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Ko AH, Oh D, Lau J, Mhatre SK, Ci B, Machado R, Li S, Bretscher MT, Reyes‐Rivera I, Zhu J, Zhang X, Patel J, Psioda MA, Ponz‐Sarvise M. Investigational Use of Real-World Data as a Hybrid Control in Pancreatic Ductal Adenocarcinoma From the Randomized Phase Ib/II MORPHEUS Trial. Clin Pharmacol Ther 2025; 117:1021-1029. [PMID: 39707623 PMCID: PMC11924154 DOI: 10.1002/cpt.3528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
Enrolling adequate numbers of patients into the control arm of randomized controlled trials (RCTs) often presents barriers. There is interest in leveraging real-world data (RWD) from electronic health records (EHRs) to construct external control (EC) arms to supplement RCT control arms and form hybrid control (HC) arms. This investigation showed the use of an HC arm in second-line metastatic pancreatic ductal adenocarcinoma (PDAC). The RCT experimental arm (atezolizumab + PEGylated recombinant human hyaluronidase (Atezo + PEGPH20)) was compared with an HC arm consisting of patients treated with modified FOLFOX6 or gemcitabine/nab-paclitaxel from the MORPHEUS PDAC internal control arm supplemented with data from a nationwide EHR-derived de-identified database as the EC arm. The EC arm was constructed by applying key inclusion/exclusion criteria from the MORPHEUS PDAC trial to patients from the real-world cohort. Baseline variables were balanced using propensity score matching and covariate adjustment. Three analysis approaches-Cox model with pooled-control data, Cox model with control arm-specific frailty, and Bayesian analysis using a commensurate prior-were assessed. Overall survival was similar between the treatment arms. The direction and magnitude of hazard ratios (HRs) from the multiple HC analyses (HRs ranged from 1.02 to 1.06) were comparable with the reported trial HR (HR 0.91; 95% CI: 0.56, 1.49). This analysis demonstrates the feasibility and applicability of leveraging RWD in clinical trial design to supplement clinical trial control arms.
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Affiliation(s)
- Andrew H. Ko
- University of California San FranciscoSan FranciscoCaliforniaUSA
| | - Do‐Youn Oh
- Seoul National University Hospital, Cancer Research InstituteSeoul National University College of MedicineSeoulRepublic of Korea
| | - Janet Lau
- Genentech, Inc.South San FranciscoCaliforniaUSA
| | - Shivani K. Mhatre
- Genentech, Inc.South San FranciscoCaliforniaUSA
- Present address:
Gilead BiosciencesFoster CityCaliforniaUSA
| | - Bo Ci
- Genentech, Inc.South San FranciscoCaliforniaUSA
| | | | - Shi Li
- Genentech, Inc.South San FranciscoCaliforniaUSA
| | | | | | - Jiawen Zhu
- Genentech, Inc.South San FranciscoCaliforniaUSA
| | - Xiaosong Zhang
- Genentech, Inc.South San FranciscoCaliforniaUSA
- Present address:
PfizerNew YorkNew YorkUSA
| | - Jilpa Patel
- Genentech, Inc.South San FranciscoCaliforniaUSA
- Present address:
Gilead BiosciencesFoster CityCaliforniaUSA
| | - Matthew A. Psioda
- Department of Biostatistics, Gillings School of Global Public HealthUniversity of North CarolinaChapel HillNorth CarolinaUSA
- Present address:
GlaxoSmithKlinePhiladelphiaPennsylvaniaUSA
| | - Mariano Ponz‐Sarvise
- Cancer Center Clinica Universidad de Navarra and Program in Solid Tumors (CIMA)Universidad de Navarra, IDISNAPamplonaSpain
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Chen J, Li XN, Lu CC, Yuan S, Yung G, Ye J, Tian H, Lin J. Considerations for master protocols using external controls. J Biopharm Stat 2025; 35:297-319. [PMID: 38363805 DOI: 10.1080/10543406.2024.2311248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 01/24/2024] [Indexed: 02/18/2024]
Abstract
There has been an increasing use of master protocols in oncology clinical trials because of its efficiency to accelerate cancer drug development and flexibility to accommodate multiple substudies. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g. external controls) for treatment effect estimation, which can further improve efficiency of master protocol trials. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands, assessment of fit-for-use real-world data, and considerations for different types of master protocols. Similarities and differences between regular randomized controlled trials and master protocols when using external controls are discussed. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing sensitivity analyses. Two illustrative examples for master protocols using external controls are discussed for their merits and possible improvement in causal effect estimation.
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Affiliation(s)
- Jie Chen
- Data Sciences, ECR Global, Shanghai, China
| | | | | | - Sammy Yuan
- Oncology Statistics, GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | - Godwin Yung
- Product Development Data and Statistical Sciences, Genentech/Roche, South San Francisco, Cambridge, USA
| | - Jingjing Ye
- Global Statistics and Data Sciences, BeiGene, Fulton, Maryland, USA
| | - Hong Tian
- Global Statistics, BeiGene, Ridgefield Park, New Jersy, USA
| | - Jianchang Lin
- Statistical & Quantitative Sciences, Takeda, Cambridge, Massachusetts, USA
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Skorupan N, Palestino Dominguez M, Ricci SL, Alewine C. Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:4209. [PMID: 36077755 PMCID: PMC9454553 DOI: 10.3390/cancers14174209] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 12/04/2022] Open
Abstract
Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.
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Affiliation(s)
- Nebojsa Skorupan
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Medical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mayrel Palestino Dominguez
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Samuel L. Ricci
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Christine Alewine
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Li C, Ferro A, Mhatre SK, Lu D, Lawrance M, Li X, Li S, Allen S, Desai J, Fakih M, Cecchini M, Pedersen KS, Kim TY, Reyes-Rivera I, Segal NH, Lenain C. Hybrid-control arm construction using historical trial data for an early-phase, randomized controlled trial in metastatic colorectal cancer. COMMUNICATIONS MEDICINE 2022; 2:90. [PMID: 35856081 PMCID: PMC9287310 DOI: 10.1038/s43856-022-00155-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Treatment for metastatic colorectal cancer patients beyond the second line remains challenging, highlighting the need for early phase trials of combination therapies for patients who had disease progression during or following two prior lines of therapy. Leveraging hybrid control design in these trials may preserve the benefits of randomization while strengthening evidence by integrating historical trial data. Few examples have been established to assess the applicability of such design in supporting early phase metastatic colorectal cancer trials. METHODS MORPHEUS-CRC is an umbrella, multicenter, open-label, phase Ib/II, randomized, controlled trial (NCT03555149), with active experimental arms ongoing. Patients enrolled were assigned to a control arm (regorafenib, 15 patients randomized and 13 analysed) or multiple experimental arms for immunotherapy-based treatment combinations. One experimental arm (atezolizumab + isatuximab, 15 patients randomized and analysed) was completed and included in the hybrid-control study, where the hybrid-control arm was constructed by integrating data from the IMblaze370 phase 3 trial (NCT02788279). To estimate treatment efficacy, Cox and logistic regression models were used in a frequentist framework with standardized mortality ratio weighting or in a Bayesian framework with commensurate priors. The primary endpoint is objective response rate, while disease control rate, progression-free survival, and overall survival were the outcomes assessed in the hybrid-control study. RESULTS The experimental arm showed no efficacy signal, yet a well-tolerated safety profile in the MORPHEUS-CRC trial. Treatment effects estimated in hybrid control design were comparable to those in the MORPHEUS-CRC trial using either frequentist or Bayesian models. CONCLUSIONS Hybrid control provides comparable treatment-effect estimates with generally improved precision, and thus can be of value to inform early-phase clinical development in metastatic colorectal cancer.
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Affiliation(s)
- Chen Li
- Roche Products Limited, Welwyn Garden City, UK
| | - Ana Ferro
- Roche Products Limited, Welwyn Garden City, UK
| | | | - Danny Lu
- Hoffmann-La Roche Limited, Mississauga, ON Canada
| | | | - Xiao Li
- Genentech, Inc., South San Francisco, CA US
| | - Shi Li
- Genentech, Inc., South San Francisco, CA US
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC Australia
| | - Marwan Fakih
- City of Hope Comprehensive Cancer Center, Duarte, CA USA
| | | | | | - Tae You Kim
- Seoul National University College of Medicine, Seoul, South Korea
| | | | - Neil H. Segal
- Memorial Sloan Kettering Cancer Center, New York City, NY USA
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Narayanan S, Vicent S, Ponz-Sarvisé M. PDAC as an Immune Evasive Disease: Can 3D Model Systems Aid to Tackle This Clinical Problem? Front Cell Dev Biol 2021; 9:787249. [PMID: 34957115 PMCID: PMC8703167 DOI: 10.3389/fcell.2021.787249] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/22/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, “hot” tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.
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Affiliation(s)
- Shruthi Narayanan
- Clinica Universidad de Navarra, Medical Oncology Department, Pamplona, Spain
- Program in Solid Tumors, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Silve Vicent
- Program in Solid Tumors, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
- *Correspondence: Silve Vicent, ; Mariano Ponz-Sarvisé,
| | - Mariano Ponz-Sarvisé
- Clinica Universidad de Navarra, Medical Oncology Department, Pamplona, Spain
- Program in Solid Tumors, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
- *Correspondence: Silve Vicent, ; Mariano Ponz-Sarvisé,
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Kole C, Charalampakis N, Tsakatikas S, Kouris NI, Papaxoinis G, Karamouzis MV, Koumarianou A, Schizas D. Immunotherapy for gastric cancer: a 2021 update. Immunotherapy 2021; 14:41-64. [PMID: 34784774 DOI: 10.2217/imt-2021-0103] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer, the fifth most frequent cancer and the fourth leading cause of cancer deaths, accounts for a devastating death rate worldwide. Since the majority of patients with gastric cancer are diagnosed at advanced stages, they are not suitable for surgery and present with locally advanced or metastatic disease. Recent advances in immunotherapy have elicited a considerable amount of attention as viable therapeutic options for several cancer types. This work presents a summary of the currently ongoing clinical trials and critically addresses the efficacy of a large spectrum of immunotherapy approaches in the general population for gastric cancer as well as in relation to tumor genetic profiling.
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Affiliation(s)
- Christo Kole
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | | | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital, Athens, 185 37, Greece
| | - Nikolaos-Iasonas Kouris
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - George Papaxoinis
- Second Department of Medical Oncology, Agios Savas Anticancer Hospital, Athens, 115 22, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National & Kapodistrian University of Athens, Athens, 115 27, Greece
| | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, 124 62, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
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Tsang ES, Lim HJ, Renouf DJ, Davies JM, Loree JM, Gill S. Real-world treatment attrition rates in advanced esophagogastric cancer. World J Gastroenterol 2020; 26:6027-6036. [PMID: 33132652 PMCID: PMC7584053 DOI: 10.3748/wjg.v26.i39.6027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/24/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Over the last decade, multiple agents have demonstrated efficacy for advanced esophagogastric cancer (EGC). Despite the availability of later lines of therapy, there remains limited real-world data about the treatment attrition rates between lines of therapy.
AIM To characterize the use and attrition rates between lines of therapy for patients with advanced EGC.
METHODS We identified patients who received at least one cycle of chemotherapy for advanced EGC between July 1, 2017 and July 31, 2018 across six regional centers in British Columbia (BC), Canada. Clinicopathologic, treatment, and outcomes data were extracted.
RESULTS Of 245 patients who received at least one line of therapy, median age was 66 years (IQR 58.2-72.3) and 186 (76%) were male, Eastern Cooperative Oncology Group (ECOG) performance status 0/1 (80%), gastric vs GEJ (36% vs 64%). Histologies included adenocarcinoma (78%), squamous cell carcinoma (8%), and signet ring (14%), with 31% HER2 positive. 72% presented with de novo disease, and 25% had received previous chemoradiation. There was a high level of treatment attrition, with patients receiving only one line of therapy n = 122, 50%), two lines n = 83, 34%), three lines n = 34, 14%), and four lines n = 6, 2%). Kaplan-Meier analysis demonstrated improved survival with increasing lines of therapy (median overall survival 7.7 vs 16.6 vs 22.8 vs 40.4 mo, P < 0.05). On multivariable Cox regression, improved survival was associated with better baseline ECOG and increased lines of therapy (P < 0.05).
CONCLUSION The steep attrition rates between therapies highlight the unmet need for more efficacious early-line treatment options for patients with advanced EGC.
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Affiliation(s)
- Erica S Tsang
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
| | - Howard J Lim
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
| | - Daniel J Renouf
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
| | - Janine M Davies
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
| | - Jonathan M Loree
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
| | - Sharlene Gill
- Department of Medicine, BC Cancer, Vancouver V5Z 4E6, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver V5Z 4E6, Canada
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Siolas D, Morrissey C, Oberstein PE. The Achilles' Heel of Pancreatic Cancer: Targeting pancreatic cancer's unique immunologic characteristics and metabolic dependencies in clinical trials. JOURNAL OF PANCREATOLOGY 2020; 3:121-131. [PMID: 33133736 PMCID: PMC7595263 DOI: 10.1097/jp9.0000000000000052] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and is notoriously refractory to multiple cancer treatments. In recent years, cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers. Despite robust pre-clinical research, these novel therapies have only had a small impact on PDAC. However, there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly (ADP-ribose) polymerase inhibitors for select subsets of PDAC patients. In this clinical review, we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets, and focus on clinical trials designed to test novel agents in PDAC. The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results, but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.
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Affiliation(s)
- Despina Siolas
- Department of Medicine, Pancreatic Cancer Center, Perlmutter Comprehensive Cancer Center, NYU Langone Health, New York, NY
| | - Christy Morrissey
- Department of Medicine, Pancreatic Cancer Center, Perlmutter Comprehensive Cancer Center, NYU Langone Health, New York, NY
| | - Paul Eliezer Oberstein
- Department of Medicine, Pancreatic Cancer Center, Perlmutter Comprehensive Cancer Center, NYU Langone Health, New York, NY
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Okusaka T, Furuse J. Recent advances in chemotherapy for pancreatic cancer: evidence from Japan and recommendations in guidelines. J Gastroenterol 2020; 55:369-382. [PMID: 31997007 PMCID: PMC7080663 DOI: 10.1007/s00535-020-01666-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 01/07/2020] [Indexed: 02/04/2023]
Abstract
The prognosis of patients with pancreatic cancer continues to remain dismal, even though numerous trials have been conducted to establish more effective therapies in Japan and throughout the world. Recent advances in treatment have been characterized by the use of novel combinations of conventional cytotoxic chemotherapies. Especially in Japan, S-1 has become one of the most widely used cytotoxic agents for the treatment of pancreatic cancer, after clinical evidence was established of the survival benefit offered by this drug for patients with resectable or unresectable pancreatic cancer. Unfortunately, with the exception of erlotinib, no targeted treatment strategies have been approved for pancreatic cancer. However, following an increase in interest in drug development in recent years, proactive attempts have been made to develop new therapeutic strategies, including neoadjuvant chemotherapy for patients with resectable or borderline resectable pancreatic cancer, multi-agent combination chemotherapy for patients with advanced pancreatic cancer, and therapies with new targeted agents or immuno-oncologic agents for patients with pancreatic cancer bearing specific gene mutations.
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Affiliation(s)
- Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Junji Furuse
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan
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Fong CYK, Burke E, Cunningham D, Starling N. Up-to-Date Tailored Systemic Treatment in Pancreatic Ductal Adenocarcinoma. Gastroenterol Res Pract 2019; 2019:7135437. [PMID: 31582971 PMCID: PMC6748185 DOI: 10.1155/2019/7135437] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/09/2019] [Indexed: 12/24/2022] Open
Abstract
Despite intensive research efforts, pancreatic ductal adenocarcinoma is still regarded as an aggressive and life-limiting malignancy. Combination chemotherapy regimens that underpin the current treatment approach in the advanced setting have led to incremental survival gains in recent years but have failed to confer patients with a median overall survival that exceeds 12 months from diagnosis. Research has since focussed on understanding the role and interplay between various components of the desmoplastic stroma and tumour microenvironment, in addition to developing targeted therapies based on molecular features to improve the prognosis associated with this malignancy. This review will summarise the available systemic treatment options and discuss potential methods to refine the resolution of patient selection to enhance responses to currently available therapies. Furthermore, it will explore newer approaches anticipated to come to the fore of future clinical practice, such as agents targeting the DNA damage response and tumour microenvironment as well as immunotherapy-based combinations.
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Affiliation(s)
| | - Emma Burke
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - David Cunningham
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - Naureen Starling
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
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