Management of Patients With Pancreatic Cancer Using the "Right Track" Model.

Pancreatic cancer is one of the few cancer types in the US with incidence and death rates continuing to rise. As the disease threatens to become the second leading cause of cancer-related deaths in the country, it is imperative to review the best practices currently available to extend and improve patient lives. To provide a roadmap for healthcare professionals detecting, diagnosing, and caring for patients with pancreatic cancer as a supplement to national guidelines focused on recommended treatment regimens, the Pancreatic Cancer Action Network (PanCAN)'s Scientific and Medical Affairs staff and expert Scientific and Medical Advisory Board have created a series of position statements. The statements are based upon scientific evidence and clinical observations published in the literature and research conducted through PanCAN's internal programs and initiatives. This review summarizes the rationale and sources for these position statements related to diagnosis, treatment, and care for pancreatic cancer and provides information about resources to make these recommendations accessible to patients and their medical teams. Pancreatic cancer is a complex and extremely challenging disease. Beyond treatment recommendations outlined in national guidelines, steps can be taken to help patients feel better and live longer. Under the framework of the "Right Track" model-right team, right tests, right treatments, data sharing-PanCAN's position statements can provide supplementary guidance to healthcare professionals for the short- and long-term management of patients with the disease.

Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

BACKGROUND: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma.

LESSONS LEARNED: This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment. BACKGROUND: Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR. METHODS: A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles. RESULTS: Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea. CONCLUSION: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.

Multi-omic molecular comparison of primary versus metastatic pancreatic tumours.

BACKGROUND: Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult. METHODS: Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support. RESULTS: No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions. CONCLUSIONS: Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

Pancreas Cancer-Associated Weight Loss.

Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.

Predictive proteomic signatures for response of pancreatic cancer patients receiving chemotherapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is characterized by its poor prognosis, rapid progression and development of drug resistance. Chemotherapy is a vital treatment option for most of PDAC patients. Stratification of PDAC patients, who would have a higher likelihood of responding to chemotherapy, could facilitate treatment selection and patient management. METHODS: A quantitative proteomic study was performed to characterize the protein profiles in the plasma of PDAC patients undergoing chemotherapy to determine if specific biomarkers could be used to predict likelihood of therapeutic response. RESULTS: By comparing the plasma proteome of the PDAC patients with positive therapeutic response and longer overall survival (Good-responders) to those who did not respond as well with shorter survival time (Limited-responders), we identified differential proteins and protein variants that could effectively segregate Good-responders from Limited-responders. Functional clustering and pathway analysis further suggested that many of these differential proteins were involved in pancreatic tumorigenesis. Four proteins, including vitamin-K dependent protein Z (PZ), sex hormone-binding globulin (SHBG), von Willebrand factor (VWF) and zinc-alpha-2-glycoprotein (AZGP1), were further evaluated as single or composite predictive biomarker with/without inclusion of CA 19-9. A composite biomarker panel that consists of PZ, SHBG, VWF and CA 19-9 demonstrated the best performance in distinguishing Good-responders from Limited-responders. CONCLUSION: Based on the cohort investigated, our data suggested that systemic proteome alterations involved in pathways associated with inflammation, immunoresponse, coagulation and complement cascades may be reporters of chemo-treatment outcome in PDAC patients. For the majority of the patients involved, the panel consisting of PZ, SHBG, VWF and CA 19-9 was able to segregate Good-responders from Limited-responders effectively. Our data also showed that dramatic fluctuations of biomarker concentration in the circulating system of a PDAC patient, which might result from biological heterogeneity or confounding complications, could diminish the performance of a biomarker. Categorization of PDAC patients in terms of their tumor stages and histological types could potentially facilitate patient stratification for treatment.

Gemcitabine and Taxane Adjuvant Therapy with Chemoradiation in Resected Pancreatic Cancer: A Novel Strategy for Improved Survival?

BACKGROUND: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit clinically in metastatic pancreatic cancer (PC). The authors present their experience with gemcitabine and docetaxel (gem/tax)-based adjuvant treatment (Rx) after surgery with curative intent. METHODS: Patients with de novo resectable PC from January 2010 to December 2015 were identified from the authors' institutional database and registry. The study included only patients who received gem/tax as their initial Rx administered exclusively at the authors' institution with or without chemoradiation (CRTx). Survival analysis was performed using Kaplan-Meier methods, and prognostic factors were investigated by Cox proportional hazard modeling. RESULTS: Of 102 patients identified, 58 met the study criteria. The median age at diagnosis was 65 years, with 55% of the patients undergoing an R1 resection (margin ≤ 1 mm). Tumor characteristics included a median tumor size of 28 mm, a poor differentiation rate of 54%, and a lymph node positivity of 67%. Most of the patients (90%, 52/58) completed 80% or more of the 24 week Rx. Of these patients, 71% received post-gem/tax CRTx Rx. Grade 3 or 4 toxicity was observed in 52% of the patients. The median follow-up period was 51.2 months, and the observed median overall survival (OS) was 52 months [95% confidence interval (CI) 27.4-not reached]. The actuarial 5-year OS was 49% (95% CI 33.7-63.4%). In the multivariate analysis, an R1 resection and American Joint Committee on Cancer (AJCC) stage 2 versus stage 1 disease were negatively associated with OS, whereas administration of CRTx was positively associated with OS. CONCLUSIONS: Adjuvant gem/tax with or without CRTx is feasible, with a favorable OS. Future prospective studies of gem/taxane-based adjuvant Rx for PC are warranted.

Initiation of adjuvant therapy following surgical resection of pancreatic ductal adenocarcinoma (PDAC): Are patients from rural, remote areas disadvantaged?

BACKGROUND AND OBJECTIVES: Although race and socioeconomic status have been shown to affect outcomes in pancreatic ductal adenocarcinoma (PDAC), the impact of rural residence on the delivery of adjuvant therapy (AT) has not been studied. METHODS: Patients with resected PDAC were identified using the National Cancer Database (NCDB). Individuals were classified as living in a metro area, urban/rural adjacent to a metro area (URA), and urban/rural remote (URR) area. Multivariate logistic regression was used to assess geographic inhabitance as a predictor of receiving AT. RESULTS: A total of 32 521 individuals who underwent pancreatectomy for PDAC were identified. Univariate analysis demonstrated individuals in URR areas were less likely to receive adjuvant chemotherapy (ACT) than those living in URA or metro areas (55.3% vs 55.6% vs 58.8%, P = 0.011). However on multivariate analysis URR inhabitance was no longer a predictor of ACT (OR = 0.911 P = 0.125) or ART (OR = 0.953 P = 0.462). Cox proportional hazard modeling demonstrated URR inhabitance remained independently associated with poor OS (HR 1.076; 95% CI [1.008, 1.149], P < 0.029). CONCLUSIONS: URR inhabitance does not impact access to AT, however it is independently associated with a decreased OS. Attention must be focused on optimizing oncologic care to patients with disparate access to healthcare.

Does mesenteric venous imaging assessment accurately predict pathologic invasion in localized pancreatic ductal adenocarcinoma?

BACKGROUND: Accurate prediction of mesenteric venous involvement in pancreatic ductal adenocarcinoma (PDAC) is necessary for adequate staging and treatment. METHODS: A retrospective cohort study was conducted in PDAC patients at a single institution. All patients with resected PDAC and staging CT and EUS between 2003 and 2014 were included and sub-divided into "upfront resected" and "neoadjuvant chemotherapy (NAC)" groups. Independent imaging re-review was correlated to venous resection and venous invasion. Sensitivity, specificity, positive and negative predictive values were then calculated. RESULTS: A total of 109 patients underwent analysis, 60 received upfront resection, and 49 NAC. Venous resection (30%) and vein invasion (13%) was less common in patients resected upfront than those who received NAC (53% and 16%, respectively). Both CT and EUS had poor sensitivity (14-44%) but high specificity (75-95%) for detecting venous resection and vein invasion in patients resected upfront, whereas sensitivity was high (84-100%) and specificity was low (27-44%) after NAC. CONCLUSIONS: Preoperative CT and EUS in PDAC have similar efficacy but different predictive capacity in assessing mesenteric venous involvement depending on whether patients are resected upfront or received NAC. Both modalities appear to significantly overestimate true vascular involvement and should be interpreted in the appropriate clinical context.

Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics.

BACKGROUND: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. CONCLUSIONS: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.

Five-Year Actual Overall Survival in Resected Pancreatic Cancer: A Contemporary Single-Institution Experience from a Multidisciplinary Perspective.

BACKGROUND: Successful surgical resection combined with effective perioperative therapy is essential for maximizing long-term survival for pancreatic adenocarcinoma. PATIENTS AND METHODS: All patients with pancreatic adenocarcinoma who underwent curative resection at our institution from January 2003 to May 2010 were reviewed. Demographic and clinical details were retrospectively collected from medical records and cancer registry data. RESULTS: Overall, 176 patients were included in the analysis (148 with de novo resectable disease and 28 with borderline resectable disease at presentation). Among 106 patients who received all perioperative therapy at our institution, 94% received neoadjuvant and/or adjuvant treatment in addition to resection. Actual all-cause 5-year overall survival (OS) for all 176 patients was 30.7%, with a median OS of 33.9 months [95% confidence interval (CI) 28.1-39.6 months]. For patients who received all perioperative therapy at our institution, actual all-cause 5-year disease-free survival (DFS) was 32.1%, with a median DFS of 28.8 months (95% CI 20.1-43.6 months). Of these patients, 67/106 (63%) recurred: 8 (8%) locoregional only; 52 (49%) systemic only; and 7 (7%) combined recurrence. No difference in survival rates or recurrence patterns was seen between resectable and borderline resectable patients. In multivariate analysis, tumor differentiation (poor vs. non-poor) and lymph node ratio >20% produced a useful clinical model. CONCLUSION: The actual OS rates for resected pancreatic cancer shown in this study are reflective of those currently achievable at a tertiary medical center dedicated to this patient population. In considering these results, both frequency and type of adjuvant/neoadjuvant therapy administered in the context of the clinical experience/management techniques of providers administering these treatments will be discussed.

Interferon-based Adjuvant Chemoradiation for Resected Pancreatic Head Cancer: Long-term Follow-up of the Virginia Mason Protocol.

OBJECTIVE: To report the long-term impact of adjuvant interferon-based chemoradiation therapy (IFN-CRT) after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC). BACKGROUND: In 2003, we reported an actuarial 5-year overall survival (OS) of 55% (22 months median follow-up) using adjuvant IFN-CRT after PD. As the original cohort is now 10 years distant from PD, we sought to examine their actual survival, describe patterns of recurrence, and determine prognostic factors. METHODS: From 1995 to 2002, 43 patients underwent PD for PDAC and received adjuvant IFN-CRT consisting of external-beam irradiation, continuous 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α. Survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using a log-rank test and a Cox proportional hazards model. RESULTS: With all patients at least 10 years from PD, the 5-year actual survival was 42% and 10-year actual survival was 28% with median OS of 42 months (95% confidence interval: 22-110 months). Nine patients survived beyond 10 years with 7 currently alive without evidence of disease. Initial recurrence included 4 local, 17 distant, and 4 combined sites at a median of 25 months. IFN-CRT was interrupted in 70% of patients because of grade 3 or 4 toxicity, whereas 42% of patients required hospitalization. Adverse prognostic factors included lymph node ratio of 50% or more, Eastern Cooperative Oncology Group performance status of 1 or higher, and IFN-CRT treatment interruption. CONCLUSIONS: Adjuvant IFN-CRT after PD can provide long-term survival in resected PDAC. Further studies should focus on patient and tumor factors to maximize benefit and minimize toxicity.

Survival and clinical outcome after endoscopic duodenal stent placement for malignant gastric outlet obstruction: comparison of pancreatic cancer and nonpancreatic cancer.

BACKGROUND: Data on endoscopic stenting of malignant gastric outlet obstruction (GOO) are based on studies predominantly involving patients with pancreatic adenocarcinoma. OBJECTIVE: To compare survival and clinical outcome after stent placement for GOO due to pancreatic cancer compared with nonpancreatic cancer. DESIGN: Retrospective study. SETTING: Single tertiary hospital. PATIENTS: A total of 292 patients with malignant GOO. INTERVENTION: Stent placement. MAIN OUTCOME MEASUREMENTS: Post-stent placement survival and clinical outcome. RESULTS: In 196 patients with pancreatic cancer and 96 with nonpancreatic cancer, median post-stent placement survival was similar (2.7 months in pancreatic cancer vs 2.4 months in nonpancreatic cancer). Overall survival was shorter in patients with pancreatic cancer (13.7 vs 17.1 months; P = .004). Clinical success rates at 2 months (71% vs 91%) and reintervention rates (30% vs 23%) were comparable. Post-stent placement chemotherapy and the absence of distant metastasis were associated with better post-stent placement survival in both groups (pancreatic cancer: chemotherapy vs no chemotherapy, 5.4 vs 1.5 months, P < .0001; metastasis vs no metastasis, 1.8 vs 4.6, P = .005; nonpancreatic cancer: chemotherapy vs no chemotherapy, 9.2 vs 1.8, P = .001; metastasis vs no metastasis, 2.1 vs 6.1, P = .009). LIMITATIONS: Retrospective study. CONCLUSIONS: In this large series of patients undergoing stent placement for malignant GOO in North America, we observed no difference in post-stent placement survival despite better overall survival in patients with nonpancreatic cancer. GOO is a marker for poor survival in malignancy, regardless of the type. Chemotherapy and the absence of distant metastasis were associated with better post-stent placement survival in both groups.

Extended neoadjuvant chemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival.

BACKGROUND: The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined. Herein we report the outcomes of an extended neoadjuvant chemotherapy regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head. METHODS: Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospectively maintained registry. Included patients were initiated on a 24-week course of neoadjuvant chemotherapy. Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent. Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed. RESULTS: Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy. Thirty-nine (61 %) met resection criteria and underwent operative exploration with curative intent, and 31 (48 %) were resected. Of the resected patients, 18 (58 %) had positive lymph nodes, 15 (48 %) required en-bloc venous resection, 27 (87 %) had a R0 resection, and 3 (10 %) had a complete pathologic response. There were no postoperative deaths at 90 days, 16 % of patients had a severe complication, and the 30-day readmission rate was 10 %. The median overall survival of all 64 patients was 23.6 months, whereas that of unresectable patients was 15.4 months. Twenty-five of the resected patients (81 %) are still alive at a median follow-up of 21.6 months. CONCLUSIONS: Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma, selects a subset of patients for curative surgery with low perioperative morbidity, and is associated with favorable survival.

Pancreatic cancer: new approaches to drug therapy.

Outcomes in pancreatic ductal adenocarcinoma (PDAC) remain poor due to a variety of biological, clinical, and societal factors. However, in recent years, PDAC has seen 1) increased precision of initial evaluation, 2) increased emphasis on supportive care, 3) deeper understanding of the translation biology of PDAC, especially as pertains to genomic alterations, and 4) foundational combination chemotherapy clinical trials across all disease stages. These advances have led to a wide range of new approaches to drug therapy for PDAC. Currently available drugs are showing added benefit, both by resequencing them with each other and also with respect to other therapeutic modalities. Molecular strategies are being developed to predict response to known therapeutic agents and to identify others. Additionally, a wide range of new drugs for PDAC are under development, including drugs which inhibit critical molecular pathways, drugs which attempt to capitalize on homologous repair deficiencies, immunotherapeutic approaches, antimetabolic agents, and drugs which attack the extracellular matrix which supports PDAC growth. These new approaches offer the promise of improved survival for future PDAC patients.

Keratin 17 is a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.

Alternating Gemcitabine/Nab-Paclitaxel (GA) and 5-FU/Leucovorin/Irinotecan (FOLFIRI) as First-Line Treatment for De Novo Metastatic Pancreatic Cancer (MPC): Safety and Effect.

BACKGROUND: Both gemcitabine- and 5-fluorouracil (5-FU)-based chemotherapy regimens have demonstrated efficacy in metastatic pancreatic cancer (MPC). Alternating these regimens may reduce toxicity, slow resistant cancer biology emergence, and provide a platform for the addition of other therapeutic agents. Alternating gemcitabine/nab-paclitaxel (GA) and 5-FU/leucovorin/irinotecan (FOLFIRI) in MPC has previously been reported at our own institution and elsewhere. An extension of our institutional observations is reported here. METHODS: Patient eligibility required the following: biopsy-proven de novo MPC, no prior evidence of disease on CT, ECOG performance status (PS) ≤ 2, and bi-dimensionally measurable disease. Treatment (Tx) entailed gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 1, (8), 15 alternating every 8 weeks (2 cycles) with FOLFIRI using standard dosing. Patients were radiographically re-staged every 8 weeks. Tx spanned up to 12 cycles. Tx thereafter was decided following patient/physician discussion. RESULTS: Median overall survival (mOS) was 13.2 months (95% CI 10.9-16.5 months). Median progression-free survival (mPFS) was 8.5 months (95% CI, 7.1-9.9). The 6-, 12-, 18-, and 24-month OS rates were 88%, 54%, 36%, and 20%, respectively. The disease control rate at 16 weeks was 83% (37% PR, 46% SD). Hematologic toxicity grade ≥ 3 included 9.3% anemia, 10.2% neutropenia, and 4.6% thrombocytopenia. Neutrophil growth factors were not used in this cohort. Non-hematologic toxicities grade ≥ 3 included neuropathy 0.9%, nausea/vomiting 0.9%, and diarrhea 0.9%. No patients experienced mucositis on this regimen. CONCLUSIONS: Alternating GA/FOLFIRI in MPC has a favorable toxicity profile in comparison to current standard regimens. Median OS was at least competitive with standard regimens, and longer-term (18 and 24 months) OS seemed particularly encouraging. Treatment for ≥48 weeks and ECOG PS of zero at the time of treatment initiation were prognostically significant. Further investigation using this regimen including randomized comparisons, the incorporation of molecular data, and use of additional agents is merited.

Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFß inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. METHODS: This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. RESULTS: One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. CONCLUSION: In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.

A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond.

BACKGROUND: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1). RESULTS: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01). CONCLUSIONS: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC. CLINICALTRIALS: gov Identifier: NCT03512756.

Standardization of surgical and pathologic variables is needed in multicenter trials of adjuvant therapy for pancreatic cancer: results from the ACOSOG Z5031 trial.

BACKGROUND: Standardization of surgical and pathologic techniques is crucial to the interpretation of studies evaluating adjuvant therapies for pancreatic cancer (PC). METHODS: To assess the degree to which treatment administered prior to enrollment of patients in trials of adjuvant therapy is quality controlled, the operative and pathology reports of patients in American College of Surgeons Oncology Group (ACOSOG) Z5031-a national trial of chemoradiation following pancreaticoduodenectomy (PD)-were rigorously evaluated. We analyzed variables with the potential to influence staging or outcome. RESULTS: 80 patients reported to have undergone R0 (75%) or R1 (25%) pylorus-preserving (38%) or standard (62%) PD were evaluated. A search for metastases was documented in 96% of cases. The proximity of the tumor to the superior mesenteric vein was reported in 69%; vein resection was required in 9% and lateral venorrhaphy in 14%. The method of dissection along the superior mesenteric artery (SMA) was described in 68%, being ultrasonic dissection (17%), stapler (24%), and clamp and cut (59%). SMA skeletonization was described in 25%, and absence of disease following resection was documented in 24%. The surgeon reported marking the critical SMA margin in 25%; inking was documented in 65% of cases and evaluation of the SMA margin was reported in 47%. A range of 1-49 lymph nodes was evaluated. Only 34% of pathology reports met College of American Pathologists criteria. CONCLUSIONS: Trials of adjuvant therapy following PD suffer from a lack of standardization and quality control prior to patient enrollment. These data suggest areas for improvement in the design of multidisciplinary treatment protocols.