Opioid-Free Discharge After Pancreatic Resection Through a Learning Health System Paradigm.

Importance: Postoperative opioid overprescribing leads to persistent opioid use and excess pills at risk for misuse and diversion. A learning health system paradigm using risk-stratified pancreatectomy clinical pathways (RSPCPs) may lead to reduction in inpatient and discharge opioid volume. Objective: To analyze the outcomes of 2 iterative RSPCP updates on inpatient and discharge opioid volumes. Design, Setting, and Participants: This cohort study included 832 consecutive adult patients at an urban comprehensive cancer center who underwent pancreatic resection between October 2016 and April 2022, comprising 3 sequential pathway cohorts (version [V] 1, October 1, 2016, to January 31, 2019 [n = 363]; V2, February 1, 2019, to October 31, 2020 [n = 229]; V3, November 1, 2020, to April 30, 2022 [n = 240]). Exposures: After V1 of the pathway established a baseline and reduced length of stay (n = 363), V2 (n = 229) updated patient and surgeon education handouts, limited intravenous opioids, suggested a 3-drug (acetaminophen, celecoxib, methocarbamol) nonopioid bundle, and implemented the 5×-multiplier (last 24-hour oral morphine equivalents [OME] multiplied by 5) to calculate discharge volume. Pathway version 3 (n = 240) required the nonopioid bundle as default in the recovery room and scheduled conversion to oral medications on postoperative day 1. Main Outcomes and Measures: Inpatient and discharge opioid volume in OME across the 3 RSPCPs were compared using nonparametric testing and trend analyses. Results: A total of 832 consecutive patients (median [IQR] age, 65 [56-72] years; 410 female [49.3%] and 422 male [50.7%]) underwent 541 pancreatoduodenectomies, 285 distal pancreatectomies, and 6 other pancreatectomies. Early nonopioid bundle administration increased from V1 (acetaminophen, 320 patients [88.2%]; celecoxib or anti-inflammatory, 98 patients [27.0%]; methocarbamol, 267 patients [73.6%]) to V3 (236 patients [98.3%], 163 patients [67.9%], and 238 patients [99.2%], respectively; P < .001). Total inpatient OME decreased from a median 290 mg (IQR, 157-468 mg) in V1 to 184 mg (IQR, 103-311 mg) in V2 to 129 mg (IQR, 75-206 mg) in V3 (P < .001). Discharge OME decreased from a median 150 mg (IQR, 100-225 mg) in V1 to 25 mg (IQR, 0-100 mg) in V2 to 0 mg (IQR, 0-50 mg) in V3 (P < .001). The percentage of patients discharged opioid free increased from 7.2% (26 of 363) in V1 to 52.5% (126 of 240) in V3 (P < .001), with 187 of 240 (77.9%) in V3 discharged with 50 mg OME or less. Median pain scores remained 3 or lower in all cohorts, with no differences in postdischarge refill requests. A subgroup analysis separating open and minimally invasive surgical cases showed similar results in both groups. Conclusions and Relevance: In this cohort study, the median total inpatient OME was halved and median discharge OME reduced to zero in association with a learning health system model of iterative opioid reduction that is freely adaptable by other hospitals. These findings suggest that opioid-free discharge after pancreatectomy and other major cancer operations is realistic and feasible with this no-cost blueprint.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

BACKGROUND: Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. PATIENTS AND METHODS: From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥ 15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. RESULTS: Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p < 0.05). SAS (HR 0.79; CI 0.76-0.81; p < 0.001) and GRT (HR 0.67; CI 0.65-0.69; p < 0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2 years vs 1.1 years; p < 0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p < 0.001). CONCLUSIONS: Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Baseline CT-based Radiomic Features Aid Prediction of Nodal Positivity after Neoadjuvant Therapy in Pancreatic Cancer.

Purpose To study the association between CT-derived textural features of pancreatic cancer and patient outcome. Materials and Methods This retrospective study evaluated 54 patients (median age, 62 years [range, 40-88 years]; 32 men) with pancreatic cancer who underwent chemoradiation followed by surgical resection and lymph node dissection from May 2012 to June 2016. Three-dimensional segmentation of the pancreatic tumor was performed on baseline dual-energy CT images: 70-keV pancreatic parenchymal phase (PPP) images and iodine material density images. Then, 15 and 19 radiomic features were extracted from each phase, respectively. Logistic regression with elastic net regularization was used to select textural features associated with outcome, and receiver operating characteristic analysis evaluated feature performance. Survival curves were generated using the Kaplan-Meier method. Results The feature of integral total (∫ T), representing the mean intensity in Hounsfield units times the contour volume in milliliters of PPP imaging (hereafter, "∫ T (HU·mL) (PPP)"), is inversely associated with posttherapy pathologic lymph node (ypN) category. A threshold ∫ T (HU·mL) (PPP) less than 507.85 predicted ypN1-2 classification with 96% sensitivity, 34% specificity, and area under the curve of 0.61. Patients with an ∫ T (HU·mL) (PPP) of less than 507.85 had decreased overall survival (median, 2.8 years) compared with patients with an ∫ T (HU·mL) (PPP) of 507.85 or greater (one event at 3.4 years) (P = .006). Patients with an ∫ T (HU·mL) (PPP) of less than 507.85 had decreased progression-free survival (median, 1.5 years) compared with patients with an ∫ T (HU·mL) (PPP) of 507.85 or greater (median, 2.7 years) (P = .001). Conclusion A CT-based radiomic signature may help predict ypN category in patients with pancreatic cancer. Keywords: CT-Dual Energy, Abdomen/GI, Pancreas, Tumor Response, Outcomes Analysis © RSNA, 2022 Supplemental material is available for this article.

Frequency of Sarcopenia, Sarcopenic Obesity, and Changes in Physical Function in Surgical Oncology Patients Referred for Prehabilitation.

PURPOSE: Sarcopenia and suboptimal performance status are associated with postoperative complications and morbidity in cancer patients. Prehabilitation has emerged as an approach to improve fitness and muscle strength in patients preoperatively. We sought to describe the frequency of sarcopenia and sarcopenic obesity (SO) in a cohort of cancer patients referred for prehabilitation and the association between body composition and physical function. METHODS: In this retrospective review of 99 consecutive cancer patients referred for prehabilitation prior to intended oncologic surgery, prehabilitation included physical medicine and rehabilitation (PM&R) physician evaluation of function and physical therapy for individualized home-based exercise. Sarcopenic A was defined using sex-adjusted norms of skeletal muscle (SKM), measured using the sliceOmatic software (TomoVision, 2012) on computed tomography images at baseline. Sarcopenic B was defined by abnormal SKM and physical function. SO was defined as sarcopenia with BMI ≥ 25. Six-minute walk test (6MWT), 5 times sit-to-stand (5×STS), and grip strength were obtained at consultation (baseline) and at preoperative follow-up (if available). RESULTS: Forty-nine patients (49%) were Sarcopenic A, 28 (28%) SO, and 38 (38%) Sarcopenic B. Age was negatively correlated with SKM (P = .0436). There were no significant associations between Sarcopenic A/B or SO with baseline or changes in physical function. Assessed by sex, Sarcopenic A females had low 5×STS (P = .04) and Sarcopenic B females had low GS (P = .037). Sarcopenic B males had low preoperative GS (P = .026). 6MWT and grip strength at baseline were lower than age- and sex-related norms (both P < .001). Preoperatively, 6MWT distance and 5×STS time improved (both P < .001). Functional improvement in the sarcopenic and nonsarcopenic patients did not differ according to sex. CONCLUSIONS: In this cohort of prehabilitation surgical oncology patients, frequencies of sarcopenia and SO were high, and baseline physical function was abnormal but improved significantly regardless of body composition. These findings suggest that patients have considerable prehabilitation needs and are capable of improving with comprehensive care.

The Role of Home-Based Exercise in Maintaining Skeletal Muscle During Preoperative Pancreatic Cancer Treatment.

Loss of skeletal muscle and inferior muscle quality are associated with poor prognosis in patients undergoing preoperative treatment for pancreatic cancer, so maintaining skeletal muscle health before surgery may help accelerate patients' functional recovery and improve their quality of life following surgery. While exercise helps maintain or increase skeletal muscle in individuals undergoing cancer treatment, its efficacy during pancreatic cancer treatment is unclear. Accordingly, in this study we compared changes in skeletal muscle quantity (skeletal muscle index [SMI]) and quality (skeletal muscle density [SMD]) during preoperative pancreatic cancer treatment in participants in a home-based exercise program (EP) and a historical cohort of patients who received the usual care (UC) with no formal exercise programming. Recommendations for the EP cohort included both aerobic and resistance exercise. We assessed changes in SMI and SMD using computed tomography scans administered at treatment planning (T0, prior to EP enrollment) and preoperative restaging (T1) for 33 EP and 64 UC patients and compared changes between groups. The UC patients had statistically significant SMI decreases from T0 to T1 (-1.4 ± 3.8 cm2/m2; p = .005), while the EP patients did not (0.2 ± 3.2 cm2/m2; p = .7). The SMI loss was significantly worse for the UC than for the EP patients (p = .03). Neither group demonstrated statistically significant changes in SMD from T0 to T1, nor did the groups differ in the amount of change in SMD. An adjusted linear regression model demonstrated that EP participation was significantly associated with better SMI maintenance (p = .02). These results suggest that participation in a home-based EP during preoperative treatment may help improve skeletal muscle health and clinical and quality of life outcomes for pancreatic cancer survivors.

Clinical Trials of Systemic Chemotherapy for Resectable Pancreatic Cancer: A Review.

Importance: Adjuvant chemotherapy is the standard of care for resected pancreatic ductal adenocarcinoma (PDAC) based on level 1 evidence, but some studies suggest that a neoadjuvant approach (which is standard for borderline resectable PDAC) may be preferable for upfront resectable PDAC. An in-depth review was conducted of all randomized clinical trials that investigated neoadjuvant and adjuvant treatment of patients with resectable or resected PDAC, focusing on trial design, characteristics of enrolled population, and long-term outcomes. Observations: The existing resectable PDAC trials have good internal validity but variable applicability because of their restrictive eligibility criteria. In these trials, overall survival is the criterion standard end point, but disease-free survival is more feasible, proximate, and specific to the assigned intervention (at the cost of subjective outcome assessment) and thus an acceptable end point in certain contexts. The prolonged survival in the PRODIGE 24 trial highlights both the success of mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the importance of patient selection. Neoadjuvant and perioperative trials have shown promising preliminary results; however, the number of patients who are not subsequently eligible for surgery reflects the limitations of this approach. Head-to-head comparisons of neoadjuvant and adjuvant treatments are limited to date in Western countries. Precision oncology with genomic and somatic testing for actionable mutations has promising preliminary results and may refine the management of PDAC, although the implications for early-stage disease and neoadjuvant therapy are unknown. Conclusions and Relevance: This review found that adjuvant chemotherapy with mFOLFIRINOX is currently the standard of care in fit patients with resected PDAC; however, the role of neoadjuvant treatment is expanding. Precision oncology may help individualize the treatment regimen and sequence and improve outcomes. Enrollment of patients with resectable PDAC in clinical trials is strongly encouraged.

Cancer Surgery Scheduling During and After the COVID-19 First Wave: The MD Anderson Cancer Center Experience.

OBJECTIVE: To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. SUMMARY OF BACKGROUND DATA: The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. METHODS: The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. RESULTS: We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. CONCLUSIONS: Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

Educating surgical oncology providers on perioperative opioid use: A departmental survey 1 year after the intervention.

BACKGROUND AND OBJECTIVES: A department-wide opioid reduction education program resulted in a 1-month change in perceptions of opioid needs and prescribing recommendations for surgical oncology patients. This study's aim was to re-evaluate if early trends were retained 1 year later. METHODS: Surgical Oncology attendings, fellows, and advanced practice providers at a Comprehensive Cancer Center were surveyed 1-year after an August 2018 opioid reduction education program, to compare departmental and individual opioid prescribing habits. RESULTS: The September 2019 response rate was 54/93 (58%), with 41 completing both the post-education and 1-year follow-up surveys. The departmental and matched cohort continued to recommend a lower quantity of discharge opioids for all five index operations (by >50%) and expected less postoperative days to zero opioid needs, when compared to pre-education perceptions. Providers continued to agree that discharge opioid prescriptions should be based on a patient's last 24 hours of inpatient opioid use. There was universal agreement that each respondent's opioid administration had decreased in the past year. CONCLUSIONS: The initial 1-month improvements in perioperative opioid prescribing perceptions were retained 1 year later by Surgical Oncology providers who recommended fewer discharge opioids, faster weaning to zero opioids, and standardized patient-specific discharge opioid volume calculations.

Home-Based Exercise Prehabilitation During Preoperative Treatment for Pancreatic Cancer Is Associated With Improvement in Physical Function and Quality of Life.

Purpose: To investigate relationships among physical activity, changes in physical function, and health-related quality of life (HRQOL) among patients with pancreatic adenocarcinoma enrolled in a home-based exercise prehabilitation program. Methods: Patients with resectable pancreatic adenocarcinoma receiving preoperative chemotherapy and/or chemoradiation were enrolled on this prospective, single-arm trial and were advised to perform ≥60 minutes each of moderate-intensity aerobic exercise and strengthening exercise weekly. Activity was measured via self-report and accelerometers, including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary activity (SA). Physical function measures at baseline and restaging follow-up included 6-minute walk test (6MWT), 5 times sit-to-stand (5×STS), handgrip strength (HGS), 3-m walk for gait speed (GS), and the PROMIS Physical Function Short Form. HRQOL was measured via the FACT-Hep questionnaire. Results: Fifty participants with mean age 66 years (standard deviation = 8 years) were enrolled. The 6MWT, 5×STS, and GS significantly improved from baseline to restaging follow-up (P=.001, P=.049, and P=.009, respectively). Increases in self-reported aerobic exercise, weekly MVPA, and LPA were associated with improvement in 6MWT (ß=.19, P=.048; ß=.18, P=.03; and ß=.08, P=.03, respectively) and self-reported physical functioning (ß=.02, P=.03; ß=.03, P=.005; and ß=.01, P=.02, respectively). Increased weekly LPA was associated with increased HRQOL (ß=.03, P=.02). Increased SA was associated with decreased HRQOL (ß=-.02,P=.01). Conclusions: Patients with potentially resectable pancreatic cancer exhibit meaningful improvement in physical function with prehabilitation; physical activity was associated with improved physical function and HRQOL. These data highlight the importance of physical activity during treatment for pancreatic cancer.

Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update.

PURPOSE: The purpose of this guideline update is to incorporate recently reported practice-changing evidence into ASCO's recommendations on potentially curable pancreatic adenocarcinoma. METHODS: ASCO convened an Expert Panel to evaluate data from PRODIGE 24/CCTG PA.6, a phase III, multicenter, randomized clinical trial of postoperative leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX) versus gemcitabine alone, presented at the 2018 ASCO Annual Meeting. In addition, PubMed was searched for additional papers that may influence the existing recommendations. RECOMMENDATIONS: The Expert Panel only updated Recommendation 4.1 as a result of the practice-changing data. Recommendation 4.1 states that all patients with resected pancreatic adenocarcinoma who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The modified combination regimen of 5-fluorouracil, oxaliplatin, and irinotecan (mFOLFIRINOX; oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 D1, and 5-fluorouracil 2.4 g/m2 over 46 hours every 14 days for 12 cycles) is now preferred in the absence of concerns for toxicity or tolerance; alternatively, doublet therapy with gemcitabine and capecitabine or monotherapy with gemcitabine alone or fluorouracil plus folinic acid alone can be offered.Additional information can be found at www.asco.org/gastrointestinal-cancer-guidelines.

Preoperative Fluorouracil, Doxorubicin, and Streptozocin for the Treatment of Pancreatic Neuroendocrine Liver Metastases.

INTRODUCTION: While preoperative chemotherapy is frequently utilized before resection of non-neuroendocrine liver metastases, patients with resectable neuroendocrine liver metastases typically undergo surgery first. FAS is a cytotoxic chemotherapy regimen that is associated with substantial response rates in locally advanced and metastatic pancreatic neuroendocrine tumors. METHODS: All patients who underwent R0/R1 resection of pancreatic neuroendocrine liver metastases at a single institution between 1998 and 2015 were included. The outcomes of patients treated with preoperative FAS were compared with those of patients who were not. RESULTS: Of the 67 patients included, 27 (40.3%) received preoperative FAS, whereas 40 (59.7%) did not. Despite being associated with higher rates of synchronous disease, lymph node metastases, and larger tumor size, patients who received preoperative FAS had similar overall survival [overall survival (OS), 108.2 months (95% confidence interval (CI) 78.0-136.0) vs. 107.0 months (95% CI 78.0-136.0), p = 0.64] and recurrence-free survival [RFS, 25.1 months (95% CI 23.2-27.0) vs. 18.0 months (95% CI 13.8-22.2), p = 0.16] as patients who did not. Among patients who presented with synchronous liver metastases (n = 46), the median OS [97.3 months (95% CI 65.9-128.6) vs. 65.0 months (95% CI 28.1-101.9), p = 0.001] and RFS [24.8 months (95% CI 22.6-26.9) vs. 12.1 months (2.2-22.0), p = 0.003] were significantly greater among patients who received preoperative FAS compared with those who did not. CONCLUSIONS: The use of FAS before liver resection is associated with improved OS compared with surgery alone among patients with advanced synchronous pancreatic neuroendocrine liver metastases.

International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017.

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.

Role of neoadjuvant therapy in the multimodality treatment of older patients with pancreatic cancer.

BACKGROUND: A well-defined treatment strategy for elderly patients with resectable pancreatic cancer is lacking. Multiple reports have described highly selected older cancer patients who have successfully undergone pancreatectomy. However, multimodality therapy is essential for long-term survival, and elderly patients are at high risk for not receiving adjuvant therapy postoperatively. We sought to describe the treatment patterns and outcomes of a series of elderly patients with pancreatic cancer who were treated with a multimodality strategy that liberally used neoadjuvant therapy. STUDY DESIGN: We retrospectively reviewed treatment plans, short-term outcomes, and overall survival of all patients 70 years old and older, presenting to our institution over a 9-year period, who were treated for potentially resectable or borderline resectable pancreatic cancer. RESULTS: There were 179 (76%) of 236 patients treated with curative intent. Of these patients, 153 (85%) initiated neoadjuvant therapy: 74 (48%) subsequently underwent pancreatectomy and 79 did not due to disease progression (n = 46), insufficient performance status (n = 23), or other reasons (n = 10). Eleven (42%) of 26 patients who underwent surgery first received postoperative therapy. Among patients treated with curative intent, the median overall survival of all patients initiating neoadjuvant therapy (16.6 months [range 2.1 to 142.7 months]) was similar to that of patients undergoing resection primarily (15.1 months [range 5.4 to 100.8 months]), p = 0.53. After pancreatectomy, patients had a 2% in-hospital mortality rate and 91% were discharged home. CONCLUSIONS: Eighty-five percent of all patients 70 years old and older, who underwent pancreatectomy for potentially resectable or borderline resectable pancreatic cancer, received multimodality therapy. More than 90% were discharged home. These data demonstrate a potential role for neoadjuvant therapy in selecting elderly patients for surgery, and support further studies to refine individualized treatment protocols for this high-risk population.

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.

Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival.

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.

Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer.

OBJECTIVES: To determine the influence of neoadjuvant chemoradiation and standardized dissection of the superior mesenteric artery upon the oncologic outcome of patients with localized pancreatic adenocarcinoma. METHODS: One hundred ninety-four patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy between 2004 and 2008 were evaluated. The retroperitoneal dissection was performed directly along the superior mesenteric artery in all cases. A standard histopathologic protocol that measured the "superior mesenteric artery (SMA) margin distance" between cancer cells and the superior mesenteric artery was employed. RESULTS: Seventy-six percent of patients received neoadjuvant chemoradiation. The SMA margin was positive in 4% of patients but an additional 22% of patients with a negative margin had a SMA margin distance of ≤1 mm. Preoperative CT images overestimated the SMA margin distance in 73% of cases. Patients who received chemoradiation had longer SMA margin distances than those who did not. Patients who received chemoradiation and had a SMA margin of >1 mm had the lowest recurrence rates. Administration of neoadjuvant chemoradiation and lower estimated blood loss were independently associated with longer progression-free survival on multivariate analysis. CONCLUSIONS: Preoperative chemoradiation and meticulous dissection of the superior mesenteric artery maximize the distance between cancer cells and the SMA margin and may influence locoregional control.

Survival and quality of life of patients with resected pancreatic adenocarcinoma treated with adjuvant interferon-based chemoradiation: a phase II trial.

PURPOSE: We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy. METHODS: Patients with a performance status of 0 or 1 were enrolled to receive interferon-alfa-2b (3 million units MWF), cisplatin (30 mg/m(2), 6 doses) and 5-fluorouracil (5-FU; 175 mg/m(2)/day), concurrent with external-beam radiation (50.4 Gy) and followed by 2 courses of systemic 5-FU. The protocol was modified to include an optional 9 day break in the middle of chemoradiation. Quality of life was assessed by use of validated instruments. RESULTS: Twenty-eight patients were eligible for analysis. The operation of 15 (54%) patients was performed at other institutions. All patients had T3 tumors, 22 (79%) had positive lymph nodes and 4 (14%) had positive (R1) margins. 24 (86%) patients completed therapy. In all, 25 (89%) patients experienced grade 3 toxicity and 3 (11%) patients were hospitalized. The most common grade 3 events were leukopenia (15, 54%) and neutropenia (12, 43%). No grade 4 toxicity occurred. Overall quality of life decreased during chemoradiation but returned to baseline thereafter and was stable throughout surveillance. 19 patients have died; the median follow-up of the 9 survivors is 62 months. The median OS duration of treated patients was 42.3 (95% confidence interval 30.5-54.2) months. CONCLUSIONS: Adjuvant interferon-based chemoradiation can be delivered safely and tolerably-though with substantial reversible toxicity-to patients of good performance status at an experienced cancer center. Therapy may be associated with an improvement in overall survival.

Current status of adjuvant therapy for pancreatic cancer.

In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.

Incidence, risk factors, and impact of severe neutropenia after hyperthermic intraperitoneal mitomycin C.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered the standard of care for patients with peritoneal dissemination of appendiceal cancer and are increasingly being evaluated for use in patients with carcinomatosis from colon cancer. Mitomycin C (MMC) is one of the most frequently used HIPEC agents in the management of peritoneal-based gastrointestinal malignancies. This study analyzes the incidence and risk factors for developing neutropenia following MMC-HIPEC combined with CRS. METHODS: All patients undergoing CRS and MMC-HIPEC for appendiceal cancer between January 1993 and October 2006 were retrospectively reviewed. Logistic regression was used to identify risk factors for the development of neutropenia, defined as an absolute neutrophil count (ANC) <1,000/mm(3). RESULTS: One hundred and twenty MMC-HIPEC were performed in 117 patients with appendiceal cancer. The incidence of neutropenia was 39%. Neutropenia occurred in 57.6% of female and 21.3% of male patients (p < 0.0001). Female gender and MMC dose per body surface area (BSA) were independent risk factors for neutropenia on multivariable logistic regression [odds ratio (OR) of neutropenia in females = 3.58 (95% confidence interval, CI: 1.52, 8.43); OR for 5 unit (mg/m(2)) increase in MMC dose per BSA = 3.37 (95% CI: 1.72, 6.63)]. Neutropenia did not increase the risk of mortality, postoperative infection or length of hospital stay. CONCLUSION: Neutropenia is a frequent complication associated with MMC-HIPEC. Female sex and MMC dose per BSA are independent risk factors for neutropenia. These differences must be considered in the management of patients undergoing MMC-HIPEC to minimize the toxicity of the procedure.