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08/12/10

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PROGRESS IN CHEMOTHERAPY OF

BILIARY TREE CARCINOMA

ADINA CROITORUDEPARTMENT OF ONCOLOGYFUNDENI CLINICAL INSTITUTEBUCHAREST

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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

(Suppl VI:vi 1-vi 9)

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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

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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:◆ type I:tumors below the confluence of the 2 hepatic ducts◆ type II:tumors reaching the confluence, without invading the left or

right hepatic ducts◆ type III: tumours occluding the common hepatic duct and either the

right (IIIA ) or left (III B) hepatic duct◆ type IV:multicentric tumours or which involve the confluence and

both hepatic ducts

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Anatomo-Pathological Classification(WHO)

A)Carcinomas of the liver : hepatocellular carcinoma combined hepatocellular-

cholangiocarcinoma(CC) intrahepatic cholangiocarcinoma biliary cystadenocarcinoma undifferentiated carcinoma

B)Extrahepatic bile duct carcinomas:

carcinoma in situ adenocarcinoma(ADK) intestinal-type ADK mucinous ADK clear cell ADK signet ring cell carcinoma adenosquamous carcinoma squamous cell carcinoma small cell carcinoma undifferentiated carcinoma

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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 (Suppl VI:vi 1-vi 9)

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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

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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 irinotecan for unresectable biliary tree carcinoma:Annals of Oncology,vol.12,no4,April 2001,pp501-503

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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 cisplatin in pts with biliary tract carcinoma: Annals of Oncology,vol 13,no 8,aug 2002,pp1192-1196

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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, Cancer,Principles & Practice of Oncology,6th edition,2001

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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, Cancer,Principles & Practice of Oncology,6th edition,2001

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Histopathological Examination

-histologic type

-histologic grade

-extention of invasion

-blood/lymphatic vessel invasion

-perineural invasion

-tumor margins

-regional lymph nodes

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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

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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; Proceedings of ASCO vol 21,2002,pp125b

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Neoadjuvant/palliative chemotherapy

MCT: 5FURR 5-20%overall survival of 6 months

PCT:RR 20-40%◆ 5FU + cisplatin :RR 10-25% ◆ 5FU+cisplatin +epidox(ECF): 5FU-5 days c.i.*

RR 32% standard in France and some other European countries


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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)


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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 docetaxel in advanced or metastatic gallblader carcinomaS,Annals of Oncology,vol 13,2002,suppl 5

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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 Oncology,vol 13,2002, suppl 5,pp196

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Gallbladder cancer rare

◆ USA:2001:6900 new cases and 3300 deaths◆ in Chile: most important cause of death through cancer in

women◆ the incidence in women is double than in men

99 % are adenocarcinomas

rapid dissemination (hepatic artery, portal vein, lymphatics, peritoneal)

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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

◆ median survival for unresectable tumors: 5-8 months◆ <5% of pts alive at 5-y

*Y.Fong,N.Kemeny,TH.Lawrence Cancer of the Liver and Biliary Tree:,chapter 33, section 5, pp1162-1204, Cancer,Principles & Practice of Oncology,6th edition,2001

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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 patientsGem 1g/m2 d1,8 iv+5FU 15mg/m2 i.a.d1-14, q 21d

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ChemotherapyPCT:

◆ Gem + 5FU + LV: Gebia: phase II trial 18 patients

median survival 8 months with 22% patients alive after 1 year◆ 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)

◆ Gem + Taxanes: 40 patients median survival 11 months, but without significant toxicity

◆ Gem + LOHP:22patients is ongoing

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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

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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

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Chemotherapy:

4 patientsFAM: 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

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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

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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

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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

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Kaplan-Meier survival curve of patients with cholangiocarcinoma

0.000

0.250

0.500

0.750

1.000

0.0 6.3 12.5 18.8 25.0

Months of survival

Surv

ival

Pro

babi

lity

Median survival : 8.12 months, 95% CI (4.12 – 12.21)

document25

Health & Medicine

clearcell carcinoma

papillary carcinoma

biliary tract carcinoma

distal cancer

resection of hilar carcinoma

c rosenberg

h c thomas

lawrence cancer