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Pancreatic Neoplasms: HELP
Articles by Philip Agop Philip
Based on 56 articles published since 2008
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Between 2008 and 2019, P. Philip wrote the following 56 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018

Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.

ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

2 Guideline Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. 2016

Sohal, Davendra P S / Mangu, Pamela B / Khorana, Alok A / Shah, Manish A / Philip, Philip A / O'Reilly, Eileen M / Uronis, Hope E / Ramanathan, Ramesh K / Crane, Christopher H / Engebretson, Anitra / Ruggiero, Joseph T / Copur, Mehmet S / Lau, Michelle / Urba, Susan / Laheru, Daniel. ·Davendra P.S. Sohal and Alok A. Khorana, Cleveland Clinic, Cleveland, OH · Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA · Manish A. Shah, The Weill Cornell Medical Center · Philip A. Philip, Karmanos Cancer Institute, Detroit · Susan Urba, University of Michigan Cancer Center, Ann Arbor, MI · Eileen M. O'Reilly, Memorial Sloan Kettering Cancer Center · Joseph T. Ruggiero, Weill Cornell Medical College, New York, NY · Hope E. Uronis, Duke University, Durham, NC · Ramesh K. Ramanathan, Mayo Clinic, Scottsdale · Michelle Lau, Community Hospital Based Cancer Center, Tempe, AZ · Christopher H. Crane, The University of Texas MD Anderson Cancer Center, Houston, TX · Anitra Engebretson, Patient Representative, Portland, OR · Mehmet S. Copur, St Francis Medical Center, Grand Island, NE · and Daniel Laheru, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. ·J Clin Oncol · Pubmed #27247222.

ABSTRACT: PURPOSE: To provide evidence-based recommendations to oncologists and others for the treatment of patients with metastatic pancreatic cancer. METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts to conduct a systematic review of the literature from April 2004 to June 2015. Outcomes were overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS: Twenty-four randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. Goals of care, patient preferences, treatment response, psychological status, support systems, and symptom burden should guide decisions for treatments. A palliative care referral should occur at first visit. FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; favorable comorbidity profile) or gemcitabine plus nanoparticle albumin-bound (NAB) -paclitaxel (adequate comorbidity profile) should be offered to patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1 based on patient preference and support system available. Gemcitabine alone is recommended for patients with ECOG PS 2 or with a comorbidity profile that precludes other regimens; the addition of capecitabine or erlotinib may be offered. Patients with an ECOG PS ≥ 3 and poorly controlled comorbid conditions should be offered cancer-directed therapy only on a case-by-case basis; supportive care should be emphasized. For second-line therapy, gemcitabine plus NAB-paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX, an ECOG PS 0 to 1, and a favorable comorbidity profile; fluorouracil plus oxaliplatin, irinotecan, or nanoliposomal irinotecan should be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, ECOG PS 0 to 1, and favorable comorbidity profile, and gemcitabine or fluorouracil should be offered to patients with either an ECOG PS 2 or a comorbidity profile that precludes other regimens. Additional information is available at www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki.

3 Guideline Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors. 2015

Strosberg, Jonathan R / Fisher, George A / Benson, Al B / Anthony, Lowell B / Arslan, Bulent / Gibbs, John F / Greeno, Edward / Iyer, Renuka V / Kim, Michelle K / Maples, William J / Philip, Philip A / Wolin, Edward M / Cherepanov, Dasha / Broder, Michael S. ·Jonathan R Strosberg, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States. ·World J Gastroenterol · Pubmed #25741154.

ABSTRACT: AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk. CONCLUSION: Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

4 Editorial Locally advanced pancreatic cancer: where should we go from here? 2011

Philip, Philip Agop. · ·J Clin Oncol · Pubmed #21969514.

ABSTRACT: -- No abstract --

5 Review Adjuvant treatment of surgically resectable pancreatic ductal adenocarcinoma. 2019

Tesfaye, Anteneh A / Philip, Philip A. ·Wayne State University, Detroit, Michigan. ·Clin Adv Hematol Oncol · Pubmed #30843899.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortality in the United States. Surgical resection of early and localized disease provides the only chance for a cure; however, the majority of patients who have PDAC present with advanced disease that cannot be removed surgically. In the minority of patients who undergo surgical resection, there is a high rate of disease recurrence that eventually leads to death. The use of systemic therapy improves the outcome of patients who undergo surgery by targeting early micrometastatic disease. This review focuses on the medical management (both chemotherapy and radiation therapy) of surgically resectable pancreatic cancer, including the findings of recent practice-changing clinical trials that favor combination chemotherapy for adjuvant treatment and neoadjuvant chemoradiation therapy. The review also highlights important ongoing trials that aim to improve outcomes in patients with resectable pancreatic cancer.

6 Review Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. 2019

Diab, Maria / Azmi, Asfar / Mohammad, Ramzi / Philip, Philip A. ·a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA. · b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA. ·Expert Opin Pharmacother · Pubmed #30592647.

ABSTRACT: INTRODUCTION: Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED: This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION: Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.

7 Review The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities. 2018

Tesfaye, Anteneh A / Kamgar, Mandana / Azmi, Asfar / Philip, Philip A. ·a Department of Oncology, School of Medicine , Wayne State University , Detroit , MI , USA. · b Department of Oncology , Barbara Ann Karmanos Cancer Institute , Detroit , MI , USA. · c Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA. ·Expert Rev Anticancer Ther · Pubmed #29254387.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches. Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches. Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches.

8 Review Evolving standards of care for resected pancreatic cancer. 2017

Weinberg, Benjamin A / Philip, Philip A / Salem, Mohamed E. ·The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. · Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. ·Clin Adv Hematol Oncol · Pubmed #28398285.

ABSTRACT: Pancreatic cancer is a devastating illness, and surgical resection offers the only chance of a cure for patients with the disease. Relatively few patients have resectable disease at diagnosis, however, and the cancer frequently recurs even after complete surgical resection. This review discusses clinical trials in which adjuvant therapy with chemotherapy or chemoradiation has prolonged survival in patients following surgery. It also highlights new data from the ESPAC-4 and JASPAC 01 studies that may change the current treatment paradigm for adjuvant therapy. The ESPAC-4 results support the use of adjuvant gemcitabine plus capecitabine in preference to the previous standard of gemcitabine alone, demonstrating that in this instance, more may be better. Finally, the review discusses ongoing trials and new approaches that aim to improve outcomes further for patients with resectable pancreatic cancer.

9 Review Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer. 2015

Philip, Philip A / Lutz, Manfred P. ·From the *Barbara Ann Karmanos Cancer Institute, Detroit, MI; and †CaritasKlinikum Saarbrücken, Saarbrücken, Germany. ·Pancreas · Pubmed #26355547.

ABSTRACT: Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

10 Review Systems biology approaches to pancreatic cancer detection, prevention and treatment. 2014

Alian, Osama M / Philip, Philip A / Sarkar, Fazlul H / Azmi, Asfar S. ·Department of Pathology, Wayne State University School of Medicine, 4100 John R, HWCRC Room 732, Detroit MI, 48201 USA. azmia@karmanos.org. ·Curr Pharm Des · Pubmed #23530496.

ABSTRACT: Pancreatic cancer [PC] is a complex disease harboring multiple genetic alterations. It is now well known that deregulation in the expression and function of oncogenes and tumor suppressor genes contributes to the development and progression of PC. The last 40 years have not seen any major improvements in the dismal overall cure rate for PC where drug resistance is an emerging and recurring obstacle for successful treatment of PC. Additionally, the lack of molecular biomarkers for patient selection limits drug availabilities for tailored therapy for patients diagnosed with PC. The very high failure rate of new drugs in Phase III clinical trials in PC calls for a more robust pre-clinical and clinical testing of new compounds. In order to rationally choose combinations of targeted agents that may improve therapeutic outcome by overcoming drug resistance, one needs to apply newer research tools such as systems and network biology. These newer tools are expected to assist in the design of effective drug combinations for the treatment of PC and are expected to become an important part in any future clinical trials. In this review we will provide background information on the current state of PC research, the reasons for drug failure and how to overcome these issues using systems sciences. We conclude this review with an example on how systems and network methodologies can help in the design efficacious drug combinations for this deadly and by far incurable disease.

11 Review Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. 2013

Katz, Matthew H G / Marsh, Robert / Herman, Joseph M / Shi, Qian / Collison, Eric / Venook, Alan P / Kindler, Hedy L / Alberts, Steven R / Philip, Philip / Lowy, Andrew M / Pisters, Peter W T / Posner, Mitchell C / Berlin, Jordan D / Ahmad, Syed A. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhgkatz@mdanderson.org ·Ann Surg Oncol · Pubmed #23435609.

ABSTRACT: BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

12 Review Defining new paradigms for the treatment of pancreatic cancer. 2011

Almhanna, Khaldoun / Philip, Philip A. ·Department of Gastrointestinal Oncolgy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. ·Curr Treat Options Oncol · Pubmed #21461670.

ABSTRACT: Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. Despite significant improvement in understanding disease biology, the 5-year survival rates remain less than 5%. Targeted agents failed to add any meaningful survival benefit in this patient population despite very promising pre-clinical data. The new paradigm for the treatment of PC must emphasize validation of targeted agents in the appropriate pre-clinical models, identification of predictive markers for disease response, and extending range of targets into cancer stem cells and tumor microenvironment. It is also necessary to perform studies that are designed to address the various stages of disease with respect to study endpoints and application of a multimodality approach in management. Phase III trials should only be considered when a strong efficacy signal is demonstrated in phase II studies that is based on a survival endpoint. This review will focus on the development of novel treatments in pancreas cancer and the proposed design of future clinical trials.

13 Review Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations. 2010

Azmi, Asfar S / Wang, Zhiwei / Philip, Philip A / Mohammad, Ramzi M / Sarkar, Fazlul H. ·Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R St, Detroit, Michigan 48201, USA. ·Mol Cancer Ther · Pubmed #21041384.

ABSTRACT: Cancer therapies that target key molecules have not fulfilled expected promises for most common malignancies. Major challenges include the incomplete understanding and validation of these targets in patients, the multiplicity and complexity of genetic and epigenetic changes in the majority of cancers, and the redundancies and cross-talk found in key signaling pathways. Collectively, the uses of single-pathway targeted approaches are not effective therapies for human malignancies. To overcome these barriers, it is important to understand the molecular cross-talk among key signaling pathways and how they may be altered by targeted agents. Innovative approaches are needed, such as understanding the global physiologic environment of target proteins and the effects of modifying them without losing key molecular details. Such strategies will aid the design of novel therapeutics and their combinations against multifaceted diseases, in which efficacious combination therapies will focus on altering multiple pathways rather than single proteins. Integrated network modeling and systems biology have emerged as powerful tools benefiting our understanding of drug mechanisms of action in real time. This review highlights the significance of the network and systems biology-based strategy and presents a proof of concept recently validated in our laboratory using the example of a combination treatment of oxaliplatin and the MDM2 inhibitor MI-219 in genetically complex and incurable pancreatic adenocarcinoma.

14 Review PAR-4 as a possible new target for pancreatic cancer therapy. 2010

Azmi, Asfar S / Philip, Philip A / Zafar, Syed F / Sarkar, Fazlul H / Mohammad, Ramzi M. ·Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA. azmia@karmanos.org ·Expert Opin Ther Targets · Pubmed #20426700.

ABSTRACT: IMPORTANCE OF THE FIELD: Pancreatic cancer (PC) is a deadly disease that is intractable to currently available treatment regimens. Although well described in different tumors types, the importance of apoptosis inducer prostate apoptosis response-4 (Par-4) in PC has not been appreciated. PC is an oncogenic kras driven disease, which is known to downregulate Par-4. Therefore, this review highlights its significance and builds a strong case supporting the role of Par-4 as a possible therapeutic target in PC. AREAS COVERED IN THIS REVIEW: Literature-based evidence spanning the last 15 years on Par-4 and its significance in PC. WHAT THE READER WILL GAIN: This review provides comprehensive knowledge of the significance of Par-4 and its association with kras status in PC, along with the crosstalk with crucial resistance and survival molecules NF-kappaB and Bcl-2 that ultimately are responsible for the overall poor outcome of different therapeutic approaches in this disease. TAKE HOME MESSAGE: Par-4 holds promise as a potential therapeutic target that can be induced by chemopreventive agents and small-molecule inhibitors either alone or in combination with standard chemotherapeutics leading to selective apoptosis in PC cells. It also acts as a chemosensitizer and therefore warrants further clinical investigations in this disease.

15 Review MDM2 inhibitors for pancreatic cancer therapy. 2010

Azmi, Asfar S / Philip, Philip A / Almhanna, Khaldoun / Beck, Frances W / Sarkar, Fazlul H / Mohammad, Ramzi M. ·Hematology and Oncology, Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, 732 HWCRC, 4100 John R Street, Detroit, MI 48201, USA. ·Mini Rev Med Chem · Pubmed #20377522.

ABSTRACT: MDM2 protein negatively regulates p53 and is found to be elevated in cancer cells. An attractive approach towards targeting MDM2 is the use of small molecule inhibitors that bind to MDM2 and disrupt the MDM2-p53 interaction. Our laboratory has been at the forefront in testing MDM2 inhibitors in pancreatic adenocarcinoma (PaCa), a deadly disease with approximately 50% wild-type p53 population. Emerging evidence suggests that apart from regulating p53, MDM2 can influence other key molecules involved in cancer. This review summarizes recent advancements in the development of MDM2 inhibitors, their novel primary and secondary targets and highlights their potential as therapeutics for PaCa.

16 Review Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. 2009

Philip, Philip A / Mooney, Margaret / Jaffe, Deborah / Eckhardt, Gail / Moore, Malcolm / Meropol, Neal / Emens, Leisha / O'Reilly, Eileen / Korc, Murray / Ellis, Lee / Benedetti, Jacqueline / Rothenberg, Mace / Willett, Christopher / Tempero, Margaret / Lowy, Andrew / Abbruzzese, James / Simeone, Diane / Hingorani, Sunil / Berlin, Jordan / Tepper, Joel. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #19858397.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

17 Clinical Trial An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204). 2018

Berlin, Jordan D / Feng, Yang / Catalano, Paul / Abbruzzese, James L / Philip, Philip A / McWilliams, Robert R / Lowy, Andrew M / Benson, Al B / Blackstock, A William. ·Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. ·Oncology · Pubmed #29040974.

ABSTRACT: OBJECTIVES: Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS: Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS: A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS: Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.

18 Clinical Trial Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. 2017

Chung, Vincent / McDonough, Shannon / Philip, Philip A / Cardin, Dana / Wang-Gillam, Andrea / Hui, Laifong / Tejani, Mohamedtaki A / Seery, Tara E / Dy, Irene A / Al Baghdadi, Tareq / Hendifar, Andrew E / Doyle, L Austin / Lowy, Andrew M / Guthrie, Katherine A / Blanke, Charles D / Hochster, Howard S. ·City of Hope National Medical Center, Duarte, California. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. · Vanderbilt University Medical Center, Nashville, Tennessee. · Washington University in St Louis, St Louis, Missouri. · Kaiser Permanente NCORP, Sacramento, California. · University of Rochester, Rochester, New York. · University of California, Irvine, Orange. · Crossroads Cancer Center/Heartland NCORP, Effingham, Illinois. · St Joseph Mercy Hospital/Michigan CRC NCORP, Ann Arbor. · Cedars-Sinai Medical Center, Los Angeles, California. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland. · University of California, San Diego, La Jolla. · SWOG Group Chair's Office/Knight Cancer Institute, Oregon Health and Science University, Portland. · Yale Cancer Center, New Haven, Connecticut. ·JAMA Oncol · Pubmed #27978579.

ABSTRACT: Importance: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration: clinicaltrials.gov Identifier: NCT01658943.

19 Clinical Trial Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. 2016

Katz, Matthew H G / Shi, Qian / Ahmad, Syed A / Herman, Joseph M / Marsh, Robert de W / Collisson, Eric / Schwartz, Lawrence / Frankel, Wendy / Martin, Robert / Conway, William / Truty, Mark / Kindler, Hedy / Lowy, Andrew M / Bekaii-Saab, Tanios / Philip, Philip / Talamonti, Mark / Cardin, Dana / LoConte, Noelle / Shen, Perry / Hoffman, John P / Venook, Alan P. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, University of Cincinnati, Cincinnati, Ohio. · Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland. · Department of Medical Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, University of California-San Francisco, San Francisco. · Department of Radiology, Columbia University, New York, New York. · Department of Pathology, Ohio State University, Columbus. · Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, University of Chicago, Chicago, Illinois. · Department of Surgery, University of California, San Diego. · Department of Medical Oncology, Ohio State University, Columbus. · Department of Medical Oncology, Karmanos Cancer Center, Detroit, Michigan. · Department of Surgery, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, Vanderbilt University, Nashville, Tennessee. · Department of Medical Oncology, University of Wisconsin-Madison, Madison, Wisconsin. · Department of Surgery, Wake Forest University, Winston Salem, North Carolina. · Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. ·JAMA Surg · Pubmed #27275632.

ABSTRACT: IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

20 Clinical Trial Multi-institutional phase I study of low-dose ultra-fractionated radiotherapy as a chemosensitizer for gemcitabine and erlotinib in patients with locally advanced or limited metastatic pancreatic cancer. 2014

Konski, Andre / Meyer, Joshua E / Joiner, Michael / Hall, Michael J / Philip, Philip / Shields, Anthony / McSpadden, Erin / Choi, Minsig / Adaire, Beth / Duncan, Gail / Meropol, Neal J / Cescon, Terrence P / Cohen, Steven J. ·Department of Radiation Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA. Electronic address: andre.konski@uphs.upenn.edu. · Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, USA. · Department of Radiation Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, USA. · Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit, USA. · Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, USA. · University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, USA. · Reading Hospital and Medical Center, Reading, USA. ·Radiother Oncol · Pubmed #25441058.

ABSTRACT: PURPOSE: Gemcitabine (G) has been shown to sensitize pancreatic cancer to radiotherapy but requires lower doses of G and thus delays aggressive systemic treatment, potentially leading to distant failure. We initiated a phase I trial combining ultra-fractionated low-dose radiotherapy with full dose G and erlotinib in the treatment of patients with advanced pancreatic cancer. METHODS: Patients with locally advanced or metastatic pancreatic cancer confined to the abdomen and an ECOG performance status (PS) of 0-1 who had received 0-1 prior regimens (without G or E) and no prior radiotherapy were eligible. Patients were treated in 21 day cycles with G IV days 1 & 8, E once PO QD, and twice daily RT fractions separated by at least 4h on days 1, 2, 8, and 9. Whole abdominal RT fields were used. Primary endpoint was to define dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). RESULTS: 27 patients (median age 64 years and 15 male) were enrolled between 11/24/08 and 4/12/12. 1 patient withdrew consent prior to receiving any protocol therapy. 17 patients had a PS of 1. The majority of patients were stage IV. One DLT was noted out of 7 patients at dose level (DL) 1. Subsequently no DLTs were noted in 3 patients each enrolled at DL2-4 or 11 patients in the expansion cohort. The majority of grade 3 toxicities were hematologic with 1 grade 5 bowel perforation in dose level 1 in cycle 4. Best response in 24 evaluable patients: PR (8), stable (15), PD 1. Median survival for the entire group was 9.1 months. CONCLUSION: This phase I study combining low-dose ultra-fractionated RT as a sensitizer to full dose G plus E was well tolerated with encouraging efficacy. This represents a novel strategy worthy of further investigation in advanced pancreatic cancer patients.

21 Clinical Trial Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). 2014

Philip, Philip A / Goldman, Bryan / Ramanathan, Ramesh K / Lenz, Heinz-Josef / Lowy, Andrew M / Whitehead, Robert P / Wakatsuki, Takeru / Iqbal, Syma / Gaur, Rakesh / Benedetti, Jacqueline K / Blanke, Charles D. ·Wayne State University, Karmanos Cancer Institute, Detroit, Michigan. ·Cancer · Pubmed #25041791.

ABSTRACT: BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

22 Clinical Trial Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. 2013

Rougier, Philippe / Riess, Hanno / Manges, Robert / Karasek, Petr / Humblet, Yves / Barone, Carlo / Santoro, Armando / Assadourian, Sylvie / Hatteville, Laurence / Philip, Philip A. ·Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France. philippe.rougier@egp.aphp.fr ·Eur J Cancer · Pubmed #23642329.

ABSTRACT: BACKGROUND: This phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m(2) i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms. RESULTS: The study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n=275) versus 6.5 months in the gemcitabine plus aflibercept arm (n=271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921-1.473, p=0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%). CONCLUSION: Adding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.

23 Clinical Trial A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. 2011

El-Rayes, Bassel Fuad / Philip, Philip A / Sarkar, Fazlul H / Shields, Anthony F / Ferris, Ann Marie / Hess, Kenneth / Kaseb, Ahmad O / Javle, Milind M / Varadhachary, Gauri R / Wolff, Robert A / Abbruzzese, James L. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. belraye@emory.edu ·Invest New Drugs · Pubmed #20107864.

ABSTRACT: BACKGROUND: The EGFR/Akt/NF-κB signalling pathway is frequently deregulated in pancreatic cancer and contributes to cell growth, metastasis and chemoresistance. An isoflavone, genistein, inactivates Akt and NF-κB and enhances the anti-tumor activity of erlotinib and gemcitabine in experimental systems of pancreas cancer. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib on survival in patients with advanced pancreatic cancer. METHODS: Eligibility included previously untreated patients with advanced pancreatic adenocarcinoma. Patients received gemcitabine 1,000 mg/m² on days 1, 8, and 15, and erlotinib 150 mg once daily P.O. on day 1 to day 28. Soy isoflavones (Novasoy®) were administered at a dose of 531 mg twice daily P.O. starting day -7 until the end of study participation. RESULTS: Twenty patients with advanced pancreas cancer were enrolled (median age 57.9 years). Sixteen patients had stage IV disease. The median number of cycles was 2 per patient. The median survival time was 5.2 months (95% CI, 4.6-N/A months). The probability of survival at 6 months was 50% (95% CI, 32-78%). CONCLUSIONS: The addition of soy isoflavones to gemcitabine and erlotinib did not appear to increase the survival of patients with advanced pancreatic cancer.

24 Clinical Trial Pain and emotional well-being outcomes in Southwest Oncology Group-directed intergroup trial S0205: a phase III study comparing gemcitabine plus cetuximab versus gemcitabine as first-line therapy in patients with advanced pancreas cancer. 2010

Moinpour, Carol M / Vaught, Nancy L / Goldman, Bryan / Redman, Mary W / Philip, Philip A / Millwood, Barbara / Lippman, Scott M / Seay, Thomas E / Flynn, Patrick J / O'Reilly, Eileen M / Rowland, Kendrith M / Wong, Ralph P / Benedetti, Jacqueline / Blanke, Charles D. ·Southwest Oncology Group Statistical Center, Seattle, WA 98105, USA. cmoinpou@fhcrc.org ·J Clin Oncol · Pubmed #20606094.

ABSTRACT: PURPOSE: S0205 was a randomized clinical trial that compared the therapeutic impact of gemcitabine versus gemcitabine plus cetuximab. Study results for patient-reported health-related quality of life (HRQL) outcomes are reported. PATIENTS AND METHODS: Patients completed the Brief Pain Inventory and a measure of emotional well-being (each measured on a 0 to 10 scale) at baseline and at weeks 5, 9, 13, and 17 postrandom assignment. Worst pain status was classified as palliated (worst pain scores < 5 maintained for 2 consecutive cycles) or not palliated (remaining patients) and tested with a chi(2) test. Change in emotional well-being and worst pain (exploratory analysis) were assessed over 17 weeks using generalized estimating equations with inverse probability of censoring weights. RESULTS: Seven hundred twenty of 766 enrolled patients contributed baseline HRQL data. The two treatment arms did not differ statistically in the percentage of patients with successful worst pain palliation. Longitudinal analyses showed significantly improved emotional well-being for patients on both arms by weeks 13 and 17 (P < .01 and P < .001). An exploratory longitudinal analysis of worst pain showed significant decreases at all time points for both arms (P < .01 and P < .001). Significant treatment arm differences for either worst pain or emotional well-being were not observed at any of the assessment times. CONCLUSION: We observed palliated pain and improved well-being for patients on this trial. However, these improvements were similar in both treatment arms, suggesting that the addition of cetuximab did not contribute to improvement in these HRQL outcomes.

25 Clinical Trial Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. 2010

Philip, Philip A / Benedetti, Jacqueline / Corless, Christopher L / Wong, Ralph / O'Reilly, Eileen M / Flynn, Patrick J / Rowland, Kendrith M / Atkins, James N / Mirtsching, Barry C / Rivkin, Saul E / Khorana, Alok A / Goldman, Bryan / Fenoglio-Preiser, Cecilia M / Abbruzzese, James L / Blanke, Charles D. ·Wayne State University, Karmanos Cancer Institute, GI Oncology, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #20606093.

ABSTRACT: PURPOSE: Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. PATIENTS AND METHODS: Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. RESULTS: A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. CONCLUSION: In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

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