Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies.

BACKGROUND: Although gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. METHODS: We performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan-Meier curves and a Cox regression model stratified on the trial. RESULTS: Two hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71-1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%-47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%-43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78-1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%-57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%-56.5%) for observation. CONCLUSION: With 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.

PURPOSE: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

Impact of homogeneous pathologic response to preoperative chemotherapy in patients with multiple colorectal liver metastases.

AIM: To analyze the homogeneity of pathologic response to preoperative chemotherapy (PRPC) after chemotherapy in patients with multiple liver metastases (LM). METHODS: From September 2011 to August 2014, patients with at least two LM undergoing preoperative chemotherapy prior to resection were included in this retrospective, single-center study. The endpoints were PRPC homogeneity (according to both the Rubbia-Brandt and MD Anderson classifications), the impact of PRPC on the MDT decision, factors associated with homogeneous PRPC and overall survival of patients with vs. without homogeneous PRPC. RESULTS: seventy-three patients with a total of 88 liver resections (including 15 two-stage procedures) were included in the study. The homogeneous PRPC rate was 55% according to the Rubbia-Brandt classification and 53% according to the MD Anderson classification. The MDT decision was modified by the PRPC in only 2.7% of patients (n = 2). CONCLUSION: The PRPC was homogeneous in only one half of patients and had very little influence on the MDT decision.

Management of colorectal cancer in patients with cirrhosis: A retrospective, case-matched study of short- and long-term outcomes.

BACKGROUND: Few studies have assessed access to postoperative chemotherapy and survival in cirrhotic patients with colorectal cancer. Aim of this study was to analyse short and long-term outcomes in these patients compared to non-cirrhotics. METHODS: A retrospective, single-centre, comparative, case-matched study comparing 40 cirrhotic patients who had undergone colorectal resection between January 2006 and January 2014, and a matched cohort of 80 non-cirrhotic patients. Data collection included rate of postoperative outcomes, chemotherapy regimen, overall and disease-free 3-year survival. RESULTS: Cirrhotics had more major postoperative complications than non-cirrhotics (57.5% vs. 26.5%, respectively; p=0.002) but no difference in anastomotic leakage (p=0.1); a higher mortality rate (p=0.0006) was observed in Child-Pugh class B patients. Cirrhotics had no difference in adjuvant chemotherapy rate compared to non-cirrhotics (55% vs. 65%, respectively p=0.8); 3-year overall survival was 71% in the Child A group vs. 92% in non-cirrhotics (p=0.03). CONCLUSION: Despite a higher postoperative complication rate and a lower overall survival of cirrhotic patients compared to non-cirrhotics, cirrhosis had no impact on oncological outcomes and access/tolerance to postoperative chemotherapy. Thus cirrhosis should not be considered as a contraindication to curative treatment of colon cancer.

Multidisciplinary management of Mirizzi syndrome with cholecystobiliary fistula: the value of minimally invasive endoscopic surgery.

Mirizzi syndrome, a rare complication of gallstones, is defined by obstruction of the main bile duct. This obstruction may worsen and thus result in cholecystobiliary fistula. Surgical management of Mirizzi syndrome is complicated by the presence of inflamed tissue around the hepatic pedicle, making it impossible to distinguish between the main bile duct and the gallbladder. The surgeon's first task is to perform subtotal cholecystotomy (from the fundus of the gallbladder to the neck) without trying to locate the cystic duct. In a second step, the gallstones are extracted and the main bile duct is then repaired. In most cases, a T-tube is used to drain the main bile duct, and abdominal drainage is left in place (in case a bile fistula forms). This study concluded that preoperative drainage of the main bile duct in the treatment of Mirizzi syndrome types II and III is feasible and might help to decrease the postoperative complication rate.

Oncological strategies for middle and low rectal cancer with synchronous liver metastases.

PURPOSES: In rectal cancer, the incidence of synchronous liver metastases (SLM) ranges from 14% to 30%. The treatment of SLM combines neo-adjuvant chemo- and/or radiotherapy with of one three surgical resection strategies (rectal resection first, liver resection first or simultaneous resection). The present study evaluated the success rate for each resection strategy. METHODS: From January 2005 to December 2013, we retrospectively included all patients with distal (middle and low) rectal cancer (MLRC) and SLM and who had been operated on with curative intent. The primary study endpoint was the proportion of complete resections at both tumour sites. The secondary endpoints were postoperative morbidity, the long-term outcome and risk factors for incomplete resection. RESULTS: 52 patients were included. There were no significant intergroup differences in the incidence of complete resection (respectively 74%, 66% and 50% in the rectum-first (n = 20), simultaneous (n = 10) and liver-first groups (n = 5); p = 0.3), the overall complication rate or mortality rate after rectal resection (p = 0.5) or liver resection (p = 0.8), overall survival (60, 47 and 38 months, respectively; p = 0.4) or disease-free survival (31, 32 and 7.8 months, respectively; p = 0.1). Emergency surgery was the only risk factor for treatment failure (p = 0.01). CONCLUSION: There were no differences in short and long-term outcomes between the three strategies. No one oncological strategy should be favoured for all cases of MLRC with SLM. The strategy should be choosen, based on the oncological emergency (rectum-first or liver-first), predictive factors for morbidity in rectal surgery and MDT discussion.

Management of colon cancer in patients with cirrhosis: A review.

INTRODUCTION: The incidence of cirrhosis is increasing in parallel with that of hepatitis C and non-alcoholic steatohepatitis. Patients with colon cancer and liver cirrhosis constitute an important at-risk group. Many colorectal surgeons and oncologists are not familiar with the management of colon cancer in patients with cirrhosis. Here, we review the literature on the management and prognosis of patients with both colon cancer and cirrhosis. METHODS: The MEDLINE, PubMed and the Cochrane Library electronic databases were systematically searched with appropriate keywords. Only publications in French or English were selected. RESULTS/CONCLUSION: For most studies, the level of evidence is weak. Child A patients should probably be managed in the same way as general population, although they have an elevated risk of morbidity and a five-year survival rate of just 70%. Child B and C patients should be managed more cautiously, although no specific recommendations can be made at present. For colon surgery, laparotomy should be preferred in patients with cirrhosis. The role of adjuvant chemotherapy is unclear, since survival is strongly associated with the improvements in liver function. Oxaliplatin appears to be associated with an elevated post-chemotherapy morbidity rate in patients with portal hypertension.

A lymph node ratio of 10% is predictive of survival in stage III colon cancer: a French regional study.

Lymph node ratio (LNR) (positive lymph nodes/sampled lymph nodes) is predictive of survival in colon cancer. The aim of the present study was to validate the LNR as a prognostic factor and to determine the optimum LNR cutoff for distinguishing between "good prognosis" and "poor prognosis" colon cancer patients. From January 2003 to December 2007, patients with TNM stage III colon cancer operated on with at least of 3 years of follow-up and not lost to follow-up were included in this retrospective study. The two primary endpoints were 3-year overall survival (OS) and disease-free survival (DFS) as a function of the LNR groups and the cutoff. One hundred seventy-eight patients were included. There was no correlation between the LNR group and 3-year OS (P=0.06) and a significant correlation between the LNR group and 3-year DFS (P=0.03). The optimal LNR cutoff of 10% was significantly correlated with 3-year OS (P=0.02) and DFS (P=0.02). The LNR was not an accurate prognostic factor when fewer than 12 lymph nodes were sampled. Clarification and simplification of the LNR classification are prerequisites for use of this system in randomized control trials. An LNR of 10% appears to be the optimal cutoff.

A Reappraisal of Chemotherapy-Induced Liver Injury in Colorectal Liver Metastases before the Era of Antiangiogenics.

Background and Aims. Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab. Methods. Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics. Results. Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, P = 0.04), especially LV5FU2 (P = 0.02). SD was associated with oxaliplatin (54.5% versus 23.5%, P = 0.05) and low body mass index (P = 0.003). NRH was associated with oxaliplatin (P = 0.03) and extensive resection (P = 0.04). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF (P = 0.03), longer hospitalization in case of surgical hepatitis (P = 0.03), and greater blood loss in case of portal fibrosis (P = 0.03). Conclusions. Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality.

BAD, a proapoptotic member of the BCL2 family, is a potential therapeutic target in hepatocellular carcinoma.

Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib.

Somatostatin receptor scintigraphy screening in advanced hepatocarcinoma: A multi-center French study.

BACKGROUND: Somatostatin receptor scintigraphy (SRS) has been reported for receptor (SSTR) screening in advanced hepatocarcinoma (aHC) prior to somatostatin analogue treatment. AIMS: To evaluate SSTR screening with SRS in aHC patients. RESULTS: Seventy aHC patients (63 men) aged 65 +/- 11 y were included, with alcohol, viral or other causes cirrhosis in 35 (50%), 23 (33%), 12 (17%) cases respectively. CLIP score was 2.7 +/- 1.7, with more than three nodules in 37 (53%) cases. Largest nodule measured 7.6 +/- 4.5 cm. Median alpha-fetoprotein was 574 UI/mL. SRS was positive in 25/70 (35.7%) livers and 7/17 (41.2%) metastatic sites. Positive SRS patients differed from others for tumor size (9.2 +/- 4 vs. 6.7 +/- 4.6 cm, p = 0.03), prothrombin time (PT) (75.2 +/- 15.2 vs. 61.9 +/- 19%, p = 0.005), albumin (34.1 +/- 5.9 vs. 30.5 +/- 7.2 g/L, p = 0.04) and Child-Pugh (6.7 +/- 1.8 vs. 7.7 +/- 2.3, p = 0.04). After multivariate analysis, only PT was associated with positive SRS (p = 0.028). Immunohistochemistry was positive for SSTR2s in 6/7 tumors (SRS uptake in 5/6 cases). METHODS: SRS was performed prior treatment, with images at 4, 24 and 48 h. For seven tumors, SSTR2 subtype was detected immunohistochemically. CONCLUSIONS: In advanced hepatocarcinoma, we report SRS uptake in 35.7% of livers and 41.2% of metastatic sites. SRS value in screening patients for somatostatin analogue treatment remains to be assessed.

Biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma with jaundice.

BACKGROUND AND AIM: The combination of photodynamic therapy and biliary stenting seems to be beneficial in the palliative treatment of unresectable cholangiocarcinoma. We aimed to assess the accuracy of photodynamic therapy in a single centre. METHODS: Fourteen selected patients, with jaundice related to unresectable cholangiocarcinoma, underwent photodynamic therapy and biliary stenting (with or without chemotherapy). Photofrin was injected intravenously (2 mg/kg) 2 days before intraluminal photoactivation. In case of malignant progression, photodynamic therapy was repeated. The outcome parameters were overall survival and quality of life. RESULTS: There were eight men and six women (median age: 67 [42-81]). Unresectability was related to a low Karnofski index (n = 2), peritoneal carcinomatosis (n = 4), vascular involvement (n = 3), invasion of the hepatoduodenal ligament (n = 2) and an under-sized liver remnant (n = 3). Biliary stenting was efficient (> or = 50% total bilirubin) in 78.5% of cases. Eight patients developed cholangitis. The mean number of photodynamic therapy procedures was two (1-4). Six (43%) patients needed > or = 2 procedures. No severe toxicity was noted. Photodynamic therapy improved the Karnofski index in 64% of cases. Six (42.8%) patients received concomitant chemotherapy (gemcitabine). The median survival time was 13.8 [0.7-29.2] months. The 3-, 6- and 12-month survival rates were 85%, 77% and 77%, respectively. CONCLUSION: These results confirm the beneficial effect of biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma in selected patients with jaundice.

Is there a role for endoscopic ultrasonography in evaluation of the left liver in colorectal liver metastasis patients selected for right hepatectomy.

BACKGROUND: Meticulous assessment of the left liver for patients scheduled for right hepatectomy is essential. Endoscopic ultrasonography (EUS) is frequently used for the locoregional staging or biopsy of pancreatic tumours and has shown some value in the evaluation of the left liver. METHODS: We prospectively enrolled 24 consecutive patients who were scheduled for at least a right hepatectomy and who underwent laparotomy for colorectal liver metastasis (CLMs). The left liver was assessed preoperatively with standard techniques [computed tomography (CT) scan, percutaneous ultrasonography] and EUS. These results were compared with those of intraoperative ultrasonography (IOUS). RESULTS: The study population consisted of 12 men and 12 women (mean age 64 years, range 47-79 years). Mean body mass index was 26 kg/m(2) (range 20-35 kg/m(2)). Standard preoperative evaluation detected 28 lesions in the left liver; EUS detected just 17 lesions, whereas IOUS detected 30 lesions in the left liver. For the left lobe of the liver (segments II and III), the standard evaluation had sensitivity of 85%, specificity of 64%, positive predictive value (PPV) of 50% and negative predictive value (NPV) of 91%; EUS had sensitivity of 55%, specificity of 86%, PPV of 71% and NPV of 76%; IOUS had sensitivity of 85.2%, specificity of 92%, PPV of 96.6% and NPV of 75%. In terms of the left liver (i.e. segments II, III and IV), the results of EUS were less good than for the left lobe of the liver. CONCLUSION: For segments II and III, EUS had higher specificity and positive predictive value than standard evaluation, but only changed our therapeutic strategy in three cases. Even though EUS can provide some valuable information, the technique is not accurate enough to merit systematic performance as part of a standard preoperative evaluation. This study underlines the main role of IOUS in the left liver, with better sensitivity, specificity, and positive predictive value than EUS and standard evaluation.

Management of patients with carcinoma of the right colon invading the duodenum or pancreatic head.

BACKGROUND: Only few case series have been published about locally advanced carcinoma of the right colon invading the duodenum or pancreas (CRCDP). We report results of a retrospective study about this rare entity focusing on management and prognosis. METHODS: We reviewed the complete data of patients operated for CRCDP between 1988 and 2005 in four French digestive-surgery departments. RESULTS: Fifteen patients were managed [12 men, 3 women, mean age 63 years (43-86)]. These patients underwent attempted curative en bloc resection including right colectomy: 12 were treated by partial duodenectomy (tumours involving only a part of the duodenum); 3 were treated by pancreaticoduodenectomy. All tumours resected had clear resection margins (R0). About 53% of patients had hepatic metastases, duodenocolic fistula, carcinomatosis, abscess or perforation at presentation. Surgery was performed in emergency in 26% of cases. About 20% of patients had serious postoperative complications (heart failure, bile duct necrosis, septic shock), and three other patients had postoperative anastomotic leaks. No patient experienced duodenal fistula after partial duodenectomy. The mean median survival in resected patients was 22 months (0-122). Overall 1 and 3 years survival were 68% (n=7) and 56% (n=4). Despite clear resection margins in all patients, 26% of patients developed recurrence (duodenal wall resection n=3; pancreaticoduodenectomy n=1). CONCLUSION: Morbidity and mortality after colectomy and en bloc partial duodenectomy or pancreaticoduodenectomy are high but in selected cases could offer prolonged survival. Aggressive surgery including major resection should be performed to obtain clear resection margins even in case of complicated forms.

Gastric MALT lymphoma presenting as Waldenström's macroglobulinemia without bone marrow involvement.

We report a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma with macroglobulinemia in a 59-year-old man who presented with melena. A computed tomography scan of the abdomen showed irregular thickening of the wall of the stomach, and endoscopic examination disclosed enlarged and inflammatory folds of the fundus. Histopathologic examination of gastric samples showed mucosal infiltration by small lymphocytes, which were positive for CD20 and negative for CD10 and CD23, confirming the diagnosis of gastric MALT lymphoma. Serum electrophoresis detected a monoclonal peak and immunoelectrophoresis revealed an immunoglobulin M kappa component. Bone marrow aspirate and biopsy results were normal. The patient received chemotherapy. After treatment, he was in complete remission, and the serum monoclonal component had disappeared. Our observation is uncommon because of important macroglobulinemia occurring in gastric MALT lymphoma without bone marrow involvement.

Assessment of baseline clinical predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer.

OBJECTIVE: To identify easily available predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer. METHODS: Retrospective analysis of patients treated with cetuximab (400 mg/m(2) in week 1, 250 mg/m(2) in subsequent weeks) plus irinotecan (180 mg/m(2) every 2 weeks). We assessed demographic data, prior response to chemotherapy, number of metastatic sites, disease and metastatic disease durations, irinotecan-free interval and tumoral immunohistochemical epidermal growth factor receptor status. RESULTS: We analyzed 311 patients. Objective response rate under cetuximab-irinotecan was 26%. In univariate analysis, prior response to irinotecan, presence of only 1 metastatic site, disease duration, metastatic disease duration and irinotecan-free interval equal or above median (24, 18 and 1.8 months, respectively) were predictive of response to cetuximab-irinotecan. Multivariate analysis confirmed independent predictive value of prior response to irinotecan, number of metastatic sites and disease duration. CONCLUSION: Prior response to irinotecan, number of metastatic sites and disease duration may contribute to better select patients suitable for cetuximab-irinotecan therapy.