Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram.

BACKGROUND: The objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC). PATIENTS AND METHODS: A nomogram was developed from 173 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA. The nomogram was externally validated in 133 patients treated at the Academic Medical Center (AMC), Amsterdam, The Netherlands. Prognostic accuracy was assessed with concordance estimates and calibration, and compared with the American Joint Committee on Cancer (AJCC) staging system. The nomogram will be available as web-based calculator at mskcc.org/nomograms. RESULTS: For all 306 patients, the median overall survival (OS) was 40 months and the median DSS 41 months. Median follow-up for patients alive at last follow-up was 48 months. Lymph node involvement, resection margin status, and tumor differentiation were independent prognostic factors in the derivation cohort (MSKCC). A nomogram with these prognostic factors had a concordance index of 0.73 compared with 0.66 for the AJCC staging system. In the validation cohort (AMC), the concordance index was 0.72, compared with 0.60 for the AJCC staging system. Calibration was good in the derivation cohort; in the validation cohort patients had a better median DSS than predicted by the model. CONCLUSIONS: The proposed nomogram to predict DSS after curative intent resection of PHC had a better prognostic accuracy than the AJCC staging system. Calibration was suboptimal because DSS differed between the two institutions. The nomogram can inform patients and physicians, guide shared decision making for adjuvant therapy, and stratify patients in future randomized, controlled trials.

Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival.

BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome. PATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival. RESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival. CONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).

BACKGROUND: The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. METHODS: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). CONCLUSIONS: GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.

Rates and patterns of recurrence for percutaneous radiofrequency ablation and open wedge resection for solitary colorectal liver metastasis.

INTRODUCTION: The purpose of this study was to compare rates and patterns of disease progression following percutaneous, image-guided radiofrequency ablation (RFA) and nonanatomic wedge resection for solitary colorectal liver metastases. METHODS: We identified 30 patients who underwent nonanatomic wedge resection for solitary liver metastases and 22 patients who underwent percutaneous RFA because of prior major hepatectomy (50%), major medical comorbidities (41%), or relative unresectability (9%). Serial imaging studies were retrospectively reviewed for evidence of local tumor progression. RESULTS: Patients in the RFA group were more likely to have undergone prior liver resection, to have a disease-free interval greater than 1 year, and to have had an abnormal carcinoembryonic antigen (CEA) level before treatment. Two-year local tumor progression-free survival (PFS) was 88% in the Wedge group and 41% in the RFA group. Two patients in the RFA group underwent re-ablation, and two patients underwent resection to improve the 2-year local tumor disease-free survival to 55%. Approximately 30% of patients in each group presented with distant metastasis as a component of their first recurrence. Median overall survival from the time of resection was 80 months in the Wedge group vs 31 months in the RFA group. However, overall survival from the time of treatment of the colorectal primary was not significantly different between the two groups. CONCLUSIONS: Local tumor progression is common after percutaneous RFA. Surgical resection remains the gold standard treatment for patients who are candidates for resection. For patients who are poor candidates for resection, RFA may help to manage local disease, but close follow-up and retreatment are necessary to achieve optimal results.

Segment-oriented approach to liver resection.

Segment-oriented liver resection is a distinct surgical approach and represents the virtuosity of hepatic surgery. It is unique in the finesse of its execution and in its oncologic efficacy and safety. The varied combinations of segmentectomy allow greater flexibility and opportunity for liver surgeons to extirpate the equally diverse nature and location of intrahepatic pathologic conditions. The technique promotes tumor clearance while con-serving uninvolved parenchyma.

The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis of 401 cases.

BACKGROUND: Patients with potentially resectable hepatobiliary malignancy are frequently found to have unresectable tumors at laparotomy. We prospectively evaluated staging laparoscopy in patients with resectable disease on preoperative imaging. METHODS: Staging laparoscopy was performed on 410 patients with potentially resectable hepatobiliary malignancy. The preoperative likelihood of resectability was recorded. Data on preoperative imaging, operative findings, and hospital course were analyzed. RESULTS: Laparoscopic inspection was complete in 291 (73%) patients. In total, 153 patients (38%) had unresectable disease, 84 of whom were identified laparoscopically, increasing resectability from 62% to 78%. On multivariate analysis, a complete examination, preoperative likelihood of resection, and primary diagnosis were significant predictors of identifying unresectable disease at laparoscopy. The highest yield was for biliary cancers, and the lowest was for metastatic colorectal cancer. In patients with unresectable disease identified at laparoscopy, the mean hospital stay was 3 days, and postoperative morbidity was 9%, compared with 8 days and 27%, respectively, in patients found to have unresectable disease at laparotomy. CONCLUSIONS: Laparoscopy spared one in five patients a laparotomy while reducing hospital stay and morbidity. Targeting laparoscopy to patients at high risk for unresectable disease requires consideration of disease-specific factors; however, the surgeons' preoperative impression of resectability is also important.

Staging laparoscopy for potentially resectable noncolorectal, nonneuroendocrine liver metastases.

BACKGROUND: Carefully selected patients with noncolorectal, nonneuroendocrine (NCNN) liver metastases may benefit from hepatic resection. The incidence of occult unresectable disease and the possible benefits of staging laparoscopy in these patients are not known. METHODS: From December 1997 to July 2000, staging laparoscopy was performed in 30 consecutive patients with NCNN metastases before planned open exploration and resection. Demographics, extent of preoperative imaging, operative and postoperative findings, and factors associated with laparoscopic identification of unresectable disease were analyzed. RESULTS: Twenty-four patients (80%) had a complete laparoscopic examination, and 23 had laparoscopic ultrasonography. All patients underwent preoperative computed tomography or magnetic resonance imaging, and 21 (70%) patients had 2 or more preoperative radiological studies. Overall, nine patients had unresectable disease, six of whom were identified by laparoscopy. Of the remaining 24 patients believed to have resectable disease at laparoscopy, 21 went on to a potentially curative procedure. Laparoscopy did not identify irresectability because of vascular involvement in three patients. Laparoscopy added a median of 30 minutes of operative time to those patients going on to laparotomy. CONCLUSIONS: Laparoscopy identified the majority of patients with occult unresectable disease, improved resectability, and should be routine in patients being considered for potentially curative hepatic resection.

Bronchobiliary fistula complicating oriental cholangiohepatitis.

Bronchio biliary fistula in adults is a rare event defined by the passage of bile into the bronchus and the sputum (biloptysis).Typically these lesions occur in the congenital form, as a result of thoracoabdominal trauma, or in rare instances as a result of iatrogenic injury or long-standing biliary tract disease and obstruction. In this paper, we report a novel case of a fatal bronchobiliary fistula that developed in a 67-year-old Chinese male with Oriental cholangiohepatitis. To our knowledge, this is the first case report of a bronchobiliary fistula complicating the clinical management of a patient with this disease.

Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes.

Intrahepatic cholangiocarcinoma (IHC) is a rare primary hepatic tumor of bile duct origin for which resection is the most effective treatment. But resectability, outcomes after resection, and recurrence patterns have not been well described. Patients with IHC were identified from a prospective database. Demographic data, tumor characteristics, and outcomes were analyzed. From March 1992 to September 2000, 53 patients with hepatic tumors underwent exploration and were found to have pure IHC on pathologic analysis. Patients with mixed hepatocellular and cholangiocarcinoma tumors were excluded. At exploration, 20 patients were unresectable for an overall resectability rate of 62% (33 of 53). Median survival for patients submitted to resection was 37.4 months versus 11.6 months for patients undergoing biopsy only (p = 0.006; median followup for surviving patients, 15.6 months). Actuarial 3-year survival was 55% versus 21%, respectively. Factors predictive of poor survival after resection included vascular invasion (p = 0.0007), histologically positive margin (p = 0.009), or multiple tumors (p = 0.003). After resection, 20 of 33 patients (61%) recurred at a median of 12.4 months. Sites of recurrence included the liver (14), retroperitoneal or hilar nodes (4), lung (4), and bone (2). The median disease-free survival was 19.4 months, with a 3-year disease-free survival rate of 22%. Factors predictive of recurrence were multiple tumors (p = 0.0002), tumor size (p = 0.001), and vascular invasion (p = 0.01). About two-thirds of patients who appeared resectable on preoperative imaging were amenable to curative resection at the time of operation. Although complete resection improved survival, recurrence was common. The majority of recurrences were local or regional, which may help guide future adjuvant therapy strategies.

Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.

OBJECTIVE: To analyze resectability and survival in patients with hilar cholangiocarcinoma according to a proposed preoperative staging scheme that fully integrates local, tumor-related factors. SUMMARY BACKGROUND DATA: In patients with hilar cholangiocarcinoma, long-term survival depends critically on complete tumor resection. The current staging systems ignore factors related to local tumor extent, preclude accurate preoperative disease assessment, and correlate poorly with resectability and survival. METHODS: Demographics, results of imaging studies, surgical findings, pathology, and survival were analyzed prospectively in consecutive patients. Using data from imaging studies, all patients were placed into one of three stages based on the extent of ductal involvement by tumor, the presence or absence of portal vein compromise, and the presence or absence of hepatic lobar atrophy. RESULTS: From March 1991 through December 2000, 225 patients were evaluated, 77% of whom were seen and treated within the last 6 years. Sixty-five patients had unresectable disease; 160 patients underwent exploration with curative intent. Eighty patients underwent resection: 62 (78%) had a concomitant hepatic resection and 62 (78%) had an R0 resection (negative histologic margins). Negative histologic margins, concomitant partial hepatectomy, and well-differentiated tumor histology were associated with improved outcome after all resections. However, in patients who underwent an R0 resection, concomitant partial hepatectomy was the only independent predictor of long-term survival. Of the 9 actual 5-year survivors (of 30 at risk), all had a concomitant hepatic resection and none had tumor-involved margins; 3 of these 9 patients remained free of disease at a median follow-up of 88 months. The rates of complications and death after resection were 64% and 10%, respectively. In the 219 patients whose disease could be staged, the proposed system predicted resectability and the likelihood of an R0 resection and correlated with metastatic disease and survival. CONCLUSION: By taking full account of local tumor extent, the proposed staging system for hilar cholangiocarcinoma accurately predicts resectability, the likelihood of metastatic disease, and survival. Complete resection remains the only therapy that offers the possibility of long-term survival, and hepatic resection is a critical component of the surgical approach.

Results of hepatic resection for sarcoma metastatic to liver.

OBJECTIVE: To evaluate the outcome of patients with liver metastases from sarcoma who underwent hepatic resection at a single institution and were followed up prospectively. SUMMARY BACKGROUND DATA: The value of hepatic resection for metastatic sarcoma is unknown. METHODS: There were 331 patients with liver metastases from sarcoma who were admitted to Memorial Hospital from 1982 to 2000, and 56 of them underwent resection of all gross hepatic disease. Patient, tumor, and treatment variables were analyzed to assess outcome. RESULTS: Of the 56 patients who underwent complete resection, 34 (61%) had gastrointestinal stromal tumors or gastrointestinal leiomyosarcomas. Half of the patients required an hepatic lobectomy or extended lobectomy. There were no perioperative deaths in the completely resected group, although 3 of the 75 patients who underwent exploration (4%) died. The postoperative 1-, 3-, and 5-year actuarial survival rates were 88%, 50%, and 30%, respectively, with a median of 39 months. In contrast, the 5-year survival rate of patients who did not undergo complete resection was 4%. On multivariate analysis, a time interval from the primary tumor to the development of liver metastasis greater than 2 years was a significant predictor of survival after hepatectomy. CONCLUSIONS: Complete resection of liver metastases from sarcoma in selected patients is associated with prolonged survival. Hepatectomy should be considered when complete gross resection is possible, especially when the time to the development of liver metastasis exceeds 2 years.

Management of 155 patients with benign liver tumours.

BACKGROUND: Benign hepatic tumours continue to represent a diagnostic and therapeutic challenge. This study evaluates the indications and results of resection compared with observation in patients with benign hepatic tumours. METHODS: Patients with a primary diagnosis of benign liver tumour were identified from a prospective database and evaluated retrospectively. RESULTS: From January 1992 to June 1999, 155 patients with benign hepatic tumours were evaluated. The diagnoses included haemangioma (n = 97), focal nodular hyperplasia (FNH) (n = 42), hepatic adenoma (n = 12) and cystadenoma (n = 4). Sixty-eight patients (44 per cent) underwent resection because of symptoms (n = 36), inability to exclude a malignancy (n = 31) or enlargement on serial imaging (n = 11). The operative morbidity and mortality rates were 21 per cent and zero respectively. Thirty patients had a preoperative percutaneous needle biopsy, 19 of which were either incorrect or indeterminate. Overall, 39 of 42 patients with symptoms attributed to the tumour were asymptomatic after resection and 18 of 21 patients with symptoms considered unrelated to the tumour were asymptomatic after a period of observation and/or treatment of unrelated conditions (median follow-up 16 months). CONCLUSION: When indicated, resection of benign liver tumours can be performed safely. Symptomatic patients with a small FNH or haemangioma can be observed because their symptoms are unlikely to be related to the liver tumour. Percutaneous needle biopsy rarely changes management.

What is the yield of intraoperative ultrasonography during partial hepatectomy for malignant disease?

BACKGROUND: Previous studies have shown that intraoperative ultrasonography (IOUS) during hepatic resection for malignancy changes the operative plan or identifies occult unresectable disease in a large proportion of patients. This study was undertaken to reassess the yield of IOUS in light of recent improvements in preoperative staging. STUDY DESIGN: Patients with potentially resectable primary or metastatic hepatic malignancies subjected to exploration, bimanual palpation of the liver, and IOUS were evaluated prospectively. Intraoperative findings were recorded, and preoperative imaging studies were reanalyzed by radiologists blinded to the intraoperative findings. The extent of disease based on preoperative imaging was compared with the intraoperative findings. RESULTS: From October 1997 until November 1998, 111 patients were evaluated. At exploration, a total of 77 new findings or findings different than suggested on the imaging studies were identified in 61 patients (55%), the most common of which was additional hepatic tumors (n = 37). Thirty-five of 77 (45%) new findings were identified by IOUS alone and 10 (13%) by palpation alone; the remainder were identified by both palpation and IOUS. Forty-seven of 61 patients (77%) underwent a complete resection despite new intraoperative findings, with a modification (n = 28) or no change (n = 19) in the planned operation. Twenty-one patients (19%) had new findings identified only on IOUS. Thirteen of these patients underwent resection with no change in the operative plan, six underwent a modified resection and two were considered to have unresectable disease based solely on the findings of IOUS. CONCLUSIONS: In patients with hepatic malignancies submitted to a potentially curative resection, new intraoperative findings or findings different than suggested on preoperative imaging studies are common. But resection with no change in the operative plan or a modified resection is still possible in the majority of patients despite such findings. The findings on IOUS alone rarely lead to a change in the operative plan.

A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases.

BACKGROUND: Laparoscopy may identify occult metastatic disease and prevent unnecessary laparotomy in some patients with potentially resectable colorectal liver metastases but is unnecessary in the majority of individuals who undergo resection. The objectives of the current study were to assess the impact of laparoscopy after extensive preoperative imaging and to determine whether a preoperative clinical risk score can identify those patients most likely to benefit from the procedure. METHODS: Between December 1997 and July 1999, 103 consecutive patients with potentially resectable colorectal liver metastases underwent laparoscopy prior to planned laparotomy and partial hepatectomy. Surgical findings, length of hospital stay, and hospital charges were analyzed. Patients were assigned a clinical risk score (CRS) based on five factors related to the primary tumor and the hepatic disease. The likelihood of finding occult unresectable disease and the yield of laparoscopy were analyzed with respect to the CRS. RESULTS: Seventy-seven patients (75%) underwent resection. Laparoscopy identified 14 of 26 patients with unresectable disease, 10 of whom were spared an unnecessary laparotomy. In patients who underwent biopsy only, the laparoscopic identification of unresectable disease shortened the hospital stay (1.2 +/- 0.6 days vs. 5.8 +/- 2.3 days; p = 0.0001) and reduced the total hospital charges by 55% (P = 0.0001). The CRS predicted the likelihood of occult unresectable disease, which was 12% in those with a score < or = 2 but increased to 42% in those with a score > 2 (P = 0.001). If laparoscopy were used only in high risk patients (CRS > 2), 57 laparoscopies would have been avoided and the net savings doubled. CONCLUSIONS: With extensive preoperative imaging, the vast majority of patients with potentially resectable hepatic colorectal metastases do not benefit from laparoscopy. However, in the minority of patients with occult unresectable disease, laparoscopy prevents unnecessary laparotomy and reduces hospital stay and the total hospital charges. The CRS, previously shown to predict survival after hepatic resection, identifies those high risk patients most likely to benefit from laparoscopy and may improve resource utilization.

Extended hepatic resection: a 6-year retrospective study of risk factors for perioperative mortality.

BACKGROUND: Extended hepatic resection (more than four liver segments) is a major operative procedure that is associated with significant risk. The purpose of this study was to assess the impact of perioperative variables on in-hospital mortality after extended hepatectomy. STUDY DESIGN: Consecutive patients who underwent extended hepatic resection were studied. The prognostic value of 29 perioperative variables was evaluated using in-hospital mortality as the endpoint. For each variable, the odds ratio (95% confidence interval) for in-hospital mortality was calculated. Those variables with a lower confidence limit > 1 were considered important risk factors. The population was stratified into categories of patients having the same number of risk factors, and mortality was estimated for each group. These data were used to develop a risk assessment algorithm. RESULTS: There were 14 deaths (6%) in 226 patients. Three preoperative variables (cholangitis, creatinine > 1.3 mg/dL, and total bilirubin > 6 mg/dL) and two operative variables (blood loss > 3 L and vena caval resection) appear to be important factors for in-hospital mortality. The mortality associated with the presence of any two of the five factors was 100% (5 of 5), and the mortality associated with the absence of these factors was 3% (6 of 191). CONCLUSIONS: Perioperative evaluation of patients undergoing extended hepatic resection should include the quantitation of mortality risk factors. The combination of any two factors among preoperative cholangitis, elevated serum creatinine, elevated serum bilirubin, high operative blood loss, and vena cava resection may carry a high mortality risk. These results require prospective validation.

Peritoneal washings are not predictive of occult peritoneal disease in patients with hilar cholangiocarcinoma.

BACKGROUND: Evaluation of peritoneal cytology provides valuable staging information in patients with gastric and pancreatic adenocarcinoma, but its usefulness in patients with extrahepatic cholangiocarcinoma is unclear. The aim of this study was to evaluate the predictive value of peritoneal cytology in patients with potentially resectable hilar cholangiocarcinoma. This study evaluated a possible association between positive peritoneal cytology and percutaneous transhepatic biliary drainage, which is commonly used in these patients and may result in peritoneal biliary leakage and peritoneal seeding. STUDY DESIGN: From October 1997 through June 2000 26 patients with hilar cholangiocarcinoma underwent staging laparoscopy immediately before planned open exploration and resection. Peritoneal washings were obtained during laparoscopic examination before any biopsies were taken. Cytologic analysis was performed using the Papanicolau technique. RESULTS: There were 18 men and 8 women, with a median age of 69 years (range 42 to 81 years). The most common presenting symptom was jaundice (n = 19). Previous biliary drainage was performed in 23 patients: 9 percutaneous and 14 endoscopic. Metastatic disease was suspected preoperatively in six patients, three to the liver, two to the peritoneum, and one to regional lymph nodes, all of which were confirmed at laparoscopy. Laparoscopy identified five additional patients with metastatic disease. Peritoneal cytology was positive for malignant cells in two patients, both of whom had gross peritoneal metastases. Nine other patients had metastatic disease to distant sites within the abdomen, but none had positive cytology. Overall, six patients had metastatic disease to the peritoneal cavity, only one of whom had undergone earlier percutaneous biliary drainage. CONCLUSIONS: Peritoneal cytology was not predictive of occult metastatic disease. Laparoscopic staging identified some patients with unresectable hilar cholangiocarcinoma, but analysis of peritoneal cytology provided no additional information. There was no association between percutaneous transhepatic biliary drainage and peritoneal tumor seeding.