Does adjuvant radiation provide any survival benefit after an R1 resections for pancreatic cancer?

BACKGROUND: The benefit of adding external beam radiation to adjuvant chemotherapy in patients that have undergone a margin positive resection for early stage, pancreatic ductal adenocarcinoma has not been determined definitively. METHODS: The National Cancer Data Base was queried to evaluate the utility of adjuvant radiation in patients with pathologic stage I-II pancreatic ductal adenocarcinoma who underwent upfront pancreatoduodenectomy with a positive margin (margin positive resection) between 2004 and 2013. RESULTS: In the study, 1,392 patients met inclusion criteria, of whom 263 (18.9%) were lymph node-negative (pathologic stages IA, IB, IIA) and 1,129 (81.1%) were node-positive (pathologic stage IIB); 938 (67.4%) patients received adjuvant radiation and chemotherapy, while 454 (32.6%) received adjuvant chemotherapy alone. Cox modeling stratified by nodal status demonstrated the benefit of radiation to be statistically significant only in node positive patients (hazard ratio 0.81, 95% confidence interval, 0.71-0.93). Node-positive patients receiving adjuvant radiation and chemotherapy had an adjusted median survival of 17.5 months vs 15.2 months for those receiving adjuvant chemotherapy alone (P=.003). In patients who had negative nodes, there was no difference in overall survival with radiation (22.5 vs 23.6 months, P=.511). CONCLUSION: Addition of radiation to adjuvant chemotherapy after a margin positive resection confers a survival benefit albeit limited (about 2 months) in patients with node-positive pancreatic head cancer. (Surgery 2017;160:XXX-XXX.).

Time to Initiation of Adjuvant Chemotherapy in Pancreas Cancer: A Multi-Institutional Experience.

BACKGROUND: Despite randomized trials addressing adjuvant therapy (AT) for pancreas cancer, the ideal time to initiate therapy remains undefined. Retrospective analyses of the ESPAC-3 trial demonstrated that time to initiation of AT did not impact overall survival (OS). Given the absence of confirmatory data outside of a clinical trial, we sought to determine if AT timing in routine clinical practice is associated with OS differences. METHODS: Perioperative data of pancreatectomies for ductal adenocarcinoma from five institutions (2005-2015) were assessed. Delay in AT was defined as initiation >12 weeks after surgery. Multivariate analysis was performed to identify predictors of mortality. RESULTS: Of 867 patients, 172 (19.8%) experienced omission of AT. Improved OS was observed in patients who received AT compared with patients who did not (24.8 vs. 19.1 months, p < 0.01). Information on time to initiation of AT was available in 488 patients, of whom 407 (83.4%) and 81 (16.6%) received chemotherapy ≤12 and >12 weeks after surgery, respectively. There were no differences in recurrence-free survival or OS (all p > 0.05) between the timely and delayed AT groups. After controlling for perioperative characteristics and tumor pathology, patients who initiated AT ≤ 12 or > 12 weeks after surgery had a 50% lower odds of mortality than patients who only underwent resection (p < 0.01). CONCLUSIONS: In a multi-institutional experience of resected pancreas cancer, delayed initiation of AT was not associated with poorer survival. Patients who do not receive AT within 12 weeks after surgery are still appropriate candidates for multimodal therapy and its associated survival benefit.

Neoadjuvant external beam radiation is associated with No benefit in overall survival for early stage pancreatic cancer.

OBJECTIVE: Neoadjuvant protocols for early stage pancreatic adenocarcinoma (PDAC) frequently involve external beam radiation used in combination with systemic chemotherapy. The benefit of radiation in these protocols has not been determined. METHODS: We examined patients with stage I and II PDAC within the National Cancer Data Base between 2006 and 2012. Propensity score matching was used to compare patients receiving neoadjuvant chemotherapy including radiation (NCRT) to those receiving neoadjuvant chemotherapy without radiation (NCT) prior to pancreaticoduodenectomy. RESULTS: Prior to matching, NCRT patients had higher rates of T3 tumors (P = 0.046) and vascular abutment (P < 0.001). Propensity score matching (1:1) yielded 397 patients per group. Patients treated with NCRT were more likely to have node negative resections (P < 0.001) but had increased rates of 90-day mortality (P = 0.015) and demonstrated a trend towards shorter overall survival (P = 0.0502) than those receiving NCT. CONCLUSION: In early stage PDAC, the addition of radiation to NCT is often utilized with more advanced disease and is associated with higher perioperative mortality and no long-term overall survival benefit.

A semi-automated assessment of sarcopenia using psoas area and density predicts outcomes after pancreaticoduodenectomy for pancreatic malignancy.

BACKGROUND: Sarcopenia has been associated with increased adverse outcomes after major abdominal surgery. Sarcopenia defined as decreased muscle volume or increased fatty infiltration may be a proxy for frailty. In conjunction with other preoperative clinical risk factors, radiographic measures of sarcopenia using both muscle size and density may enhance prediction of outcomes after pancreaticoduodenectomy (PD) for malignancy. METHODS: Preoperative computed tomography (CT) scans of patients undergoing PD for malignancy were analyzed from a prospective pancreatic surgery database. Sarcopenia was assessed both manually and with a semi-automated technique by measuring the total psoas area index (TPAI) and average Hounsfield units (HU) at the L3 lumbar level to estimate psoas muscle volume and density, respectively. Adjusting for known pre-operative risk factors, preoperative sarcopenia measurements were analyzed relative to perioperative outcomes. RESULTS: Sarcopenia assessments of 116 subjects demonstrated good correlation between the semi-automated and the manual techniques (P<0.0001). Lower TPAI (OR 0.34, P=0.009) and HU (OR 0.84, P=0.002) measurements were predictive of discharge to skilled nursing facility (SNF), but not major complications, length of stay, readmissions or recurrence on univariate analysis. Lower TPAI was protective against the risk of organ/space surgical site infection (SSI) including pancreatic fistula (OR 3.12, P=0.019). On multivariate analysis, the semi-automated measurements of TPAI and HU remained as independent predictors of organ/space SSI including pancreatic fistula (OR 4.23, P=0.014) and discharge to SNF (OR 0.79, P=0.019) respectively. CONCLUSIONS: When combined with preoperative clinical assessments in patients with pancreatic malignancy, semi-automated sarcopenia metrics are a simple, reproducible method that may enhance prediction of outcomes after PD and help guide clinical management.

A Multi-institutional Comparison of Perioperative Outcomes of Robotic and Open Pancreaticoduodenectomy.

OBJECTIVES: Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD). METHODS: Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011-1/2015) were assessed. Univariate analyses of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes. RESULTS: Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (<3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5-133.3, P = 0.01], reduced blood loss (mean difference = -181 mL, 95% CI -355-(-7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47-0.85, P = 0.003). No associations were demonstrated between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (<12 lymph nodes harvested). CONCLUSIONS: Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed.

Perioperative chemotherapy is associated with a survival advantage in early stage adenocarcinoma of the pancreatic head.

BACKGROUND: The value of neoadjuvant chemotherapy in the treatment of early stage pancreatic cancer is not yet clear. METHODS: We evaluated patients from the National Cancer Data Base who underwent pancreaticoduodenectomy for clinical stage I and II pancreatic adenocarcinoma between 2006 and 2012. RESULTS: In total, 7,881 patients were identified. Of these, 27.5% received no chemotherapy, 57.4% received adjuvant chemotherapy, 10.2% received neoadjuvant chemotherapy alone, and 4.9% received perioperative chemotherapy, both preoperative and postoperative chemotherapy. Neoadjuvant chemotherapy use (neoadjuvant chemotherapy alone and perioperative chemotherapy) increased from 12.0% in 2006 to 20.2% in 2012. Patients who received chemotherapy prior to the operation (neoadjuvant chemotherapy alone and perioperative chemotherapy) had greater rates of margin negative (80.2% vs 73.0%, P < .001) and node negative (58.2% vs 28.7%, P < .001) resections and shorter mean durations of stay (12.0 vs 11.1 days, P = .012) than those receiving either adjuvant chemotherapy or no chemotherapy at all. There were no differences in 30-day unplanned readmissions (P = .074) and 90-day mortality (P = .227). On Cox survival analysis, adjusted for clinical variables including age and comorbid disease, patients undergoing perioperative chemotherapy, adjuvant chemotherapy, and neoadjuvant chemotherapy alone demonstrated significantly improved overall survival relative to that of patients undergoing resection alone (all P < .001). Patients receiving perioperative chemotherapy demonstrated a significant overall survival advantage compared with those receiving adjuvant chemotherapy (hazard ratio 0.75; 95% confidence interval, 0.65-0.85). Neoadjuvant chemotherapy alone had a marginal overall survival benefit compared with adjuvant chemotherapy (hazard ratio 0.89; 95% confidence interval, 0.81-0.98). CONCLUSION: Early stage pancreatic cancer patients who receive perioperative chemotherapy have better overall survival than those receiving no chemotherapy, adjuvant chemotherapy, or neoadjuvant chemotherapy alone. Patterns of postoperative morbidity are similar regardless of the sequence of therapy. Neoadjuvant chemotherapy should be considered for patients presenting with early stage pancreatic cancer.

A Graded Evaluation of Outcomes Following Pancreaticoduodenectomy with Major Vascular Resection in Pancreatic Cancer.

Previous studies examining short- and long-term outcomes of pancreaticoduodenectomy with vascular resection for pancreatic adenocarcinoma have not graded perioperative complication severity. These studies may provide incomplete assessments of the efficacy of vascular resection. In the current study, we evaluated 36 patients who had pancreaticoduodenectomy with major vascular resection. These were matched 1:3 by tumor stage and age to patients who had pancreaticoduodenectomy without vascular resection. Charts were reviewed to identify all complications and 90-day readmissions. Complications were graded as either severe or minor adverse postoperative outcomes, taking into account the total length of stay. There were no statistical differences in patient demographics, comorbidities, or symptoms between the groups. Patients who had vascular resection had significantly increased rates of severe adverse postoperative outcomes, readmissions, lengths of hospital stay, as well as higher hospital costs. Hypoalbuminemia and major vascular resection were independent predictors of severe adverse postoperative outcomes. On multivariate Cox-regression survival analysis, patients who had vascular resection had decreased recurrence-free (12 vs. 17 months) and overall (17 vs. 29 months) survival. Major vascular resection was a predictor of mortality, may be an independent prognostic factor for survival, and may warrant incorporation into future staging systems.

Early National Experience with Laparoscopic Pancreaticoduodenectomy for Ductal Adenocarcinoma: A Comparison of Laparoscopic Pancreaticoduodenectomy and Open Pancreaticoduodenectomy from the National Cancer Data Base.

BACKGROUND: There is considerable debate about the safety and clinical equivalence of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDCA). STUDY DESIGN: We queried the National Cancer Data Base to identify patients undergoing LPD and OPD for PDCA between 2010 and 2011. Chi-square and Student's t-tests were used to evaluate differences between the 2 approaches. Multivariable logistic regression modeling was performed to identify patient, tumor, or facility factors associated with perioperative mortality. RESULTS: Four thousand and thirty-seven (91%) patients underwent OPD. Three hundred and eighty-four (9%) patients underwent LPD. There were no statistical differences between the 2 surgical cohorts with regard to age, race, Charlson score, tumor size, grade, stage, or treatment with neoadjuvant chemoradiotherapy. Laparoscopic pancreaticoduodenectomy demonstrated a shorter length of stay (10 ± 8 days vs 12 ± 9.7 days; p < 0.0001) and lower rates of unplanned readmission (5% vs 9%; p = 0.027) than OPD. In an unadjusted comparison, there was no difference in 30-day mortality between the LPD and OPD cohorts (5.2% vs 3.7%; p = 0.163). Multivariable logistic regression modeling predicting perioperative mortality controlling for age, Charlson score, tumor size, nodal positivity, stage, facility type, and pancreaticoduodenectomy volume identified age (odds ratio [OR] = 1.05; p < 0.0001), positive margins (OR = 1.45; p = 0.030), and LPD (OR = 1.89; p = 0.009) as associated with an increased probability of 30-day mortality; higher hospital volume was associated with a lower risk of 30-day mortality (OR = 0.98; p < 0.0001). In institutions that performed ≥10 LPDs, the 30-day mortality rate of the laparoscopic approach was equal to that for the open approach (0.0% vs 0.7%; p = 1.00). CONCLUSIONS: Laparoscopic pancreaticoduodenectomy is equivalent to OPD in length of stay, margin-positive resection, lymph node count, and readmission rate. There is a higher 30-day mortality rate with LPD, but this appears driven by a surmountable learning curve for the procedure.

The laparoscopic approach to distal pancreatectomy for ductal adenocarcinoma results in shorter lengths of stay without compromising oncologic outcomes.

BACKGROUND: The oncologic equivalence of laparoscopic distal pancreatectomy (LDP) to open pancreatectomy (ODP) for ductal adenocarcinoma (DAC) is not established. METHODS: The National Cancer Data Base was used to compare perioperative outcomes following LDP and ODP for DAC between 2010 and 2011. RESULTS: One hundred forty-five patients underwent LDP; 625 underwent ODP. Compared with ODP, patients undergoing LDP were older (68 ± 10.1 vs 66 ± 10.5 years, P = .027), more likely treated in academic centers (70% vs 59%, P = .01), and had shorter hospital stays (6.8 ± 4.6 vs 8.9 ± 7.5 days, P < .001). Demographic data, lymph node count, 30-day unplanned readmission, and 30-day mortality were identical between groups. Multivariable regression identified a lower probability of prolonged length of stay with LDP (odds ratio .51, 95% confidence interval .327 to .785, P = .0023). There was no association between surgical approach and node count, readmission, or mortality. CONCLUSION: LDP for DAC provides shorter postoperative lengths of stay and rates of readmission and 30-day mortality similar to OPD without compromising perioperative oncologic outcomes.

Comparison of tumor markers for predicting outcomes after resection of nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: This study compares the predictability of 5 tumor markers for distant metastasis and mortality in pancreatic neuroendocrine tumors (PNETs). METHODS: A total of 128 patients who underwent pancreatectomy for nonfunctioning PNETs between 1998 and 2011 were evaluated. Tumor specimens were stained via immunochemistry for cytoplasmic and nuclear survivin, cytokeratin 19 (CK19), c-KIT, and Ki67. Univariate and multivariate regression analyses and receiver operating characteristics curve were used to evaluate the predictive value of these markers. RESULTS: A total of 116 tumors (91%) were positive for cytoplasmic survivin, 95 (74%) for nuclear survivin, 85 (66.4%) for CK19, 3 for c-KIT, and 41 (32%) for Ki67 >3%. Twelve (9%) tumors expressed none of the markers. Survivin, CK19, and c-KIT had no substantial effect on distant metastasis or mortality. Age >55 years, grade 3 histology, distant metastasis, and Ki67 >3% were associated with mortality (P < .05). A cut-off of Ki67 >3% was the best predictor (83%) of mortality with an area under the curve of 0.85. Ki67 >3% also predicted occurrence of distant metastases with odds ratio of 9.22 and 95% confidence interval of 1.55-54.55 (P < .015). CONCLUSION: Of the 5 markers studied, only Ki67 >3% was greatly associated with distant metastasis and death. Survivin, CK19, and c-KIT had no prognostic value in nonfunctioning PNETs.

Using a modification of the Clavien-Dindo system accounting for readmissions and multiple interventions: defining quality for pancreaticoduodenectomy.

BACKGROUND: The Clavien-Dindo system (CD) does not change the grade assigned a complication when multiple readmissions or interventions are required to manage a complication. We apply a modification of CD accounting for readmissions and interventions to pancreaticoduodenectomy (PD). METHODS: PDs done between 1999 and 2009 were reviewed. CD grade IIIa complications requiring more than one intervention and II and IIIa complications requiring significantly prolonged lengths of stay including all 90-day readmissions were classified severe-adverse-postoperative-outcomes (SAPO). CD IIIb, IV, and V complications were also classified SAPOs. All other complications were considered minor-adverse-postoperative-outcomes (MAPO). RESULTS: Four-hundred forty three of 490 PD patients (90.4%) had either no complication or a complication of low to moderate CD grade (I, II, IIIa). When reclassified by the new metric, 92 patient-outcomes (19%) were upgraded from CD II or IIIa to SAPO. One-hundred thirty nine patients (28.4%) had a SAPO. Multivariable regression identified age >75 years, pylorus preservation and operative blood loss >1,500 ml as predictors of SAPO. Age was not associated with poor outcome using the unmodified CD system. CONCLUSIONS: Established systems may under-grade the severity of some complications following PD. We define a procedure-specific modification of CD accounting for readmissions and multiple interventions. Using this modification, advanced age, pylorus preservation, and significant blood loss are associated with poor outcome.

CA 19-9 nonproduction is associated with poor survival after resection of pancreatic adenocarcinoma.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is the most common serum biomarker used in pancreatic adenocarcinoma (PC). Elevated preoperative levels have been shown to correlate with more advanced stage, greater risk of unresectability, and overall worse survival. The prognostic value of CA 19-9 nonproduction, which is present in an estimated 5% to 15% of the population, is unclear. We sought to determine whether CA 19-9 nonproduction was associated with worse survival after PC resection. METHODS: We retrospectively reviewed our institution's prospective pancreatic database for all PC patients with documented preoperative CA 19-9 values who underwent resection with curative intent from March 1992 to August 2009. After excluding 10 perioperative deaths, 200 patients remained for analysis. RESULTS: Mean and median follow-up was 23.3 and 16.1 months, respectively. Median survival in months for patients with preoperative CA 19-9 levels in U/mL by category was as follows: normal (5.1 to 36.9): 32, nonproduction (≤ 5): 21, mildly elevated (37 to 99.9): 35, highly elevated (100+): 16. Factors significantly associated with worse overall survival were: nonwhite race, nonproduction or highly elevated preoperative CA 19-9 (≥ 100 U/mL), estimated blood loss ≥ 1 L, tumor size (≥ 2 cm), lymph node-positivity, and advanced (3/4) histologic grade. On multivariate analysis, only CA 19-9 nonproduction or highly elevated production, estimated blood loss ≥ 1 L, advanced histologic grade, and node positivity remained significant in the final model. CONCLUSIONS: CA 19-9 nonproduction is not associated with improved survival after pancreatic cancer resection, as has previously been asserted, when compared with patients with normal and elevated levels.

Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors.

PURPOSE: The biologic potential of nonfunctioning pancreatic neuroendocrine tumors (PNETs) is highly variable and difficult to predict before resection. This study was conducted to identify clinical and pathologic factors associated with malignant behavior and death in patients diagnosed with PNETs. METHODS: We used International Classification of Diseases 9th edition codes to identify patients who underwent pancreatectomy for PNETs from 1998 to 2011 in the databases of 4 institutions. Functioning PNETs were excluded. Multivariate regression Cox proportional models were constructed to identify clinical and pathologic factors associated with distant metastasis and survival. RESULTS: The study included 128 patients-57 females and 71 males. The age (mean ± standard deviation) was 55 ± 14 years. The body mass index was 28 ± 5 kg/m(2). Eighty-nine (70%) patients presented with symptoms, and 39 (30%) had tumors discovered incidentally. The tumor size was 3.3 ± 2 cm with 56 (44%) of the tumors measuring ≤2 cm. Seventy-three (57%) patients had grade 1 histology tumors, 37 (29%) had grade 2, and 18 (14%) had grade 3. Peripancreatic lymph node involvement was present in 31 patients (24%), absent in 75 (59%), and unknown in 22 (17%). Distant metastasis occurred in 18 patients (14%). There were 12 deaths, including 1 perioperative, 8 disease related, and 3 of unknown cause. With a median follow-up of 33 months, the overall 5-year survival was 75%. Multivariate Cox regression analysis identified age >55 (hazard ratio [HR], 5.89; 95% confidence interval [CI], 1.64-20.58), grade 3 histology (HR, 6.08; 95% CI, 1.32-30.2), and distant metastasis (HR, 8.79; 95% CI, 2.67-28.9) as risk factors associated with death (P < .05). Gender, race, body mass index, clinical symptoms, lymphovascular and perineural invasion, and tumor size were not related to metastasis or survival (P > .05). Three patients with tumors ≤2 cm developed distant metastasis resulting in 2 disease-related deaths. CONCLUSION: Age >55 years, grade 3 histology, and distant metastasis predict a greater risk of death from nonfunctioning PNETs. Resection or short-term surveillance should be considered regardless of tumor size.