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  • 1. PROGRESS IN CHEMOTHERAPY OF BILIARY TREE CARCINOMA ADINA CROITORU DEPARTMENT OF ONCOLOGY FUNDENI CLINICAL INSTITUTE 08/12/10 BUCHAREST 1
  • 2. Introduction  risk of mortality is increasing in the last 30 years*  possible explanation:  improvement in diagnosing techniques  changes in coding practice  poor prognosis  may appear anywhere in the bile ducts(*) *S A Khan,B R Davidson,R Goldin,S P Pereira,W M C Rosenberg,S D Taylor -Robinson, H C Thomas,M R Thursz, H Wasan Guidelines for the diagnosis and treatment of cholangiocarcinoma:Consensus Document Gut 2002; 51 2 (Suppl VI:vi 1-vi 9)
  • 3. Introduction  etiology is unknown  risk factors:-age over 65 years -primary sclerosing cholangitis +/- ulcerative colitis -biliary gall stones -biliary papillomatosis -Carolis disease -choledocal cysts -smoking -thorotrast 3
  • 4. Definition  Anatomical classification:  intrahepatic (20-25%)  perihilar(50-60%):(Klatskin tumors)-involving the bifurcation of the ducts;  extrahepatic (distal): :20-25%  multifocal (5%)  Klatskin tumours: x type I:tumors below the confluence of the 2 hepatic ducts x type II:tumors reaching the confluence, without invading the left or right hepatic ducts x type III: tumours occluding the common hepatic duct and either the right (IIIA ) or left (III B) hepatic duct x type IV:multicentric tumours or which involve the confluence and both hepatic ducts 4
  • 5. Anatomo-Pathological Classification(WHO) B)Extrahepatic bile A)Carcinomas of the liver : duct carcinomas:  hepatocellular carcinoma  carcinoma in situ  combined hepatocellular-  adenocarcinoma(ADK) cholangiocarcinoma(CC)  intestinal-type ADK  mucinous ADK  intrahepatic cholangiocarcinoma  clear cell ADK  biliary cystadenocarcinoma  signet ring cell carcinoma  undifferentiated carcinoma  adenosquamous carcinoma  squamous cell carcinoma  small cell carcinoma  undifferentiated carcinoma 5
  • 6. Histological Classification*  the majority (95%) of the cholangiocarcinomas are ADKs -gr1-4 (depending on the ability to form glandular tissue)  carcinoma in situ,clear-cell carcinoma and papillary carcinoma -are not graded  signet ring cell carcinoma are gr.3  small cell carcinoma are gr.4  cholangiocarcinoma is associated with: - inactivation of tumor suppressor genes: p53,bcl-2, APC, p16 - mutation in oncogenes:K-ras ,c-myc,c-neu,c-erb B-2 - have no established role in diagnostic/prognosis * S A Khan,B R Davidson,R Goldin,S P Pereira,W M C Rosenberg,S D Taylor -Robinson, H C Thomas,M R Thursz, H Wasan Guidelines for the diagnosis and treatment of cholangiocarcinoma:Consensus Document Gut 2002;51 6 (Suppl VI:vi 1-vi 9)
  • 7. TNM Stadialisation  St I: tumor invades the mucosal or muscular layer  St II:local invasion  St III: tumor invades the mucosal or muscular layer + positive regional and hepatoduodenal lymph nodes  St IV: extensive invasion of the liver, adjacent structures, or lymph nodes and/or distant metastases 7
  • 8. Problems  Gallblader carcinoma-aggressive disease median survival :6months  Cholangiocarcinoma-more indolent median survival :12months  are histologically identical*  have poor responses to chemotherapy*  in most studies have been evaluated together * P.M.Sanz Altamira,E.O’Reilly,K.E.Stuart,L.Raeburn,C.Steger,N.E.Kemeny,L.B.Saltz A phase II trial of 8 irinotecan for unresectable biliary tree carcinoma:Annals of Oncology,vol.12,no4,April 2001,pp501-503
  • 9. Problems  five-year survival:10%(including resectable cases)*  with a performant surgery:5-y survival-20%  80% of pts are not eligible for a potentially curative surgery*  almost 50% of patients with lymph node invasion have also peritoneal involvement  at presentation, 10-20% of patients have already peritoneal metastases  the histological confirmation is sometimes difficult to obtain  the differential diagnosis with metastatic ADK can be very difficult * J.Taieb, E.Mitry, V.Boige, P.Artru, J.Ezenfis, T.Lecomte,M.C.Clavero-Fabri, J.N.Vaillant, P.Rougier & M.Ducreux, Optimization of 5FU/cisplatin combination chemotherapy with a new schedule of LV,5FU and 9 cisplatin in pts with biliary tract carcinoma: Annals of Oncology,vol 13,no 8,aug 2002,pp1192-1196
  • 10. Therapy  Surgery:curative -proximal lesions:5-year survival: 9-18% -distal lesions: 5-year survival: 20-30%  Resection for distal bile duct cancer has* = results duodenum cancer  < favorable than ampullary or neuroendocrine cancer  > favorable than ADK of the pancreas  > favorable than after resection of hilar carcinoma?  the resectability is higher for distal cancer  the likelihood of achieving a negative margin is greater * Y.Fong,N.Kemeny,TH.Lawrence Cancer of the Liver and Biliary Tree:,chapter 33, section 5,pp1162-1204, 10 Cancer,Principles & Practice of Oncology,6th edition,2001
  • 11. Therapy  long survival is highly dependent on the effectiveness of surgical therapy  survival depends on:-tumor stage -tumor free margins -lymph node invasion  in distal CC-no use of adjuvant therapy*  in proximal CC-no chemotherapy has shown activity* * Y.Fong,N.Kemeny,TH.Lawrence Cancer of the Liver and Biliary Tree:,chapter 33, section 5,pp1162-1204, 11 Cancer,Principles & Practice of Oncology,6th edition,2001
  • 12. Histopathological Examination -histologic type -histologic grade -extention of invasion -blood/lymphatic vessel invasion -perineural invasion -tumor margins -regional lymph nodes 12
  • 13. Locally advanced/metastasis disease:  tumors that invade  the portal vein/hepatic artery/both biliary ducts  peritoneal/other metastases  elderly patients/severe cardiac, respiratory, renal diseases  biliary drainage:  diminishes pruritus and the incidence of cholangitis  to make chemo/radiotherapy possible 13
  • 14. Locally advanced/metastatic disease:  a review of over 65 studies using chemo and/or RT: -no strong evidence of survival benefit  however most of these studies:biases - were small and lacked control groups - are difficult to interpret from theoretically point of view  chemotherapy versus best supportive care: -a survival benefit of 4 months  no standard chemotherapy*  the chance to respond at chemotherapy seems to be correlated with the performance status *L.Duck,Y.Humblet,J-F.Gigot,M.Lonneux,J.F.Baurain,J.P.Machiels;Gemcitabine in advanced colangiocarcinoma; 14 Proceedings of ASCO vol 21,2002,pp125b
  • 15. Neoadjuvant/palliative chemotherapy  MCT: 5FU  RR 5-20%  overall survival of 6 months  PCT:RR 20-40% x 5FU + cisplatin :RR 10-25% x 5FU+cisplatin +epidox(ECF): 5FU-5 days c.i.*  RR 32%  standard in France and some other European countries * J.Taieb, E.Mitry, V.Boige, P.Artru, J.Ezenfis, T.Lecomte,M.C.Clavero-Fabri, J.N.Vaillant, P.Rougier & M.Ducreux, Optimization of 5FU/cisplatin combination chemotherapy with a new schedule of LV,5FU and 15 cisplatin in pts with biliary tract carcinoma: Annals of Oncology,vol 13,no 8,aug 2002,pp1192-1196
  • 16. Neoadjuvant/palliative chemotherapy  5FU + Carboplatin :  RR 21%  grade 3 and 4 toxicity in 40-70% patients  5FU (De Gramont) + Cisplatin(LV5FU2-P)* LV 200mg/m2 in 2h+5FU400mg/m2iv bolus+5FU 600mg/m2 c.i. 22h d1,d2,+CDDP50mg/m2 d2,repeated every 2weeks  RR 34% (even a CR)  an improvement in quality of life (low toxicity) * J.Taieb, E.Mitry, V.Boige, P.Artru, J.Ezenfis, T.Lecomte,M.C.Clavero-Fabri, J.N.Vaillant, P.Rougier & M.Ducreux, Optimization of 5FU/cisplatin combination chemotherapy with a new schedule of LV,5FU and 16 cisplatin in pts with biliary tract carcinoma: Annals of Oncology,vol 13,no 8,aug 2002,pp1192-1196
  • 17. Neoadjuvant/palliative chemotherapy  Gemcitabine 1g/m2 days 1,8,15 repeated at 4 weeks -improvement in quality of life -median survival: 6,8 months (2-18 months)  Gemcitabine +Cisplatin: - RR 30-50% - even with downstaging and conversion to operability in a few pts  Gemcitabine+Docetaxel* Gem 1g/m2+Docetaxel 35mg/m2 d1,8,15,q28d - RR 63%,median survival 11.3mos(1-65mos) - is well tolerated *R.Kuhn,K.Ridwelski,S.Rudolph,C.Schimdt,J.Fahlke,H.Lippert:Phase II study of weekly gemcitabine and 17 docetaxel in advanced or metastatic gallblader carcinomaS,Annals of Oncology,vol 13,2002,suppl 5
  • 18. Neoadjuvant/palliative chemotherapy  Mit C+5FU:RR-10-20%*  Median survival:5-12mos  Mit C+capecitabine/Mit C+Gem**  RR:35%/27.8%  Median survival: 4.5/5mos  Intraarterial chemotherapy : RR 44% but of short duration  Biliary drainage through a catheter lined with Carboplatin *P. Passoni,M. Reni,A. Zanello,L. Ceresoli,M.G.Panucci,I.Schiavetto,E.Bonetto,V.Gregorc,E.Villa:Preliminary results of a phase II trial of PEFG in advanced GB,biliary tract,ampulla of Vater,Annals of Oncology,vol 13,2002, suppl 5,pp195 **G.V.Kornek,K.Schimdt,B.Schuell,M.Raderer,W.Kwasny,K.Haider,D.Depisch,F.Lang,W.Scheithauer:Mit C+cape/ HD gemcitabine in advanced biliary cancer:preliminary results of a parallel phase II trial:Annals of 18 Oncology,vol 13,2002, suppl 5,pp196
  • 19. Gallbladder cancer  rare x USA:2001:6900 new cases and 3300 deaths x in Chile: most important cause of death through cancer in women x the incidence in women is double than in men  99 % are adenocarcinomas  rapid dissemination (hepatic artery, portal vein, lymphatics, peritoneal) 19
  • 20. Gallbladder cancer-therapy*  stage 0 ,I: laparoscopic cholecystectomy  5-y survival:85-100%  stage II,III,IV:  radical cholecystectomy+ lymphadenectomy+ hepatic resection  palliative surgery for  treatment of sepsis  treatment of jaundice  palliation of pain  palliation of bowel obstruction x median survival for unresectable tumors: 5-8 months x <5% of pts alive at 5-y *Y.Fong,N.Kemeny,TH.Lawrence Cancer of the Liver and Biliary Tree:,chapter 33, section 5, pp1162- 20 1204, Cancer,Principles & Practice of Oncology,6th edition,2001
  • 21. Neoadjuvant/palliative Chemotherapy  disappointing results:  RR 10-20% with a  duration of a few weeks/months  MCT:Gemcitabine  RR 7,7% with survival without progression of 7 months  Dobrila-Dintinjana: 18 patients  median survival 22 weeks with an evident clinical benefit  Arrayo: 42 patients  1 CR, 13 PR, and 11 SD, with an overall survival of 6,5 months  Gem 2,2g/m2 at 2 weeks: 32 patients  median survival 11,5 months  Gem 1,5g/m2 fixed rate infusion: 15 patients  minimal results, but important toxicity  Gem administered intraarterial at 4 weeks  important toxicity  71% of patients alive at 4 months  Gem iv + 5FU ia: 17 patients Gem 1g/m2 d1,8 iv+5FU 15mg/m2 i.a.d1-14, q 21d 21
  • 22. Chemotherapy  PCT: x Gem + 5FU + LV:  Gebia: phase II trial 18 patients  median survival 8 months with 22% patients alive after 1 year x Gem + 5FU: 23 patients Gem 1g/m2 (40’c.i.), followed by 5FU 500 mg/m2(3h pev) d 1, 8, 15, q 28d  median survival 9 months (6-38 months) Gem 1g/mp (days 1 and 8) + 5FU (De Gramont):22patients  median survival 11 months(2-22mos) x Gem + Taxanes: 40 patients  median survival 11 months, but without significant toxicity x Gem + LOHP:22patients  is ongoing 22
  • 23. Neoadjuvant / palliative radiotherapy  Improves survival and the quality of life  but local and systemic toxicity are greater  Palliative for painful localized metastases, uncontrolled bleedings  Intraluminal RT+ external RT:  survival benefit of 3 months in comparison with the patients who had only biliary stents  Intraluminal RT with iridium + external RT + 5FU:  survival of 13 months  Hepatic and peritoneal metastases are the cause of progression  The patients must be advised to participate in clinical trials 23
  • 24. Our experience Method  retrospective study  period:1997-2001  12 patients with advanced/metastatic biliary tract tumors treated in the department of oncology,Fundeni Clinical Institute  survival  the toxicity of schedules 24
  • 25. Chemotherapy:  4 patients  FAM: 5FU 600 mg/m2 d1, 8, 29, 36 + ADB 30 mg/m2d1, 29 + Mit C 10 mg/m2 d 1, repeated at 8 weeks  4 patients  Gem 1 g/m2 days 1, 8, 15 q 28d  2 patients  5FU iv in bolus:5FU425mg/m2 d1-5+LV 20mg/m2d1-5, q28d  2 patients  chemolipiodolisation: ADB 50mg + lipiodol 5cm3 q 28d 25
  • 26. Patients characteristics:  Number 12  Median age 46,6 y (36-63 y)  Sex :M/F 3/9  Performance status: ECOG 0, 1/ 2 4/8  Tumor localization: -gallbladder 2 -Klatskin tumor 3 -intrahepatic tumor 7 26
  • 27. Patients characteristics  Surgical intervention A) curative: - hepatectomy right 3 left 1 centrale 1 - coledocal resection 2 B) palliative: - bioptique laparatomy 3 - hepatic arterial catheter placement 2 - biliary drainage 1  Histopathological examination: +/_ 11/1  Metastases at the time of diagnosis 1 metastasis 2 pts 2 metastases 4 pts 27
  • 28. Toxicity and results  Medullary: - anemia 8 - leucopenia 4 - thrombocytopenia 2  Digestive: - nausea and vomiting 9 - diarrhea 4 - stomatitis 6  Results: - complete response 0 - partial response 1 - stable disease 5 - progressive disease 6 28
  • 29. Kaplan-Meier survival curve of patients with cholangiocarcinoma 1.000 0.750 Survival Probability 0.500 0.250 0.000 0.0 6.3 12.5 18.8 25.0 Months of survival Median survival : 8.12 months, 95% CI (4.12 – 12.21) 29
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