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Pancreatic Neoplasms: HELP
Articles by Andrew X. Zhu
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Andrew X. Zhu wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. 2019

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Clark, Jeffrey W / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Ly, Leilana / Baglini, Christian V / Blaszkowsky, Lawrence S / Ferrone, Cristina R / Parikh, Aparna R / Weekes, Colin D / Nipp, Ryan D / Kwak, Eunice L / Allen, Jill N / Corcoran, Ryan B / Ting, David T / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Berger, David L / Qadan, Motaz / Lillemoe, Keith D / Talele, Nilesh / Jain, Rakesh K / DeLaney, Thomas F / Duda, Dan G / Boucher, Yves / Fernández-Del Castillo, Carlos / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·JAMA Oncol · Pubmed #31145418.

ABSTRACT: Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. Main Outcomes and Measures: R0 resection rate. Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. Trial Registration: ClinicalTrials.gov identifier: NCT01821729.

2 Clinical Trial Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. 2018

Murphy, Janet E / Wo, Jennifer Y / Ryan, David P / Jiang, Wenqing / Yeap, Beow Y / Drapek, Lorraine C / Blaszkowsky, Lawrence S / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Faris, Jason E / Zhu, Andrew X / Goyal, Lipika / Lillemoe, Keith D / DeLaney, Thomas F / Fernández-Del Castillo, Carlos / Ferrone, Cristina R / Hong, Theodore S. ·Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston. ·JAMA Oncol · Pubmed #29800971.

ABSTRACT: Importance: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted. Objective: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy. Design, Setting, and Participants: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion. Interventions: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine. Main Outcomes and Measures: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS). Results: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%. Conclusions and Relevance: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01591733.

3 Clinical Trial A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. 2014

Hong, Theodore S / Ryan, David P / Borger, Darrell R / Blaszkowsky, Lawrence S / Yeap, Beow Y / Ancukiewicz, Marek / Deshpande, Vikram / Shinagare, Shweta / Wo, Jennifer Y / Boucher, Yves / Wadlow, Raymond C / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Zhu, Andrew X / Ferrone, Cristina R / Mamon, Harvey J / Adams, Judith / Winrich, Barbara / Grillo, Tarin / Jain, Rakesh K / DeLaney, Thomas F / Fernandez-del Castillo, Carlos / Duda, Dan G. ·Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: tshong1@partners.org. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. ·Int J Radiat Oncol Biol Phys · Pubmed #24867540.

ABSTRACT: PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

4 Clinical Trial A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. 2013

Chan, Jennifer A / Blaszkowsky, Lawrence / Stuart, Keith / Zhu, Andrew X / Allen, Jill / Wadlow, Raymond / Ryan, David P / Meyerhardt, Jeffrey / Gonzalez, Marielle / Regan, Eileen / Zheng, Hui / Kulke, Matthew H. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. ·Cancer · Pubmed #23733618.

ABSTRACT: BACKGROUND: Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). A phase 1/2 study was performed to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients who have advanced pancreatic NET. METHODS: Patients were treated with temozolomide at a dose of 150 mg/m(2) per day on days 1 through 7 and days 15 through 21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival. RESULTS: A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached. CONCLUSIONS: Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted.

5 Article Pilot study on the impact of F18-labeled thymidine PET/CT on gross tumor volume identification and definition for pancreatic cancer. 2018

Pretz, Jennifer L / Blake, Michael A / Killoran, Joseph H / Mamon, Harvey J / Wo, Jennifer Y / Zhu, Andrew X / Hong, Theodore S. ·Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: jpretz@partners.org. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Pract Radiat Oncol · Pubmed #29042120.

ABSTRACT: PURPOSE: Accurate target definition for radiation therapy planning in localized pancreatic cancer is critical, particularly when using strategies that omit elective coverage. Standard imaging modalities such as computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasound have limited concordance with pathologic evaluation. Biologic imaging with [F18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can also be difficult to interpret because increased activity is indicative of increased glucose metabolism, rather than cellular proliferation. [F18]-3'-deoxy-3'-fluorothymidine labeled thymidine (FLT) is a proliferative marker which exploits the expression of pyrimidine-metabolizing enzymes. We evaluate the impact of FLT-PET on pancreatic target definition for radiation planning. METHODS AND MATERIALS: Patients with biopsy-proven, newly diagnosed, untreated pancreatic adenocarcinoma were enrolled on an institutional review board-approved prospective study. Patients were injected with FLT and scanned 20 to 30 minutes later. Two physicians (referred to as observer 1 and observer 2) independently contoured the gross tumor volume (GTV) and involved nodes on CT scan only and then again with the assistance of coregistered FLT-PET. Conformality index (CI), the ratio of the volumes of intersection and union, was used as the metric for volume comparison (where CI = 0 represents no overlap and CI = 1 represents perfect overlap). RESULTS: Nine patients were enrolled in this study. FLT-avidity was discerned in 8 of 9 patients. Average CT-GTV volume for observers 1 and 2 was 38.1 and 26.5 mL, respectively. Average FLT-GTV volume for observers 1 and 2 was 39.1 and 25.0 mL, respectively. For the 8 patients with FLT-avid tumors, addition of FLT data improved concordance of GTV definition between physicians in 6 of 8 tumors. Average CI for interobserver CT-GTV was 0.325. Addition of FLT-PET information improved the average CI to 0.400. CONCLUSIONS: FLT-PET improves interobserver concordance in GTV definition. Further studies will focus on verification of these findings, pathologic verification of the FLT-PET signal, and optimization of the FLT-PET signal threshold for autosegmentation.

6 Article Tolerability and Long-term Outcomes of Dose-Painted Neoadjuvant Chemoradiation to Regions of Vessel Involvement in Borderline or Locally Advanced Pancreatic Cancer. 2018

Wo, Jennifer Y / Niemierko, Andrzej / Ryan, David P / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Kwak, Eunice L / Lillemoe, Keith D / Drapek, Lorraine N / Zhu, Andrew X / Allen, Jill N / Faris, Jason E / Murphy, Janet E / Nipp, Ryan / Fernandez-Del Castillo, Carlos / Ferrone, Cristina R / Hong, Theodore S. ·Departments of Radiation Oncology. · Medical Oncology. · General Surgery, Massachusetts General Hospital, Boston, MA. ·Am J Clin Oncol · Pubmed #28134673.

ABSTRACT: PURPOSE: We reviewed our experience involving patients with borderline resectable or locally advanced pancreatic cancer, treated with the dose-painted (DP) boost technique to regions of vessel involvement which preclude upfront surgical resection. We evaluated patient outcomes with respect to tolerability and treatment outcomes. MATERIALS AND METHODS: We retrospectively reviewed 99 patients with borderline resectable (n=25) or locally advanced pancreatic cancer (n=74) treated with DP-neoadjuvant chemoradiation from 2010 to 2015. Tumor and regional lymph nodes were prescribed 50.4 Gy and the region around the involved blood vessel was boosted to 58.8 Gy in 28 fractions. The primary outcome was acute toxicity and late duodenal toxicity. Secondary outcomes included conversion to surgical resectability, local failure, disease-free survival, and overall survival (OS). Cox proportional hazards models were performed to evaluate for predictors of survival. RESULTS: All but 1 patient completed chemoradiation. The rates of grade 2+ and 3+ nausea were 40% and 12%, respectively. With regards to late toxicity, 5 patients developed potential RT-related grade 3+ duodenal complications including duodenal ulceration/bleeding (n=3) and duodenal stricture (n=2). With a median follow-up of 15 months, the median OS was 18.1 months. Among 99 patients in our study, 37 patients underwent surgical resection. For patients who underwent surgical resection (n=37), the median OS was 30.9 months. On multivariate analysis, only normalization of CA 19-9 post-RT was associated with improved OS. CONCLUSIONS: We found that DP-neoadjuvant chemoradiation to regions of vessel involvement is both feasible and well tolerated. In addition, we demonstrated that over one third of patients with initially deemed unresectable disease were able to undergo surgical resection after receiving neoadjuvant therapy including DP-chemoradiation.

7 Article Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. 2017

Farshidfar, Farshad / Zheng, Siyuan / Gingras, Marie-Claude / Newton, Yulia / Shih, Juliann / Robertson, A Gordon / Hinoue, Toshinori / Hoadley, Katherine A / Gibb, Ewan A / Roszik, Jason / Covington, Kyle R / Wu, Chia-Chin / Shinbrot, Eve / Stransky, Nicolas / Hegde, Apurva / Yang, Ju Dong / Reznik, Ed / Sadeghi, Sara / Pedamallu, Chandra Sekhar / Ojesina, Akinyemi I / Hess, Julian M / Auman, J Todd / Rhie, Suhn K / Bowlby, Reanne / Borad, Mitesh J / Anonymous5350899 / Zhu, Andrew X / Stuart, Josh M / Sander, Chris / Akbani, Rehan / Cherniack, Andrew D / Deshpande, Vikram / Mounajjed, Taofic / Foo, Wai Chin / Torbenson, Michael S / Kleiner, David E / Laird, Peter W / Wheeler, David A / McRee, Autumn J / Bathe, Oliver F / Andersen, Jesper B / Bardeesy, Nabeel / Roberts, Lewis R / Kwong, Lawrence N. ·Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · University of California Santa Cruz, Santa Cruz, CA 95064, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA. · University of Alabama at Birmingham, Birmingham, AL 35294, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. · Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA. · Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · National Cancer Institute, Bethesda, MD 20892, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: jesper.andersen@bric.ku.dk. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: roberts.lewis@mayo.edu. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lkwong@mdanderson.org. ·Cell Rep · Pubmed #28297679.

ABSTRACT: Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

8 Article Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. 2016

Deshpande, Vikram / Konstantinidis, Ioannis T / Castillo, Carlos Fernandez-Del / Hezel, Aram F / Haigis, Kevin M / Ting, David T / Bardeesy, Nabeel / Goyal, Lipika / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. vdeshpande@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. ·J Gastrointest Surg · Pubmed #26956004.

ABSTRACT: PURPOSE: Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS: Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS: Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS: Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials.

9 Article Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. 2015

Ferrone, Cristina R / Marchegiani, Giovanni / Hong, Theodore S / Ryan, David P / Deshpande, Vikram / McDonnell, Erin I / Sabbatino, Francesco / Santos, Daniela Dias / Allen, Jill N / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Faris, Jason E / Goyal, Lipika / Kwak, Eunice L / Murphy, Janet E / Ting, David T / Wo, Jennifer Y / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·*Department of Surgery †Department of Radiation Oncology; and ‡Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #25599322.

ABSTRACT: PURPOSE: On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. PATIENTS AND METHODS: Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. RESULTS: Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. CONCLUSIONS: After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

10 Article Delaying chemoradiation until after completion of adjuvant chemotherapy for pancreatic cancer may not impact local control. 2014

Wo, Jennifer Y / Childs, Stephanie K / Szymonifka, Jackie / Mamon, Harvey J / Ryan, David P / Blaszkowsky, Lawrence S / Kwak, Eunice L / Ferrone, Cristina R / Allen, Jill N / Zhu, Andrew X / Wolpin, Brian M / Chan, Jennifer A / Abrams, Thomas A / McCleary, Nadine J / Fernandez-Del Castillo, Carlos / Hong, Theodore S. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: jwo@partners.org. · Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Pract Radiat Oncol · Pubmed #24890357.

ABSTRACT: BACKGROUND: Timing of administration of adjuvant chemoradiation (CRT) for pancreatic cancer has varied across studies. To date, the impact of timing of adjuvant CRT on long-term outcomes has not been evaluated. This study evaluates the effect of timing of adjuvant CRT on locoregional control (LRC) and overall survival (OS). METHODS AND MATERIALS: We performed a review of 159 patients with resected pancreatic adenocarcinoma who received adjuvant CRT between 1998 and 2010. Median dose of CRT was 50.4 Gy. The primary study variable was timing of CRT, dichotomized as immediate CRT versus delayed CRT. Consistent with Radiation Therapy Oncology Group (RTOG) 9704, immediate chemoradiation was defined as after ≤1 cycle of chemotherapy, whereas delayed CRT was defined as after >1 cycle. Cox multivariate analysis (MVA) was performed. RESULTS: Median follow-up was 55 months. Seventy-four percent of patients received immediate CRT, and 26% patients received delayed CRT. Patients treated with delayed CRT were more likely to receive adjuvant gemcitabine (100% vs 53%; P < .001). Timing of adjuvant CRT was not associated with LRC or OS on univariate or MVA. Preoperative carcinoembryonic antigen ≥1.3 ng/mL (hazard ratio, 3.18; P = .017) and positive margins (hazard ratio, 5.35; P < .001) were associated with lower rates LRC on MVA. Higher lymph node positivity ratio and not receiving adjuvant gemcitabine were independently associated with worse OS. CONCLUSIONS: Timing of adjuvant CRT for resectable pancreatic cancer may not significantly affect LRC or OS. These findings support the ongoing RTOG 0848 trial design, and provide reassurance that delaying CRT until completion of chemotherapy should not significantly impact LRC.

11 Article FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. 2013

Faris, Jason E / Blaszkowsky, Lawrence S / McDermott, Shaunagh / Guimaraes, Alexander R / Szymonifka, Jackie / Huynh, Mai Anh / Ferrone, Cristina R / Wargo, Jennifer A / Allen, Jill N / Dias, Lauren E / Kwak, Eunice L / Lillemoe, Keith D / Thayer, Sarah P / Murphy, Janet E / Zhu, Andrew X / Sahani, Dushyant V / Wo, Jennifer Y / Clark, Jeffrey W / Fernandez-del Castillo, Carlos / Ryan, David P / Hong, Theodore S. ·Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. jfaris@partners.org ·Oncologist · Pubmed #23657686.

ABSTRACT: The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.

12 Article Pancreatic neuroendocrine tumors with involved surgical margins: prognostic factors and the role of adjuvant radiotherapy. 2012

Arvold, Nils D / Willett, Christopher G / Fernandez-del Castillo, Carlos / Ryan, David P / Ferrone, Cristina R / Clark, Jeffrey W / Blaszkowsky, Lawrence S / Deshpande, Vikram / Niemierko, Andrzej / Allen, Jill N / Kwak, Eunice L / Wadlow, Raymond C / Zhu, Andrew X / Warshaw, Andrew L / Hong, Theodore S. ·Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA, USA. ·Int J Radiat Oncol Biol Phys · Pubmed #22414286.

ABSTRACT: PURPOSE: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. METHODS AND MATERIALS: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). RESULTS: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. CONCLUSIONS: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further evaluation.

13 Article Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer. 2012

Arvold, Nils D / Ryan, David P / Niemierko, Andrzej / Blaszkowsky, Lawrence S / Kwak, Eunice L / Wo, Jennifer Y / Allen, Jill N / Clark, Jeffrey W / Wadlow, Raymond C / Zhu, Andrew X / Fernandez-Del Castillo, Carlos / Hong, Theodore S. ·Harvard Radiation Oncology Program, Boston, Massachusetts, USA. ·Cancer · Pubmed #22020923.

ABSTRACT: BACKGROUND: Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow-up. METHODS: Seventy consecutive patients with unresectable (n = 46) or borderline resectable (n = 24) locally advanced pancreatic cancer were treated with CRT from 2005 to 2009. Patients typically received 50.4 grays in 28 fractions (91%) with concurrent 5-fluorouracil (84%) or capecitabine (14%). Forty patients received CRT alone, and 30 patients received neoadjuvant chemotherapy before CRT for a median of 4 months, typically gemcitabine (93%). All patients without progression after neoadjuvant chemotherapy were offered CRT. RESULTS: Median follow-up was 14.2 months (range, 3-57 months). Fifty-three percent of patients in the CRT group versus 83% in the neoadjuvant chemotherapy before CRT group had unresectable tumors at diagnosis; after completion of CRT, 20% of patients in both groups underwent resection. Compared with CRT alone, the neoadjuvant chemotherapy before CRT group demonstrated improved median overall survival (OS; 18.7 vs 12.4 months; P = .02) and progression-free survival (11.4 vs 6.7 months; P = .02). On multivariate analysis, receipt of neoadjuvant chemotherapy (adjusted hazard ratio [HR], 0.49; 95% CI, 0.28-0.87; P = .02) and surgical resection (adjusted HR, 0.38; 95% CI, 0.17-0.85; P = .02) were associated with increased OS. CONCLUSIONS: Gemcitabine-based neoadjuvant chemotherapy confers a significant OS advantage by allowing the selection of patients who will derive greatest benefit from CRT. Median survival with this approach was similar to that seen with surgical resection.