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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; 122:19-30. [PMID: 39761799 DOI: 10.1016/j.ijrobp.2024.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 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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Wong RX, Yang VSW, Chia CS, Looi WS, Nei WL, Ong CAJ. Feasibility and safety study of ultra-hypofractionated neoadjuvant radiotherapy to margins-at-risk in retroperitoneal sarcoma. Radiat Oncol J 2025; 43:6-12. [PMID: 39928964 PMCID: PMC12010885 DOI: 10.3857/roj.2024.00297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 02/12/2025] Open
Abstract
PURPOSE Retroperitoneal sarcomas (RPS) are rare tumors that present unique challenges, often due to late presentation, and the proximity of critical organs makes complete surgical resection challenging. This study aimed to assess the feasibility of neoadjuvant short-course radiotherapy (SCRT) targeting margins-at-risk and to assess its potential impact on outcomes. MATERIALS AND METHODS This is a single-center, prospective, non-randomized feasibility study. SCRT was administered via image-guided volumetric modulated arc therapy, consisting of 5 fractions of daily radiotherapy followed by immediate surgery. As a starting dose, patients were prescribed 25 Gy in 5 fractions. For the escalation stage, patients were prescribed 30 Gy in 5 fractions. Only the presumed threatened surgical margins were delineated for large tumors. RESULTS Patients with either primary or recurrent RPS were recruited. Eight patients underwent SCRT but one patient did not have a resection as planned. Seven patients underwent surgical resection, of whom one passed away 3 months postoperative from a cardiac event. After a median follow-up of 20.5 months for the six postoperative survivors, there were no overt long-term toxicities and one patient relapsed out-of-radiotherapy-field. CONCLUSION SCRT to RPS with a margin boost followed by immediate surgery is worth investigating. A starting dose of 30 Gy in 5 fractions is recommended for further studies. Longer-term follow-up is necessary.
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Affiliation(s)
- Ru-Xin Wong
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Valerie Shi Wen Yang
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
- Translational Precision Oncology Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Clarame Shulyn Chia
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
- Division of Surgery and Surgical Oncology, Department of Sarcoma, Peritoneal and Rare Tumours, National Cancer Centre Singapore, Singapore
- Division of Surgery and Surgical Oncology, Department of Sarcoma, Peritoneal and Rare Tumours, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Wen Shen Looi
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Wen Long Nei
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Chin-Ann Johnny Ong
- SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
- Division of Surgery and Surgical Oncology, Department of Sarcoma, Peritoneal and Rare Tumours, National Cancer Centre Singapore, Singapore
- Division of Surgery and Surgical Oncology, Department of Sarcoma, Peritoneal and Rare Tumours, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore
- Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Research Entities, Singapore
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Basree MM, Witt JS, Uboha NV, Lubner M, Minter R, Weber S, Ronnekleiv-Kelly S, Abbott D, Kratz J, Patel M, Zafar SN, LoConte N, Lubner SJ, Deming D, Ritter MA, Mohindra P, Bassetti MF. Neoadjuvant SBRT plus Elective Nodal Irradiation with Concurrent Capecitabine for Patients with Resectable Pancreatic Cancer: Survival Analysis of a Prospective Phase 1 Trial. Pract Radiat Oncol 2025:S1879-8500(25)00011-6. [PMID: 39924052 DOI: 10.1016/j.prro.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/22/2024] [Accepted: 01/08/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND AND PURPOSE Elective nodal irradiation (ENI) in resectable pancreatic cancer remains undefined, though occult nodal disease is common. This study investigated the use of neoadjuvant stereotactic body radiation therapy (SBRT) to primary disease with ENI, with concurrent capecitabine. Safety data for this protocol were previously reported. In this report, we provide an updated survival analysis. MATERIALS AND METHODS This is a prospective, single institution, phase IA/B dose-escalation trial that enrolled patients with biopsy-proven, resectable, pancreatic adenocarcinoma between 2014 - 2019 (NCT1918644). Patients were enrolled into one of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine (1650 mg/m2). All patients received ENI 5 Gy x 5 fractions. Our initial report found no dose-limiting toxicities. Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier (KM) curves were employed for survival analysis. RESULTS Of 17 enrolled patients, 16 were evaluable (94.1%). Thirteen (76.5%) proceeded to surgery. Median follow up was 28.0 months (1.7 - 71.9). Four patients (25.0%) received neoadjuvant chemotherapy and six (37.5%) received adjuvant chemotherapy. Pathologic nodal involvement (69.2%) was associated with a higher risk of any relapse (p<0.01) and distant metastasis (p=0.02). Local failure occurred in 4 (25%) patients with 2/4 of those failures occurring partially within the 25 Gy elective nodal field and 1/4 occurred in the 25 Gy elective nodal field and partially within the 35 Gy tumor field. The median overall survival (OS) and disease-free survival (DFS) were 31.1 months (range, 2.3 - 73.6) and 12.0 months (range, 0.4 - 71.9), respectively. Three-year OS and DFS were 50% and 31.3% overall, and 61.5% and 38.5% for the surgical cohort. Patients with pN+ had worse median OS (23.9 vs 69.3 months; p=0.002) and DFS (9.9 vs 58.9 months; p=0.002). No further radiation related toxicities were noted since the prior report. CONCLUSION Neoadjuvant SBRT to the primary tumor with ENI and radiosensitizing chemotherapy is a feasible approach that may improve outcomes in patients with resectable and borderline pancreatic cancer, despite high rates of pathological nodal involvement. Further investigation of this strategy is warranted in a larger cohort.
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Affiliation(s)
- Mustafa M Basree
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
| | - Jacob S Witt
- Cancer Care Specialists of Illinois/Cancer Care Center of O'Fallon, O'Fallon, IL, USA
| | - Nataliya V Uboha
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Meghan Lubner
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Rebecca Minter
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sharon Weber
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sean Ronnekleiv-Kelly
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Daniel Abbott
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jeremy Kratz
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Monica Patel
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Syed Nabeel Zafar
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Noelle LoConte
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sam J Lubner
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Dustin Deming
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Mark A Ritter
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Pranshu Mohindra
- Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA
| | - Michael F Bassetti
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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Poyia F, Neophytou CM, Christodoulou MI, Papageorgis P. The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives. Int J Mol Sci 2024; 25:9555. [PMID: 39273502 PMCID: PMC11395109 DOI: 10.3390/ijms25179555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Pancreatic cancer comprises different subtypes, where most cases include ductal adenocarcinoma (PDAC). It is one of the deadliest tumor types, with a poor prognosis. In the majority of patients, the disease has already spread by the time of diagnosis, making full recovery unlikely and increasing mortality risk. Despite developments in its detection and management, including chemotherapy, radiotherapy, and targeted therapies as well as advances in immunotherapy, only in about 13% of PDAC patients does the overall survival exceed 5 years. This may be attributed, at least in part, to the highly desmoplastic tumor microenvironment (TME) that acts as a barrier limiting perfusion, drug delivery, and immune cell infiltration and contributes to the establishment of immunologically 'cold' conditions. Therefore, there is an urgent need to unravel the complexity of the TME that promotes PDAC progression and decipher the mechanisms of pancreatic tumors' resistance to immunotherapy. In this review, we provide an overview of the major cellular and non-cellular components of PDAC TME, as well as their biological interplays. We also discuss the current state of PDAC therapeutic treatments and focus on ongoing and future immunotherapy efforts and multimodal treatments aiming at remodeling the TME to improve therapeutic efficacy.
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Affiliation(s)
- Fotini Poyia
- Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Christiana M Neophytou
- Apoptosis and Cancer Chemoresistance Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Maria-Ioanna Christodoulou
- Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Panagiotis Papageorgis
- Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
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Fogaroli RC, Castro DG, Silva ML, Pellizzon ACA, Gondim GR, Chen MJ, Ramos H, Neto ES, Abrahão CH. Involved-Field Radiation Therapy for Patients With Unresectable Pancreatic Adenocarcinomas: Failure Pattern Analysis. Cureus 2023; 15:e48106. [PMID: 37920425 PMCID: PMC10619996 DOI: 10.7759/cureus.48106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Introduction Unresectable pancreatic tumors are frequently diagnosed. Initial treatment is carried out with chemotherapy. Eventually, in selected cases, radiotherapy may be used to improve local control rates and relieve the symptoms. The volume of radiotherapy treatment fields is the subject of controversy in the literature. The use of involved fields with the gross tumor volume encompassing the primary tumor and lymph nodes considered clinically positive is associated with a lower rate of side effects, but can lead to a higher rate of regional loco failures, especially in regional lymph nodes. The purpose of this article is to analyze the failure pattern of chemotherapy and involved-field radiation therapy (IFRT) for treating patients with unresectable pancreatic adenocarcinomas. Methods Clinical records of thirty consecutive patients treated from March 2016 to June 2020 for unresectable pancreatic adenocarcinoma were analyzed. The patients were treated with initial systemic chemotherapy (median: 6 cycles) with regimens based on gemcitabine or oxaliplatin-irinotecan (folfirinox/folfox) followed by radiotherapy (total dose of 50-54 Gy/with fractionation of 2 Gy/day). The patients were treated with IFRT. Local failure (LF) was defined as an increase in radiographic abnormality within the planning target volume (PTV). Elective nodal failure (ENF) was defined as recurrence in any lymph node region outside the PTV. Any other failure was defined as distant failure (DF). Results The median age of the patients was 68 years (range: 44-80 years); 20 patients (66.7%) were men, and 11 (36.6%) and 19 (63.4%) patients presented with tumors of stage II and III, respectively. Most patients (63.3%) had tumors in the pancreatic head. The median survival was 17.2 months. Tumor recurrences were classified as LF, DF, LF and DF in 7 (23.3%), 17 (56.7%), and 5 (16.7%) patients, respectively. Only one patient (3.3%) had both LF and ENF. No severe side effects related to radiotherapy were reported. Conclusion The use of IFRT did not cause a significant amount of ENF, besides presenting low morbidity, which is of special importance for patients with locally advanced tumors or low performance status. The predominant failure pattern was distant metastases.
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Affiliation(s)
| | | | - Maria L Silva
- Radiation Oncology, A.C. Camargo Cancer Center, São Paulo, BRA
| | | | | | - Michael J Chen
- Radiation Oncology, A.C. Camargo Cancer Center, São Paulo, BRA
| | | | - Elson S Neto
- Radiotherapy, A.C. Camargo Cancer Center, São Paulo, BRA
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Kobeissi JM, Simone CB, Lin H, Hilal L, Hajj C. Proton Therapy in the Management of Pancreatic Cancer. Cancers (Basel) 2022; 14:2789. [PMID: 35681769 PMCID: PMC9179382 DOI: 10.3390/cancers14112789] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 02/04/2023] Open
Abstract
Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like the stomach, duodenum, and bowel. Clinically, standard doses of proton radiation treatment have not been shown to be statistically different from photon radiation treatment in terms of oncologic outcomes and toxicity rates as per non-randomized comparative studies. Fractionation schedules and concurrent chemotherapy combinations are yet to be optimized for proton therapy and are the subject of ongoing trials.
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Affiliation(s)
- Jana M. Kobeissi
- Department of Radiation Oncology, School of Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (J.M.K.); (L.H.)
| | - Charles B. Simone
- Department of Radiation Oncology, New York Proton Center, New York, NY 10035, USA; (C.B.S.II); (H.L.)
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Haibo Lin
- Department of Radiation Oncology, New York Proton Center, New York, NY 10035, USA; (C.B.S.II); (H.L.)
| | - Lara Hilal
- Department of Radiation Oncology, School of Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (J.M.K.); (L.H.)
| | - Carla Hajj
- Department of Radiation Oncology, New York Proton Center, New York, NY 10035, USA; (C.B.S.II); (H.L.)
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
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Elective Target Coverage for Pancreatic Cancer: When Less Does Not Clearly Achieve More. Int J Radiat Oncol Biol Phys 2022; 112:143-145. [PMID: 34919872 DOI: 10.1016/j.ijrobp.2021.08.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 01/08/2023]
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Matsumoto Y, Fukumitsu N, Ishikawa H, Nakai K, Sakurai H. A Critical Review of Radiation Therapy: From Particle Beam Therapy (Proton, Carbon, and BNCT) to Beyond. J Pers Med 2021; 11:jpm11080825. [PMID: 34442469 PMCID: PMC8399040 DOI: 10.3390/jpm11080825] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/20/2021] [Accepted: 08/22/2021] [Indexed: 12/24/2022] Open
Abstract
In this paper, we discuss the role of particle therapy—a novel radiation therapy (RT) that has shown rapid progress and widespread use in recent years—in multidisciplinary treatment. Three types of particle therapies are currently used for cancer treatment: proton beam therapy (PBT), carbon-ion beam therapy (CIBT), and boron neutron capture therapy (BNCT). PBT and CIBT have been reported to have excellent therapeutic results owing to the physical characteristics of their Bragg peaks. Variable drug therapies, such as chemotherapy, hormone therapy, and immunotherapy, are combined in various treatment strategies, and treatment effects have been improved. BNCT has a high dose concentration for cancer in terms of nuclear reactions with boron. BNCT is a next-generation RT that can achieve cancer cell-selective therapeutic effects, and its effectiveness strongly depends on the selective 10B accumulation in cancer cells by concomitant boron preparation. Therefore, drug delivery research, including nanoparticles, is highly desirable. In this review, we introduce both clinical and basic aspects of particle beam therapy from the perspective of multidisciplinary treatment, which is expected to expand further in the future.
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Affiliation(s)
- Yoshitaka Matsumoto
- Department of Radiation Oncology, Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; (K.N.); (H.S.)
- Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan
- Correspondence: ; Tel.: +81-29-853-7100
| | | | - Hitoshi Ishikawa
- National Institute of Quantum and Radiological Science and Technology Hospital, Chiba 263-8555, Japan;
| | - Kei Nakai
- Department of Radiation Oncology, Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; (K.N.); (H.S.)
- Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan
| | - Hideyuki Sakurai
- Department of Radiation Oncology, Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; (K.N.); (H.S.)
- Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan
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9
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Michelakos T, Cai L, Villani V, Sabbatino F, Kontos F, Fernández-Del Castillo C, Yamada T, Neyaz A, Taylor MS, Deshpande V, Kurokawa T, Ting DT, Qadan M, Weekes CD, Allen JN, Clark JW, Hong TS, Ryan DP, Wo JY, Warshaw AL, Lillemoe KD, Ferrone S, Ferrone CR. Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy. J Natl Cancer Inst 2021; 113:182-191. [PMID: 32497200 DOI: 10.1093/jnci/djaa073] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/08/2020] [Accepted: 05/11/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. METHODS Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. RESULTS Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. CONCLUSIONS Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.
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Affiliation(s)
- Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lei Cai
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Vincenzo Villani
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Francesco Sabbatino
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Teppei Yamada
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Azfar Neyaz
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Martin S Taylor
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tomohiro Kurokawa
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David T Ting
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Motaz Qadan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Colin D Weekes
- Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jill N Allen
- Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jeffrey W Clark
- Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David P Ryan
- Department of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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10
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Witt JS, Kuczmarska-Haas A, Lubner M, Reeder SB, Cho SY, Minter R, Weber S, Ronnekleiv-Kelly S, Abbott D, LoConte N, Mulkerin DL, Lubner SJ, Uboha NV, Deming D, Ritter MA, Mohindra P, Bassetti MF. A Phase 1 Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2020; 109:458-463. [PMID: 32942002 DOI: 10.1016/j.ijrobp.2020.09.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 07/23/2020] [Accepted: 09/08/2020] [Indexed: 11/19/2022]
Abstract
PURPOSE The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. METHODS AND MATERIALS Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT. RESULTS A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume. CONCLUSIONS SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.
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Affiliation(s)
- Jacob S Witt
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Aleksandra Kuczmarska-Haas
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Meghan Lubner
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Scott B Reeder
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Steve Y Cho
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Rebecca Minter
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sharon Weber
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sean Ronnekleiv-Kelly
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Daniel Abbott
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Noelle LoConte
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Daniel L Mulkerin
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sam J Lubner
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Nataliya V Uboha
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Dustin Deming
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Mark A Ritter
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Pranshu Mohindra
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore Maryland
| | - Michael F Bassetti
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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11
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Honselmann KC, Pergolini I, Castillo CFD, Deshpande V, Ting D, Taylor MS, Bolm L, Qadan M, Wellner U, Sandini M, Bausch D, Warshaw AL, Lillemoe KD, Keck T, Ferrone CR. Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer. Ann Surg 2020; 272:357-365. [PMID: 32675550 PMCID: PMC6639153 DOI: 10.1097/sla.0000000000003123] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Our aim was to evaluate recurrence patterns of surgically resected PDAC patients with negative (pN0) or positive (pN1) lymph nodes. SUMMARY BACKGROUND DATA Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer death by 2030. This is mostly due to early local and distant metastasis, even after surgical resection. Knowledge about patterns of recurrence in different patient populations could offer new therapeutic avenues. METHODS Clinicopathologic data were collected for 546 patients who underwent resection of their PDAC between 2005 and 2016 from 2 tertiary university centers. Patients were divided into an upfront resection group (n = 394) and a neoadjuvant group (n = 152). RESULTS Tumor recurrence was significantly less common in pN0 patients as compared with pN1 patients, (upfront surgery: 55% vs. 77%, P < 0.001 and 64% vs. 78%, P = 0.040 in the neoadjuvant group). In addition, time to recurrence was significantly longer in pN0 versus pN1 patients in the upfront resected patients (median 16 mo pN0 vs. 10 mo pN1 P < 0.001), and the neoadjuvant group (pN0 21 mo vs. 11 mo pN1, P < 0.001). Of the patients who recurred, 62% presented with distant metastases (63% of pN0 and 62% of pN1, P = 0.553), 24% with local disease (27% of pN0 and 23% of pN1, P = 0.672) and 14% with synchronous local and distant disease (10% of pN0 and 15% of pN1, P = 0.292). Similarly, there was no difference in recurrence patterns between pN0 and pN1 in the neoadjuvant group, in which 68% recurred with distant metastases (76% of pN0 and 64% of pN1, P = 0.326) and 18% recurred with local disease (pN0: 22% and pN1: 15%, P = 0.435). CONCLUSION Time to recurrence was significantly longer for pN0 patients. However, patterns of recurrence for pN0 vs. pN1 patients were identical. Lymph node status was predictive of time to recurrence, but not location of recurrence.
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Affiliation(s)
- Kim C Honselmann
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Ilaria Pergolini
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Carlos Fernandez-Del Castillo
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Vikram Deshpande
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - David Ting
- MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Martin S Taylor
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Louisa Bolm
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Motaz Qadan
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Ulrich Wellner
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Marta Sandini
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Dirk Bausch
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Andrew L Warshaw
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Keith D Lillemoe
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Tobias Keck
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Cristina R Ferrone
- Department of Gastrointestinal Surgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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12
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Liermann J, Shinoto M, Syed M, Debus J, Herfarth K, Naumann P. Carbon ion radiotherapy in pancreatic cancer: A review of clinical data. Radiother Oncol 2020; 147:145-150. [PMID: 32416281 DOI: 10.1016/j.radonc.2020.05.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/15/2020] [Accepted: 05/08/2020] [Indexed: 12/14/2022]
Abstract
Despite all efforts, pancreatic cancer remains a highly lethal disease. Only surgical resection offers a realistic chance of survival. But at diagnosis the majority of patients suffer from unresectable disease. Whereas guidelines clearly recommend systemic treatments in metastatic disease, data is limited to support a specific treatment option for locally advanced or borderline resectable pancreatic cancer. Therefore, there is an urgent need to improve treatment schemes addressing patients that suffer from unresectable pancreatic cancer. Chemotherapy, photon radiotherapy and combinations of both have shown improved local control rates but there is still a lack of evidence demonstrating an overall survival benefit of photon radiotherapy if no surgical resection is achieved. Impressive results of Japanese Phase I/II-trials investigating carbon ion radiotherapy in pancreatic cancer attracted global attention. Several studies have been initiated to validate and intensify this promising issue. This review gives an overview of the evidence and current use of carbon ion radiotherapy in pancreatic cancer.
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Affiliation(s)
- Jakob Liermann
- Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany.
| | - Makoto Shinoto
- Ion Beam Therapy Center, SAGA HIMAT Foundation, Saga, Japan.
| | - Mustafa Syed
- Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany.
| | - Jürgen Debus
- Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany; Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Heidelberg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Klaus Herfarth
- Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany; National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany; Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Heidelberg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Patrick Naumann
- Heidelberg University Hospital, Department of Radiation Oncology, 69120 Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany; Heidelberg Ion-Beam Therapy Center (HIT), 69120 Heidelberg, Germany.
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13
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Gupta P, Pérez-Mancera PA, Kocher H, Nisbet A, Schettino G, Velliou EG. A Novel Scaffold-Based Hybrid Multicellular Model for Pancreatic Ductal Adenocarcinoma-Toward a Better Mimicry of the in vivo Tumor Microenvironment. Front Bioeng Biotechnol 2020; 8:290. [PMID: 32391339 PMCID: PMC7193232 DOI: 10.3389/fbioe.2020.00290] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/19/2020] [Indexed: 12/11/2022] Open
Abstract
With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumor niche. Advancements in the field of tissue engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, polyurethane (PU) scaffold-based, long-term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells, and stellate cells. Recognizing the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumor compartment consisting of cancer cells [fibronectin (FN)-coated] and a surrounding stromal compartment consisting of stellate and endothelial cells [collagen I (COL)-coated]. Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported timeframe in vitro. Furthermore, the hybrid model showed extensive COL production by the cells, mimicking desmoplasia, one of PDAC's hallmark features. Fibril alignment of the stellate cells was observed, which attested to their activated state. All three cell types expressed various cell-specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low-cost tool for in vitro studies of PDAC, as well as for treatment screening.
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Affiliation(s)
- Priyanka Gupta
- Bioprocess and Biochemical Engineering Group (BioProChem), Department of Chemical and Process Engineering, University of Surrey, Guildford, United Kingdom
| | - Pedro A. Pérez-Mancera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Hemant Kocher
- Centre for Tumour Biology and Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Andrew Nisbet
- Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
| | - Giuseppe Schettino
- Department of Physics, University of Surrey, Guildford, United Kingdom
- Medical Radiation Science Group, The National Physical Laboratory, Teddington, United Kingdom
| | - Eirini G. Velliou
- Bioprocess and Biochemical Engineering Group (BioProChem), Department of Chemical and Process Engineering, University of Surrey, Guildford, United Kingdom
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14
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Rutenberg MS, Nichols RC. Proton beam radiotherapy for pancreas cancer. J Gastrointest Oncol 2020; 11:166-175. [PMID: 32175120 PMCID: PMC7052755 DOI: 10.21037/jgo.2019.03.02] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 03/07/2019] [Indexed: 12/17/2022] Open
Abstract
Pancreatic carcinoma is a challenging malignancy to manage with a very poor prognosis. Despite continued difficulties in its management, there have been incremental improvements in outcomes over the past several decades. Achieving the best oncologic outcomes requires a multimodality approach including surgery, chemotherapy, and radiotherapy. Proton radiotherapy enables the delivery of high-dose radiotherapy to the tumor or resection bed while sparing nearby critical organs. Due to their unique physical properties, protons can deliver radiotherapy dose distributions that are not achievable with photons (X-rays) even with advanced photon delivery techniques (e.g., intensity-modulated radiotherapy). Improved dose distributions can lead to reduced treatment toxicity and enable treatment intensification. As better chemotherapy regimens lead to better systemic disease control, it will become increasingly important that local-regional control is achieved. This will in part be accomplished by combining better radiotherapy with more active chemotherapies. Proton radiotherapy provides an excellent means for achieving this.
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Affiliation(s)
- Michael S Rutenberg
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Romaine C Nichols
- Department of Radiation Oncology, University of Florida College of Medicine, Jacksonville, FL, USA
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15
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Dell’Oro M, Short M, Wilson P, Bezak E. Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12010163. [PMID: 31936565 PMCID: PMC7017270 DOI: 10.3390/cancers12010163] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/03/2020] [Accepted: 01/06/2020] [Indexed: 02/08/2023] Open
Abstract
Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE® database search in April 2019. Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology.
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Affiliation(s)
- Mikaela Dell’Oro
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide SA 5001, Australia; (M.S.); (E.B.)
- Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide SA 5000, Australia;
- Correspondence: ; Tel.: +61-435214264
| | - Michala Short
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide SA 5001, Australia; (M.S.); (E.B.)
| | - Puthenparampil Wilson
- Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide SA 5000, Australia;
- School of Engineering, University of South Australia, Adelaide SA 5001, Australia
| | - Eva Bezak
- Cancer Research Institute and School of Health Sciences, University of South Australia, Adelaide SA 5001, Australia; (M.S.); (E.B.)
- Department of Physics, University of Adelaide, Adelaide SA 5005, Australia
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16
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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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17
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Nakamura A, Prichard HA, Wo JY, Wolfgang JA, Hong TS. Elective nodal irradiation with simultaneous integrated boost stereotactic body radiotherapy for pancreatic cancer: Analyses of planning feasibility and geometrically driven DVH prediction model. J Appl Clin Med Phys 2019; 20:71-83. [PMID: 30636367 PMCID: PMC6370996 DOI: 10.1002/acm2.12528] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 12/05/2018] [Accepted: 12/14/2018] [Indexed: 12/31/2022] Open
Abstract
PURPOSE We evaluate the feasibility of the elective nodal irradiation strategy in stereotactic body radiotherapy (SBRT) for pancreatic cancer. METHODS Three simultaneous integrated boost (SIB)-SBRT plans (Boost1, Boost2, and Boost3) were retrospectively generated for each of 20 different patients. Boost1 delivered 33 and 25 Gy to PTV1 and PTV2, respectively. Boost2 delivered 40, 33, and 25 Gy to boostCTV, PTV1, and PTV2, respectively. Boost3 delivered 33 and 25 Gy to PTV1 and PTV3, respectively. PTV1 covered the initial standard SBRT plan (InitPlan) gross tumor volume (GTV). PTV2 covered CTVgeom which was created by a 10-mm expansion (15 mm posterior) of GTV. PTV3 covered CTVprop which included elective nodal regions. The boostCTV included GTV as well as involved vasculature. The planning feasibility in each scenario and dose-volume histograms (DVHs) were analyzed and compared with the InitPlan (delivered 33 Gy only to PTV1) by paired t-test. Next, a novel DVH prediction model was developed and its performance was evaluated according to the prediction accuracy (AC) of planning violations. Then, the model was used to simulate the impacts of GTV-to-organs at risk (OAR) distance and gastrointestinal (GI) OAR volume variations on planning feasibility. RESULTS Significant dose increases were observed in GI-OARs in SIB-SBRT plans when compared with InitPlan. All dose constraints were met in 63% of cases in InitPlan, Boost1, and Boost2, whereas Boost3 developed DVH violations in all cases. Utilizing previous patient anatomy, the novel DVH prediction model achieved a high AC in the prediction of violations for GI-OARs; the positive predictive value, negative predictive value, and AC were 66%, 90%, and 84%, respectively. Experiments with the model demonstrated that the larger proximity volume of GI-OAR at the shorter distance substantially impacted on planning violations. CONCLUSIONS SIB-SBRT plan with geometrically defined prophylactic areas can be dosimetrically feasible, but including all nodal areas with 25 Gy in five fractions appears to be unrealistic.
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Affiliation(s)
- Akira Nakamura
- Department of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Hugh A. Prichard
- Department of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Jennifer Y. Wo
- Department of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - John A. Wolfgang
- Department of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Theodore S. Hong
- Department of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
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18
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Gupta P, Totti S, Pérez-Mancera PA, Dyke E, Nisbet A, Schettino G, Webb R, Velliou EG. Chemoradiotherapy screening in a novel biomimetic polymer based pancreatic cancer model. RSC Adv 2019; 9:41649-41663. [PMID: 35541584 PMCID: PMC9076463 DOI: 10.1039/c9ra09123h] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 12/09/2019] [Indexed: 11/21/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly and aggressive disease with a very low survival rate. This is partly due to the resistance of the disease to currently available treatment options. Herein, we report for the first time the use of a novel polyurethane scaffold based PDAC model for screening the short and relatively long term (1 and 17 days post-treatment) responses of chemotherapy, radiotherapy and their combination. We show a dose dependent cell viability reduction and apoptosis induction for both chemotherapy and radiotherapy. Furthermore, we observe a change in the impact of the treatment depending on the time-frame, especially for radiation for which the PDAC scaffolds showed resistance after 1 day but responded more 17 days post-treatment. This is the first study to report a viable PDAC culture in a scaffold for more than 2 months and the first to perform long-term (17 days) post-treatment observations in vitro. This is particularly important as a longer time-frame is much closer to animal studies and to patient treatment regimes, highlighting that our scaffold system has great potential to be used as an animal free model for screening of PDAC. Poly-urethane scaffold based 3D pancreatic cancer model enables realistic long term chemotherapy and radiotherapy screening. This model can be used for personalised treatment screening.![]()
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Affiliation(s)
- Priyanka Gupta
- Bioprocess and Biochemical Engineering Group (BioProChem)
- Department of Chemical and Process Engineering
- University of Surrey
- Guildford
- UK
| | - Stella Totti
- Bioprocess and Biochemical Engineering Group (BioProChem)
- Department of Chemical and Process Engineering
- University of Surrey
- Guildford
- UK
| | | | - Eleanor Dyke
- Department of Medical Physics
- The Royal Surrey County Hospital
- NHS Foundation Trust
- Guildford
- UK
| | - Andrew Nisbet
- Department of Medical Physics
- The Royal Surrey County Hospital
- NHS Foundation Trust
- Guildford
- UK
| | - Giuseppe Schettino
- Department of Physics
- University of Surrey
- Guildford GU2 7XH
- UK
- Medical Radiation Science Group
| | - Roger Webb
- The Ion Beam Centre
- University of Surrey
- Guildford
- UK
| | - Eirini G. Velliou
- Bioprocess and Biochemical Engineering Group (BioProChem)
- Department of Chemical and Process Engineering
- University of Surrey
- Guildford
- UK
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19
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Stefanowicz S, Stützer K, Zschaeck S, Jakobi A, Troost EGC. Comparison of different treatment planning approaches for intensity-modulated proton therapy with simultaneous integrated boost for pancreatic cancer. Radiat Oncol 2018; 13:228. [PMID: 30466468 PMCID: PMC6249773 DOI: 10.1186/s13014-018-1165-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/30/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Neoadjuvant radio(chemo)therapy of non-metastasized, borderline resectable or unresectable locally advanced pancreatic cancer is complex and prone to cause side-effects, e.g., in gastrointestinal organs. Intensity-modulated proton therapy (IMPT) enables a high conformity to the targets while simultaneously sparing the normal tissue such that dose-escalation strategies come within reach. In this in silico feasibility study, we compared four IMPT planning strategies including robust multi-field optimization (rMFO) and a simultaneous integrated boost (SIB) for dose-escalation in pancreatic cancer patients. METHODS For six pancreatic cancer patients referred for adjuvant or primary radiochemotherapy, four rMFO-IMPT-SIB treatment plans each, consisting of two or three (non-)coplanar beam arrangements, were optimized. Dose values for both targets, i.e., the elective clinical target volume [CTV, prescribed dose Dpres = 51Gy(RBE)] and the boost target [Dpres = 66Gy(RBE)], for the organs at risk as well as target conformity and homogeneity indexes, derived from the dose volume histograms, were statistically compared. RESULTS All treatment plans of each strategy fulfilled the prescribed doses to the targets (Dpres(GTV,CTV) = 100%, D95%,(GTV,CTV) ≥ 95%, D2%,(GTV,CTV) ≤ 107%). No significant differences for the conformity index were found (p > 0.05), however, treatment plans with a three non-coplanar beam strategy were most homogenous to both targets (p < 0.045). The median value of all dosimetric results of the large and small bowel as well as for the liver and the spinal cord met the dose constraints with all beam arrangements. Irrespective of the planning strategies, the dose constraint for the duodenum and stomach were not met. Using the three-beam arrangements, the dose to the left kidney could be significant decreased when compared to a two-beam strategy (p < 0.045). CONCLUSION Based on our findings we recommend a three-beam configuration with at least one non-coplanar beam for dose-escalated SIB with rMFO-IMPT in advanced pancreatic cancer patients achieving a homogeneous dose distribution in the target while simultaneously minimizing the dose to the organs at risk. Further treatment planning studies on aspects of breathing and organ motion need to be performed.
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Affiliation(s)
- Sarah Stefanowicz
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.,Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Kristin Stützer
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.,Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Sebastian Zschaeck
- Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Annika Jakobi
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.,Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany
| | - Esther G C Troost
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany. .,Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. .,Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany. .,German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and; Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
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Simulation study of dosimetric effect in proton beam therapy using concomitant boost technique for unresectable pancreatic cancers. Jpn J Radiol 2018; 36:456-461. [DOI: 10.1007/s11604-018-0743-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/06/2018] [Indexed: 12/25/2022]
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21
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Raldow AC, Hong TS. Will There Be a Clinically Significant Role for Protons in Patients With Gastrointestinal Malignancies? Semin Radiat Oncol 2018; 28:125-130. [PMID: 29735188 DOI: 10.1016/j.semradonc.2017.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Gastrointestinal malignancies inherently arise amidst visceral organs that are very radiation sensitive. While radiation therapy is an integral part of cancer treatment, its use has historically been limited by normal tissue toxicity. Proton therapy is a form of external-beam radiation associated with several dosimetric advantages as compared to photon therapy. Proton radiation may allow for the delivery of tumoricidal doses while minimizing side effects by decreasing the dose to adjacent organs at risk. We discuss the rationale for and challenges of using protons in the treatment of gastrointestinal cancers. We describe the available data and ongoing trials using proton radiation to treat these tumors. Finally, we discuss the unique challenges of using protons to treat gastrointestinal malignancies.
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Affiliation(s)
- Ann C Raldow
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.
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22
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Jethwa KR, Tryggestad EJ, Whitaker TJ, Giffey BT, Kazemba BD, Neben-Wittich MA, Merrell KW, Haddock MG, Hallemeier CL. Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. Adv Radiat Oncol 2018; 3:314-321. [PMID: 30202800 PMCID: PMC6128024 DOI: 10.1016/j.adro.2018.04.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/25/2018] [Accepted: 04/04/2018] [Indexed: 12/22/2022] Open
Abstract
Purpose Pencil-beam scanning intensity modulated proton therapy (IMPT) may allow for an improvement in the therapeutic ratio compared with conventional techniques of radiation therapy delivery for pancreatic cancer. The purpose of this study was to describe the clinical implementation of IMPT for intact and clinically localized pancreatic cancer, perform a matched dosimetric comparison with volumetric modulated arc therapy (VMAT), and report acute adverse event (AE) rates and patient-reported outcomes (PROs) of health-related quality of life. Methods and materials Between July 2016 and March 2017, 13 patients with localized pancreatic cancer underwent concurrent capecitabine or 5-fluorouracil-based chemoradiation therapy (CRT) utilizing IMPT to a dose of 50 Gy (radiobiological effectiveness: 1.1). A VMAT plan was generated for each patient to use for dosimetric comparison. Patients were assessed prospectively for AEs and completed PRO questionnaires utilizing the Functional Assessment of Cancer Therapy-Hepatobiliary at baseline and upon completion of CRT. Results There was no difference in mean target coverage between IMPT and VMAT (P > .05). IMPT offered significant reductions in dose to organs at risk, including the small bowel, duodenum, stomach, large bowel, liver, and kidneys (P < .05). All patients completed treatment without radiation therapy breaks. The median weight loss during treatment was 1.6 kg (range, 0.1-5.7 kg). No patients experienced grade ≥3 treatment-related AEs. The median Functional Assessment of Cancer Therapy-Hepatobiliary scores prior to versus at the end of CRT were 142 (range, 113-163) versus 136 (range, 107-173; P = .18). Conclusions Pencil-beam scanning IMPT was feasible and offered significant reductions in radiation exposure to multiple gastrointestinal organs at risk. IMPT was associated with no grade ≥3 gastrointestinal AEs and no change in baseline PROs, but the conclusions are limited due to the patient sample size. Further clinical studies are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.
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Affiliation(s)
- Krishan R Jethwa
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Broc T Giffey
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Bret D Kazemba
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
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Dreher C, Habermehl D, Jäkel O, Combs SE. Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: higher doses alone, higher RBE or both? Radiat Oncol 2017; 12:203. [PMID: 29282139 PMCID: PMC5745986 DOI: 10.1186/s13014-017-0945-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 12/14/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer.
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Affiliation(s)
- Constantin Dreher
- Department of Radiation Oncology, University Hospital Rechts der Isar, Technical University Munich (TUM), Ismaninger Str. 22 Munich, Germany
| | - Daniel Habermehl
- Department of Radiation Oncology, University Hospital Rechts der Isar, Technical University Munich (TUM), Ismaninger Str. 22 Munich, Germany
- Department of Radiation Sciences (DRS), Institute of Innovative Radiotherapy (iRT), Helmholtz Zentrum München, Oberschleißheim, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site München, München, Germany
| | - Oliver Jäkel
- Department of Medical Physics in Radiation Oncology, German Cancer Research Center, INF, 280 Heidelberg, Germany
- Heidelberg Ion Beam Therapy Center (HIT), INF 450, 69120 Heidelberg, Germany
| | - Stephanie E. Combs
- Department of Radiation Oncology, University Hospital Rechts der Isar, Technical University Munich (TUM), Ismaninger Str. 22 Munich, Germany
- Department of Radiation Sciences (DRS), Institute of Innovative Radiotherapy (iRT), Helmholtz Zentrum München, Oberschleißheim, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site München, München, Germany
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Ahmed KA, Demetriou SK, McDonald M, Johnstone PA. Clinical Benefits of Proton Beam Therapy for Tumors of the Skull Base. Cancer Control 2017; 23:213-9. [PMID: 27556661 DOI: 10.1177/107327481602300304] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The unique radiobiological properties of protons have been understood for many years. In addition, many of the clinical benefits of radiotherapy were first noted in tumors involving the skull base. More public attention has been given to proton beam therapy due to the increasing number of centers now in operation or in the planning stages for offering this treatment option. METHODS We reviewed the physical properties of protons and the clinical studies performed to justify their use in the management of skull-base tumors and determine the benefits of proton beam therapy. RESULTS Published reports suggest a benefit to proton beam therapy for use in tumors of the skull base, including craniopharyngiomas, chordomas, skull-base sarcomas, and unresectable meningiomas. CONCLUSIONS Use of proton beam therapy may be beneficial in select patients. Surgical and medical oncologists should have a general understanding of such cases to facilitate their appropriate referral.
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Affiliation(s)
- Kamran A Ahmed
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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25
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Hong JC, Czito BG, Willett CG, Palta M. A current perspective on stereotactic body radiation therapy for pancreatic cancer. Onco Targets Ther 2016; 9:6733-6739. [PMID: 27826200 PMCID: PMC5096771 DOI: 10.2147/ott.s99826] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pancreatic cancer is a formidable malignancy with poor outcomes. The majority of patients are unable to undergo resection, which remains the only potentially curative treatment option. The management of locally advanced (unresectable) pancreatic cancer is controversial; however, treatment with either chemotherapy or chemoradiation is associated with high rates of local tumor progression and metastases development, resulting in low survival rates. An emerging local modality is stereotactic body radiation therapy (SBRT), which uses image-guided, conformal, high-dose radiation. SBRT has demonstrated promising local control rates and resultant quality of life with acceptable rates of toxicity. Over the past decade, increasing clinical experience and data have supported SBRT as a local treatment modality. Nevertheless, additional research is required to further evaluate the role of SBRT and improve upon the persistently poor outcomes associated with pancreatic cancer. This review discusses the existing clinical experience and technical implementation of SBRT for pancreatic cancer and highlights the directions for ongoing and future studies.
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Affiliation(s)
- Julian C Hong
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | - Brian G Czito
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | | | - Manisha Palta
- Department of Radiation Oncology, Duke University, Durham, NC, USA
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Verma V, Lin SH, Simone CB, Mehta MP. Clinical outcomes and toxicities of proton radiotherapy for gastrointestinal neoplasms: a systematic review. J Gastrointest Oncol 2016; 7:644-64. [PMID: 27563457 DOI: 10.21037/jgo.2016.05.06] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Proton beam radiotherapy (PBT) is frequently shown to be dosimetrically superior to photon radiotherapy (RT), though supporting data for clinical benefit are severely limited. Because of the potential for toxicity reduction in gastrointestinal (GI) malignancies, we systematically reviewed the literature on clinical outcomes (survival/toxicity) of PBT. METHODS A systematic search of PubMed, EMBASE, abstracts from meetings of the American Society for Radiation Oncology, Particle Therapy Co-Operative Group, and American Society of Clinical Oncology was conducted for publications from 2000-2015. Thirty-eight original investigations were analyzed. RESULTS Although results of PBT are not directly comparable to historical data, outcomes roughly mirror previous data, generally with reduced toxicities for PBT in some neoplasms. For esophageal cancer, PBT is associated with reduced toxicities, postoperative complications, and hospital stay as compared to photon radiation, while achieving comparable local control (LC) and overall survival (OS). In pancreatic cancer, numerical survival for resected/unresected cases is also similar to existing photon data, whereas grade ≥3 nausea/emesis and post-operative complications are numerically lower than those reported with photon RT. The strongest data in support of PBT for HCC comes from phase II trials demonstrating very low toxicities, and a phase III trial of PBT versus transarterial chemoembolization demonstrating trends towards improved LC and progression-free survival (PFS) with PBT, along with fewer post-treatment hospitalizations. Survival and toxicity data for cholangiocarcinoma, liver metastases, and retroperitoneal sarcoma are also roughly equivalent to historical photon controls. There are two small reports for gastric cancer and three for anorectal cancer; these are not addressed further. CONCLUSIONS Limited quality (and quantity) of data hamper direct comparisons and conclusions. However, the available data, despite the inherent caveats and limitations, suggest that PBT offers the potential to achieve significant reduction in treatment-related toxicities without compromising survival or LC for multiple GI malignancies. Several randomized comparative trials are underway that will provide more definitive answers.
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Affiliation(s)
- Vivek Verma
- 1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA ; 2 Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA ; 3 Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; 4 Miami Cancer Institute, Baptist Health South Florida, Coral Gables, FL, USA
| | - Steven H Lin
- 1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA ; 2 Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA ; 3 Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; 4 Miami Cancer Institute, Baptist Health South Florida, Coral Gables, FL, USA
| | - Charles B Simone
- 1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA ; 2 Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA ; 3 Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; 4 Miami Cancer Institute, Baptist Health South Florida, Coral Gables, FL, USA
| | - Minesh P Mehta
- 1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA ; 2 Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA ; 3 Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; 4 Miami Cancer Institute, Baptist Health South Florida, Coral Gables, FL, USA
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Eskander MF, Bliss LA, Tseng JF. Pancreatic adenocarcinoma. Curr Probl Surg 2016; 53:107-54. [DOI: 10.1067/j.cpsurg.2016.01.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/04/2016] [Indexed: 12/17/2022]
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Russo S, Ammori J, Eads J, Dorth J. The role of neoadjuvant therapy in pancreatic cancer: a review. Future Oncol 2016; 12:669-85. [PMID: 26880384 DOI: 10.2217/fon.15.335] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Controversy remains regarding neoadjuvant approaches in the treatment of pancreatic cancer. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients and increased margin-negative resection rate. At present, there are no randomized data favoring neoadjuvant over adjuvant therapy and multiple neoadjuvant approaches are under investigation. Combination chemotherapy regimens including 5-fluorouracil, irinotecan and oxaliplatin, gemcitabine with or without abraxane, or docetaxel and capecitabine have been used in the neoadjuvant setting. Radiation and chemoradiation have also been incorporated into neoadjuvant strategies, and delivery of alternative fractionation regimens is being explored. This review provides an overview of neoadjuvant therapies for pancreatic cancer.
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Affiliation(s)
- Suzanne Russo
- Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
| | - John Ammori
- Department of Surgery, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
| | - Jennifer Eads
- Department of Medicine, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
| | - Jennifer Dorth
- Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
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Spot-scanned pancreatic stereotactic body proton therapy: A dosimetric feasibility and robustness study. Phys Med 2016; 32:331-42. [DOI: 10.1016/j.ejmp.2015.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 11/15/2015] [Accepted: 12/27/2015] [Indexed: 12/31/2022] Open
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Ahn DH, Williams TM, Goldstein DA, El-Rayes B, Bekaii-Saab T. Adjuvant therapy for pancreas cancer in an era of value based cancer care. Cancer Treat Rev 2016; 42:10-7. [PMID: 26620819 PMCID: PMC4976619 DOI: 10.1016/j.ctrv.2015.11.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/08/2015] [Accepted: 11/12/2015] [Indexed: 12/16/2022]
Abstract
In resected pancreas cancer, adjuvant therapy improves outcomes and is considered the standard of care for patients who recover sufficiently post operatively. Chemotherapy or combined chemotherapy and radiation therapy (chemoradiation; CRT) are strategies used in the adjuvant setting. However, there is a lack of evidence to suggest whether the addition of RT to chemotherapy translates to an improvement in clinical outcomes. This is true even when accounting for the subset of patients with a higher risk for recurrence, such as those with R1 and lymph node positive disease. When considering the direct and indirect costs, impact on quality of life and questionable added clinical benefit, the true "net health benefit" from added RT to chemotherapy becomes more uncertain. Future directions, including the utilization of modern RT, integration of novel therapies, and intensifying chemotherapy regimens may improve outcomes in resected pancreas cancer.
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Affiliation(s)
- Daniel H Ahn
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Terence M Williams
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Daniel A Goldstein
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Bassel El-Rayes
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Tanios Bekaii-Saab
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States.
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31
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Nichols RC, Huh S, Li Z, Rutenberg M. Proton therapy for pancreatic cancer. World J Gastrointest Oncol 2015; 7:141-147. [PMID: 26380057 PMCID: PMC4569591 DOI: 10.4251/wjgo.v7.i9.141] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/03/2015] [Accepted: 07/22/2015] [Indexed: 02/05/2023] Open
Abstract
Radiotherapy is commonly offered to patients with pancreatic malignancies although its ultimate utility is compromised since the pancreas is surrounded by exquisitely radiosensitive normal tissues, such as the duodenum, stomach, jejunum, liver, and kidneys. Proton radiotherapy can be used to create dose distributions that conform to tumor targets with significant normal tissue sparing. Because of this, protons appear to represent a superior modality for radiotherapy delivery to patients with unresectable tumors and those receiving postoperative radiotherapy. A particularly exciting opportunity for protons also exists for patients with resectable and marginally resectable disease. In this paper, we review the current literature on proton therapy for pancreatic cancer and discuss scenarios wherein the improvement in the therapeutic index with protons may have the potential to change the management paradigm for this malignancy.
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Abstract
Multimodality therapy for gastrointestinal (GI) cancers carries considerable risk for toxicity; even single-modality radiation therapy in this population carries with it a daunting side effect profile. Supportive care can certainly mitigate some of the morbidity, but there remain numerous associated acute and late complications that can compromise the therapy and ultimately the outcome. Gastrointestinal cancers inherently occur amid visceral organs that are particularly sensitive to radiotherapy, creating a very narrow therapeutic window for aggressive cell kill with minimal normal tissue damage. Radiation therapy is a critical component of locoregional control, but its use has historically been limited by toxicity concerns, both real and perceived. Fundamental to this is the fact that long-term clinical experience with radiation in GI cancers derives almost entirely from 2-dimensional radiation (plain x-ray-based planning) and subsequently 3-dimensional conformal radiation. The recent use of intensity-modulated photon-based techniques is not well represented in most of the landmark chemoradiation trials. Furthermore, the elusive search for efficacious but tolerable local therapy in GI malignancies raises the possibility that proton radiotherapy's physical and dosimetric differences relative to conventional therapy may make it better suited to the challenge. In many sites, local recurrences after chemoradiation pose a particular challenge, and reirradiation in these sites may be done successfully with proton radiotherapy.
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Chu KY, Eccles CL, Brunner TB. Endobiliary Stent Position Changes during External-beam Radiotherapy. J Med Imaging Radiat Sci 2015; 46:57-64. [PMID: 26090069 PMCID: PMC4467517 DOI: 10.1016/j.jmir.2014.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2022]
Abstract
PURPOSE Endobiliary stents can be used as surrogates for pancreatic localization when using cone-beam computed tomography (CBCT) during external-beam radiotherapy (EBRT). This work reports on interfraction stent position changes during EBRT for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS Six patients with endobiliary stents who underwent EBRT for LAPC were assessed. Measurements from the most superior aspect of the stent (sup stent) and the most inferior aspect of the stent (inf stent) to the most inferior, posterior aspect of the L1 vertebra central spinous process were determined from daily treatment CBCTs and compared with those determined from the planning computed tomography (CT) scan. Changes in stent-L1 measurements were interpreted as changes in relative stent position. RESULTS Three patients showed mean interfraction stent position changes of ≥1 cm when treatment measurements were compared with planning measurements. The sup stent for patient A moved to the right (2.66 ± 2.77 cm) and inferiorly (3.0 ± 3.12 cm), and the inf stent moved to the right (1.92 ± 2.02 cm) inferiorly (3.23 ± 3.34 cm) and posteriorly (1.41 ± 1.43 cm). The inf stent for patient B moved superiorly (2.23 ± 0.49 cm) and posteriorly (1.72 ± 0.59 cm). The sup and inf stent for patient F moved inferiorly (0.98 ± 0.35 cm and 1.21 ± 0.38 cm, respectively). The remaining three patients C, D, and E showed interfraction position changes of <1 cm. CONCLUSION Endobiliary stent migration and deformation were observed in a small subset of patients. Further investigation is required before confirming their use as surrogates for LAPC target localization during image-guided EBRT.
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Affiliation(s)
- Kwun-Ye Chu
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom ; Radiotherapy Department, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
| | - Cynthia L Eccles
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom ; Radiotherapy Department, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
| | - Thomas B Brunner
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom ; Department of Radiation Oncology, University of Freiburg, Freiburg im Breisgau, Germany
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Ling TC, Slater JM, Mifflin R, Nookala P, Grove R, Ly AM, Patyal B, Slater JD, Yang GY. Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848. J Gastrointest Oncol 2015; 6:108-14. [PMID: 25830030 DOI: 10.3978/j.issn.2078-6891.2014.094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 10/29/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines. MATERIALS Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord. RESULTS There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT. CONCLUSIONS For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans.
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Affiliation(s)
- Ted C Ling
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Jerry M Slater
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Rachel Mifflin
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Prashanth Nookala
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Roger Grove
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Anh M Ly
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Baldev Patyal
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Jerry D Slater
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Gary Y Yang
- Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
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Franke AJ, Rosati LM, Pawlik TM, Kumar R, Herman JM. The role of radiation therapy in pancreatic ductal adenocarcinoma in the neoadjuvant and adjuvant settings. Semin Oncol 2014; 42:144-62. [PMID: 25726059 DOI: 10.1053/j.seminoncol.2014.12.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic adenocarcinoma (PCA) is associated with high rates of cancer-related morbidity and mortality. Yet despite modern treatment advances, the only curative therapy remains surgical resection. The adjuvant therapeutic standard of care for PCA in the United States includes both chemotherapy and chemoradiation; however, an optimal regimen has not been established. For patients with resectable and borderline resectable PCA, recent investigation has focused efforts on evaluating the feasibility and efficacy of neoadjuvant therapy. Neoadjuvant therapy allows for early initiation of systemic therapy and identification of patients who harbor micrometastatic disease, thus sparing patients the potential morbidities associated with unnecessary radiation or surgery. This article critically reviews the data supporting or refuting the role of radiation therapy in the neoadjuvant and adjuvant settings of PCA management, with a particular focus on determining which patients may be more likely to benefit from radiation therapy.
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Affiliation(s)
- Aaron J Franke
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lauren M Rosati
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Timothy M Pawlik
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Rachit Kumar
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Joseph M Herman
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
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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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Sen N, Falk S, Abrams RA. Role of chemoradiotherapy in the adjuvant and neoadjuvant settings for resectable pancreatic cancer. Clin Oncol (R Coll Radiol) 2014; 26:551-9. [PMID: 25024090 DOI: 10.1016/j.clon.2014.06.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 03/21/2014] [Accepted: 06/05/2014] [Indexed: 01/24/2023]
Abstract
Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death. Worldwide, the mortality incidence ratio approaches 98%. Although only 15-20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm. Despite advances in surgical technique, peri-operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20-25%. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies.
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Affiliation(s)
- N Sen
- Department of Radiation Oncology, Rush University Medical Center, Chicago, USA.
| | - S Falk
- Department of Oncology, Bristol Haematology and Oncology Centre, Bristol, UK
| | - R A Abrams
- Department of Radiation Oncology, Rush University Medical Center, Chicago, USA
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Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014; 20:11142-11159. [PMID: 25170201 PMCID: PMC4145755 DOI: 10.3748/wjg.v20.i32.11142] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/11/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
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Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, Deshpande V, Shinagare S, Wo JY, Boucher Y, Wadlow RC, Kwak EL, Allen JN, Clark JW, Zhu AX, Ferrone CR, Mamon HJ, Adams J, Winrich B, Grillo T, Jain RK, DeLaney TF, Fernandez-del Castillo C, Duda DG. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys 2014; 89:830-8. [PMID: 24867540 PMCID: PMC4791180 DOI: 10.1016/j.ijrobp.2014.03.034] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 03/10/2014] [Accepted: 03/21/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.
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MESH Headings
- Aged
- Aged, 80 and over
- Antimetabolites, Antineoplastic/therapeutic use
- Biomarkers, Tumor/analysis
- CA-19-9 Antigen/blood
- Capecitabine
- Carcinoembryonic Antigen/blood
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/chemistry
- Carcinoma, Pancreatic Ductal/mortality
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/therapy
- Chemoradiotherapy, Adjuvant/methods
- Chemoradiotherapy, Adjuvant/mortality
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/therapeutic use
- Female
- Fluorouracil/analogs & derivatives
- Fluorouracil/therapeutic use
- Genes, ras/genetics
- Hepatocyte Growth Factor/blood
- Humans
- Male
- Middle Aged
- Pancreatic Neoplasms/blood
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/mortality
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/therapy
- Pancreaticoduodenectomy
- Prognosis
- Prospective Studies
- Proto-Oncogene Proteins/analysis
- Proto-Oncogene Proteins p21(ras)
- Proton Therapy/methods
- Receptors, CXCR/analysis
- ras Proteins/analysis
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Affiliation(s)
- Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - David P Ryan
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Darrell R Borger
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lawrence S Blaszkowsky
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Beow Y Yeap
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Marek Ancukiewicz
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shweta Shinagare
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yves Boucher
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Raymond C Wadlow
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Eunice L Kwak
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jill N Allen
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jeffrey W Clark
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew X Zhu
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Harvey J Mamon
- Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Judith Adams
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Barbara Winrich
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Tarin Grillo
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rakesh K Jain
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Thomas F DeLaney
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Dan G Duda
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Youl M, Hashem S, Brade A, Cummings B, Dawson LA, Gallinger S, Hedley D, Jiang H, Kim J, Krzyzanowska MK, Ringash J, Wong R, Brierley J. Induction gemcitabine plus concurrent gemcitabine and radiotherapy for locally advanced unresectable or resected pancreatic cancer. Clin Oncol (R Coll Radiol) 2014; 26:203-9. [PMID: 24462333 DOI: 10.1016/j.clon.2014.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 12/16/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022]
Abstract
AIMS To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m(2)) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m(2)). RESULTS After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. CONCLUSION This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I-II study. The benefit to patients with a gross tumour volume >48 cm(3) may be limited.
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Affiliation(s)
- M Youl
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - S Hashem
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - A Brade
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - B Cummings
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - L A Dawson
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - S Gallinger
- Department of Surgical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - D Hedley
- Department of Medical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - H Jiang
- Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - J Kim
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - M K Krzyzanowska
- Department of Medical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - J Ringash
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - R Wong
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada
| | - J Brierley
- Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada.
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Schlaff CD, Krauze A, Belard A, O'Connell JJ, Camphausen KA. Bringing the heavy: carbon ion therapy in the radiobiological and clinical context. Radiat Oncol 2014; 9:88. [PMID: 24679134 PMCID: PMC4002206 DOI: 10.1186/1748-717x-9-88] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 03/16/2014] [Indexed: 12/23/2022] Open
Abstract
Radiotherapy for the treatment of cancer is undergoing an evolution, shifting to the use of heavier ion species. For a plethora of malignancies, current radiotherapy using photons or protons yields marginal benefits in local control and survival. One hypothesis is that these malignancies have acquired, or are inherently radioresistant to low LET radiation. In the last decade, carbon ion radiotherapy facilities have slowly been constructed in Europe and Asia, demonstrating favorable results for many of the malignancies that do poorly with conventional radiotherapy. However, from a radiobiological perspective, much of how this modality works in overcoming radioresistance, and extending local control and survival are not yet fully understood. In this review, we will explain from a radiobiological perspective how carbon ion radiotherapy can overcome the classical and recently postulated contributors of radioresistance (α/β ratio, hypoxia, cell proliferation, the tumor microenvironment and metabolism, and cancer stem cells). Furthermore, we will make recommendations on the important factors to consider, such as anatomical location, in the future design and implementation of clinical trials. With the existing data available we believe that the expansion of carbon ion facilities into the United States is warranted.
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Affiliation(s)
| | | | | | | | - Kevin A Camphausen
- Radiation Oncology Branch, National Cancer Institute, 10 Center Drive Magnuson Clinical Center Room B3B100, Bethesda, MD 20892, USA.
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Wo JY, Mamon HJ, Ferrone CR, Ryan DP, Blaszkowsky LS, Kwak EL, Tseng YD, Napolitano BN, Ancukiewicz M, Swanson RS, Lillemoe KD, Fernandez-del Castillo C, Hong TS. Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. Radiother Oncol 2014; 110:160-4. [PMID: 24231241 DOI: 10.1016/j.radonc.2013.10.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 09/30/2013] [Accepted: 10/16/2013] [Indexed: 01/08/2023]
Abstract
PURPOSE In this phase I study, we sought to determine the feasibility and tolerability of neoadjuvant short course radiotherapy (SC-CRT) delivered with photon RT with concurrent capecitabine for resectable pancreatic adenocarcinoma. MATERIALS AND METHODS Ten patients with localized, resectable pancreatic adenocarcinoma were enrolled from December 2009 to August 2011. In dose level I, patients received 3 Gy × 10. In dose level 2, patients received 5 Gy × 5 (every other day). In dose level 3, patients received 5 Gy × 5 (consecutive days). Capecitabine was given during weeks 1 and 2. Surgery was performed 1-3 weeks after completion of chemotherapy. RESULTS With an intended accrual of 12 patients, the study was closed early due to unexpected intraoperative complications. Compared to the companion phase I proton study, patients treated with photons had increased intraoperative RT fibrosis reported by surgeons (27% vs. 63%). Among those undergoing a Whipple resection, increased RT fibrosis translated to an increased mean OR time of 69 min. Dosimetric comparison revealed significantly increased low dose exposure to organs at risk for patients treated with photon RT. CONCLUSIONS This phase I experience evaluating the tolerability of neoadjuvant SC-CRT with photon RT closed early due to unexpected intraoperative complications.
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Affiliation(s)
- Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
| | - Harvey J Mamon
- Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
| | - Cristina R Ferrone
- Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | - David P Ryan
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | - Lawrence S Blaszkowsky
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | - Eunice L Kwak
- Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | | | - Brian N Napolitano
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | - Marek Ancukiewicz
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | - Richard S Swanson
- Department of General Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
| | - Keith D Lillemoe
- Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
| | | | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
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Lee RY, Nichols RC, Huh SN, Ho MW, Li Z, Zaiden R, Awad ZT, Ahmed B, Hoppe BS. Proton therapy may allow for comprehensive elective nodal coverage for patients receiving neoadjuvant radiotherapy for localized pancreatic head cancers. J Gastrointest Oncol 2013; 4:374-9. [PMID: 24294509 DOI: 10.3978/j.issn.2078-6891.2013.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 07/17/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Neoadjuvant radiotherapy has the potential to improve local disease control for patients with localized pancreatic cancers. Concern about an increased risk of surgical complications due to small bowel and gastric exposure, however, has limited enthusiasm for this approach. Dosimetric studies have demonstrated the potential for proton therapy to reduce intestinal exposure compared with X-ray-based therapy. We sought to determine if neoadjuvant proton therapy allowed for field expansions to cover high-risk nodal stations in addition to the primary tumor. METHODS Twelve consecutive patients with nonmetastatic cancers of the pancreatic head underwent proton-based planning for neoadjuvant radiotherapy. Gross tumor volume was contoured using diagnostic computed tomography (CT) scans with oral and intravenous contrast. Four-dimensional planning scans were utilized to define an internal clinical target volume (ICTV). Five-mm planning target volume (PTV) expansions on the ICTV were generated to establish an initial PTV (PTV1). A second PTV was created using the initial PTV but was expanded to include the high-risk nodal targets as defined by the RTOG contouring atlas (PTV2). Optimized proton plans were generated for both PTVs for each patient. All PTVs received a dose of 50.4 cobalt gray equivalent (CGE). Normal-tissue exposures to the small bowel space, stomach, right kidney, left kidney and liver were recorded. Point spinal cord dose was limited to 45 CGE. RESULTS Median PTV1 volume was 308.75 cm(3) (range, 133.33-495.61 cm(3)). Median PTV2 volume was 541.75 cm(3) (range, 399.44-691.14 cm(3)). In spite of the substantial enlargement of the PTV when high-risk lymph nodes were included in the treatment volume, normal-tissue exposures (stomach, bowel space, liver, and kidneys) were only minimally increased relative to the exposures seen when only the gross tumor target was treated. CONCLUSIONS Proton therapy appears to allow for field expansions to cover high-risk lymph nodes without significantly increasing critical normal-tissue exposure in the neoadjuvant setting.
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Affiliation(s)
- Richard Y Lee
- Radiation Medicine, Roswell Park Cancer Institute, University at Buffalo, NY, USA
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44
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Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, Laheru DA, Jaffee E, Cameron JL, Tran PT, Hobbs RF, Wolfgang CL, Herman JM. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys 2013; 87:1007-15. [PMID: 24267969 PMCID: PMC3971882 DOI: 10.1016/j.ijrobp.2013.09.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 09/01/2013] [Accepted: 09/05/2013] [Indexed: 12/27/2022]
Abstract
PURPOSE To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. METHODS AND MATERIALS Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach. RESULTS Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. CONCLUSIONS Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy.
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MESH Headings
- Adenocarcinoma/blood supply
- Adenocarcinoma/diagnostic imaging
- Adenocarcinoma/pathology
- Adenocarcinoma/radiotherapy
- Adenocarcinoma/surgery
- Adult
- Aged
- Aged, 80 and over
- Algorithms
- Carcinoma, Pancreatic Ductal/blood supply
- Carcinoma, Pancreatic Ductal/diagnostic imaging
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/radiotherapy
- Carcinoma, Pancreatic Ductal/surgery
- Female
- Follow-Up Studies
- Humans
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood supply
- Neoplasm Recurrence, Local/diagnostic imaging
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/radiotherapy
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/diagnostic imaging
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/radiotherapy
- Pancreatic Neoplasms/surgery
- Pancreaticoduodenectomy
- Radiotherapy Dosage
- Radiotherapy Planning, Computer-Assisted/methods
- Radiotherapy, Adjuvant/methods
- Radiotherapy, Conformal/methods
- Radiotherapy, Intensity-Modulated/methods
- Tomography, X-Ray Computed/methods
- Tumor Burden
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Affiliation(s)
- Avani S. Dholakia
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | - Rachit Kumar
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | - Siva P. Raman
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph A. Moore
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | - Susannah Ellsworth
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | - Todd McNutt
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | - Daniel A. Laheru
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center
| | - Elizabeth Jaffee
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center
| | - John L. Cameron
- Department of Surgery, Sidney Kimmel Comprehensive Cancer Center
| | - Phuoc T. Tran
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center
| | - Robert F. Hobbs
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
| | | | - Joseph M. Herman
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center
- Department of Surgery, Sidney Kimmel Comprehensive Cancer Center
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45
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Habrand JL, Datchary J, Alapetite C, Bolle S, Calugaru V, Feuvret L, Helfre S, Stefan D, Delacroix S, Demarzi L, Dendale R. Évolution des indications cliniques en hadronthérapie 2008–2012. Cancer Radiother 2013; 17:400-6. [DOI: 10.1016/j.canrad.2013.07.141] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 07/16/2013] [Indexed: 12/25/2022]
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Dosimetric predictors of nausea and vomiting: an exploratory analysis of a prospective phase I/II trial with neoadjuvant accelerated short-course radiotherapy and capecitabine for resectable pancreatic cancer. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s13566-013-0114-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Nichols RC, George TJ, Zaiden RA, Awad ZT, Asbun HJ, Huh S, Ho MW, Mendenhall NP, Morris CG, Hoppe BS. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol 2013; 52:498-505. [PMID: 23477361 DOI: 10.3109/0284186x.2012.762997] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution. MATERIAL AND METHODS From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE. RESULTS Median follow-up for all patients was 11 (range 5-36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure. DISCUSSION Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.
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Affiliation(s)
- R. Charles Nichols
- University of Florida Proton Therapy Institute,
Jacksonville, Florida, USA
| | - Thomas J. George
- Department of Hematology and Medical Oncology, University of Florida,
Gainesville and Jacksonville, Florida, USA
| | - Robert A. Zaiden
- Department of Hematology and Medical Oncology, University of Florida,
Gainesville and Jacksonville, Florida, USA
| | - Ziad T. Awad
- Department of Surgery, University of Florida,
Jacksonville, FL, USA
| | | | - Soon Huh
- University of Florida Proton Therapy Institute,
Jacksonville, Florida, USA
| | - Meng Wei Ho
- University of Florida Proton Therapy Institute,
Jacksonville, Florida, USA
| | | | | | - bradford S. Hoppe
- University of Florida Proton Therapy Institute,
Jacksonville, Florida, USA
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48
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Malik NK, May KS, Chandrasekhar R, Wee W, Flaherty L, Iyer R, Gibbs J, Kuvshinoff B, Wilding G, Warren G, Yang GY. Treatment of locally advanced unresectable pancreatic cancer: a 10-year experience. J Gastrointest Oncol 2012. [PMID: 23205309 DOI: 10.3978/j.issn.2078-6891.2012.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE We retrospectively analyzed the results of patients with locally advanced unresectable pancreatic cancer (LAPC) treated with either chemoradiation (CRT) or chemotherapy alone over the past decade. METHODS AND MATERIALS Between December 1998 and October 2009, 116 patients with LAPC were treated at our institution. Eighty-four patients received concurrent chemoradiation [RT (+) group], primarily 5-flourouracil based (70%). Thirty-two patients received chemotherapy alone [RT (-) group], the majority gemcitabine based (78%). Progression-free survival (PFS) and overall survival (OS) were calculated from date of diagnosis to date of first recurrence and to date of death or last follow-up, respectively. Univariate statistical analysis was used to determine significant prognostic factors for overall survival. RESULTS Median patient age was 67 years. Sixty patients were female (52%). Median follow-up was 11 months (range, 1.6-59.4 months). The RT (+) group received a median radiation dose of 50.4 Gy, was more likely to present with ECOG 0-1 performance status, and experienced less grade 3-4 toxicity. PFS was 10.9 versus 9.1 months (P=0.748) and median survival was 12.5 versus 9.1 months (P=0.998) for the RT (+) and RT (-) groups respectively (P=0.748). On univariate analysis, patients who experienced grade 3-4 toxicity had worse overall survival than those who did not (P=0.02). CONCLUSIONS Optimal management for LAPC continues to evolve. Patients who developed treatment-related grade 3-4 toxicity have a poorer prognosis. Survival rates were not statistically significant between chemotherapy and chemoradiotherapy groups.
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Affiliation(s)
- Nadia K Malik
- Departments of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California, USA
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Shinoto M, Yamada S, Yasuda S, Imada H, Shioyama Y, Honda H, Kamada T, Tsujii H, Saisho H. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer 2012; 119:45-51. [PMID: 22744973 DOI: 10.1002/cncr.27723] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 05/23/2012] [Accepted: 05/31/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND The authors evaluated the tolerance and efficacy of carbon-ion radiotherapy (CIRT) as a short-course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue. METHODS Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short-course, dose-escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT. RESULTS The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty-one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5-year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively. CONCLUSIONS Preoperative, short-course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity.
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Affiliation(s)
- Makoto Shinoto
- Hospital of Research Center for Charged Particle Therapy, National Institute of Radiological Sciences. Chiba, Japan.
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Goodman KA, Hajj C. Role of radiation therapy in the management of pancreatic cancer. J Surg Oncol 2012; 107:86-96. [PMID: 22532174 DOI: 10.1002/jso.23137] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 04/03/2012] [Indexed: 12/16/2022]
Abstract
Local failure remains a major issue for patients with both resectable and locally advanced pancreatic cancer. The role of radiation therapy in the management of this disease is less clear and represents an area of some controversy. The objective of this review is to present the rationale for radiation therapy in pancreatic cancer, as well as to discuss the potential limitations and caveats of the currently available studies.
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Affiliation(s)
- Karyn A Goodman
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
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