SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma.

PURPOSE: The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. PATIENTS AND METHODS: Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. RESULTS: A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. CONCLUSION: This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.

BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

CD24 expression predicts distant metastasis in extrahepatic bile duct cancer.

AIM: To evaluate the prognostic significance of CD24 expression in patients undergoing adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS: Eighty-four patients with EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled in this study. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to a median of 40 Gy (range: 40-56 Gy). All patients also received fluoropyrimidine chemotherapy for radiosensitization during radiotherapy. CD24 expression was assessed with immunohistochemical staining on tissue microarray. Clinicopathologic factors as well as CD24 expression were evaluated in multivariate analysis for clinical outcomes including loco-regional recurrence, distant metastasis-free and overall survival. RESULTS: CD24 was expressed in 36 patients (42.9%). CD24 expression was associated with distant metastasis, but not with loco-regional recurrence nor with overall survival. The 5-year distant metastasis-free survival rates were 55.1% and 29.0% in patients with negative and positive expression, respectively (P = 0.0100). On multivariate analysis incorporating N stage, histologic differentiation and CD24 expression, N stage was the only significant factor predicting distant metastasis-free survival (P = 0.0089), while CD24 expression had borderline significance (P = 0.0733). In subgroup analysis, CD24 expression was significantly associated with 5-year distant metastasis-free survival in node-positive patients (38.4% with negative expression vs 0% with positive expression, P = 0.0110), but not in node-negative patients (62.0% with negative expression vs 64.0% with positive expression, P = 0.8599). CONCLUSION: CD24 expression was a significant predictor of distant metastasis for patients undergoing curative resection followed by adjuvant chemoradiotherapy especially for node-positive EHBD cancer.

Adjuvant chemoradiotherapy after curative resection for extrahepatic bile duct cancer: a long-term single center experience.

OBJECTIVES: To analyze the outcome of adjuvant chemoradiotherapy for patients with extrahepatic bile duct (EHBD) cancer, and to identify the prognostic factors for these patients. METHODS: Between January 1995 and December 2002, 86 patients with adenocarcinoma of EHBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 59 male and 27 female patients, and median age was 59 years (range, 34 to 73 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/d) was given on day 1 to 3 of each split course. The median follow-up period was 83 months for survivors. RESULTS: Forty-eight patients failed the treatment: locoregional recurrence in 20, distant metastasis in 38, and both locoregional and distant relapses in 10 patients. Five-year locoregional relapse-free survival rate was 70.3%. On multivariate analysis, resection margin status was the only significant prognosticator (P=0.0299). Five-year distant metastasis-free survival rate was 53.6%. Three or more involved lymph nodes had an adverse impact on distant metastasis-free survival (P=0.0334). Five-year overall survival rate was 44.7%, and poorly differentiated tumor was associated with inferior overall survival (P=0.0297). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival in patients with EHBD cancer. Resection margin status, number of involved lymph nodes, and histologic differentiation are associated with locoregional relapse, distant metastasis, and overall survival, respectively. Distant metastasis was the major pattern of failure, possibly due to the increased locoregional control by use of adjuvant chemoradiotherapy. Intensification of systemic treatment is warranted.

Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers.

BACKGROUND: Extrahepatic biliary duct cancers (EBDC) are uncommon malignancies characterized by a poor prognosis with high rate of loco-regional recurrence. The purpose of the present study is to assess the feasibility and the potential impact of adjuvant radiotherapy (RT) in a series of patients treated in one institution. METHODS: Twenty three patients with non-metastatic bile duct cancer treated surgically with curative intent (4 gallbladder, 7 ampullary and 12 cholangiocarcinoma) received 3D conformal external beam RT to a median total dose of 50.4 Gy. Concurrent chemotherapy based on 5-FU was delivered to 21 patients (91%). Surgical margins were negative in 11 patients (48%), narrow in 2 (9%), and microscopically involved in 8 (35%). Eleven patients (55%) had metastatic nodal involvement. The average follow-up time for all patients was 30 months (ranging from 3-98). RESULTS: Acute gastrointestinal grade 2 toxicity (RTOG scale) was recorded in 2 patients (9%). Nausea or vomiting grade 1 and 2 was observed in 8 (35%) and 2 patients (9%) respectively. Only one patient developed a major late radiation-induced toxicity. The main pattern of recurrence was both loco-regional and distant (liver, peritoneum and/or lung). No difference was observed in loco-regional control according to the tumor location. The 5-year actuarial loco-regional control rate was 48.3% (67% and 30% for patients operated on with negative and positive/narrow/unknown margins respectively, p=0.04). The 5-year actuarial overall survival was of 35.9% for the entire group (61.4% in case of negative margins and 16.7% in case of positive/narrow/unknown margins, p=0.07). CONCLUSIONS: Postoperative RT with 50-60 Gy is feasible with acceptable acute and late toxicities. The potential benefit observed in our series may support the use of adjuvant RT in patients with locally advanced disease. Prospective randomized trials are warranted to confirm definitively the role of RT in this tumor location.

Influence of glutamine on morphological and functional changes of liver in the presence of extrahepatic biliary obstruction in rats.

PURPOSE: To study the influence of glutamine on functional and morphological changes of liver in the extrahepatic biliary obstruction through an experimental model in rats. METHODS: Seventy Wistar rats were divided into four groups: control (group C) fictitious operation, (group FO), submitted to laparotomy with handling of bile ducts, but without hepatic duct ligation, (group EBO) submitted to laparotomy and hepatic duct ligation, one of them submitted to supplementation with glutamine 2% (group G). The control group consisted of 6 animals. The animals from groups FO, EBO and G were divided into three groups consisting of 6 animals each, being sacrificed at 7, 14 and 21 days after operation, respectively. Blood samples were collected for biochemical analysis and a fragment of liver tissue was collected from the middle lobe for histological analysis. RESULTS: Both for biochemical analysis (BT, aspartate and alanine aminotransferase AST, ALT and alkaline phosphatase FAL) and for histopathological changes (fibrosis, portal inflammation, parenchymal inflammation, hepatocytic changes and duct proliferation), no statistical difference between groups submitted to extrahepatic biliary obstruction (EBO) with and without treatment with glutamine (G) was observed. CONCLUSION: Glutamine supplementation did not alter the prognosis of liver enzymes and histopathological changes in animals submitted to extrahepatic biliary obstruction.

Influence of glutamine on morphological and functional changes of liver in the presence of extrahepatic biliary obstruction in rats / Influência da glutamina em alterações funcionais e morfológicas do fígado na vigência de obstrução biliar extra-hepática em ratos

PURPOSE: To study the influence of glutamine on functional and morphological changes of liver in the extrahepatic biliary obstruction through an experimental model in rats. METHODS: Seventy Wistar rats were divided into four groups: control (group C) fictitious operation, (group FO), submitted to laparotomy with handling of bile ducts, but without hepatic duct ligation, (group EBO) submitted to laparotomy and hepatic duct ligation, one of them submitted to supplementation with glutamine 2 percent (group G). The control group consisted of 6 animals. The animals from groups FO, EBO and G were divided into three groups consisting of 6 animals each, being sacrificed at 7, 14 and 21 days after operation, respectively. Blood samples were collected for biochemical analysis and a fragment of liver tissue was collected from the middle lobe for histological analysis. RESULTS: Both for biochemical analysis (BT, aspartate and alanine aminotransferase AST, ALT and alkaline phosphatase FAL) and for histopathological changes (fibrosis, portal inflammation, parenchymal inflammation, hepatocytic changes and duct proliferation), no statistical difference between groups submitted to extrahepatic biliary obstruction (EBO) with and without treatment with glutamine (G) was observed. CONCLUSION: Glutamine supplementation did not alter the prognosis of liver enzymes and histopathological changes in animals submitted to extrahepatic biliary obstruction.

OBJETIVO: Estudar a influência da glutamina em alterações funcionais e morfológicas do fígado na obstrução biliar extra-hepática por meio de um modelo experimental desenvolvido em ratos. MÉTODOS: Setenta ratos Wistar distribuídos em quatro grupos: controle (grupo C); operação fictícia (grupo OF), submetido à laparotomia com manuseio das vias biliares, mas sem ligadura do ducto hepático; (grupo OBE), submetido à laparotomia exploradora e ligadura do ducto hepático, sendo um deles submetido à suplementação com glutamina a 2 por cento (grupo G). O grupo controle era composto por seis animais. Os animais dos grupos OF, OBE e G foram divididos em três grupos compostos por seis animais cada e que foram sacrificados no 7°, 14° e 21° dias após a operação, respectivamente. Foi colhido sangue para análise bioquímica e um fragmento de tecido hepático do lobo médio para estudo histológico. RESULTADOS: Tanto em relação à analise bioquímica (BT, aspartate and alanine aminotransferase AST, ALT e FAL) quanto em relação às alterações histopatológicas (fibrose, inflamação portal, inflamação parenquimatosa, alterações hepatocíticas e proliferação de ducto), não houve diferença estatística entre os grupos submetido a obstrução biliar extra-hepática sem (OBE) e com tratamento com glutamina (G). CONCLUSÃO: A suplementação com glutamina não alterou o prognóstico em relação às enzimas hepáticas e alterações histopatológicas nos animais submetidos à obstrução biliar extra-hepática.

Gamma knife-treated hepatoma: case of obstructive jaundice and management.

Gamma knife therapy is becoming more frequently applied in solid tumor treatment. This article reports a unique case of severe obstructive jaundice arising as a complication of treatment of hepatoma at the hepatic hilum using a gamma knife.While planning an intervention, some images seem to promise success but actually lead to failure. Radiation damage to specific organs is difficult to predict because of several variables. Radiation-induced fibrosis and necrosis are the most common long-term adverse effects of radiotherapy; they are usually considered irreversible and result in induration and firmness of the tissue.To minimize radiation fibrosis, accurate patient positioning and tumor relocalization are essential for gamma knife use in the liver and other extracranial sites. Even when practiced frequently, any intervention must be delivered with caution if the liver has been treated with radiation. Otherwise, even with much experience, the unwary doctor can be trapped by deceptive images.

Bleeding tendency as a first symptom in children with congenital biliary dilatation.

AIM OF THE STUDY: Although a bleeding tendency as a first symptom is a critical condition in congenital biliary dilatation (CBD), the clinical details of this symptom remain unclear. We assessed this condition in children with CBD in this paper. MATERIALS AND METHODS: Sixty-five children with CBD were treated at our institute between 1983 and 2004. The children, initially presenting with bleeding manifestations such as intracranial hemorrhage and bloody stools, were defined as the bleeding group, and the remaining children with digestive symptoms such as abdominal pain and vomiting were defined as the digestive group. The clinical features were compared between these two groups. RESULTS: In 6 of the 65 cases, bleeding manifestations were noted (9.2 %). All six had cystic-type choledochal dilatation. The mean age of the bleeding group was significantly younger than that of the digestive group, and bleeding was more frequent, especially in infants less than 12 months of age. In a laboratory study, the bleeding group showed a more prolonged blood coagulation time than the digestive group did. Serum amylase and lipase levels in the bleeding group were almost normal, while those in the digestive group were significantly higher. The direct bilirubin level in the bleeding group was significantly higher than that in the digestive group. CONCLUSIONS: Disturbed blood coagulation due to vitamin K deficiency related to cholestasis results in a bleeding tendency in children with CBD. Therefore, pediatric surgeons should be aware of this rare but critical condition which can be prevented by rapid and precise treatment with vitamin K supplementation.