Advances in cholangiocarcinoma

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Advances in cholangiocarcinoma
Rachna Shroff, MD

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Advances in cholangiocarcinoma

  1. 1. AUBHO 2014 Rachna T. Shroff, MD, MS Assistant Professor, Dept of GI Medical Oncology M.D. Anderson Cancer Center rshroff@mdanderson.org
  2. 2. None with the subject matter to be presented Research Funding: Celgene Clovis Oncology
  3. 3. >7,0000 cases annually in 2009 5-year survival is <15% Most patients present with locally advanced or metastatic disease Treatment commonly administered in the community, at low-volume centers.
  4. 4. Obesity, Metabolic Syndrome Chronic inflammation (hepatitis, ETOH, smoking, occupational) Parasitic infections Primary sclerosing cholangitis, Crohns disease Cysts, anomalous pancreatobiliary ducts Biliary polyps (>10 mm)
  5. 5. J Hepatol. 2004;40(3):472-7
  6. 6. 180 160 140 120 100 80 60 40 20 0 New Cases 2009 2010 2011 2012 Medical Oncology Referrals or New Cases Causes: Reclassification from CUP True increase: Obesity, Hepatitis, Better Detection with Imaging/ Pathology
  7. 7. Adenocarcinoma • Nodular • Sclerosing • Papillary Squamous cell carcinoma Mixed hepatocellular/cholangiocarcinoma IHC CK7+, CK20-, CA19.9+
  8. 8. Al Jaffiry, WJG 2009
  9. 9. Extrahepatic • Painless jaundice • Weight loss • Fever Intrahepatic • Constitutional Symptoms • Pain • Hepatomegaly • Abnormal Liver Chemistries
  10. 10. Hilar Intrahepatic
  11. 11. Hilar Cholangio Biliary Obstruction common Cholangitis life threatening Local-directed therapies (TACE, Y90, RFA) increased risk of abscess/ complications Intrahepatic Cholangio Course can be relatively indolent Local therapies for advanced disease feasible, particularly radiation
  12. 12. Surgical resection is the standard of care Post operative radiation/ chemoradiation therapy improves recurrence-free survival in R1 disease Role of adjuvant therapy in R0 resection is debatable Role of liver transplantation in unresectable hilar cholangiocarcinoma. NCCN Guidelines
  13. 13. Surgical resection results in 20-30% long term survival > 5 years Klatskin tumors-junction of the hepatic ducts are complicated by extensive perineural and lymphatic invasion, bilateral liver involvement, and vascular encasement Intrahepatic cholangiocarcinoma is a contraindication for liver transplant at most centers.
  14. 14. Unresectable CCA or resectable Cholangio with PSC Tumor size < 3 cm Tumor above cystic duct No intra- or extrahepatic metastases No intrahepatic CCA or GB involvement Vascular encasement of the hilar vessels is not a contraindication CA 19-9 > 100 with mass; Biliary ploidy by FISH with bile duct stricture
  15. 15. Neoadjuvant EBRT: 4000 to 4500 cGy + 5-FU 2000 to 3000 cGy transcatheter iridium Capecitabine until transplantation 5-year survival with neoadjuvant therapy = 55% 5-year survival after transplantation = 71%. Rosen HPB (Oxford). 2008
  16. 16. American Association for the Study of Liver Diseases Heimbach J, et al: Liver Transplantation 10; 65-68, 2004
  17. 17. Disease-related factors • Uncommon malignancies • Unwell, elderly population, infection/obstruction • Histological / cytological confirmation difficult Lack of evidence • Disease often not measurable • Primarily small phase II and one phase III study of gemcitabine-based combinations
  18. 18. Eligible patients (n=400*) Arm A Gem 1000 mg/m2 D1,8,15 q 28d 24 weeks (6 cycles) Arm B Cisplatin 25 mg/m2 + Gem 1000 mg/m2 24 weeks (8 cycles) Randomized 1:1 (stratified by centre, primary site, PS, prior therapy and locally advanced vs. metastatic) Upon disease progression, management will be on clinician’s discretion (mostly best supportive care) D1,8 q 21d * Including 86 patients in ABC-01 + QoL
  19. 19.  Main inclusion criteria:  Histologically / cytologically verified disease  Adequate biliary drainage, no uncontrolled infection  ECOG PS 0-2  LFTs: bilirubin  1.5 x ULN, ALT/ AST/ alk phos  3 x ULN ( 5 if liver metastases)  Measureable disease was not mandated
  20. 20. Primary endpoint: OVERALL SURVIVAL Secondary endpoints:  Progression-free survival  Toxicity  Quality of life (EORTC QLQ C- 30) Sample size:  Powered to detect increase in MS from 8 to 11 months Log-rank test with 80% power and two-sided a 5% level
  21. 21. Toxicity by patient Gem Cis/Gem n % n % White blood cells 18 11.0% 24 15.1% Platelets 13 8.0% 13 8.2% Hemoglobin 6 3.7% 10 6.3% Neutrophils 29 17.9% 36 22.6% Infection + neutropenia 12 7.5% 16 10.2% Infection - neutropenia 14 8.6% 10 6.4%
  22. 22. Toxicity by patient Gem (n, %) Cis/Gem (n, %) Anorexia 4 2.5% 3 1.9% Lethargy 27 16.6% 29 18.6% Nausea 5 3.1% 5 3.2% Renal function 2 1.2% 3 1.9% Vomiting 8 3.0% 8 5.1% Constipation 3 1.8% 2 1.3% Diarrhea 4 2.5% 7 4.5% Dyspnea 2 1.2% 5 3.2% Pedal oedema 5 3.1% 4 2.6% Pain 12 7.5% 14 9.0% Any grade ≥3 events 108 65.5% 102 64.2%
  23. 23. Result Gem n (%) Gem + Cis n (%) Not assessed * 74 (36%) 56 (27%) Assessed * 132 (64%) 148 (73%) Complete Response 1 (0.8%) 1 (0.7%) Partial Response 20 (15.2%) 37 (25.0%) Stable Disease 73 (55.3%) 79 (53.4%) Progressive Disease 33 (25.0%) 28 (18.9%) CR + PR + SD 94 (71.2%) 117 (79.1%) p-value 0.256 * Patients not required to have measurable disease at study entry, some patients still in follow-up
  24. 24. Treatment arm Gem Gem + Cis Number of patients n=206 n=204 PFS events n(%) 155 (75.2) 135 (66.2) Median PFS (mo) 6.5 8.4 Log rank p value 0.003 Hazard ratio (95% CI) 0.72 (0.57, 0.90)
  25. 25. ABC-02 - Results: Overall Survival (ITT) Treatment arm Gem Gem + Cis Number of patients n=206 n=204 Deaths n(%) 141 (68.5) 122 (59.8) Median survival (mo) 8.3 11.7 Log rank p value 0.002 Hazard ratio (95% CI) 0.70 (0.54, 0.89)
  26. 26. Cisplatin and gemcitabine significantly improves overall survival compared with gemcitabine monotherapy (11.7 vs. 8.3 months) Benefit gained with no clinically significant added toxicity CisGem is recommended as a worldwide standard of care and the backbone for further studies Caution required in patients with PS > 2
  27. 27. Gastrointest Cancer Res. 2011;4(5-6):155-60.
  28. 28. Rogers JE, et al. J Gastrointest Oncol 2014
  29. 29. Agents Target Patients RR PFS Author Combination Regimens First line therapy GEMOX-cetuximab EGFR 51 - 61% (4 mths) Malka GEMOX-bevacizumab VEGF 35 40 7 months (median) Zhu Single Agent Regimens First or Second line AZD6244 MEK1/2 22 14 5.4 months (median) Bekaii-Saab Erlotinib EGFR 43 7 2.6 months (median) Philip et al Lapatinib EGFR/HER2 17 0 1.8 months (median) Ramanathan Sorafenib BRAF/VEGFR 36 6 2 months (median) El-Khoueiry Sorafenib BRAF/VEGFR 46 2 2.3 months (median) Bengala Zhu et al, JCO, 2009
  30. 30. Bile Acids Induce EGFR in CCA cells via TGF-α and COX-2 Hepatol. 2004;41(5):808-14
  31. 31. Wide range reported k-ras mutation in biliary cancer (10-45%) More likely in anomalous pancreato-biliary ducts Less likely in the setting of pre-existing adenoma In Wt k-ras, EGFR-directed TKIs or Monoclonal antibodies are a consideration
  32. 32. Endpoint Estimate Partial response 8% Stable disease 43% 24- week progression-free 17% Overall survival 7.5 mos J Clin Oncol. 2006 (19):3069-3074
  33. 33. GEMOX + Cetuximab 500 mg/m2 bi-weekly Pri-endpoint: 4 month PFS (<40%: control; >60% study arm) 101 pts enrolled Interim analysis: manageable toxicity 4 mth PFS 44% vs 61% (Interim Analysis) J Clin Oncl 27:15s, 2009
  34. 34. 268 pts randomized: GEMOX + Erlotinib PR higher in erlotinib group (40 vs. 21, p=0.005) Higher PFS with erlotinib (5·9 months vs 3·0 months) (p=0·049) Median overall survival was the same in both groups Lancet Oncol. 2012;13(2):181-8.
  35. 35. Phase 2: GEMOX+ Bevacizumab (10 mg/kg bi-weekly) 35 pts enrolled Median PFS 7 months (6 months was 63%) Toxicities: neutropenia, hypertension, AST elevation, neuropathy Partial responses or SD associated with significant improvement in SUV Lancet Oncol Nov 2009 (Epub)
  36. 36. Sorafenib: 400 mg twice a day 46 patients were treated; 26 (56%) had received chemotherapy earlier Progression-free survival (PFS) was 2.3 months (range: 0-12 months) Median overall survival was 4.4 months (range: 0-22 months). El Khoureiy, ASCO 2007
  37. 37. Therapeutic Target Chemotherapy Agent Phase MEK Nil ARRY-438162; AZD6244 II Raf kinase GemOx Sorafenib II VEGF+ EGFR Gemcitabine Vandetanib Randomized II VEGFR Gemcitabine/ Cisplatin Cediranib (AZD2171) Randomized II/III EGFR Gemcitabine + Erlotinib, Cetuximab, Panitumamab II/Randomized
  38. 38. MRN Mutations 1 PTEN TP53 ARID1A IDH1 2 MCL1 3 FBXW7 KRAS TP53 SMAD4 MLL2 CREBB 4 STK11KRAS MCL1 5 <none> 6 CDKN2A KRAS SMAD4 TP53 7 KRAS SMAD4 GRIN2A TP53 8 BAP1 CDKN2A/B PBRM1 9 PIK3CA KRAS MCL1 MYC 10 ARID1A TSC2 11 BRAF PIK3R1 12 ARID1IDH1 13 KRAS ARID1A IDH2 14 <none> 15 <none> 16 KRAS FBXW7 ARID1A MSH2 TP53 17 BAP1 18 KRAS 19 KRAS FBXW7 TP53 20 PTEN KRAS MDM2 21 KRAS TP53 22 CDK4 MYC 23 <none> 24 ERBB2 FBXW7 CDKN2A SMAD4 TP53 25 ERBB2 ATM SMAD4 26 KRAS TP53 27 EGFR PIK3CA CCND1 TP53 28 IDH1 29 MCL1 MYST3 30 IDH1 31 NRAS ARID1A IDH1 32 MDM2KRAS ARID2 33 PIK3CA MCL1 ARID1A CDH1 EPHA7 EPHB1 MSH6 34 BAP1 34 BRCA1 PTCH FBXW7 35 FGFR3-TACC
  39. 39. 1.00 0.75 0.50 0.25 0.00 Proportion Surviving p = 0.028 0 6 12 18 24 30 36 42 48 54 60 Months KRAS-Negative KRAS-Positive
  40. 40. 33 patients with intrahepatic cholangioca Median tumor size - 8.8 cm 88% previously chemotherapy Dose: 50.4 Gy (range, 35–70 Gy), most with xeloda 1-year PFS: 47%, and 1-year OS: 62% 1-year OS rate was 100% with RT dose ≥ 60 Gy Gastrointest Cancer Res. 2010 Nov-Dec; (Suppl 1): S34
  41. 41. Intrahepatic Cholangio: 67.5 Gy in 15 fractions. No concurrent chemotherapy N=57 1 and 2-year OS is 69% and 58% PFS is 41% and 28% respectively.
  42. 42. Locoregional Therapy: Y90 48 90Y treatments were administered to hepatic segments or lobes. Fatigue, abdominal pain common Rare: grade 3 bilirubin toxicity, gastroduodenal ulcer. PR 6 pts (27%), SD 15 patients (68%), and PD in 1 patient (5%). Median OS was 14.9 months. OS for pts without and with prior chemo was 31.8 months and 4.4 months, respectively (P = .02). Cancer. 2008;113(8):2119-28.
  43. 43. Vascularity is lower than HCC, thus limiting the value of TACE Retrospective Study 60 cases DEB-TACE: PFS of 3.9 mos, OS 11.7 mos, cTACE: PFS of 1.8 mos OS of 5.7 mos Chemo (GEMOX): PFS of 6.2 mos and OS of 11.0 mos Eur J Gastroenterol Hepatol. 2012 (4):437-43.
  44. 44. Ann Surg Oncol. 2013 Jul 12
  45. 45. Approach to management of intrahepatic cholangiocarcinoma Patel, T. (2011) Cholangiocarcinoma—controversies and challenges Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.20
  46. 46. Localized Induction Chemo followed by ChemoRT Disseminated Systemic Chemotherapy NGS Add targeted agents based on molecular phenotype Clinical trials: MEK + Pazopanib FGFR Inhibitor Proton Therapy Select cases with SD/PR> 6 mos on chemo, consider OLT (investigational)

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