*4.1.2 Adjuvant treatment*

The role of adjuvant chemoradiotherapy is not well defined because of a lack of randomized trials. Most of the published studies are retrospective with small numbers of patients and a mix of gallbladder and bile duct tumors.

**109**

*Gall Bladder Carcinoma: Clinical Presentations and Different Modalities of Treatment*

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 (chemotherapy (CT), radiotherapy (RT) or radiochemotherapy (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 than 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) [23]. There is no randomized trial of adjuvant RT or RCT. However, there are only heterogeneous retrospective series, addressing the issue of adjuvant radiation therapy. In these small series, differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to pinpoint the exact role of adjuvant therapy in GBC [24, 25]. Bilcap study is a phase III study that included patients with completely resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, hematological and liver function and ECOG PS ≤ 2. It demonstrated that capecitabine improved overall survival when used as adjuvant

A small Scandinavian randomized controlled trial showed that a chemotherapy by 5Fluorouracil and (more etoposide so good general condition) increased the quality of life and survival compared exclusive supportive care in patients with advanced pancreatic or biliary cancer (6.0 vs. 2.5 months, p < 0.01), however not significantly in the patient subgroup with biliary cancer, and at the cost of considerable toxicity (grade 3–4, 41%) [27]. A single-center Indian randomized controlled trial in 81 patients with carcinoma of the gallbladder has shown a global survival benefit of chemotherapy by gemcitabine and oxaliplatin not only compared to exclusive supportive care but also compared to a chemotherapy with 5FU and folinic acid (9.5, 4.5 and 4.6 months respectively, p = 0.039) [28]. Collectively, these two trials show that first-line chemotherapy is legitimate in patients with advanced biliary cancer whose general condition is not too

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 <1.5 N), superiority of gemcitabine-cisplatin combination (GEMCIS regimen) on gemcitabine alone (survival overall: 11.7 vs. 8.1 months, hazard ratio [HR]: 0.64 [95% CI, 0.52–0.80], p < 0.001) [29]. The benefit of survival with the GEMCIS regimen was independent not only of tumor stage (locally advanced or metastatic) but also of the primary tumor site (intra- or extrahepatic bile ducts, hile, gallbladder, vater bulb). These results were supported by those of the randomized trial Phase II Japanese BT-22 in 84 patients (ECOG 0-1: 100%) [30]. These results make the GEMCIS regimen the first standard of first-line chemotherapy in patients with advanced biliary cancer. The GEMOX scheme [31] is an alternative, despite the lack of a randomized controlled trial comparing these two regimens. The treatment of metastatic forms is to be discussed according to the general condition (PS, age). In case of PS > 2, it is recommended to do exclusive support care. In case of PS between 0 and 2, it is the indication of a palliative CT by gemcitabine-

*DOI: http://dx.doi.org/10.5772/intechopen.81263*

and should become standard of care [26].

cisplatin. The GEMOX scheme is an alternative.

**4.2 Metastatic GCC**

impaired (PS 0–2).

*Gall Bladder Carcinoma: Clinical Presentations and Different Modalities of Treatment DOI: http://dx.doi.org/10.5772/intechopen.81263*

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 (chemotherapy (CT), radiotherapy (RT) or radiochemotherapy (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 than 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) [23]. There is no randomized trial of adjuvant RT or RCT. However, there are only heterogeneous retrospective series, addressing the issue of adjuvant radiation therapy. In these small series, differences in patient selection criteria, staging systems, extent of resections, radiation therapy techniques and doses and chemotherapy schedules, it is difficult to pinpoint the exact role of adjuvant therapy in GBC [24, 25]. Bilcap study is a phase III study that included patients with completely resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, hematological and liver function and ECOG PS ≤ 2. It demonstrated that capecitabine improved overall survival when used as adjuvant and should become standard of care [26].

#### **4.2 Metastatic GCC**

*Digestive System - Recent Advances*

*4.1.1.2 Locally advanced tumors >T2*

*Photos d'une bi-segmentectomy IVb-V.*

**Figure 5.**

mended for tumors >T2.

*4.1.1.3 Palliative surgery*

entire survival patients [22].

*4.1.2 Adjuvant treatment*

The extent of liver resection remains controversial. Thus, an IVb-V bisegmentectomy or a more extensive hepatic resection of the trisegmentectomy type may be proposed, and for tumors invading the hepatic pedicle, an enlarged right hepatectomy or a central hepatectomy (IV, V, VIII) associated with a segment I resection. Segment I resection is especially useful 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 are high. 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 curling, extended to the celiac trunk, to the trunk of the superior mesenteric artery down the anterior aspect of the aorta (para-aortic ganglia). 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 [22]. In addition, removal of the main bile duct facilitates nodal dissection of the hepatic pedicle. It is therefore recom-

Surgical biliary shunts (and trans-tumor intubations) have not been demonstrated 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, the surgical biliary drainage usually allows prolonged palliation to the

The role of adjuvant chemoradiotherapy is not well defined because of a lack of randomized trials. Most of the published studies are retrospective with small

numbers of patients and a mix of gallbladder and bile duct tumors.

**108**

A small Scandinavian randomized controlled trial showed that a chemotherapy by 5Fluorouracil and (more etoposide so good general condition) increased the quality of life and survival compared exclusive supportive care in patients with advanced pancreatic or biliary cancer (6.0 vs. 2.5 months, p < 0.01), however not significantly in the patient subgroup with biliary cancer, and at the cost of considerable toxicity (grade 3–4, 41%) [27]. A single-center Indian randomized controlled trial in 81 patients with carcinoma of the gallbladder has shown a global survival benefit of chemotherapy by gemcitabine and oxaliplatin not only compared to exclusive supportive care but also compared to a chemotherapy with 5FU and folinic acid (9.5, 4.5 and 4.6 months respectively, p = 0.039) [28]. Collectively, these two trials show that first-line chemotherapy is legitimate in patients with advanced biliary cancer whose general condition is not too impaired (PS 0–2).

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 <1.5 N), superiority of gemcitabine-cisplatin combination (GEMCIS regimen) on gemcitabine alone (survival overall: 11.7 vs. 8.1 months, hazard ratio [HR]: 0.64 [95% CI, 0.52–0.80], p < 0.001) [29]. The benefit of survival with the GEMCIS regimen was independent not only of tumor stage (locally advanced or metastatic) but also of the primary tumor site (intra- or extrahepatic bile ducts, hile, gallbladder, vater bulb). These results were supported by those of the randomized trial Phase II Japanese BT-22 in 84 patients (ECOG 0-1: 100%) [30]. These results make the GEMCIS regimen the first standard of first-line chemotherapy in patients with advanced biliary cancer. The GEMOX scheme [31] is an alternative, despite the lack of a randomized controlled trial comparing these two regimens. The treatment of metastatic forms is to be discussed according to the general condition (PS, age). In case of PS > 2, it is recommended to do exclusive support care. In case of PS between 0 and 2, it is the indication of a palliative CT by gemcitabinecisplatin. The GEMOX scheme is an alternative.
