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Chhabra AM, Amos RA, Simone CB, Kaiser A, Perles LA, Giap H, Hallemeier CL, Johnson JE, Lin H, Wroe AJ, Diffenderfer ES, Wolfgang JA, Sakurai H, Lu HM, Hong TS, Koay EJ, Terashima K, Vitek P, Rule WG, Apisarnthanarax SJ, Badiyan SN, Molitoris JK, Chuong M, Nichols RC. Proton Beam Therapy for Pancreatic Tumors: A Consensus Statement from the Particle Therapy Cooperative Group Gastrointestinal Subcommittee. Int J Radiat Oncol Biol Phys 2025:S0360-3016(24)03769-6. [PMID: 39761799 DOI: 10.1016/j.ijrobp.2024.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 11/02/2024] [Accepted: 12/14/2024] [Indexed: 01/24/2025]
Abstract
Radiation therapy manages pancreatic cancer in various settings; however, the proximity of gastrointestinal (GI) luminal organs at risk (OARs) poses challenges to conventional radiation therapy. Proton beam therapy (PBT) may reduce toxicities compared to photon therapy. This consensus statement summarizes PBT's safe and optimal delivery for pancreatic tumors. Our group has specific expertise using PBT for GI indications and has developed expert recommendations for treating pancreatic tumors with PBT. Computed tomography (CT) simulation: Patients should be simulated supine (arms above head) with custom upper body immobilization. For stomach/duodenum filling consistency, patients should restrict oral intake within 3 hours before simulation/treatments. Fiducial markers may be implanted for image guidance; however, their design and composition require scrutiny. The reconstruction field-of-view should encompass all immobilization devices at the target level (CT slice thickness 2-3 mm). Four-dimensional CT should quantify respiratory motion and guide motion mitigation. Respiratory gating is recommended when motion affects OAR sparing or reduces target coverage. Treatment planning: Beam-angle selection factors include priority OAR-dose minimization, water-equivalent-thickness stability along the beam path, and enhanced relative biological effect consideration due to the increased linear energy transfer at the proton beam end-of-range. Posterior and right-lateral beam angles that avoid traversing GI luminal structures are preferred (minimizing dosimetric impacts of variable anatomies). Pencil beam scanning techniques should use robust optimization. Single-field optimization is preferable to increase robustness, but if OAR constraints cannot be met, multifield optimization may be used. Treatment delivery: Volumetric image guidance should be used daily. CT scans should be acquired ad hoc as necessary (at minimum every other week) to assess the dosimetric impacts of anatomy changes. Adaptive replanning should be performed as required. Our group has developed recommendations for delivering PBT to safely and effectively manage pancreatic tumors.
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Affiliation(s)
- Arpit M Chhabra
- Department of Radiation Oncology, New York Proton Center, New York, New York.
| | - Richard A Amos
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Charles B Simone
- Department of Radiation Oncology, New York Proton Center, New York, New York
| | - Adeel Kaiser
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida
| | - Luis A Perles
- Department of Radiation Physics, MD Anderson Cancer Center, Houston, Texas
| | - Huan Giap
- Department of Radiation Oncology, OSF HealthCare Cancer Institute, Peoria, IL
| | | | | | - Haibo Lin
- Department of Radiation Oncology, New York Proton Center, New York, New York
| | - Andrew J Wroe
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida
| | - Eric S Diffenderfer
- Department of Radiation Oncology, University of Pennsylvania Perelmen School of Medicine, Philadelphia, Pennsylvania
| | - John A Wolfgang
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Hideyuki Sakurai
- Department of Radiation Oncology, University of Tsukuba Faculty of Medicine, Tsukuba, Japan
| | - Hsiao-Ming Lu
- Department of Radiation Oncology, Hefei Ion Medical Center, Hefei, Anhui, People's Republic of China
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Eugene J Koay
- Department of GI Radiation Oncology, MD Anderson Cancer Center, Houston, Texas
| | - Kazuki Terashima
- Department of Radiology, Hyogo Ion Beam Medical Center, Tatsuno, Japan
| | - Pavel Vitek
- Department of Radiation Oncology, Proton Therapy Center Czech, Prague, Czech Republic
| | - William G Rule
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona
| | | | - Shahed N Badiyan
- Department of Radiation Oncology, UT Southwestern, Dallas, Texas
| | - Jason K Molitoris
- Department of Radiation Oncology, University of Maryland Medical System, Baltimore, Maryland
| | - Michael Chuong
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida
| | - Romaine C Nichols
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, Florida
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Miller ED, Ashman JB, Hawkins MA, Jethwa KR, Kim H, Sanford NN, Wojcieszynski AP, Chuong MD. The Dust Has Finally Settled, but Is the View Any Clearer? Int J Radiat Oncol Biol Phys 2024; 120:917-925. [PMID: 39424587 DOI: 10.1016/j.ijrobp.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 10/21/2024]
Affiliation(s)
- Eric D Miller
- Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
| | | | - Maria A Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Krishan R Jethwa
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Hyun Kim
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Nina N Sanford
- Department of Radiation Oncology, University of Texas Southwestern, Dallas, Texas
| | | | - Michael D Chuong
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida
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Iyengar S, Nevala-Plagemann C, Garrido-Laguna I. Updates on adjuvant and neoadjuvant treatment strategies for surgically resectable and borderline resectable pancreatic ductal adenocarcinoma. Ther Adv Med Oncol 2021; 13:17588359211045861. [PMID: 34552668 PMCID: PMC8450613 DOI: 10.1177/17588359211045861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/25/2021] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is the third leading cause of cancer-related mortality in the US. Outcomes for patients with pancreatic cancer are poor as curative approaches are only available to the minority of patients who have localized tumors for which surgery may be an option. The past decade has established fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as the new standard of care following resection for fit patients with resectable pancreatic tumors. However, most patients will relapse and a large number of patients treated with upfront resection are unable to receive or complete adjuvant chemotherapy. There is therefore considerable interest in neoadjuvant treatment strategies for patients with resectable and borderline resectable pancreatic cancer as a way to provide early systemic treatment of micrometastatic disease, facilitate lymph node downstaging, and increase the likelihood of negative resection margins (R0). This review will focus on key aspects of completed trials evaluating adjuvant therapy in resectable pancreatic cancer and will provide an overview of emerging evidence supporting the use of neoadjuvant treatment strategies for both resectable and borderline resectable pancreatic cancer.
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Affiliation(s)
- Siddharth Iyengar
- Department of Internal Medicine, University of Utah School of Medicine, 50 Medical Dr N, Salt Lake City, UT 84132-0002, USA
| | | | - Ignacio Garrido-Laguna
- Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Shi X, Peng J, Jiang H, Gao Y, Wang W, Zhou F. Impact of Adjuvant Chemoradiotherapy on Survival of Resected Pancreatic Adenocarcinoma Cancer: A Surveillance, Epidemiology and End Results (SEER) Analysis. Front Oncol 2021; 11:651671. [PMID: 34277405 PMCID: PMC8281351 DOI: 10.3389/fonc.2021.651671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/15/2021] [Indexed: 12/24/2022] Open
Abstract
Background The benefits of postoperative adjuvant chemoradiotherapy (CRT) for pancreatic cancer remain controversial. The purpose of this study is to determine if adjuvant CRT can improve the overall survival of postoperative pancreatic cancer patients compared to adjuvant chemotherapy (CT). Methods Patients with resected pancreas adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016). Multivariate Cox regression was used to determine the factors related to survival rate. Selection bias was reduced to a minimum through propensity matching analysis. Subgroup analyses by clinical characteristics were performed. Results This study identified 10,097 patients who received adjuvant CT (n = 5,454) or adjuvant CRT (n = 4,643). On multivariate analysis, age, sex, tumor size, site, grade, stage, T stage, and lymph node metastasis were independent risk factors for OS. The basic clinical characteristics were well balanced after propensity matching. After propensity matching, CRT can improve the survival rate compared with CT [median OS: 22 months vs 23 months (HR, 0.928; 95% CI, 0.881–0.977; P = 0.004)]. Subgroup analysis indicated that the survival benefit of adjuvant chemoradiotherapy was more significant in patients with female (HR, 0.860; 95% CI, 0.798–0.926; P = 0.005 for interaction) or T3 (HR, 0.905; 95% CI, 0.855–0.957; P = 0.04 for interaction) or lymph nodes positive (HR, 0.883; 95% CI, 0.832–0.938; P = 0.005 for interaction). Conclusion Adjuvant CRT was associated with improved survival compared with adjuvant CT in patients with resection of pancreatic ductal adenocarcinoma. The benefit was more significant in patients with female or T3 or lymph nodes positive.
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Affiliation(s)
- Xiaomao Shi
- Department of Chemotherapy and Radiation Therapy, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Jin Peng
- Department of Chemotherapy and Radiation Therapy, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Huangang Jiang
- Department of Chemotherapy and Radiation Therapy, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yu Gao
- Department of Chemotherapy and Radiation Therapy, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Wenbo Wang
- Department of Chemotherapy and Radiation Therapy, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Fuxiang Zhou
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, China.,Department of Chemotherapy and Radiation Therapy, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
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Bouchart C, Navez J, Closset J, Hendlisz A, Van Gestel D, Moretti L, Van Laethem JL. Novel strategies using modern radiotherapy to improve pancreatic cancer outcomes: toward a new standard? Ther Adv Med Oncol 2020; 12:1758835920936093. [PMID: 32684987 PMCID: PMC7343368 DOI: 10.1177/1758835920936093] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 05/22/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid tumours with an estimated 5-year overall survival rate of 7% for all stages combined. In this highly resistant disease that is located in the vicinity of many radiosensitive organs, the role of radiotherapy (RT) and indications for its use in this setting have been debated for a long time and are still under investigation. Although a survival benefit has yet to be clearly demonstrated for RT, it is the only technique, other than surgery, that has been demonstrated to lead to local control improvement. The adjuvant approach is now strongly challenged by neoadjuvant treatments that could spare patients with rapidly progressive systemic disease from unnecessary surgery and may increase free margin (R0) resection rates for those eligible for surgery. Recently developed dose-escalated RT treatments, designed either to maintain full-dose chemotherapy or to deliver a high biologically effective dose, particularly to areas of contact between the tumour and blood vessels, such as hypofractionated ablative RT (HFA-RT) or stereotactic body RT (SBRT), are progressively changing the treatment landscape. These modern strategies are currently being tested in prospective clinical trials with encouraging preliminary results, paving the way for more effective treatment combinations using novel targeted therapies. This review summarizes the current literature regarding the use of RT for the treatment of primary PDAC, describes the limitations of conventional RT, and discusses the emerging role of dose-escalated RT and heavy-particle RT.
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Affiliation(s)
- Christelle Bouchart
- Department of Radiation-Oncology, Institut Jules Bordet, Boulevard de Waterloo, 121, Brussels, 1000, Belgium
| | - Julie Navez
- Department of Hepato-Biliary-Pancreatic Surgery, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean Closset
- Department of Hepato-Biliary-Pancreatic Surgery, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Alain Hendlisz
- Department of Gastroenterology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Dirk Van Gestel
- Department of Radiation-Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Luigi Moretti
- Department of Radiation-Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Luc Van Laethem
- Department of Gastroenterology, Hepatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
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Novel Radiotherapy Technologies in the Treatment of Gastrointestinal Malignancies. Hematol Oncol Clin North Am 2019; 34:29-43. [PMID: 31739949 DOI: 10.1016/j.hoc.2019.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Over the past 2 decades, major technical advances in radiation therapy planning and delivery have made it possible to deliver higher doses to select high-risk volumes. This has helped to expand the role of radiation therapy in the treatment of gastrointestinal malignancies. Whereas dose escalation was previously limited by the radiosensitivity of normal tissues within and adjacent to the gastrointestinal tract, advances in target delineation, patient immobilization, treatment planning, and image-guided treatment delivery have greatly improved the therapeutic ratio. More conformal radiation modalities can offer further dose optimization to target volumes while sparing normal tissue from toxicity.
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Nichols RC, Rutenberg M. Optimizing neoadjuvant radiotherapy for resectable and borderline resectable pancreatic cancer using protons. World J Gastrointest Surg 2019; 11:303-307. [PMID: 31602289 PMCID: PMC6783690 DOI: 10.4240/wjgs.v11.i7.303] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/25/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023] Open
Abstract
Approximately 25% of patients diagnosed with pancreatic cancer present with non-metastatic resectable or borderline resectable disease. Unfortunately, the cure rate for these “curable” patients is only in the range of 20%. Local-regional failure rates may exceed 50% after margin-negative, node-negative pancreatectomy, but up to 80% of resections are associated with regional lymph node or margin positivity. While systemic drug therapy and chemotherapy may prevent or delay the appearance of distant metastases, it is unlikely to have a significant impact on local-regional disease control. Preoperative radiotherapy would represent a rational intervention to improve local-regional control. The barrier to preoperative radiotherapy is the concern that it could potentially complicate what is already a long and complicated operation. When the radiotherapy is delivered with X-rays (photons), the entire cylinder of the abdomen is irradiated; therefore, an operating surgeon may be reluctant to accept the associated risk of increased toxicity. When preoperative radiotherapy is delivered with protons, however, significant bowel and gastric tissue-sparing is achieved and clinical outcomes indicate that proton therapy does not increase the risk of operative complications nor extend the length of the procedure.
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Affiliation(s)
- Romaine Charles Nichols
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL 32206, United States
| | - Michael Rutenberg
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL 32206, United States
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8
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Yegya-Raman N, Shah MM, Grandhi MS, Poplin E, August DA, Kennedy TJ, Malhotra U, Spencer KR, Carpizo DR, Jabbour SK. Adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma. ACTA ACUST UNITED AC 2018; 1. [PMID: 30687847 DOI: 10.21037/apc.2018.07.05] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.
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Affiliation(s)
- Nikhil Yegya-Raman
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Mihir M Shah
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Miral S Grandhi
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Elizabeth Poplin
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - David A August
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Timothy J Kennedy
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Usha Malhotra
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Kristen R Spencer
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Darren R Carpizo
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
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Jin WH, Hoffe SE, Shridhar R, Strom T, Venkat P, Springett GM, Hodul PJ, Pimiento JM, Meredith KL, Malafa MP, Frakes JM. Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail. J Gastrointest Oncol 2018; 9:487-494. [PMID: 29998014 PMCID: PMC6006031 DOI: 10.21037/jgo.2018.02.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. METHODS Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. RESULTS Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20-25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. CONCLUSIONS Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS.
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Affiliation(s)
- William H. Jin
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Sarah E. Hoffe
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ravi Shridhar
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Tobin Strom
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Puja Venkat
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Pamela J. Hodul
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jose M. Pimiento
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Mokenge P. Malafa
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jessica M. Frakes
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA
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10
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A Tale of Two Cities: Reconsidering Adjuvant Radiation in Pancreatic Cancer Care. J Gastrointest Surg 2016; 20:85-92; discussion 92. [PMID: 26427374 DOI: 10.1007/s11605-015-2951-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 09/14/2015] [Indexed: 01/31/2023]
Abstract
Adjuvant chemotherapy plays a critical role in the treatment of resected pancreatic cancer patients. However, the role of adjuvant radiation remains controversial. This study compares survival between resected pancreatic cancer patients who received adjuvant radiation and no adjuvant radiation. Medical records of patients with pancreatic ductal adenocarcinoma who underwent surgical resection from January 2003 through 2013 at medical centers in Boston and Leiden were retrospectively reviewed. Propensity score matching was used to correct for potential selection bias in the allocation of adjuvant chemoradiation versus chemotherapy alone. Three hundred fifty total patients were identified, of whom 138 (39.4%) received adjuvant radiation. On pathological staging, 245 (70.0%) had positive lymph nodes, and these patients gained a significant survival benefit from adjuvant radiation (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.56-0.99) in the complete cohort. After propensity score matching, adjuvant radiation lost its prognostic significance in the complete cohort. However, after matching, patients who survived longer than 12 months and had positive lymph nodes (n = 108) demonstrated a significant (log-rank p = 0.04) survival benefit from adjuvant radiation. This study, while non-randomized, suggests that adjuvant radiation may be associated with a survival benefit for resected pancreatic cancer patients in specific situations.
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Du L, DeFoe M, Ruzinova MB, Olsen JR, Wang-Gillam A. Perioperative Therapy for Surgically Resectable Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am 2015; 29:717-26. [PMID: 26226906 DOI: 10.1016/j.hoc.2015.04.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
It is estimated that 10% to 20% of patients with pancreatic cancer present with resectable disease. Although surgery offers curative intent, the median survival after curative resection is less than 2 years. To improve clinical outcomes in this patient population, clinical studies have investigated the role of perioperative therapy, including neoadjuvant and adjuvant treatment in resectable pancreatic cancer. The role of adjuvant therapy has been well established by large randomized phase III studies, whereas benefit of the neoadjuvant approach remains inconclusive. Here, we review various treatment modalities and their clinical benefits in resectable pancreatic cancer.
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Affiliation(s)
- Lingling Du
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA; Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
| | - Melissa DeFoe
- Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
| | - Marianna B Ruzinova
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
| | - Jeffrey R Olsen
- Department of Radiation Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
| | - Andrea Wang-Gillam
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA; Division of Medical Oncology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
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12
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In H, Posner MC. Research gaps in pancreatic cancer research and comparative effectiveness research methodologies. Cancer Treat Res 2015; 164:165-94. [PMID: 25677024 DOI: 10.1007/978-3-319-12553-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Despite advances in cancer care, pancreatic adenocarcinoma remains one of the most lethal tumors. Most patients with pancreatic cancer are diagnosed with late stage disease, and approximately 6 % of patients are alive 5 years after diagnosis. Of the 10-20 % of patients who are candidates for resection and multi-modality therapy, most will succumb to the disease with 5-year survival rates only reaching approximately 25 % (Lim et al. in Annals of surgery 237(1):74-85, 2003 [1]; Trede et al. in Annals of surgery 211(4):447-458, 1990 [2]; Crist et al. in Annals of surgery 206(3):358-365, 1987 [3]). Clearly, there is a need to improve the management of this disease. To identify gaps in research and formulate strategies to address these issues, we designed a framework to encompass the scope of research for pancreatic cancer. In this chapter, we will examine each topic heading within this framework for gaps in knowledge and present research strategies focusing on diverse comparative effectiveness research (CER) methodologies to address the identified gaps.
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Affiliation(s)
- Haejin In
- Departments of Surgery and Epidemiology, Albert Einstein College of Medicine, Bronx, NY, USA,
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13
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McDonald AM, Dulaney CR, López-Araujo J, Posey JA, Keene KS, Christein JD, Heslin MJ, Wood TE, Jacob R. Patterns of Failure for Lymph Node-Positive Resected Pancreatic Adenocarcinoma After Adjuvant Radiotherapy or Gemcitabine-based Chemotherapy Alone. J Gastrointest Cancer 2015; 46:149-55. [DOI: 10.1007/s12029-015-9702-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
The last two decades of research in the adjuvant setting of pancreas adenocarcinoma have established the value of adjuvant systemic therapy as being able to delay recurrence and increase overall survival. International standards of care in the adjuvant setting include either 6 months of gemcitabine or 5-fluorouracil and leucovorin. The added value of additional agents in the adjuvant setting is being evaluated in several large adjuvant studies. The role of a targeted agent in the adjuvant setting remains investigational. Other major areas of exploration include the integration of adjuvant immunotherapeutic approaches, which provide promise in a setting of micrometastatic disease volumes where such approaches may have greatest value.
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Affiliation(s)
- Daneng Li
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Eileen M O'Reilly
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
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Hoffe S, Rao N, Shridhar R. Neoadjuvant vs adjuvant therapy for resectable pancreatic cancer: the evolving role of radiation. Semin Radiat Oncol 2014; 24:113-25. [PMID: 24635868 DOI: 10.1016/j.semradonc.2013.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A major challenge with pancreatic cancer management is in the discrimination of clearly resectable tumors from those that would likely be accompanied by a positive resection margin if upfront surgery was attempted. The standard of care for clearly resectable pancreatic cancer remains surgery followed by adjuvant therapy, but there is considerable controversy over whether such therapeutic adjuvant strategies should include radiotherapy. Furthermore, in a malignancy with such high rates of distant metastasis, investigators are now exploring the feasibility and outcomes of delivering therapy in the neoadjuvant setting, both for clearly resectable as well as borderline resectable tumors. In this review, we explore the current standard of care of upfront surgery for clearly resectable cancers followed by adjuvant therapy, focusing on the role of radiotherapy. We highlight the difficulties in interpreting a literature fraught with inconsistencies in how resectable vs borderline resectable cancers are defined and treated. Finally, we explore the role of neoadjuvant strategies in the modern era.
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Affiliation(s)
- Sarah Hoffe
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL.
| | - Nikhil Rao
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL
| | - Ravi Shridhar
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL
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Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer. Int J Radiat Oncol Biol Phys 2014; 90:911-7. [PMID: 25220717 DOI: 10.1016/j.ijrobp.2014.07.024] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 07/03/2014] [Accepted: 07/16/2014] [Indexed: 12/29/2022]
Abstract
PURPOSE To determine the impact of chemoradiation therapy (CRT) on overall survival (OS) after resection of pancreatic adenocarcinoma. METHODS AND MATERIALS A multicenter retrospective review of 955 consecutive patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive carcinoma (T1-4; N0-1; M0) of the pancreas was performed. Exclusion criteria included metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiation therapy (IORT), and a histological diagnosis of no ductal carcinoma, or postoperative death (within 60 days of surgery). In all, 623 patients received postoperative radiation therapy (RT), 575 patients received concurrent chemotherapy (CT), and 462 patients received adjuvant CT. RESULTS Median follow-up was 21.0 months. Median OS after adjuvant CRT was 39.9 versus 24.8 months after no adjuvant CRT (P<.001) and 27.8 months after CT alone (P<.001). Five-year OS was 41.2% versus 24.8% with and without postoperative CRT, respectively. The positive impact of CRT was confirmed by multivariate analysis (hazard ratio [HR] = 0.72; confidence interval [CI], 0.60-0.87; P=.001). Adverse prognostic factors identified by multivariate analysis included the following: R1 resection (HR = 1.17; CI = 1.07-1.28; P<.001), higher pT stage (HR = 1.23; CI = 1.11-1.37; P<.001), positive lymph nodes (HR = 1.27; CI = 1.15-1.41; P<.001), and tumor diameter >20 mm (HR = 1.14; CI = 1.05-1.23; P=.002). Multivariate analysis also showed a better prognosis in patients treated in centers with >10 pancreatic resections per year (HR = 0.87; CI = 0.78-0.97; P=.014) CONCLUSION: This study represents the largest comparative study on adjuvant therapy in patients after resection of carcinoma of the pancreas. Overall survival was better in patients who received adjuvant CRT.
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Sultana A, Jackson RJ, Cox T, Palmer D, Neoptolemos J, Ghaneh P. Chemotherapy, radiotherapy, chemoradiotherapy and combination therapy in localised and locally advanced pancreatic cancer. Hippokratia 2014. [DOI: 10.1002/14651858.cd011044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Asma Sultana
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - Richard J Jackson
- Liverpool University; North West Surgical Trials Centre; Brownlow Street Liverpool UK L69 3GL
| | - Trevor Cox
- University of Liverpool; Liverpool Cancer Research UK Cancer Trials Unit; Liverpool UK
| | - Daniel Palmer
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - John Neoptolemos
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
| | - Paula Ghaneh
- University of Liverpool; Department of Molecular and Clinical Cancer Medicine; Liverpool UK
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Hall WA, Colbert LE, Liu Y, Gillespie T, Lipscomb J, Hardy C, Kooby DA, Prabhu RS, Kauh J, Landry JC. The influence of adjuvant radiotherapy dose on overall survival in patients with resected pancreatic adenocarcinoma. Cancer 2013; 119:2350-7. [PMID: 23625519 DOI: 10.1002/cncr.28047] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 12/18/2012] [Accepted: 01/22/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose. METHODS National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels < 40 grays (Gy), 40 Gy to < 50 Gy, 50 Gy to < 55 Gy, and ≥ 55 Gy. RESULTS A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose ≥ 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy. CONCLUSIONS A-RT doses of < 40 Gy, 40 Gy to < 50 Gy, and ≥ 55 Gy were found to be associated with an inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for patients with resected PAC is needed.
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Affiliation(s)
- William A Hall
- Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
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Evolving Concepts Regarding the Use of Radiotherapy in the Adjuvant Management of Periampullary Pancreatic Adenocarcinoma. Cancer J 2012. [DOI: 10.1097/ppo.0b013e3182758c84] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Wang F, Kumar P. The role of radiotherapy in management of pancreatic cancer. J Gastrointest Oncol 2012; 2:157-67. [PMID: 22811846 DOI: 10.3978/j.issn.2078-6891.2011.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 07/26/2011] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the leading causes of cancer death. The treatment options in pancreatic cancer remain limited. This review provides an overview of the role of radiotherapy (RT) alone or in combination with systemic treatment at different settings of treatment strategy. Neoadjuvant chemoradiotherapy (CRT) may downstage the borderline resectable disease and make resection possible, which could translate to a survival benefit. Although the benefit of adjuvant CRT remains controversial due to inconsistent outcome of randomized trials, in North America it is still a common recommendation of the treatment. For locally advanced pancreatic cancer, the treatment option could either be chemotherapy or chemoradiotherapy. By using advanced radiotherapy modalities, the toxicity of RT could be reduced and RT dose escalation becomes possible to improve locoregional control.
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Affiliation(s)
- Fen Wang
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
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O'Reilly EM. Adjuvant therapy for pancreas adenocarcinoma. J Surg Oncol 2012; 107:78-85. [PMID: 22886586 DOI: 10.1002/jso.23230] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 07/10/2012] [Indexed: 01/04/2023]
Abstract
Adjuvant therapy for pancreas adenocarcinoma in 2012 includes consideration of systemic therapy based on high level evidence and combined chemoradiotherapy based on less robust data. Current major adjuvant questions are examining the role of the addition of a second agent, either cytotoxic or targeted agent, to gemcitabine and whether or not the utilization of combined chemoradiotherapy improves overall survival. Progress to date has been modest and incremental in the adjuvant setting.
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Affiliation(s)
- Eileen M O'Reilly
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
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22
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Abrams RA. Radiotherapy in the adjuvant management of pancreatic adenocarcinoma: is it helpful? Expert Rev Gastroenterol Hepatol 2012; 6:149-61. [PMID: 22375521 DOI: 10.1586/egh.12.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Curative-intent management for pancreatic adenocarcinoma requires gross total resection. Only 15-20% of patients are eligible for resection and of these only approximately 20% are long-term survivors. Adjuvant and neoadjuvant approaches have been, and are being, sought to improve upon surgical results. Radiotherapy has a role in the adjuvant management of many gastrointestinal malignancies and historically has also had a role in the adjuvant management of pancreatic adenocarcinoma. However, the role of radiotherapy in the management of pancreatic adenocarcinoma has been called into question. This review examines this controversy and the underlying issues and considers current efforts towards resolving them, as well as some likely future developments.
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Affiliation(s)
- Ross A Abrams
- Department of Radiation Oncology, Rush University Medical Center, Atrium Bldg, Ground Floor, 500 S. Paulina, Chicago, IL 60612, USA.
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Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. Int J Radiat Oncol Biol Phys 2012; 83:158-63. [PMID: 22245197 DOI: 10.1016/j.ijrobp.2011.05.045] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 05/17/2011] [Accepted: 05/20/2011] [Indexed: 02/06/2023]
Abstract
PURPOSE To determine the potential role for adjuvant proton-based radiotherapy (PT) for resected pancreatic head cancer. METHODS AND MATERIALS Between June 2008 and November 2008, 8 consecutive patients with resected pancreatic head cancers underwent optimized intensity-modulated radiotherapy (IMRT) treatment planning. IMRT plans used between 10 and 18 fields and delivered 45 Gy to the initial planning target volume (PTV) and a 5.4 Gy boost to a reduced PTV. PTVs were defined according to the Radiation Therapy Oncology Group 9704 radiotherapy guidelines. Ninety-five percent of PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Normal tissue constraints were as follows: right kidney V18 Gy to <70%; left kidney V18 Gy to <30%; small bowel/stomach V20 Gy to <50%, V45 Gy to <15%, V50 Gy to <10%, and V54 Gy to <5%; liver V30 Gy to <60%; and spinal cord maximum to 46 Gy. Optimized two- to three-field three-dimensional conformal proton plans were retrospectively generated on the same patients. The team generating the proton plans was blinded to the dose distributions achieved by the IMRT plans. The IMRT and proton plans were then compared. A Wilcoxon paired t-test was performed to compare various dosimetric points between the two plans for each patient. RESULTS All proton plans met all normal tissue constraints and were isoeffective with the corresponding IMRT plans in terms of PTV coverage. The proton plans offered significantly reduced normal-tissue exposure over the IMRT plans with respect to the following: median small bowel V20 Gy, 15.4% with protons versus 47.0% with IMRT (p = 0.0156); median gastric V20 Gy, 2.3% with protons versus 20.0% with IMRT (p = 0.0313); and median right kidney V18 Gy, 27.3% with protons versus 50.5% with IMRT (p = 0.0156). CONCLUSIONS By reducing small bowel and stomach exposure, protons have the potential to reduce the acute and late toxicities of postoperative chemoradiation in this setting.
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Abstract
Pancreatic cancer is a challenging malignancy to treat, as less than one-fifth of diagnosed cases are resectable, surgery is complex and postoperative recovery slow, treated patients tend to relapse and overall survival rates are low. It is one of the leading causes of cancer-related mortality. Adjuvant therapy has been employed in resectable disease, to target micrometastases and improve prognosis. Chemotherapy, chemoradiotherapy (chemoRT) and chemoradiotherapy (chemoRT) followed on by chemotherapy have been evaluated in randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 trials clearly established the survival advantage of adjuvant chemotherapy with 5 fluorouracil (5FU) plus folinic acid and gemcitabine respectively over no chemotherapy. The ESPAC-3 (version 2) trial demonstrated equivalence between 5FU plus folinic acid and gemcitabine in terms of survival parameters, though gemcitabine had a better toxicity profile. The results of these key studies, together with smaller ones have been subjected to meta-analyses, with confirmation of improved survival with adjuvant systemic chemotherapy. The EORTC-40891 and ESPAC-1 trials found no survival advantage with adjuvant chemoRT compared to observation, and this has been reflected in a subsequent meta-analysis. The popularisation of chemoRT, with follow on chemotherapy (versus observation) was based on the small underpowered GITSG trial. The ESPAC-1 trial was unable to find a survival benefit for chemoRT, with follow on chemotherapy compared to observation. The RTOG-9704 trial assessed chemoRT with follow on chemotherapy in both arms and found no difference between survival in the gemcitabine and 5FU arms. There has never been a published head-to-head randomised comparison of adjuvant chemotherapy to chemoRT, with follow on chemotherapy. Ongoing randomised trials are looking into adjuvant combination chemotherapy, chemotherapy with follow on chemoRT, and neoadjuvant therapy. Novel agents continue to be assessed in early phase trials with a major emphasis on predictive and prognostic biomarkers. Based on the available evidence, adjuvant chemotherapy with gemcitabine or 5FU/folinic acid is the current recommended gold standard in the management of resected pancreatic cancer.
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Affiliation(s)
- Asma Sultana
- Department of Molecular and Clinical Cancer Medicine Centre, University of Liverpool, Liverpool, L69 3GA, UK
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O'Reilly EM. Adjuvant therapy for pancreas adenocarcinoma: where are we going? Expert Rev Anticancer Ther 2011; 11:173-7. [PMID: 21342036 DOI: 10.1586/era.10.232] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Evaluation of: Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304(10), 1073-1081 (2010). Over the last decade, adjuvant therapy in the treatment of resected pancreas adenocarcinoma has had its value established. Such treatment incrementally increases 5-year survivorship and delays time to tumor recurrence. The backbone of adjuvant therapy is the single-agent gemcitabine, based primarily on results from the Charité Onkologie Clinical (CONKO)-001 study. Based on the combined results of the European Study Group for Pancreas Cancer (ESPAC)-1 and ESPAC-3 trials, Neoptolemos and colleagues have established both bolus 5-fluorouracil and leucovorin and gemcitabine as standard options for resected pancreatic cancer. Gemcitabine remains the main standard therapy based on its ease of administration and a more favorable toxicity profile; however, there is now a clearly validated alternate option of 5-fluororuacil and leucovorin based on the results of ESPAC-3. Moving forward, the integration of novel cytotoxic and targeted agents into adjuvant therapy, along with refining the role of neoadjuvant therapy for patients with resectable pancreas cancer, will hopefully accrue a more substantial improvement in outcome for patients with resected pancreas adenocarcinoma.
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Affiliation(s)
- Eileen M O'Reilly
- Department of Medicine, Gastrointestinal Oncology Service, 1275 York Avenue, Box 324, New York, NY 10065, USA.
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Abrams RA, Winter KA, Regine WF, Safran H, Hoffman JP, Lustig R, Konski AA, Benson AB, Macdonald JS, Rich TA, Willett CG. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 2011; 82:809-16. [PMID: 21277694 DOI: 10.1016/j.ijrobp.2010.11.039] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 11/08/2010] [Accepted: 11/11/2010] [Indexed: 10/18/2022]
Abstract
PURPOSE In Radiation Therapy Oncology Group 9704, as previously published, patients with resected pancreatic adenocarcinoma received continuous infusion 5-FU and concurrent radiotherapy (5FU-RT). 5FU-RT treatment was preceded and followed by randomly assigned chemotherapy, either 5-FU or gemcitabine. This analysis explored whether failure to adhere to specified RT guidelines influenced survival and/or toxicity. METHODS AND MATERIALS RT requirements were protocol specified. Adherence was scored as per protocol (PP) or less than per protocol (<PP). Scoring occurred after therapy but before trial analysis and without knowledge of individual patient treatment outcomes. Scoring was done for all tumor locations and for the subset of pancreatic head location. RESULTS RT was scored for 416 patients: 216 PP and 200 <PP. For all pancreatic sites (head, body/tail) median survival (MS) for PP vs. <PP was 1.74 vs. 1.46 years (log-rank p = 0.0077). In multivariate analysis, PP vs. <PP score correlated more strongly with MS than assigned treatment arm (p = 0.014, p = NS, respectively); for patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p = 0.016, p = 0.043, respectively). For all tumor locations, PP score was associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, a trend toward reduced Grade 4/5 nonhematologic toxicity (p = 0.065). CONCLUSIONS This is the first Phase III, multicenter, adjuvant protocol for pancreatic adenocarcinoma to evaluate the impact of adherence to specified RT protocol guidelines on protocol outcomes. Failure to adhere to specified RT guidelines was associated with reduced survival and, for patients receiving gemcitabine, trend toward increased nonhematologic toxicity.
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Affiliation(s)
- Ross A Abrams
- Department of Radiation Oncology, Rush University Medical Center, Chicago, IL 60612, USA
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Hsu CC, Herman JM, Corsini MM, Winter JM, Callister MD, Haddock MG, Cameron JL, Pawlik TM, Schulick RD, Wolfgang CL, Laheru DA, Farnell MB, Swartz MJ, Gunderson LL, Miller RC. Adjuvant chemoradiation for pancreatic adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Ann Surg Oncol 2010; 17:981-90. [PMID: 20087786 PMCID: PMC2840672 DOI: 10.1245/s10434-009-0743-7] [Citation(s) in RCA: 216] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Survival for pancreatic ductal adenocarcinoma is low, the role of adjuvant therapy remains controversial, and recent data suggest adjuvant chemoradiation (CRT) may decrease survival compared with surgery alone. Our goal was to examine efficacy of adjuvant CRT in resected pancreatic adenocarcinoma compared with surgery alone. MATERIALS AND METHODS Patients with pancreatic adenocarcinoma at Johns Hopkins Hospital (n = 794, 1993-2005) and Mayo Clinic (n = 478, 1985-2005) following resection who were observed (n = 509) or received adjuvant 5-FU based CRT (median dose 50.4 Gy; n = 583) were included. Cox survival and propensity score analyses assessed associations with overall survival. Matched-pair analysis by treatment group (1:1) based on institution, age, sex, tumor size/stage, differentiation, margin, and node positivity with N = 496 (n = 248 per treatment arm) was performed. RESULTS Median survival was 18.8 months. Overall survival (OS) was longer among recipients of CRT versus surgery alone (median survival 21.1 vs. 15.5 months, P < .001; 2- and 5-year OS 44.7 vs. 34.6%; 22.3 vs. 16.1%, P < .001). Compared with surgery alone, adjuvant CRT improved survival in propensity score analysis for all patients by 33% (P < .001), with improved survival when stratified by age, margin, node, and T-stage (RR = 0.57-0.75, P < .05). Matched-pair analysis demonstrated OS was longer with CRT (21.9 vs. 14.3 months median survival; 2- and 5-year OS 45.5 vs. 31.4%; 25.4 vs. 12.2%, P < .001). CONCLUSIONS Adjuvant CRT is associated with improved survival after pancreaticoduodenectomy. Adjuvant CRT was not associated with decreased survival in any risk group, even in propensity score and matched-pair analyses. Further studies evaluating adjuvant chemotherapy compared with adjuvant chemoradiation are needed to determine the most effective combination of systemic and local-regional therapy to achieve optimal survival results.
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Affiliation(s)
- Charles C. Hsu
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, MD USA
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA USA
| | - Joseph M. Herman
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, MD USA
| | | | - Jordan M. Winter
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD USA
| | | | | | - John L. Cameron
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD USA
| | | | | | | | - Daniel A. Laheru
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD USA
| | | | - Michael J. Swartz
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore, MD USA
| | | | - Robert C. Miller
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN USA
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Review and commentary on the role of radiation therapy in the adjuvant management of pancreatic cancer. Am J Clin Oncol 2010; 33:101-6. [PMID: 19636239 DOI: 10.1097/coc.0b013e31819171b9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Currently, pancreatic cancer is fatal in over 90% of cases. Complete resection (if possible) is required for cure but the optimal adjuvant therapy is controversial. Given that pancreatic cancer frequently recurs both locoregionally and distantly, oncologic principles support the role of both adjuvant chemotherapy and radiotherapy. The historic trials evaluating chemoradiotherapy are too limited to provide clear guidance, but when viewed together with single institution data they suggest that chemoradiotherapy is beneficial. New data strongly support the use of adjuvant gemcitabine chemotherapy, but the benefit of the addition of radiation is still under investigation and no consensus exists on a standard of care. Clearly, no combination of currently available agents is sufficient to provide acceptable cure rates in pancreatic cancer and novel therapies must be found.
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Hattangadi JA, Hong TS, Yeap BY, Mamon HJ. Results and patterns of failure in patients treated with adjuvant combined chemoradiation therapy for resected pancreatic adenocarcinoma. Cancer 2009; 115:3640-50. [PMID: 19514088 DOI: 10.1002/cncr.24410] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although adjuvant chemoradiation is used commonly in the United States for the treatment of resected pancreatic cancer, there is no consensus on the benefit of this therapy, because the results from randomized trials are conflicting. The authors of this report reviewed their experience in a consecutive, unselected series of patients who received adjuvant 5-fluorouracil (5-FU) and radiation therapy (RT) for resected pancreatic adenocarcinoma. METHODS Eighty-six patients with resected pancreatic adenocarcinoma who received adjuvant therapy from 1998 to 2005 were identified, and their medical records were reviewed. Ninety-three percent of patients were treated with external beam RT to > or =50.4 grays, and 91% of patients received concurrent 5-FU by continuous infusion. Forty-five percent of patients went on to receive adjuvant gemcitabine. RESULTS The median follow-up was 31 months (range, 21-62 months) among the 20 patients who remained alive. Less than half of patients had positive (33%) or close (<1 mm; 15%) resection margins, 81% of tumors were classified as T3, and 66% of patients had involved lymph nodes. The median overall survival (OS) for all patients was 22 months. Negative lymph node status (P = .016) was a significant prognostic factor for improved OS, whereas treatment with gemcitabine trended toward improved OS (P = .080). The median disease-free survival (DFS) for all patients was 10 months: Treatment with gemcitabine (P = .044) and the receipt of any chemotherapy (P = .047) were significant predictors of DFS. Seventy-five patients (87%) had disease recurrence, and the majority recurred with peritoneal metastases (55%) or liver metastases (53%). Patients who had negative lymph nodes trended toward a lower rate of distant failure (P = .060). CONCLUSIONS The median survival of the current cohort was greater than that of the chemoradiation arms of European Organization for Research and Treatment of Cancer trials and European Study Group for Pancreatic Cancer 1 trials and was comparable to the survival observed on the Gastrointestinal Tumor Study Group chemoradiation arm. Lymph node status and treatment with adjuvant chemotherapy were significant predictors of OS and DFS, respectively. Future survival improvements should be directed at reducing peritoneal and liver metastases. Further randomized trials will be required to define the role of adjuvant therapy for pancreatic adenocarcinoma.
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Affiliation(s)
- Jona A Hattangadi
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA, USA
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Bergenfeldt M, Albertsson M. Current state of adjuvant therapy in resected pancreatic adenocarcinoma. Acta Oncol 2009; 45:124-35. [PMID: 16546857 DOI: 10.1080/02841860600554238] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Pancreatic carcinoma cannot generally be cured by surgery alone. This review summarizes the development of adjuvant therapy over the past two decades. Four randomized controlled trials compare long-term survival of different treatments. The small GITSG-study supports combined chemoradiation, but the EORTC-study found no significant effect. A Norwegian study of adjuvant chemotherapy found an increased median survival, but no effect beyond two years. The large ESPAC-1 study shows a benefit for 5-FU based chemotherapy, while chemoradiation had a negative effect. Thus, evidence favours adjuvant therapy, but 5-FU may not be the ultimate drug. Support for gemcitabine is given by preliminary data from a German randomized trial, and further American and European studies are upcoming. However, postoperative therapy is problematic, as 20-30% of resected patients never undergo treatment because of slow recovery or other reasons. Preoperative therapy has some theoretical advantages, and moreover, patients with rapidly progressive disease may be spared surgery. Randomized controlled trials are lacking, but published results compare well with postoperative, adjuvant therapy. The value of locally targeted therapy is difficult to assess. Reasonable results have been obtained with regional chemotherapy, whereas intraoperative radiotherapy does not seem to increase survival despite reducing reducing local recurrences.
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Affiliation(s)
- Magnus Bergenfeldt
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgical Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
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Stage-Specific Survival Differences Associated with Postoperative Radiotherapy for Gastrointestinal Cancers. J Gastrointest Cancer 2009; 39:86-99. [DOI: 10.1007/s12029-009-9053-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Accepted: 02/05/2009] [Indexed: 10/21/2022]
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Adjuvant radiotherapy for pancreatic cancer is associated with a survival benefit primarily in stage IIB patients. J Gastroenterol 2009; 44:84-91. [PMID: 19159077 DOI: 10.1007/s00535-008-2280-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Accepted: 08/12/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND The role of adjuvant radiotherapy (RT) for pancreatic cancer remains controversial despite the completion of three multi-institutional randomized trials. This study examines the survival impact of postoperative RT in a large population-based database. METHODS Patients with pancreatic cancer diagnosed from 1988 to 2003 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The cohort was limited to patients who underwent resection of nonmetastatic disease to yield a population of 3252 patients. The primary end point was overall survival. Survival analyses were conducted using corrections for perioperative mortality as well as a propensity score analysis to account for baseline differences in patient characteristics. RESULTS Multiple independent factors were associated with RT use, including patient age and disease stage (P < 0.0001). In general, younger patients and those with more advanced disease were more likely to receive RT. Disease stage significantly affected survival (P < 0.0001). For patients who survived at least 6 months, adjuvant RT was associated with increased survival [hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.80-0.96]. On subgroup analysis, only stage IIB (T1-3N1) patients enjoyed a statistically significant benefit associated with RT (HR, 0.70; 95% CI, 0.62-0.79). CONCLUSIONS Adjuvant RT is frequently given to patients in the United States after resection of their pancreatic cancer. Although RT is associated with a survival benefit for nonmetastatic patients as a whole, this trend appears to predominantly derive from a survival benefit in patients with stage IIB disease.
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Yamamoto M, Imagawa DK, Katz MH. Multidisciplinary management of resectable adenocarcinoma of the pancreatic head. Expert Rev Anticancer Ther 2009; 8:1611-21. [PMID: 18925853 DOI: 10.1586/14737140.8.10.1611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Although surgery is considered the only treatment to offer patients with localized pancreatic adenocarcinoma a chance of cure, resection alone is rarely sufficient for long-term survival. High rates of postoperative recurrence and subsequent disease-related mortality have, over the past two decades, encouraged the study and use of multimodality strategies that include adjuvant systemic chemotherapy and radiation. These modalities have been utilized both preoperatively and postoperatively with encouraging results. Moreover, their use has led increasingly to the development of institutional multidisciplinary groups with a focused interest in the care of patients with pancreatic malignancy, which have become responsible for the diagnosis, staging, treatment, follow-up and study of these patients. We review the rationale for the use of and the outcomes that may be achieved through the use of a multidisciplinary approach to patients with resectable adenocarcinoma of the pancreatic head.
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Affiliation(s)
- Maki Yamamoto
- Department of Surgery, The University of California at Irvine, Orange, CA 92868-3298, USA.
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Merchant N, Berlin J. Past and Future of Pancreas Cancer: Are We Ready to Move Forward Together? J Clin Oncol 2008; 26:3478-80. [DOI: 10.1200/jco.2008.17.0811] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Nipun Merchant
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Jordan Berlin
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Abrams RA. Comment on "adjuvant therapy in pancreatic cancer: a critical appraisal". Drugs 2008; 67:2481-5; discussion 2491-3. [PMID: 18034585 DOI: 10.2165/00003495-200767170-00001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Ross A Abrams
- Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois 60612-3833, USA.
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Abstract
Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. In this article we review the current status of investigations into several classes of agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The scientific rationale, mechanism of action, and clinical trial data for these novel agents are discussed.
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Affiliation(s)
- Simona M Pino
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 426, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Keedy VL, Berlin J. Adjuvant and neoadjuvant approaches to treat surgically resectable pancreatic cancer. Curr Treat Options Oncol 2006; 7:381-8. [PMID: 16904055 DOI: 10.1007/s11864-006-0006-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Adjuvant therapy for pancreatic cancer is currently a controversial topic. Very little is known about the potential components of adjuvant therapy. All published randomized trials evaluating adjuvant therapy for pancreatic cancer have limitations that prevent the establishment of an absolute "standard of care." However, with the recent report of Charite Onkologie Clinical Studies in Gastrointestinal Cancer in abstract form and European Study Group for Pancreatic Cancer-1, it is clear that chemotherapy has an effect as adjuvant therapy. The role of radiation remains unclear. The future of adjuvant therapy is dependent on the investigators designing better trials that answer the important remaining questions: the role of radiation therapy, the integration of newer agents, and the best regimen of those currently available.
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Affiliation(s)
- Vicki L Keedy
- Vanderbilt University Medical Center, 777 Preston Research Building, Nashville, TN 37232, USA.
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Garofalo M, Flannery T, Regine W. The case for adjuvant chemoradiation for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20:403-16. [PMID: 16549335 DOI: 10.1016/j.bpg.2005.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Despite the best current therapies, treatment outcomes in pancreatic cancer continue to be poor. Surgery remains the single most important curative modality for the minority of patients who present with resectable disease and continues to be the cornerstone of curative-intent therapy in such patients. The value of adjuvant treatment in these patients has been the subject of much debate and has led to several phase III randomized clinical trials in both the United States and Europe. Inconsistent trial results as well as trial design critiques have led to differing conclusions with regard to the value of adjuvant chemoradiotherapy. This chapter will critically review the randomized trials that have led to this controversy and establish a rationale for the use of adjuvant chemoradiation in patients with resectable pancreatic cancer. Modern radiotherapy delivery techniques will also be discussed and future trial designs suggested.
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Affiliation(s)
- Michael Garofalo
- Department of Radiation Oncology, University of Maryland Medical Center, 22 S Greene Street, Baltimore, MD 21201, USA.
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Niedergethmann M, Shang E, Farag Soliman M, Saar J, Berisha S, Willeke F, Post S. Early and enduring nutritional and functional results of pylorus preservation vs classic Whipple procedure for pancreatic cancer. Langenbecks Arch Surg 2006; 391:195-202. [PMID: 16491403 DOI: 10.1007/s00423-005-0015-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Accepted: 10/18/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND AND AIMS There have been many supportive data that the pylorus-preserving pancreatoduodenectomy (PPPD) might be equal to the classic Whipple pancreatoduodenectomy (PD) in terms of oncological radicality. However, few reports are available on the early postoperative and enduring functional changes, nutritional status, body composition, and quality of life years after surgery. The aim of this study was to compare nutritional and functional results of the different techniques in a retrospective evaluation and prospective cohort study. PATIENTS AND METHODS In May 1998, the standard surgical approach in the Department of Surgery, University-Hospital Mannheim, changed from PD to PPPD. The early postoperative and enduring functional changes, quality of life, oncological radicality, and nutritional status after years were compared between 128 patients after PD and 111 patients after PPPD. In a retrospective manner, the intra- and postoperative course was evaluated. In survivors, we prospectively analyzed the functional, nutritional, and oncological outcomes after 54 months (mean) in PD and after 24 months (mean) in PPPD patients. RESULTS The PPPD and PD groups did not differ according to age, gender, preoperative condition, or tumor localization. The PPPD group demonstrated favorable results (p<0.05) for operation time (PPPD 341+/-74 vs PD 386+/-89 min), blood loss (793+/-565 vs 1,000+/-590 ml), blood transfusions (416+/-691 vs 653+/-776 ml), delayed gastric emptying (6 vs 13%), and hospital stay (20 vs 24 days). However, a possible bias has to be mentioned since more T4 stages were diagnosed in the PD group (3 vs 11%), and even more extended (venous) resections were performed in the PD group (7 vs 24%). Morbidity (32 vs 30%) and mortality (5 vs 3%) did not differ between the two groups. After 24 months (PPPD, n=22) and 54 months (PD, n=16), there was no difference in global quality of life in recurrence-free patients. While the preoperative body weight was reached after 4 months (median) in the PPPD group, it was reached after 6 months (p<0.05) in the PD group. Bioelectrical impedance analysis (BIA) revealed a significantly (p<0.05) lower total body water (55 vs 60%) and significantly higher total body fat (26 vs 18%) in PPPD than in PD patients. Long-term follow-up showed no significant statistical differences in survival between both groups. CONCLUSION Besides favorable postoperative outcome in specific aspects and equal oncological outcome of PPPD, pylorus preservation seems to have advantages in enduring functional and nutritional status years after surgery for pancreatic cancer.
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Affiliation(s)
- Marco Niedergethmann
- Department of Surgery, University-Hospital Mannheim, University of Heidelberg, 68135, Mannheim, Germany.
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Abstract
Exocrine pancreatic cancer (pancreatic ductal adenocarcinoma) is one of the leading causes of cancer deaths in the western world, accounting for 5% of all cancer-related deaths. Only a small percentage of patients with pancreatic cancer are able to undergo potentially curative resection, even in specialized centres, and prognosis remains poor after successful surgery. Over the last few years efforts have been directed towards the development of adjuvant therapies in attempts to improve outcome. The main trials of adjuvant chemotherapy, chemoradiotherapy and chemoradiotherapy with follow-on chemotherapy are described in this paper, followed by the results of the ESPAC-1 trial and the status of ESPAC-2 and -3 trials.
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Affiliation(s)
- Asma Sultana
- Division of Surgery and Oncology, University of LiverpoolLiverpoolUK
| | - John Neoptolemos
- Division of Surgery and Oncology, University of LiverpoolLiverpoolUK
| | - Paula Ghaneh
- Division of Surgery and Oncology, University of LiverpoolLiverpoolUK
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Reni M, Passoni P, Bonetto E, Balzano G, Panucci MG, Zerbi A, Ronzoni M, Staudacher C, Villa E, Di Carlo V. Final results of a prospective trial of a PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) regimen followed by radiotherapy after curative surgery for pancreatic adenocarcinoma. Oncology 2005; 68:239-45. [PMID: 16015040 DOI: 10.1159/000086780] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2004] [Accepted: 08/02/2004] [Indexed: 01/24/2023]
Abstract
BACKGROUND Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial. METHODS The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18-70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) > or =70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (alpha 0.05; beta 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery. RESULTS Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3-4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 +/- 7%. Two-year overall survival was 53 +/- 7%. CONCLUSION Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome.
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Affiliation(s)
- Michele Reni
- Department of Radiochemotherapy, S. Raffaele H. Scientific Institute, Milan, Italy.
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Abstract
In the last decade, continued efforts in pancreas cancer research have led to the development of new, more effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for the development of more effective treatment strategies. Recent clinical trials have provided reason for hope that novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for patients with this disease. This article will summarize the data that has led to the current standards of therapy for patients with resectable and advanced pancreatic cancer and review new treatment strategies for this disease.
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Affiliation(s)
- A Craig Lockhart
- Department of Medicine, Division of Hematology/Oncology, Vanderbilt University, Medical Center, Nashville, Tennessee 37232-6307, USA
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Abrams RA, Yeo CJ. Combined modality adjuvant therapy for resected periampullary pancreatic and nonpancreatic adenocarcinoma: a review of studies and experience at The Johns Hopkins Hospital, 1991-2003. Surg Oncol Clin N Am 2004; 13:621-38, ix. [PMID: 15350938 DOI: 10.1016/j.soc.2004.06.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In 1991 a multidisciplinary group consisting of surgeons, radiation oncologists, medical oncologists, pathologists, research nurses, and laboratory scientists was organized at the Johns Hopkins Hospital to accelerate progress in understanding the clinical and basic biology of pancreatic carcinoma and to develop research protocols aimed at improving clinical outcomes. This article discusses the studies, data, and conclusions generated to date, in some cases preliminarily, for the clinical trials and algorithms the Johns Hopkins team applied to the postoperative adjuvant management of periampullary pancreatic and nonpancreatic periampullary adenocarcinomas during the interval 1991 to 2003.
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Affiliation(s)
- Ross A Abrams
- Department of Radiation Oncology, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA.
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44
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Xiong HQ, Abbruzzese JL. Adjuvant therapy for pancreatic cancer: current status and future directions. Surg Oncol Clin N Am 2004; 13:737-49, xi. [PMID: 15350945 DOI: 10.1016/j.soc.2004.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
This article summarizes the important past and ongoing adjuvant therapy trials for pancreatic cancer. The recent developments in the fields of radiosensitization, chemotherapy, and molecular-targeted therapy are outlined. Finally, the future study strategies for adjuvant therapy trials are discussed.
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Affiliation(s)
- Henry Q Xiong
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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45
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Joensuu TK, Kiviluoto T, Kärkkäinen P, Vento P, Kivisaari L, Tenhunen M, Westberg R, Elomaa I. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004; 60:444-52. [PMID: 15380578 DOI: 10.1016/j.ijrobp.2004.03.026] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2003] [Revised: 03/03/2004] [Accepted: 03/08/2004] [Indexed: 01/14/2023]
Abstract
PURPOSE Define the maximum tolerated dose (MTD), tolerability, and efficacy of gemcitabine given concomitantly with radiotherapy in patients with locally advanced pancreatic cancer. METHODS AND MATERIALS Patients were required to have locally advanced T1-T3 resectable pancreatic cancer. Gemcitabine, given twice weekly before irradiation as a 30-min infusion, was tested at 3 dose levels: 20, 50, and 100 mg/m(2). The radiation dose was 50.4 Gy (ICRU) in 28 fractions. The targeted irradiation volume included the tumor, edema, and a 1-cm margin. RESULTS Twenty-eight of 34 patients was eligible for analysis of the treatment. The median age was 67 years (range 38-82). Six patients had T1, 9 had T2, and 19 had T3 diseases (AJCC). Dose-limiting toxicities were Grade 4, fatigue and nausea; Grade 3, thrombocytopenia, diarrhea, and infection. The MTD established was at the 50-mg/m(2) gemcitabine dose. A total of 21 of 28 patients underwent surgery: 18 had pancreaticoduodenectomy, 2 had total pancreatectomy, and 1 for palliative surgery. At the time of analysis, 13 of 28 (46%) were disease-free. The estimated median survival was 25 months and overall survival rate at 2 years (Kaplan-Meier) was 55%. CONCLUSION Gemcitabine 50 mg/m(2) given twice weekly with concomitant irradiation induces acceptable and manageable toxicity and might prolong survival.
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Affiliation(s)
- Timo K Joensuu
- Oncology, Helsinki University Central Hospital, Helsinki, Finland.
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Garofalo MC, Kwok Y, Regine WF. The evolving role of postoperative adjuvant radiation therapy for pancreatic cancer. Surg Oncol Clin N Am 2004; 13:589-604, viii. [PMID: 15350936 DOI: 10.1016/j.soc.2004.06.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The benefit of postoperative adjuvant chemoradiation in the treatment of resected pancreatic cancers was first established by a randomized trial conducted by the Gastrointestinal Tumor Study Group in 1974. During the past 3 decades, treatment has evolved toward more dose-intensive regimens of chemoradiation. Historical split-course conventional radiation therapy has been replaced by continuous-course radiotherapy to higher doses, and gemcitabine is being actively investigated as a potentially more effective agent than 5-fluorouracil. This article critically examines the results of important randomized multi-institutional trials and reviews the evolution toward dose-intensive adjuvant treatment regimens. Implications of the recently completed intergroup study are discussed, modern radiation therapy delivery techniques are reviewed, and suggestions for future trials are made.
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Affiliation(s)
- Michael C Garofalo
- Department of Radiation Oncology, University of Maryland at Baltimore, 22 South Green Street, Baltimore, MD 21201, USA.
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47
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Pino SM, Xiong HQ, McConkey D, Abbruzzese JL. Novel therapies for pancreatic adenocarcinoma. Curr Gastroenterol Rep 2004; 6:119-25. [PMID: 15191689 DOI: 10.1007/s11894-004-0038-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. In this article we review the current status of investigations into several classes of agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The scientific rationale, mechanism of action, and clinical trial data for these novel agents are discussed.
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Affiliation(s)
- Simona M Pino
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 426, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Milano MT, Chmura SJ, Garofalo MC, Rash C, Roeske JC, Connell PP, Kwon OH, Jani AB, Heimann R. Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 2004; 59:445-53. [PMID: 15145161 DOI: 10.1016/j.ijrobp.2003.11.003] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2003] [Revised: 10/01/2003] [Accepted: 11/10/2003] [Indexed: 12/19/2022]
Abstract
PURPOSE To assess the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in pancreatic and bile duct (cholangiocarcinoma) malignancies. METHODS AND MATERIALS Twenty-five patients with pancreatic and bile duct cancer were treated with IMRT. Twenty-three received concurrent 5-fluoruracil. One patient with a pancreatic primitive neuroectodermal tumor received concurrent etoposide and ifosfamide. Eight patients had resected tumors, and 17 had unresectable primary (n = 14) or recurrent (n = 3) tumors. Six patients underwent treatment planning with conventional three-dimensional four-field techniques for dosimetric comparison with IMRT. RESULTS Compared with conventional RT, IMRT reduced the mean dose to the liver, kidneys, stomach, and small bowel. IMRT was well tolerated, with 80% experiencing Grade 2 or less acute upper GI toxicity. At a median follow-up of 10.2 months, no resected patients had local failure, and only 1 of 10 assessable patients with unresectable cancer had local progression. The median survival and distant metastasis-free survival of the 24 patients with adenocarcinoma was 13.4 and 7.3 months, respectively. Grade 4 late liver toxicity occurred in 1 patient surviving >5 years. The remainder of the assessable patients experienced no (n = 9) or Grade 1 (n = 4) late toxicity. CONCLUSION In this hypothesis-generating analysis, the acute and chronic toxicity profile with IMRT in the treatment of pancreatic and bile duct cancer was encouraging. Local control was not compromised, despite efforts to increase conformality and avoid doses to normal structures. Distant failure remains a major obstacle in pancreatic cancer.
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Affiliation(s)
- Michael T Milano
- Department of Radiation and Cellular Oncology, University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA.
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Abstract
Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15-20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise.
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Affiliation(s)
- Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas, M D Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, TX 77030, USA
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