect?) 1 2 Vern-Gross et al, IJROBP 2011;81:189–198

13. The Christie NHS Foundation Trust Registry studies (SEER): IH-CC SEER database 1988-2003 IH-CC N=3,839 patients Aged: 73 (22-102 yrs) Male: 52% More likely not to have radiation therapy: Distant disease Ethnic minorities Recent years (!)

14. The Christie NHS Foundation Trust Registry studies (SEER): IH-CC Prognostic factors: Multivariate analysis: Age Stage Race / Ethnicity Year of diagnosis (post 1993) Surgery + XRT Radiotherapy: Surgery + XRT vs. surgery alone: Median OS: 11 vs. 6 mo., p=0.014 HR (adjusted): 0.82; 95% CI, 0.70–0.96 “However, although radiation did prolong survival in these patients, it did not appear to cure their disease” Shinohara et al, IJROBP 208;72,1495–1501

15. The Christie NHS Foundation Trust Registry studies (SEER): Gallbladder Mojica 2007 1 N Age (median) Female (%) 3187 73 years 74% Multivariate covariates (significant) Age, Sex, Stage XRT Grade Received XRT22% Higher stage of disease EBRT (97%) XRT effectOS 14 vs. 8 mo. (p<0.0001) CommentsGreatest benefit if N+ (16 vs. 5 mo, p<0.001) T3+N0 (14 vs. 11 mo, p=0.011) No benefit in stage I 1 Mojica J Surg Oncol 2007;96:8-13; 2 Wang JCO 2008;26:2112-7; 3 Wang JCO 2011;29:4627-32

16. The Christie NHS Foundation Trust Registry studies (SEER): Gallbladder Mojica 2007 1 Wang 2008 2 N Age (median) Female (%) 3187 73 years 74% 4180 72 years 73% Multivariate covariates (significant) Age, Sex, Stage XRT Grade Age, Sex, Stage XRT Papillary histology Race (Asian/Pacific Is) Received XRT22% Higher stage of disease EBRT (97%) 18% Stage T2+, N+ Younger patients (68 vs. 74 yrs, p<0.0001) XRT effectOS 14 vs. 8 mo. (p<0.0001)OS 15 vs. 8 mo. (p<0.0001) CommentsGreatest benefit if N+ (16 vs. 5 mo, p<0.001) T3+N0 (14 vs. 11 mo, p=0.011) No benefit in stage I In addition to other study: Nomogram developed Updated 2011 3 : chemo-RT better than chemo alone 1 Mojica J Surg Oncol 2007;96:8-13; 2 Wang JCO 2008;26:2112-7; 3 Wang JCO 2011;29:4627-32

17. The Christie NHS Foundation Trust What can we learn from registry studies? SEER (extra-hepatic cholangiocarcinoma) No improvement in survival observed from XRT SEER (intra-hepatic cholangiocarcinoma) Improved survival observed from XRT Median OS: 11 vs. 6 mo., p=0.014 HR (adjusted): 0.82; 95% CI, 0.70–0.96 SEER (gallbladder) Improved survival observed from XRT Median OS: 14-15 vs. 8 mo. (p<0.0001) Greatest benefit in T2+ or N+ disease Vern-Gross et al, IJROBP 2011;81:189–198 Shinohara et al, IJROBP 208;72,1495–1501 Mojica et al, J Surg Oncol 2007;96:8-13 Wang et al, JCO 2008;26:2112-7 Wang JCO 2011;29:4627-32

18. The Christie NHS Foundation Trust Registry studies (SEER) Limitations No information available regarding: Tumour-related factors Location Extent of surgical resection Post-op complications Resection status (R0/R1) Lymphovascular invasion Adjuvant XRT detail Dose Dose-intensity Therapy fields Treatment length and QA Time from surgery to XRT Patient-related factors Performance status Co-morbidities Subsequent therapy Any adjuvant chemotherapy Details of disease relapse Treatment on relapse

19. The Christie NHS Foundation Trust Adjuvant RT: EH-CC meta-analysis Systematic review Jan 1995 – Dec 2008 Studies using conventional 3D radiotherapy techniques Including EH-CCA, GB, ampullary Excluding IH-CCA +/- concurrent chemotherapy Eligible studies: Total n=44 Adjuvant radiotherapy 24 studies 32 patients per study Surgery alone 35 studies 58 patients per study Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

20. The Christie NHS Foundation Trust Adjuvant RT: EH-CC meta-analysis Findings Radiotherapy >50% of patients had R1 or N1 disease OS 13-34 months Relapses up to 70% Surgery alone More likely (60%-80%+) if R0 or N0 OS 16-38 months OS 30-60 mo if R0/N0 OS <22 mo if R1 Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

21. The Christie NHS Foundation Trust Adjuvant RT: EH-CC meta-analysis Forest plot for all tumour locations, using a random effects model. Px, proximal; Dx, distal; EHC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer. Amp GB

22. The Christie NHS Foundation Trust Adjuvant RT: EH-CC meta-analysis Forest plot of studies for EH-cholangiocarcinoma Pooled HR for overall survival using a random effects model. Px, proximal; Dx, distal. Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

23. The Christie NHS Foundation Trust Adjuvant RT: EH-CC meta-analysis Limitations of meta- analysis: Not randomised Not prospectively designed Bias: radiotherapy offered to patients with adverse features Indirect methods to obtain HR Late toxicities GI ulceration Biliary stenosis Anastomotic stenosis Cholangitis Bleeding Intestinal obstruction Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

24. The Christie NHS Foundation Trust All-treatment meta-analysis Systematic review – eligible studies: CCA and GB (not ampullary) Chemotherapy and/or XRT Studies including surgery-alone as comparator R0 and R1 only Analysis with / without registry data Horgan et al. JCO 2012;30:1934-1940

25. The Christie NHS Foundation Trust All-treatment meta-analysis Findings: 20 studies phase III [1] registries [2] institutional series [17] 6,712 patients 4,915 surgery alone 1,797 with adjuvant Rx Overall population: No benefit for adjuvant therapy (OR 0.74 (95%-CI 0.55 – 1.01, p=0.06) If registry data excluded: Benefit for adjuvant therapy: (OR 0.53 (95%CI 0.39-0.72, p<0.001) Greatest benefit for chemotherapy or chemo-radiotherapy Chemo: OR 0.39 (95%-CI 0.23-0.66; p=0.001) CRT: OR 0.61 (95%-CI 0.38-0.99; p=0.049) XRT: OR 0.98 (95%-CI 0.67-1.43; p=0.90) Horgan et al. JCO 2012;30:1934-1940

26. The Christie NHS Foundation Trust ◄ Efficacy outcomes for node-positive disease OR 0.49; 95%-CI 0.30-0.80; p=0.004 Majority of those treated were with chemotherapy alone (77%) Efficacy outcomes for margin- positive disease OR 0.36; 95%-CI 0.19-0.68; p=0.002 Note: Radiation benefits only patients with R1 disease with uncertain benefit / “possible harm” (NS) in R0 ► Horgan JCO 2012;30:1934

27. The Christie NHS Foundation Trust Forthcoming data: chemotherapy Study (n) [clinicaltrials.gov number] (n)PopulationArmsPrimary endpo int UK - BilCap [NCT00363584] 360Cholangio and GBObservation vs. capecitabine 2Y DFS France - PRODIGE12 [NCT01313377] 190Cholangio and GBObservation vs. gemcitabine & oxaliplatin DFS and QoL Japan - BCAT [UMIN000000820] 300*EH-CCObservation vs. gemcitabine OS Germany - ACTICCA-1 280Cholangio and GBObservation vs. cisplatin & gemcitabine DFS JapanTBCCholangio and GBObservation vs. S1TBC GB=gallbladder; cholangio=cholangiocarcinoma; DFS=disease-free survival; OS=overall survival; TBC=to be confirmed; studies in italics are in set-up; *study closed to accrual before target reached Source: ClinicalTrials.gov

28. The Christie NHS Foundation Trust Primary end-point: 2-year DFS Secondary: 5YS, RFS, toxicity, QoL, health economics BilCap: A randomized clinical trial evaluating adjuvant capecitabine compared to expectant treatment alone following surgery for biliary tract cancer [NCT00363584] PS 0,1,2 Histologically confirmed intrahepatic cholangiocarcinoma extrahepatic/hilar cholangiocarcinoma muscle-invasive gallbladder cancer (T2+) and cancer of the distal bile duct Including resection of the liver OR pancreatic resection OR less commonly both Chief Investigators: Prof. John Primrose & Dr John Bridgewater Stratified by centre, tumour site, resection (RO/RI) and PS

29. The Christie NHS Foundation Trust Accrual update: 289 of 360 patients randomized (30/05/12) BilCap: A randomized clinical trial evaluating adjuvant capecitabine compared to expectant treatment alone following surgery for biliary tract cancer [NCT00363584]

30. The Christie NHS Foundation Trust Summary – status in 2012 (i) Surgery remains the mainstay of cure for patients with BTC Only phase III study to date suggests benefit for adjuvant chemotherapy in Ca GB (but unconventional regimen) Registry data suggest benefit of adjuvant XRT in IH-CC and Ca GB but not EH-CC (many limitations) Systematic reviews suggest: Benefit for adjuvant XRT in EH-CC Benefit for adjuvant chemo in node-positive disease Benefit for adjuvant radiotherapy in margin-positive disease Observation for low-risk (R0 / N0) still an option

31. The Christie NHS Foundation Trust Summary – status in 2012 (ii) Understanding of patterns of relapse important Is need for XRT decreasing with improved surgery? Patients & physicians need to know magnitude of benefit to make informed choice Ongoing prospective phase III trials will help to improve understanding  insightful study design & collaboration are essential