Bas Groot Koerkamp

Circulating Tumor Cells and Prognosis of Patients with Resectable Colorectal Liver Metastases or Widespread Metastatic Colorectal Cancer: A Meta-Analysis

BackgroundWe performed a systematic review and meta-analysis to investigate the prognostic value of tumor cells in blood (circulating tumor cells [CTCs]) or bone marrow (BM) (disseminated tumor cells) of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer (CRC).Materials and MethodsThe following databases were searched in May 2011: MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cochrane Library. Studies that investigated the association between tumor cells in blood or BM and long-term outcome in patients with metastatic CRC were included. We extracted hazard ratios (HRs) and confidence intervals (CIs) from the included studies and performed random-effects meta-analyses for survival outcomes.ResultsThe literature search yielded 16 studies representing 1,491 patients. The results of 12 studies representing 1,329 patients were suitable for pooled analysis. The overall survival (HR, 2.47; 95xa0% CI 1.74–3.51) and progression-free survival (PFS) (HR, 2.07; 95xa0% CI 1.44–2.98) were worse in patients with CTCs. The subgroup of studies with more than 35xa0% CTC-positive patients was the only subgroup with a statistically significant worse PFS. All eight studies that performed multivariable analysis identified the detection of CTCs as an independent prognostic factor for survival.ConclusionThe detection of CTCs in peripheral blood of patients with resectable colorectal liver metastases or widespread metastatic CRC is associated with disease progression and poor survival.

Recurrence Rate and Pattern of Perihilar Cholangiocarcinoma after Curative Intent Resection

BACKGROUNDnThe aim of this study was to investigate the rate and pattern of recurrence after curative intent resection of perihilar cholangiocarcinoma (PHC).nnnSTUDY DESIGNnPatients were included from 2 prospectively maintained databases. Recurrences were categorized by site. Time to recurrence and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to identify independent poor prognostic factors.nnnRESULTSnBetween 1991 and 2012, 306 consecutive patients met inclusion criteria. Median overall survival was 40 months. A recurrence was diagnosed in 177 patients (58%). An initial local recurrence was found in 26% of patients: liver hilum (11%), hepaticojejunostomy (8%), liver resection margin (8%), or distal bile duct remnant (2%). An initial distant recurrence was observed in 40% of patients: retroperitoneal lymph nodes (14%), intrahepatic away from the resection margin (13%), peritoneum (12%), and lungs (8%). Only 18% of patients had an isolated initial local recurrence. The estimated overall recurrence rate was 76% at 8 years. After a recurrence-free period of 5 years, 28% of patients developed a recurrence in the next 3 years. Median RFS was 26 months. Independent prognostic factors for RFS were resection margin, lymph node status, and tumor differentiation. Only node-positive PHC precluded RFS beyond 7 years.nnnCONCLUSIONSnPerihilar cholangiocarcinoma will recur in most patients (76%) after resection, emphasizing the need for better adjuvant strategies. The high recurrence rate of up to 8 years justifies prolonged surveillance. Only patients with an isolated initial local recurrence (18%) may have benefited from a more extensive resection or liver transplantation. Node-positive PHC appears incurable.

Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone.

Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone.

Observation versus Resection for Small Asymptomatic Pancreatic Neuroendocrine Tumors: A Matched Case–Control Study

ObjectiveTo analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain.MethodsIncidentally discovered, sporadic, small (<3xa0cm), stage I–II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied.ResultsA total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59xa0years, pxa0=xa00.04) and tended towards shorter follow-up (44 vs. 57xa0months, pxa0=xa00.06). Within the observation group, 26 of the 104 patients (25xa0%) underwent subsequent tumor resection after a median observation interval of 30xa0months (range 7–135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2xa0cm, pxa0=xa00.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95xa0%) tumors and 5 (6xa0%) developed a recurrence, which occurred after a median of 5.1 (range 2.9–8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6xa0%) patients.ConclusionsIn this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44xa0months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients.

American Joint Committee on Cancer staging for resected perihilar cholangiocarcinoma: a comparison of the 6th and 7th editions

OBJECTIVESnThis study was conducted to evaluate the prognostic value of, respectively, the 6th and 7th editions of the American Joint Committee on Cancer (AJCC) staging system for patients with resected perihilar cholangiocarcinoma (PHC).nnnMETHODSnPatients who underwent resection of PHC between 1991 and 2012 were identified from prospective databases at two centres. Overall survival was estimated using the Kaplan-Meier method and compared across stage groups with the log-rank test. The concordance index and Brier score were used to compare the prognostic accuracy of the staging systems.nnnRESULTSnData for a total of 306 patients were analysed. Staging according to the 7th edition upstaged 63% of patients in comparison with staging by the 6th edition. The log-rank P-value for both staging systems was highly statistically significant (P < 0.001). Staging according to the 6th edition categorized 93% of patients as having stage I or II disease, whereas staging according to the 7th edition distributed patients more equally across stages. Prognostic accuracy was similar between the staging systems: the concordance index was 0.59 and the Brier score 0.17 for both the 6th and 7th editions. The same prognostic accuracy was achieved using an alternative tumour-node-metastasis (TNM) stage grouping simplified to four rather than six stage groups.nnnCONCLUSIONSnThe 6th and 7th editions of the AJCC staging system for PHC have similar prognostic accuracy. Other prognostic factors can potentially improve individual patient prognostication.

Preoperative biliary drainage in perihilar cholangiocarcinoma: identifying patients who require percutaneous drainage after failed endoscopic drainage

BACKGROUND AND STUDY AIMSnPreoperative biliary drainage is often initiated with endoscopic retrograde cholangiopancreatography (ERCP) in patients with potentially resectable perihilar cholangiocarcinoma (PHC), but additional percutaneous transhepatic catheter (PTC) drainage is frequently required. This study aimed to develop and validate a prediction model to identify patients with a high risk of inadequate ERCP drainage.nnnPATIENTS AND METHODSnPatients with potentially resectable PHC and (attempted) preoperative ERCP drainage were included from two specialty center cohorts between 2001 and 2013. Indications for additional PTC drainage were failure to place an endoscopic stent, failure to relieve jaundice, cholangitis, or insufficient drainage of the future liver remnant. A prediction model was derived from the European cohort and externally validated in the USA cohort.nnnRESULTSnOf the 288 patients, 108 (38%) required additional preoperative PTC drainage after inadequate ERCP drainage. Independent risk factors for additional PTC drainage were proximal biliary obstruction on preoperative imaging (Bismuth 3 or 4) and predrainage total bilirubin level. The prediction model identified three subgroups: patients with low risk (7%), moderate risk (40%), and high risk (62%). The high-risk group consisted of patients with a total bilirubin level above 150 µmol/L and Bismuth 3a or 4 tumors, who typically require preoperative drainage of the angulated left bile ducts. The prediction model had good discrimination (area under the curve 0.74) and adequate calibration in the external validation cohort.nnnCONCLUSIONSnSelected patients with potentially resectable PHC have a high risk (62%) of inadequate preoperative ERCP drainage requiring additional PTC drainage. These patients might do better with initial PTC drainage instead of ERCP.

The Impact of Primary Tumor Location on Long-Term Survival in Patients Undergoing Hepatic Resection for Metastatic Colon Cancer

BackgroundThe impact of primary tumor location on overall survival (OS), recurrence-free survival (RFS), and long-term outcomes has not been well established in patients undergoing potentially curative resection of colorectal liver metastases (CRLM).MethodsA single-institution database was queried for initial resections for CRLM 1992–2004. Primary tumor location determined by chart review (rightxa0=xa0cecum to transverse; leftxa0=xa0splenic flexure to sigmoid). Rectal cancer (distal 16xa0cm), multiple primaries, and unknown location were excluded. Kaplan–Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3xa0years of disease-free follow-up.ResultsA total of 907 patients were included with a median follow-up of 11xa0years; 578 patients (64%) had left-sided and 329 (36%) right-sided primaries. Median OS for patients with a left-sided primary was 5.2xa0years (95% confidence interval [CI] 4.6–6.0) versus 3.6xa0years (95% CI 3.2–4.2) for right-sided (pxa0=xa00.004). On multivariable analysis, the hazard ratio for right-sided tumors was 1.22 (95% CI 1.02–1.45, pxa0=xa00.028) after adjusting for common clinicopathologic factors. Median RFS was marginally different stratified by primary location (1.3 vs. 1.7xa0years; pxa0=xa00.065). On multivariable analysis, location of primary was not significantly associated with RFS (pxa0=xa00.105). Observed cure rates were 22% for left-sided and 20% for right-sided tumors.ConclusionsAmong patients undergoing resection of CRLM, left-sided primary tumors were associated with improved median OS. However, long-term survival and recurrence-free survival were not significantly different stratified by primary location. Patients with left-sided primary tumors displayed a prolonged clinical course suggestive of more indolent biology.

Actual 10-year survival after hepatic resection of colorectal liver metastases: what factors preclude cure?

Background: Hepatic resection of colorectal liver metastases is associated with long‐term survival. This study analyzes actual 10‐year survivors after resection of colorectal liver metastases, reports the observed rate of cure, and identifies factors that preclude cure. Methods: A single‐institution, prospectively maintained database was queried for all initial resections for colorectal liver metastases for the years 1992–2004. Observed cure was defined as actual 10‐year survival with either no recurrence or resected recurrence with at least 3 years of disease‐free follow‐up. Clinical risk score was dichotomized into low (0–2) and high (3–5). Semiparametric proportional hazards mixture cure model was utilized to estimate probability of cure. Results: We included 1,211 patients with a median follow‐up for survivors of 11 years. Median disease‐specific survival was 4.9 years (95% CI: 4.4–5.3). 295 patients (24.4%) were actual 10‐year survivors. The observed cure rate was 20.6% (n = 250). Among 250 cured patients, 192 (76.8%) had no recurrence and 58 (23.2%) had a resected recurrence with at least 3 years of disease‐free follow‐up. Extrahepatic disease (n = 88), carcinoembryonic antigen >200 ng/mL (n = 119), positive margin (n = 109), and >10 tumors (n = 31) had observed cure rates less than 10%. In cure model analysis, patients with both extrahepatic disease and high clinical risk score (n = 31) had an estimated probability of cure of 3.5%. Conclusion: Actual 10‐year survival after resection of colorectal liver metastases is 24% with an observed 20% cure rate. Patients with both high clinical risk score and extrahepatic disease have an estimated probability of cure less than 5%. When such factors are identified, strong consideration may be given to preoperative strategies, such as neoadjuvant chemotherapy, to help select patients for surgical therapy.

Preoperative Risk Score to Predict Occult Metastatic or Locally Advanced Disease in Patients with Resectable Perihilar Cholangiocarcinoma on Imaging

BACKGROUNDnMany patients with resectable perihilar cholangiocarcinoma (PHC) on imaging are diagnosed intraoperatively with occult metastatic or locally advanced disease, precluding a curative-intent resection. This study aimed to develop and validate a preoperative risk score.nnnSTUDY DESIGNnPatients with resectable PHC on imaging who underwent operations in 2 high-volume centers (US and Europe) between 2000 and 2015 were included. Multivariable logistic regression analysis was used to develop the risk score. Cross-validation was used to validate the score, alternating the 2 centers as training and testing datasets.nnnRESULTSnOf 566 patients who underwent operations, 309 (55%) patients had a resection, and in 257 (45%) patients, a curative-intent resection was precluded due to distant metastasis (nxa0= 151 [27%]) or locally advanced disease (nxa0= 106 [19%]). Preoperative predictors included bilirubin >2 mg/dL, bile duct involvement on imaging, portal vein involvement on imaging (≥180 degrees), hepatic artery involvement on imaging (≥180 degrees), and suspicious lymph nodes on imaging. The new risk score (c-index 0.75 after cross-validation) provided significantly more accurate predictions than the Bismuth classification (c-index 0.62), Blumgart T-staging (c-index 0.67), and cTNM staging (c-index 0.68). The new risk score identified 4 risk groups for occult metastatic or locally advanced disease: low (14.7%), intermediate (29.5%), high (47.3%), and very high risk (81.3%). The preoperative score groups also predicted survival after operation, irrespective of intraoperative findings (pxa0<xa00.001).nnnCONCLUSIONSnThe validated risk score can predict occult distant metastatic or locally advanced PHC basedxa0on 5 preoperatively available factors. The score can be useful in preoperative shared decision making and selection of patients in neoadjuvant clinical trials.