CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Identifying Clinical Factors Which Predict for Early Failure Patterns Following Resection for Pancreatic Adenocarcinoma in Patients Who Received Adjuvant Chemotherapy Without Chemoradiation.

OBJECTIVES: The role of radiation therapy (RT) in resected pancreatic cancer (PC) remains incompletely defined. We sought to determine clinical variables which predict for local-regional recurrence (LRR) to help select patients for adjuvant RT. MATERIALS AND METHODS: We identified 73 patients with PC who underwent resection and adjuvant gemcitabine-based chemotherapy alone. We performed detailed radiologic analysis of first patterns of failure. LRR was defined as recurrence of PC within standard postoperative radiation volumes. Univariate analyses (UVA) were conducted using the Kaplan-Meier method and multivariate analyses (MVA) utilized the Cox proportional hazard ratio model. Factors significant on UVA were used for MVA. RESULTS: At median follow-up of 20 months, rates of local-regional recurrence only (LRRO) were 24.7%, LRR as a component of any failure 68.5%, metastatic recurrence (MR) as a component of any failure 65.8%, and overall disease recurrence (OR) 90.5%. On UVA, elevated postoperative CA 19-9 (>90 U/mL), pathologic lymph node positive (pLN+) disease, and higher tumor grade were associated with increased LRR, MR, and OR. On MVA, elevated postoperative CA 19-9 and pLN+ were associated with increased MR and OR. In addition, positive resection margin was associated with increased LRRO on both UVA and MVA. CONCLUSIONS: About 25% of patients with PC treated without adjuvant RT develop LRRO as initial failure. The only independent predictor of LRRO was positive margin, while elevated postoperative CA 19-9 and pLN+ were associated with predicting MR and overall survival. These data may help determine which patients benefit from intensification of local therapy with radiation.

Survival benefit of conversion surgery for patients with initially unresectable pancreatic cancer who responded favorably to nonsurgical treatment.

BACKGROUND: Conversion surgery (CS) is expected as a new therapeutic strategy for patients with unresectable pancreatic cancer (UR-PC). We analyzed outcomes of CS for patients with UR-PC and evaluated the survival benefit of CS. METHODS: Thirty-four patients diagnosed with UR-PC according to the National Comprehensive Cancer Network guideline underwent CS in our hospital. Resectability was considered by multimodal images in patients who underwent nonsurgical treatment (NST) for more than 6 months. CS was performed only in patients who were judged to be able to undergo R0 resection. RESULTS: Twenty-six patients had locally advanced PC, and eight had distant metastases. The median duration of NST was 9 (range 5-44) months. R0 resection was achieved in 30 patients (88.2%). Six patients (17.6%) showed Evans grade ≥III. Three- and 5-year overall survival (OS) rates from initial treatment were 74% and 56.9%, respectively, with median survival time (MST) of 5.3 years. The actual 5-year OS rate in 19 patients was 47.4% with an MST of 4.0 years. Patients with Evans grade ≥III had a better prognosis than those with Evans grade

What Are the Most Significant Cost and Value Drivers for Pancreatic Resection in an Integrated Healthcare System?

BACKGROUND: An initiative was established to improve value-based care for pancreatic surgery in a large nonprofit health system. Cost data were presented bimonthly to a hepatobiliary clinical performance group via videoconference. STUDY DESIGN: The direct costs were calculated for all patients undergoing distal pancreatectomy (DP) and pancreaticoduodenectomy (PD) between January 2014 and July 2017. Median length of stay, 30-day and 90-day mortality rates, readmission rate, and costs were stratified by surgeon volume using 2 published criteria: "volume pledge" criteria (≥5 PDs/year) and Leapfrog criteria (≥11 PDs/year). RESULTS: There were 270 DPs and 526 PDs performed in 14 hospitals spanning 4 states. Median PD costs were lower for high-volume surgeons (≥5 PDs/year), $21,026 vs $24,706 (p = 0.005). High-volume surgeons had a shorter length of stay (9 days vs 11 days; p < 0.001) for PD and DP (6 days vs 7 days; p = 0.001). Increased costs for low-volume surgeons included operative/anesthesia costs ($7,321 vs $6,325; p = 0.03), room and board ($5,828 vs $4,580; p = 0.01), and intensive care costs ($4,464 vs $3,113; p = 0.04). Operating time was increased for high-volume surgeons for DP and PD (p < 0.001). There was no difference in 30-day or 90-day mortality rates or readmissions for DP or PD when stratified by volume pledge criteria. There was no difference in total costs for DP or PD when stratified by Leapfrog criteria. CONCLUSIONS: There was a significant cost reduction for PD but not DP when the threshold of 5 PDs was used as a definition of high volume. The sharing of detailed financial data with HPB surgeons on a regular basis provides an opportunity to evaluate practice patterns and thereby reduce direct costs.

Evolution in the Treatment of Delayed Postpancreatectomy Hemorrhage: Surgery to Interventional Radiology.

OBJECTIVES: We summarized a single center's evolution in the management of postpancreatectomy hemorrhage (PPH) from surgical toward endovascular management. METHODS: Between 2003 and 2013, 337 patients underwent Whipple procedures. Using the International Study Group of Pancreatic Surgery (ISGPS) consensus definition, patients with PPH were identified and retrospectively analyzed for the presentation of hemorrhage, type of intervention, and 90-day mortality outcome measures. RESULTS: Management evolved from operative intervention alone, to combined operative and on-table angiographic intervention, to endovascular intervention alone. The prevalence of PPH was 3.0%. Delayed PPH occurred with a mean of 13.8 days. On angiography, visceral arteries affected were the gastroduodenal artery, hepatic artery, jejunal branches of the superior mesenteric artery, pancreaticoduodenal artery, and inferior phrenic artery. Ninety-day mortality for PPH was 20%. From early to recent experience, the mortality rate was 100% for operative intervention alone, 25% for combined operative and on-table angiographic intervention, and 0% for endovascular intervention alone. CONCLUSIONS: Our 10-year experience supports current algorithms in the management of PPH. Key considerations include the recognition of the sentinel bleed, the presence of a pancreatic fistula, and the initial operative role of a long gastroduodenal artery stump with radiopaque marker for safe and effective embolization should PPH occur.

Approach to patients with pancreatic cancer without detectable metastases.

The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis.

Impact of distal pancreatectomy on outcomes of peritoneal surface disease treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Left upper quadrant involvement by peritoneal surface disease (PSD) may require distal pancreatectomy (DP) to obtain complete cytoreduction. Herein, we study the impact of DP on outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: Analysis of a prospective database of 1,019 procedures was performed. Malignancy type, performance status, resection status, comorbidities, Clavien-graded morbidity, mortality, and overall survival were reviewed. RESULTS: DP was a component of 63 CRS/HIPEC procedures, of which 63.3 % had an appendiceal primary. While 30-day mortality between patients with and without DP was no different (2.6 vs. 3.2 %; p = 0.790), 30-day major morbidity was worse in patients receiving a DP (30.2 vs. 18.8 %; p = 0.031). Pancreatic leak rate was 20.6 %. Intensive care unit days and length of stay were longer in DP versus non-DP patients (4.6 vs. 3.5 days, p = 0.007; and 22 vs. 14 days, p < 0.001, respectively). Thirty-day readmission was similar for patients with and without DP (29.2 vs. 21.1 %; p = 0.205). Median survival for low-grade appendiceal cancer (LGA) patients requiring DP was 106.9 months versus 84.3 months when DP was not required (p = 0.864). All seven LGA patients undergoing complete cytoreduction inclusive of DP were alive at the conclusion of the study (median follow-up 11.8 years). CONCLUSIONS: CRS/HIPEC including DP is associated with a significant increase in postoperative morbidity but not mortality. Survival was similar for patients with LGA whether or not DP was performed. Thus, the need for a DP should not be considered a contraindication for CRS/HIPEC procedures in LGA patients when complete cytoreduction can be achieved.

Hepatic arterial infusion chemotherapy reduced hepatic metastases from pancreatic cancer after pancreatectomy.

BACKGROUND/AIMS: This study aims to investigate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) on liver metastases from pancreatic cancer after pancreatectomy. METHODOLOGY: We randomly assigned 106 patients with pancreatic cancer after pancreatectomy between 2005 and 2010 to receive 2 cycles of HAIC plus 4 cycles of systemic chemotherapy (Combined Therapy) or 6 cycles of systemic chemotherapy alone (Monotherapy). Both the HAIC and systemic chemotherapy regimen consisted of a 5-hour infusion of 5-fluorouracil 1000 mg/m2 on day 1 followed by gemcitabine 800 mg/m2 as an over 30-min infusion on day 1 and day 8. The treatment was started on an average of 21.2 days after surgery and repeated every 4 weeks. The disease-free survival, overall survival and liver metastases-free survival were compared. RESULTS: There was no significant difference in adverse effects between two groups. Significant differences were found in 3-year overall survival (Combined Therapy, 23.08 %; Monotherapy, 14.81%; P=0.0473) and liver metastases-free survival (Combined Therapy, 80.77%; Monotherapy, 55.56%; P=0.0014). CONCLUSIONS: HAIC effectively and safely prevents liver metastases and improves the prognosis of patients with pancreatic cancer after pancreatectomy.

Serum carbohydrate antigen 19-9 represents a marker of response to neoadjuvant therapy in patients with borderline resectable pancreatic cancer.

OBJECTIVES: The purpose of this study was to determine the relationship between carbohydrate antigen (CA) 19-9 levels and outcome in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy (NT). METHODS: This study included all patients with borderline resectable pancreatic cancer, a serum CA 19-9 level of ≥40 U/ml and bilirubin of ≤2 mg/dl, in whom NT was initiated at one institution between 2001 and 2010. The study evaluated the associations between pre- and post-NT CA 19-9, resection and overall survival. RESULTS: Among 141 eligible patients, CA 19-9 declined during NT in 116. Following NT, 84 of 141 (60%) patients underwent resection. For post-NT resection, the positive predictive value of a decline and the negative predictive value of an increase in CA 19-9 were 70% and 88%, respectively. The normalization of CA 19-9 (post-NT <40 U/ml) was associated with longer median overall survival among both non-resected (15 months versus 11 months; P = 0.022) and resected (38 months versus 26 months; P = 0.020) patients. Factors independently associated with shorter overall survival were no resection [hazard ratio (HR) 3.86, P < 0.001] and failure to normalize CA 19-9 (HR 2.13, P = 0.001). CONCLUSIONS: The serum CA 19-9 level represents a dynamic preoperative marker of tumour biology and response to NT, and provides prognostic information in both non-resected and resected patients with borderline resectable pancreatic cancer.

Clinical Significance of Adjuvant Surgical Resection for Initially Unresectable Pancreatic Cancer Responsive to Arterial Infusion Chemotherapy.

BACKGROUND/AIMS: We have reported a clinically meaningful local-control effect and a hepatic metastatic tumor-regression effect of transcatheter peripancreatic arterial embolization-hepatic and splenic arterial infusion chemotherapy (TPPAE-HSAIC) for unresectable advanced pancreatic cancer. The aim of this study was to evaluate the clinical significance, of adjuvant surgical resection after TPPAE-HSAIC. METHODOLOGY: We assessed histopathological findings and outcomes of 6 patients who underwent surgical resection of tumors judged to be radically resectable after attaining tumor down-staging or long-term tumor control following TPPAE-HSAIC for pancreatic cancer initially diagnosed as unresectable. RESULTS: Clinical stage at the initial diagnosis was T4N0M0 Stage III in 4 patients and T4N0M1 Stage IV in 2 patients. The durations of TPPAE-HSAIC ranged from 5 to 46 months with a median of 19 months. An R0 resection was performed in 5 of the 6 patients (83%) and pathological down-staging, from the viewpoint of clinical stage, was observed in 4 patients. Of the 5 patients with R0 resection, one died from a postoperative complication at 7 months and another from pulmonary metastasis at 30 months post-operatively, while the other 3 patients have survived for 45 to 83 months to date. CONCLUSIONS: If surgical resection of pancreatic cancer initially diagnosed as unresectable can be carried out in patients responding favorably to TPPAE-HSAIC, the likelihood of long-term survival might be increased.

Risk factors for hepatic steatosis after pancreatectomy: a retrospective observational cohort study of the importance of nutritional management.

OBJECTIVES: The occurrence of hepatic steatosis after pancreatectomy has been previously known. However, this condition has been neglected because its clinical course has been considered benign. The aims of this study were to identify the risk factors for hepatic steatosis after pancreatectomy, to clarify the impact of this condition on long-term prognosis, and to suggest methods for preventing hepatic steatosis. METHODS: One hundred two patients, who were diagnosed with postoperative computed tomography, were enrolled. The severity of hepatic steatosis was determined by using unenhanced computed tomography. The variables that might influence the development of hepatic steatosis were compared between the groups with and without hepatic steatosis. RESULTS: The incidence of postoperative hepatic steatosis was 31.4%. Multivariate analysis showed that absence of postoperative insulin use (P < 0.01) and decrease in postoperative body mass index of greater than 3 kg/m(2) (P < 0.01) were independent risk factors for hepatic steatosis. The cumulative recurrence-free survival rate of the group with hepatic steatosis was poorer than that of the group without (P = 0.053). CONCLUSIONS: Postoperative hepatic steatosis may affect long-term prognosis after pancreatectomy. Surgeons should take care of nutritional management including insulin therapy for patients with hepatic steatosis after pancreatectomy.

Quality improvement of pancreatic surgery by centralization in the western part of the Netherlands.

BACKGROUND: Centralization of pancreatic surgery in high-volume hospitals is under debate in many countries. In the western part of the Netherlands, the professional network of surgical oncologists agreed to centralize all pancreatic surgery from 2006 in two high-volume hospitals. Our aim is to evaluate whether centralization of pancreatic surgery has improved clinical outcomes and has changed referral patterns. MATERIALS AND METHODS: Data of the Comprehensive Cancer Centre West (CCCW) of all 249 patients who had a resection for suspected pancreatic cancer between 1996 and 2008 in the western part of the Netherlands were analyzed. Multivariable modeling was used to evaluate survival for 3 time periods; 1996-2000, 2001-2005 (introduction of quality standards), and 2006-2008 (after centralization). In addition, the differences in referral pattern were analyzed. RESULTS: From 2006, all pancreatic surgery was centralized in 2 hospitals. The 2-year survival rate increased after centralization from 39% to 55% (P =.09) for all patients who had a pancreatic resection for pancreatic cancer. After adjustment for age, tumor location, stage, histology, and adjuvant treatment, the latter period was significantly associated with improved survival (hazard ratio [HR] 0.50; 95% confidence interval [95% CI] 0.34-0.73). CONCLUSIONS: Centralization of pancreatic surgery was successful and has resulted in improved clinical outcomes in the western part of the Netherlands, demonstrating the effectiveness of centralization.

Pancreatic cancer: progress made.

Pancreatic cancer remains a deadly disease. Despite advances on many fronts, surgeons play a leading role in the diagnosis and management of pancreatic cancer. Preoperative staging is best provided by "pancreas-protocol" abdominal CT, although endoscopic ultrasound and diagnostic laparoscopy can add value in selected patients. Surgical resection, which remains the only curative option, is now accomplished with uniformly low perioperative mortality in high-volume centers (<3%), although complications remain frequent. Unfortunately, the long-term prognosis for pancreatic cancer remains poor with 5-year survival rates only 15-23% with median survival of 13 to 18 months. Recent data from randomized trials have supported the role for adjuvant chemotherapy and questioned the traditional role of radiation. Early diagnosis and targeted multimodality treatments would appear essential to optimizing the results of surgical therapy.

Factors influencing survival after total pancreatectomy in patients with pancreatic cancer.

A retrospective analysis of factors influencing short-term and long-term survival after total pancreatectomy for pancreatic cancer was done in 86 patients. Among the 41 factors studied, hospital mortality was significantly affected by age over 70 years, preoperative diabetes, pain as presenting symptom, S-bilirubin, preoperative bile drainage, prophylactic antibiotic treatment, stage of the tumor, and experience of the surgeon. The only factors which had a statistically significant influence on long-term survival were stage of the tumor and sex of the patient. It is concluded that improvement of long-term survival can mainly be achieved by earlier identification and removal of the tumors and by introduction of more efficient adjuvant therapy. Whereas these goals probably will require a long time to be reached, the majority of factors associated with worsening of hospital mortality may be avoided by a strict selection of the patient, the tumor and the surgeon.