bile duct cancer | 8. CANCER OF BILIARY TRACT (LATEST UPDATED

8. CANCER OF BILIARY TRACT (LATEST UPDATED



Working Group and Reviewers8.1. Introduction8.2. Pre-therapeutic exploration8.3. Screening for family forms8.4. Traitement8.5. Post-therapeutic surveillance8.6. Treatment of recurrence8.7. Bibliographic referencesTables
Chap. : Cancer of the bile ducts (updated on 24/01/2014)

Working Group and Reviewers




Responsible

Dr. David MALKA: Department of Digestive Oncology, Department of Oncology Medicine, Gustave Roussy, Villejuif

Work group

Pr Laurence CHICHE: Department of Digestive and Endocrine Surgery, CHU, Bordeaux
Professor Thierry De BAERE: Department of Interventional Radiology, Gustave Roussy, Villejuif
Dr Clarisse DROMAIN: Department of Diagnostic Radiology, Gustave Roussy, Villejuif
Pr Frédéric PRAT: Hepato-Gastroenterology Department, CHU Cochin, Paris
Pr Jean-Robert DELPERO: Department of Visceral Surgery, Paoli Calmettes Institute, Marseille
Pr Olivier ROSMORDUC: Hepato-Gastroenterology Department, CHU Saint-Antoine, Paris

reviewers

Dr. Bruno LANDI, Hepato-Gastroenterology Department, Georges Pompidou European Hospital, Paris
Pr Ahmet AYAV, Department of General Surgery and Digestive, CHU, Vandoeuvre-les-Nancy
Dr Emmanuel BUC, Department of General Surgery and Digestive, CH, Thiers
Dr. Philippe LAPLAIGE, Polyclinic of Blois, The Chaussée St Victor
Dr. Alexandra HEURGUE-BERLOT, University Hospital, Reims


8.1. Introduction
8.1.1. Méthodologie8.1.2. Incidence8.1.3. classifications




8.1.1. Methodology
This work is based on the recommendations (internal publications) of the Francophone Federation of Digestive Oncology (FFCD) of the Study and Clinical Research Group in Radiation Oncology (GERCOR), the French Society of Digestive Surgery (SFCD) and the Association of Hepatobiliary Surgery and Hepatic Transplantation (ACHBT) [Slim 2009] and the European Society of Medical Oncology (ESMO) [Eckel 2011], and their updating by a bibliographic research. This was based on the extraction of randomized trials, meta-analyzes, consensus conferences and clinical practice recommendations from the Medline database in January 2014 with the keywords "biliary neoplasms", "gallbladder carcinoma" And "cholangiocarcinoma", in English or French, with no date limitation.

These recommendations have been graded according to the level of evidence available in the literature, or if there is insufficient evidence in the opinion of experts.

8.1.2. Impact
Biliary cancers are relatively rare, with an incidence of about 2000 new cases per year in France, or about 3% of digestive cancers [Bouvier 2004]. This incidence, variable in the world (higher in Asians), is increasing, especially for intrahepatic cholangiocarcinomas. The latter are most often sporadic or associated with chronic inflammatory diseases of the bile ducts. Recently, other risk factors have been identified such as alcohol consumption, HBV and HCV infections (relative risk of about 5) and especially the presence of cirrhosis (relative risk greater than 20) [Palmer 2012 , Rizvi 2013]. However, there are currently no validated recommendations for screening for cholangiocarcinoma in patients at risk.

8.1.3. classifications
Biliary cancers should be classified according to the TNM-AJCC-UICC 2010 classification (7th edition) [Sobin 2010] according to their location:

Cholangiocarcinomas (about one-third of biliary cancers):
intrahepatic ("peripheral") (Table 1);
proximal extrahepatic (peri-hilar or Klatskin tumors) (Table 2);
extra-hepatic distal (Table 3);
Gallbladder carcinoma (Table 4).
For peri-hilar tumors, the classification of Bismuth-Corlette is also used [Bismuth 1975] (Table 5). This classification is of little use as it does not evaluate vascular invasion.

About 5-10% of biliary cancers are diffuse or multifocal.

8.2. Pre-therapeutic exploration
Imaging - It is essential for positive and differential diagnosis (cyto / histological evidence sometimes difficult to obtain), extension assessment and treatment planning. It must determine the hepatic invasion, the degree of obstruction of the bile ducts, the extension to the vascular structures and the ganglionic and metastatic extension:

Magnetic resonance imaging (MRI): it must combine hepatic MRI sequences with injection and cholangiography sequences (cholangiography-MRI). Its sensitivity of detection is 95% and it allows a reliable assessment of the extension to the bile ducts in 90%. Cholangi-MRI also allows for biliary mapping if drainage is considered. It is the reference examination of proximal and distal extrahepatic forms [Romagnuolo 2003];
Thoraco-abdominopelvic CT scan: it remains the reference examination for the lymph node and metastatic extension assessment. In addition, it can replace liver MRI if it is not feasible or of insufficient quality [Ruys 2012];
18F-FDG Positron Emission Tomography (PET): its sensitivity and specificity are about 80-90% for the diagnosis of vesicular cancer or nodular cholangiocarcinoma, but its sensitivity is much lower (<20% in some studies) in the case of infiltrating cholangiocarcinoma and its lower specificity in cases of primary sclerosing cholangitis, biliary prosthesis or granulomatous disease [Kluge 2001]. Its sensitivity is also limited (<50%) for assessing lymph node involvement [Ruys 2012]. It may be useful before complex surgery for curative purposes but must not delay the therapeutic management;
Echoendoscopy: it contributes to the diagnosis and the loco-regional extension assessment of extrahepatic tumors and allows the puncture of lymphadenopathy;
Direct cholangiography (percutaneous transhepatic [CTH] or endoscopic retrograde [CRE]): it should be reserved for therapeutic purposes or tumor sampling;
Other imaging techniques (ultrasound with contrast medium, cholangioscopy, minisonde endosonography, ...): not validated and inaccessible, they should only be performed in clinical trials.


Serum tumor markers - None are specific for biliary cancers. Carbohydrate antigen (CA) 19.9 has a sensitivity and specificity of about 80% (studied mainly in cases of primary sclerosing cholangitis). Carcinoembryonic antigen (CEA) and CA 125 are less sensitive (30-50%) and not more specific [Ramage 1995]. All three can be raised during benign biliary obstructions. Persistent elevation after biliary drainage is suggestive of cancer.



Differential diagnosis - In case of diagnostic doubt (especially with liver metastasis (s) of a non-biliary adenocarcinoma), other examinations may be useful: thoracic CT, mammography, PET, digestive endoscopies, serum tumor markers, tumor immunohistochemistry, ....



Diagnostic confirmation - Cytological evidence (per-cholangiographic biliary brushing ...) or histological evidence of biliary cancer is sometimes difficult to obtain. It is essential before palliative treatment (unresectable tumor) or neo-adjuvant, but can be avoided in the majority of cases before surgery for curative purposes given the risk of tumor swarming along the puncture path.



Resecability - It should be evaluated promptly by an experienced medico-surgical team in any patient considered operable, before any opacification or biliary drainage (inflammation or induced biliary infection may hinder this assessment). The usual submucosal tumor infiltration, 1 to 2 cm beyond the extension defined by the radiological examinations, must be taken into account. Liver mass CT should be performed before major hepatectomy. Resectability can often only be affirmed (or reversed) definitively during surgical exploration. Laparoscopy may alter the surgical indication, including avoiding a heavy pre-hepatectomy program of biliary drainage and portal embolization. Its profitability increases with tumor extension [Weber 2002].
REFERENCE

Hepatic MRI with cholangiography and MRI.
CT thoraco-abdominopelvic.
Biliary cytology by cholangiography, percutaneous biopsy or endoscopic puncture required before palliative treatment (unresectable tumor) or neo-adjuvant.
Hepatic volumetry CT before major hepatectomy.
NB: Preoperative imaging is useless in cases of gall bladder cancer that does not reach the serosa.


OPTIONS

Abdominopelvic CT, color ultrasound and / or cholangiography if MRI not feasible or insufficient.
Echoendoscopy (± puncture) if suspicion of extrahepatic biliary tumor and other insufficient investigations.
If diagnostic doubt with liver metastasis (s) of a non-biliary adenocarcinoma: 18F-FDG PET, mammography, digestive endoscopies, serum tumor markers, tumor immunohistochemistry ...
Cyto- or histological confirmation to be discussed before curative surgery.
If call signs: cerebral CT, bone scintigraphy.
If resection considered: discuss exploratory laparoscopy (if high risk of non-resectability), 18F-FDG PET, bone scintigraphy.
8.3. Screening for family forms




 Biliary cancers can be part of a syndrome of Lynch syndrome (autosomal dominant hereditary predisposition syndrome to colorectal cancer, endometrium, stomach, ovary, urinary tract, ...).
Exceptional familial aggregations of biliary malignancies, whose genetic substratum is unknown, have been reported [Hemminki 2003].
8.4. Treatment
8.4.1. Operable patient and resectable tumor8.4.2. Unresectable tumor and / or inoperable patient
8.4.1. Operable patient and resectable tumor
8.4.1.1. General principles
Surgical resection with R0 margins, which alone allows for prolonged survival, should always be discussed. However, even after R0 resection, 5-year survival does not exceed 5-10% for vesicular cancer and 10-40% for cholangiocarcinoma.
Microscopic invasion of resection margins (R1 status) (5-year survival <10%), ganglionic invasion (5-year survival <5%) and vascular invasion are poor prognoses. Surgical exploration with extemporaneous histological examination of the biliary section slice (s) is therefore essential.
Major or pancreatic liver resections have greater morbidity and mortality than the same resections performed for other indications and that of biliary resections alone, particularly because of the often advanced age or an impaired general state. be discussed and carried out only by very experienced teams.
The morbidity and mortality of major hepatectomies can be reduced by preoperative biliary drainage of the future remaining liver in case of jaundice and, if appropriate, preoperative portal embolization of the liver to resect in order to hypertrophy the future liver remaining if the volume of it is insufficient to the TDM volumetry.
A standardized pathological report should be established: associated (pre) neoplastic lesions (carcinoma in situ, primary sclerosing cholangitis), tumor type, grade, stage, margins (R0, R1, R2), lymphatic invasion, vascular, peri-nervous , ganglionic, visceral contiguity and metastatic.
8.4.1.2. Features by location
8.4.1.2.1. Intrahepatic cholangiocarcinomas
Resection R0 is imperative. By assimilation to other tumors, a margin of safety of 1 cm is recommended (expert agreement). On the other hand, neither the systematic resection of the segment I and / or the main bile duct, nor the anatomic hepatic resection (bulk resection of the tumor and the relevant portal territory centered on a glissonian pedicle) and / or major are justified.
8.4.1.2.2. Cholangiocarcinoma of the hile
The only presence of suspicious lymph nodes on the morphological assessment (whose status is unknown) should not be a contraindication to resection, especially in a young patient. Neither lymph node size nor imaging predicts the risk of lymph node metastasis [Burke 1998, Jarnagin 2001, Kitagawa 2001].
Surgical resection includes at least resection of the main bile duct (type I Bismuth) with regional lymph node lymphadenectomy. The interest of a cleaning extended to retro-duodenopancreas, or even more, is not demonstrated. It is currently accepted that for type II, III or IV lesions, hepatectomy must be combined to increase the percentage of R0 margins and survival at 5 years [Neuhaus 1999].
 The choice of the type of hepatic resection is guided by the existence of hepatic dysmorphism and / or unilateral vascular involvement, and by biliary extension which, even if limited, may require a sometimes major resection. Thus, reaching the ceiling of the main biliary convergence (type ≥ 2 Bismuth) requires the resection of segment I (caudate lobe or lobe Spiegel), because its bile ducts are then invaded in about 90% of cases. Thus, there is currently a trend towards standardization of hepatic resection, particularly of the right hepatectomy enlarged to segment I for technical reasons (greater length of the left hepatic duct) and carcinological (frequent invasion of the right arterial branch), so optimize the probability of obtaining a status of R0 margins.
 Resection of the portal vein may be necessary in cases of tumor invasion. It does not increase operative morbidity. On the other hand, the resection of the hepatic artery must remain exceptional, the oncological benefit not being proven.
The oncological resection rate for finally benign hilar lesions can reach up to 10% of cases in some series [Juntermanns 2011].
8.4.1.2.3. Carcinomas of the gallbladder
Tis, T1a, T1b and T2 cancers discovered incidentally on the cholecystectomy room
Tis and T1a Cancers-Lymph node involvement is nil (Tis) at low (2-5%) (T1a). Survival at 5 years after cholecystectomy alone is 85-100% [Yamaguchi 1992, Shirai 2001].
Cancers T1b and T2- The ganglionic invasion rate is 15-20% (T1b) at 20-60% (T2) [Yamaguchi 1992, Shirai 2001, Toyonaga 2003, Suzuki 2004]. Survival is significantly improved after curative secondary resection in tumors ≥ T2, with no clear pejorative influence of the cholelithecal or laparotomic approach (provided there is no perforation of the cholecystectomy). vesicle during this one. Survival is better and the rate of tumor recurrence is lower in patients who have had early secondary resection [Shirai 2001].
The secondary intervention of reference is the IVb-V bisegmentectomy with lymph node dissection and possibly resection of the bile duct. Bisegmentectomy can be discussed in favor of resection of the vesicular bed for these "small cancers", especially if the cancer is located on the free side of the gallbladder. Similarly, resection of the bile duct is recommended only in cases of cystic involvement or patent nodal invasion (expert agreement).
Systematic secondary resection of trocar orifices [Z graggen 1998] is currently controversial [Maker 2012].
A conversion is recommended in cases of percoloscopic suspicion of gall bladder cancer.


Locally advanced tumors> T2



The extent of liver resection remains controversial. Thus, IVb-V bi-segmentectomy or more extensive liver resection of the trisegmentectomy type may be proposed, and for tumors invading the hepatic pedicle, extended right hepatectomy or central hepatectomy (IV, V, VIII) associated with resection of the hepatic pedicle. segment I. Resection of segment I is useful especially for tumors invading the hepatic hilum.
Direct invasion of the colon, duodenum or liver is not an absolute contraindication to resection but the morbidity and mortality of these combined resections is high.
 In the case of ganglionic invasion, the 5-year survival is weak to nil, especially when more than one to two ganglia are invaded [Dixon 2005, Endo 2006]. Ganglion dissection should include extensive resection of the hepatic pedicle ganglia, anterior and posterior pancreatic ganglia and peeling of the hepatic artery until birth in the celiac trunk. Some authors recommend extensive, extended echocardiographic trimming of the upper mesenteric artery down the anterior aspect of the aorta (para-aortic ganglia) [Kondo 2000].
Involvement of the hepatic pedicle and the main bile duct is early in gallbladder cancer without necessarily having a clinical impact (jaundice) or contact with the tumor [Shimizu 2004]. In addition, removal of the main bile duct facilitates nodal dissection of the hepatic pedicle. It is therefore recommended for tumors> T2.

RECOMMENDATIONS


Table recommendations

Table recommendations
8.4.1.3. Neo-adjuvant treatment
Neo-adjuvant treatment is frequently impossible due to jaundice and deterioration of the general condition.
There is no randomized trial of neoadjuvant chemotherapy (CT), radiotherapy (RT) or radiochemotherapy (RCT).
8.4.1.4. Adjuvant treatment
A single randomized, methodologically objectionable trial (inclusion of ampullary and pancreatic cancers, many patients excluded from the analysis, eligibility criteria not met), suggested a benefit of adjuvant CT (5FU continuous-mitomycin C then oral 5FU) in terms of 5-year survival in the only subgroup of patients operated for gall bladder cancer (26% vs 14%, p = 0.04). In contrast, the overall analysis of all patients with biliary cancer showed no survival benefit with adjuvant CT, either after R0 resection or not [Takada 2002].
There is no randomized trial of adjuvant RT or RCT.
A systematic review and meta-analysis of published data from 20 studies between 1960 and 2010 (6712 patients) showed a nonsignificant improvement in overall survival with any adjuvant therapy (CT, RT or RCT) compared to curative surgery alone (HR 0.74, p = 0.06). There was no difference between gall bladder tumors and bile duct tumors (p = 0.68). The association became significant when both cancer registries were excluded, with a significantly higher benefit of CT or RCT compared to RT alone (OR: 0.39, 0.61 and 0.98, respectively; p = 0.02). The greatest benefit of adjuvant treatments was observed with N + status (OR: 0.49, p = 0.004) or R1 (OR: 0.36, p = 0.002) [Horgan 2012]. The results of two Phase III CT adjuvant trials are pending: 1) the British BILCAP trial (capecitabine vs surveillance alone); 2) the French PRODIGE 12 ACCORD 18 trial (GEMOX85 vs surveillance alone).


REFERENCE

There is no indication for neoadjuvant or adjuvant CT, RT or RCT.



THERAPEUTIC TRIALS

No.

8.4.1.5. Liver transplantation
The survival rates 5 years after liver transplantation for resectable or unresectable biliary cancer are of the order of 25-30%. However, the majority of patients reoffend within 2 years.
A retrospective US multicenter study in 287 patients with initially unresectable hilar cholangiocarcinoma treated between 1993 and 2010 by RCT, brachytherapy and neoadjuvant CT, then exploratory laparotomy, and finally liver transplantation showed a 5-year survival rate of up to 53%, a rate comparable to that observed for other recognized indications of liver transplantation. However, if the analysis was intended to treat (as soon as the patients were on the list), it was only for patients who had completed neo-adjuvant therapy and exploratory laparotomy. In addition, two-thirds of them had primary sclerosing cholangitis and a relatively smaller tumor than other patients [Darwish Murad 2012].


REFERENCE

Biliary cancers are not a validated indication of liver transplantation, which should ideally be performed only in clinical trials in particular situations (cancer starting on primary sclerosing cholangitis with available living donor, ...).

8.4.2. Unresectable tumor and / or inoperable patient
The median survival for unresectable tumor is 9-15 months. The primary goal of palliative treatment should be maintenance or improvement of quality of life (jaundice, pruritus, pain).
Palliative treatment should not be delayed simply because of the absence of histological confirmation.
8.4.2.1. Palliative surgery
Macroscopically palliative resections (R2) are of no interest, survival being comparable to that after palliative endoscopic treatment.
Surgical biliary shunts (and intubations) have not been demonstrated to be superior to prosthetic drainage in terms of quality of life or survival time. Their mortality (> 25% in several series) and their morbidity are not negligible. However, surgical biliary drainage usually allows prolonged palliation for the entire survival of patients.
The analgesic efficacy of celiac neurolysis is not demonstrated during biliary cancers.
8.4.2.2. Biliary drainage
Biliary drainage is the main palliative therapeutic measure for unresectable tumors or inoperable patients. It is essential in case of cholangitis, uncontrolled pruritus, and if normal bilirubinemia is required before CT. It lengthens the survival of patients.
Drainage should be as complete as possible, focusing on functional areas and minimizing iatrogenic risk (drainage of any opacified area, antibiotic therapy) [Vienna 2010]. It must be entrusted to an expert center with expertise in endoscopy and interventional radiology, which must frequently be used successively or simultaneously, especially in complex peri-hilar tumors. Cholangio-MRI, possibly supplemented by a CT, is in this situation the examination of choice to plan the prosthesis (s), in order to limit the risk of post-procedure angiocholitis.
The approach depends on the location and extent of the cancer: endoscopic in extrahepatic cholangiocarcinomas (percutaneous if failed), endoscopic or percutaneous (depending on local expertise) in peri-hilar type II to IV cholangiocarcinoma.
Longer permeable metal prostheses have been demonstrated by more efficient and cost-effective randomized trials than plastic prostheses with presumed survival times greater than 6 months (especially in the absence of liver metastases and tumor size <3 cm) ; an alternative is the systematic change of plastic prosthesis every 3 months. The longest permeability of covered prostheses has not been demonstrated.
The hilar metallic prostheses are to be reserved strictly for palliative treatments (surgery definitively excluded). The placement of a unilateral metallic prosthesis on a hilar tumor obstacle could, according to some, be as effective as a bilateral pose. However, subsequent gestures can be made more difficult: their pose must be carefully thought through by an experienced operator.
Percutaneous external drainage is the only solution in case of failure or impossibility of internal prosthetic drainage.
8.4.2.3. Photodynamic therapy
Photodynamic therapy (PDT) (injection of a photosensitizing agent followed by direct endoscopic illumination of the tumor) significantly improved the quality of biliary drainage, Karnofsky's index, quality of life and survival (493 vs 98 days, p <0.0001) compared with bilateral biliary prosthetic drainage alone in a randomized phase III trial in 39 patients with advanced perilhilar cholangiocarcinoma, at the cost of moderate toxicity and some constraints (ablation and subsequent biliary prostheses, confinement in dark room for 3-4 days after injection, repeated sessions). However, patients with effective biliary drainage were excluded from this trial, suggesting that some of the benefit may be due to improved drainage rather than the antitumor effect of PDT [Ortner 2003]. In addition, a UK multicenter phase III randomized trial was discontinued prematurely because of a significantly lower overall survival in the TPD arm compared to the control arm (biliary drainage alone) [Pereira 2010].
8.4.2.4. RT and RCT palliative
No randomized controlled trial has demonstrated a survival benefit of RT alone or in combination with brachytherapy or RCT compared to biliary drainage alone in locally advanced biliary malignancies.
The randomized phase III trial FFCD 9902 compared RCT (50 Gy, 5FU and cisplatin) with systemically elevated CT in patients with locally advanced (unresectable, non-metastatic) bile duct cancer using a GEMOX regimen. The trial was prematurely closed after 34 inclusions out of 72 planned due to an insufficient rate of inclusion, thus reducing its statistical power. Progression-free survival was 5.8 and 11.0 months (HR 0.65 [0.32-1.33]) and overall survival was 13.5 and 19.9 months (HR 0.69). [0.31-1.55]) in the RCT and CT arms, respectively [Balosso 2013].
Results from phase II studies suggest the efficacy and safety of hepatic arterial embolization by yttrium-90 in patients with chemotherapy failure. The best results (overall survival: 22 months, time to progression: 9.8 months) were observed for patients with peripheral tumor, non-infiltrating and without portal thrombosis, a general state preserved (performance status [PS] ECOG 0) and objective response or tumor stabilization [Hoffmann 2012, Rafi 2013]. These results must be confirmed by prospective randomized studies.
8.4.2.5. Regional palliative CT
CT or hepatic intra-arterial chemoembolization is a logical approach, the biliary tree being mostly vascularized by the hepatic artery.
Encouraging response rates have been observed in pilot studies. However, these techniques require an experienced team, have their own iatrogenicity (hepatic toxicity, catheter occlusion, ...) and expose to a significant risk of extrahepatic tumor progression.
8.4.2.6. Systemic palliative CT
A small Scandinavian randomized controlled trial showed that CT per 5FU and folinic acid (plus etoposide so good general condition) increased quality of life and survival compared to proprietary supportive care in patients with pancreatic or biliary cancer advanced (6.0 vs 2.5 months, p <0.01), however not significantly in the biliary cancer subgroup, and at considerable toxicity (grade 3-4, 41 %) [Glimelius 1996]. A single-center Indian randomized controlled trial in 81 patients with advanced gallbladder carcinoma showed overall survival benefit of gemcitabine and oxaliplatin chemotherapy compared to proprietary supportive care, but also compared to 5FU and acidic chemotherapy folinic (9.5, 4.5 and 4.6 months respectively, p = 0.039) [Sharma 2010]. Collectively, these two trials show that first-line chemotherapy is legitimate in patients with advanced biliary
eneral is not too much altered (PS 0 to 2).
The British randomized controlled trial ABC-02 demonstrated, in 410 patients with PS ECOG 0-2 (ECOG 0-1: 88%) and controlled biliary obstruction (total bilirubinemia <1.5N), the superiority of the combination gemcitabine-cisplatin (GEMCIS regimen) on gemcitabine alone (overall survival: 11.7 vs 8.1 months, hazard ratio [HR]: 0.64 [95% CI: 0.52-0.80], p <0.001) [ Valle 2010]. Notably, the low unit dose of cisplatin (25 mg / m² in 1 h in 1 liter of physiological saline on D1 and D8, D1 = D21) requires only reduced hydration (500 ml of physiological saline in 30 minutes before gemcitabine [1 g / m² in 30 minutes on D1 and D8, D1 = 21]). The survival benefit with the GEMCIS regimen was independent of the tumor stage (locally advanced or metastatic), but also of the primary tumor site (intra- or extrahepatic bile ducts, hilum, gallbladder, vater bulb). These results were supported by those of the Japanese BT-22 randomized phase II trial in 84 patients (ECOG 0-1: 100%) [Okusaka 2010]. These results make the GEMCIS regimen the first standard of first-line chemotherapy in patients with advanced biliary cancer. The GEMOX scheme [Andre 2004, Malka 2014, Phelip 2013] is an alternative, despite the absence of a randomized controlled trial comparing these two regimens.
Since no randomized trials are available in the literature, no data can be used to define therapeutic options in the second line or beyond. The very merits of a second line are not formally established, including in patients whose general condition still allows discussion. In a systematic review of 104 first-line chemotherapy trials reported between 1985 and 2006 (5 to 65 patients per study, 2810 patients analyzed in total) and all non-randomized except three (two randomized phase II trials and one randomized phase III in 47 patients), fluoropyrimidines, gemcitabine and platinums were the three types of cytotoxic agents that seemed to be preferred, with overall response rates (median: 23%), time to progression (median: 4.1 months) and overall survival (median: 8.2 months) remains low [Eckel 2007]. Fluopyrimidine-based chemotherapy could therefore be proposed as second-line therapy.
The Franco-German randomized phase II trial BINGO randomized 150 patients between GEMOX plus cetuximab and GEMOX alone. The main objective (achieving a 4-month progression-free survival rate of at least 60% in the experimental arm) was achieved (63% vs. 54%). However, progression-free survival (6.1 vs. 5.5 months) and overall survival (11.0 vs 12.4 months) were similar in both arms. The presence of KRAS (19%) or BRAF (5%) mutations did not significantly modify these results [Malka 2014]. In a randomized phase II trial in 122 patients, the response rate (primary endpoint, 27% vs. 17%) and median progression-free survival (6.7 vs. 4.1 months, p = 0.06) were numerically superior with the modified GEMOX combination (mGEMOX: gemcitabine reduced to 800 mg / m² and oxaliplatin at 85 mg / m²) plus cetuximab compared to mGEMOX alone, without significant benefit in terms of overall survival (10.6 vs. 9.8 months ); surprisingly, the results seemed more favorable with the combination in patients with mutated KRAS tumor (36% of cases) [Chen 2013]. In a Phase III South Korean trial comparing GEMOX alone or GEMOX plus erlotinib (100 mg / d), the primary endpoint (progression-free survival) was not significantly improved (5.8 vs 4.2 months, p = 0.0796) in the overall population of the trial (n = 268), but was in the subgroup of patients with cholangiocarcinoma (n = 180) (5.9 vs. 3.0 months, p = 0.0495). Note that despite a higher response rate (34% vs 18%), the control rate was similar, as was overall survival (9.5 months in both arms, p = 0.61) [Lee 2012] .
                   

REFERENCE

If jaundice: endoscopic and / or percutaneous biliary drainage, or surgical failure in patients with good life expectancy, or if tumor found unresectable at laparoscopy or laparotomy.
Then treatment to discuss according to the general state (PS):
PS greater than 2: exclusive support care;
 PS between 0 and 2: CT by gemcitabine-cisplatin (GEMCIS scheme).
OPTIONS

CT Alternatives:
In 1st line:
GEMOX if cisplatin contraindicated;
Gemcitabine alone if contraindicated plates;
Fluoropyrimidine (alone or in combination with platinum) if gemcitabine is contraindicated;
2nd line: fluoropyrimidine-based CT after 1st line with gemcitabine.


THERAPEUTIC TESTS

SUN-CK (promoter: GERCOR, coordinator: Pr Eric Raymond, Beaujon Hospital, Clichy): a multicenter phase II trial evaluating sunitinib in the 2nd line after failure of a first line containing gemcitabine and platinum in patients with intraocular cholangiocarcinoma advanced hepatic.
INCa's AcSé Program (promoter: Unicancer, biliary cancer referral: Dr. David Malka, Gustave Roussy, Villejuif): national phase II trial providing secure access for patients with tumors with genomic alteration biological targets of the molecule:
to crizotinib:
biliary cancer with translocation of ROS1;
new cohort rare tumors with abnormality on one of crizotinib targets:
translocation / amplification / mutation of ALK;
amplification / mutation of MET.
soon to vemurafenib: biliary cancer with BRAF mutation.
8.5. Post-therapeutic surveillance




The interest of a surveillance is not demonstrated.
The value of repeated serum assays of one or more tumor markers for follow-up during treatment or post-treatment surveillance is not demonstrated.


REFERENCE

After curative resection: clinical monitoring every 3 months the first year then every 6 months up to 5 years.
OPTIONS

Abdominal imaging (ultrasound, CT) every 3 to 6 months for 5 years;
Chest imaging (X-ray, CT) yearly for 5 years;
Other examinations (bone scans, cerebral CT, ...) if sign of call;
After stent drainage: clinical monitoring + bilirubinemia on D8 and D30 and then every 6-8 weeks, or no systematic monitoring (ultrasound, and liver tests for jaundice recurrence and / or signs).