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Should patients with resected bile duct cancer receive an adjuvant treatment?

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. Disclosures. Honoraria and unrestricted educational grant funding Lilly Oncology. Outline.

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Should patients with resected bile duct cancer receive an adjuvant treatment?

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  1. 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. Disclosures Honoraria and unrestricted educational grant funding • Lilly Oncology

  3. Outline • Background • Phase III data • What do registry studies tell us? • What do systematic reviews tell us? • Forthcoming data • Summary – status in 2012

  4. “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 Background From Aljiffry et al. 3 1 Vauthey Sem Liver Dis 1994; 2 Taylor-Robinson Gut 2001, 3 Aljiffry et al. World J Gastroenterol 2009

  5. 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. 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. 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? Different patterns of relapse Jarnagin et al, Cancer 2003;98:1689–700.

  8. 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+ Importance of Margin and LN status in cholangiocarcinoma deOliveira et al. Ann Surg 2007; 245:755-762

  9. (Only) one phase III study to date • No benefit: • Pancreas • BTC • Ampullary • Improved DFS and OS: • Ca gallbladder • 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 RANDOMISATION 1o end-point: survival Observation * 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 • 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

  10. 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. 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%) Registry studies (SEER): EH-CC

  12. 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?) Registry studies (SEER): EH-CC 1 2 Vern-Gross et al, IJROBP 2011;81:189–198

  13. 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 (!) Registry studies (SEER): IH-CC

  14. 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 Registry studies (SEER): IH-CC “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. Registry studies (SEER): Gallbladder 1 Mojica J Surg Oncol 2007;96:8-13; 2 Wang JCO 2008;26:2112-7; 3 Wang JCO 2011;29:4627-32

  16. Registry studies (SEER): Gallbladder 1 Mojica J Surg Oncol 2007;96:8-13; 2 Wang JCO 2008;26:2112-7; 3 Wang JCO 2011;29:4627-32

  17. 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. 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 Patient-related factors Performance status Co-morbidities Adjuvant XRT detail Dose Dose-intensity Therapy fields Treatment length and QA Time from surgery to XRT Subsequent therapy Any adjuvant chemotherapy Details of disease relapse Treatment on relapse

  19. 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 Adjuvant RT: EH-CC meta-analysis Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

  20. 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 Adjuvant RT: EH-CC meta-analysis Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

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

  22. 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. 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 Adjuvant RT: EH-CC meta-analysis Bonet Beltrán et al. Cancer Treat Rev 2012;38:111-119

  24. 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. 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) All-treatment meta-analysis Horgan et al. JCO 2012;30:1934-1940

  26. ◄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. Forthcoming data: chemotherapy 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. 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 Stratified by centre, tumour site, resection (RO/RI) and PS Primary end-point: 2-year DFS Secondary: 5YS, RFS, toxicity, QoL, health economics Chief Investigators: Prof. John Primrose & Dr John Bridgewater

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

  30. 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. 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

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