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1
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Wang X, Chen X, Zhu J, Li S. Quantifying the impact of metronomic chemotherapy chemo-switch regimen and the sequencing of chemotherapy and radiotherapy on pancreatic ductal adenocarcinoma treatment. J Theor Biol 2025; 599:112033. [PMID: 39725272 DOI: 10.1016/j.jtbi.2024.112033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Metronomic chemotherapy (MCT) is a novel chemotherapy approach characterized by a high-frequency, low-dose administration strategy. The "chemo-switch" regimen involves the sequential use of two dosing strategies: maximum tolerated dose (MTD) chemotherapy and MCT. For patients with pancreatic ductal adenocarcinoma (PDAC), selecting novel chemotherapy regimens appropriately according to their physical conditions may help address the challenges associated with MTD chemotherapy, such as excessive toxicity, prolonged tumor recovery, and suboptimal efficacy. There is currently limited research on mathematical models related to novel chemotherapy regimens and PDAC, as well as on the impact of different drug administration strategies and the sequence of chemoradiotherapy in combined treatment. To address these gaps, we propose a two-dimensional multiscale mathematical model. Initially, we model the individual effects of MTD chemotherapy, antiangiogenic therapy, and radiotherapy. Subsequently, we analyze the anti-tumor effects of various chemotherapy regimens and their underlying mechanisms. Furthermore, we assess how different drug administration regimens and the sequencing of chemotherapy and radiotherapy affect treatment outcomes. Simulation results indicate that, compared to standard MTD chemotherapy, using the MCT regimen or introducing MCT during MTD chemotherapy (chemo-switch regimen) demonstrates better anti-tumor efficacy and sustained tumor perfusion, enhancing drug accumulation within tumor regions. Combined therapy exhibits superior efficacy compared to monotherapy. Placing radiotherapy after anti-angiogenic therapy and chemotherapy suggests more effective in suppressing tumor growth and sustaining tumor perfusion. It is noteworthy that while this study focuses on PDAC treatment, its findings can be extrapolated to other fibrotic tumors, thereby facilitating similar analyses across different tumor types.
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Affiliation(s)
- Xu Wang
- College of Information Engineering, Zhejiang University of Technology, Hangzhou, China
| | - Xi Chen
- Department of General Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jinhui Zhu
- Department of General Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Sheng Li
- College of Information Engineering, Zhejiang University of Technology, Hangzhou, China.
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2
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Bae SH, Park HC. Letter regarding "Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab". JOURNAL OF LIVER CANCER 2023; 23:402-404. [PMID: 37680020 PMCID: PMC10565551 DOI: 10.17998/jlc.2023.08.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/09/2023]
Affiliation(s)
- Sun Hyun Bae
- Department of Radiation Oncology, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hee Chul Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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3
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Zhang P, Mao R, Zhang C, Qiu Y, Chen M. Gastrointestinal injury induced by immunomodulators: A review article. Therap Adv Gastroenterol 2023; 16:17562848231158549. [PMID: 37113189 PMCID: PMC10126616 DOI: 10.1177/17562848231158549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 02/02/2023] [Indexed: 04/29/2023] Open
Abstract
An increasing number of immunomodulators, either anti-inflammatory or immunity-enhancing, have brought about a revolutionary effect in the management of a variety of autoimmune disorders and malignancies. However, their ability to cause gastrointestinal (GI) injury and induce GI symptoms has been increasingly and unexpectedly recognized. GI injury associated with immunomodulators may demonstrate various histologic and endoscopic patterns. Optimal diagnosis and treatment require a multidisciplinary approach. This review aims to provide an overview of the literature on its pathogenesis, the clinical, endoscopic, and histologic features, and suggested approaches to manage these newly recognized immunomodulator-induced GI adverse effects (AEs). We also reviewed current biomarkers predictive of GI toxicity and potential risk factors to identify susceptible patients. In addition, these immune-mediated AEs were compared with inflammatory bowel disease, a well-documented form of inflammation-driven GI injury. We hope this review will raise awareness and vigilance among clinicians of these entities to increase early diagnosis and rapid referral to specialist care.
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Affiliation(s)
- Pingxin Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Ren Mao
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Chuhan Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | | | - Minhu Chen
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
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4
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Koay EJ, Zaid M, Aliru M, Bagereka P, Van Wieren A, Rodriguez MJ, Jacobson G, Wolff RA, Overman M, Varadhachary G, Pant S, Wang H, Tzeng CW, Ikoma N, Kim M, Lee JE, Katz MH, Tamm E, Bhosale P, Taniguchi CM, Holliday EB, Smith GL, Ludmir EB, Minsky BD, Crane CH, Koong AC, Das P, Wang X, Javle M, Krishnan S. Nab-Paclitaxel, Capecitabine, and Radiation Therapy After Induction Chemotherapy in Treating Patients With Locally Advanced and Borderline Resectable Pancreatic Cancer: Phase 1 Trial and Imaging-based Biomarker Validation. Int J Radiat Oncol Biol Phys 2022; 114:444-453. [PMID: 35863672 DOI: 10.1016/j.ijrobp.2022.06.089] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 10/31/2022]
Abstract
PURPOSE Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response. METHODS AND MATERIALS Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m2) with concurrent capecitabine and RT in cohort sizes of 3 starting at the lowest dose. Dose limiting toxicity was defined as grade 3 or higher toxicity. Patients were restaged 4 to 6 weeks post-CRT completion, and surgical resection was offered to those with stable/responsive disease. We scored the tumor interface response (IR) postchemotherapy and post-CRT into type I (remained/became more defined) and type II (became less defined). Overall survival (OS) and progression-free survival (PFS) from time of CRT were estimated using Kaplan-Meier method. P ≤ .05 was considered significant. RESULTS Twenty-three patients started and finished on protocol (LAPC = 14, BRPC = 9). No grade 3 and 4 toxicities were reported in level 1 (n = 3) or level 2 (n = 3) initial groups. Two patients in the initial level 3 group developed dose limiting toxicity, establishing level 2 dose as the maximal tolerated dose. Level 2 group was expanded for additional 15 patients (for a total of 23 on trial), 5 of whom developed grade 3 toxicities. Seven patients underwent surgical resection. Median OS and PFS were 21.2 and 8.1 months, respectively. Type I IR was associated with better OS (P = .004) and PFS (P = .03) compared with type II IR. CONCLUSIONS We established the maximum tolerated dose for nab-paclitaxel in a consolidative CRT regimen for pancreatic ductal adenocarcinoma. Preliminary efficacy results warrant phase 2 trial evaluation. IR may be used for personalized treatment.
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Affiliation(s)
- Eugene J Koay
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
| | - Mohamed Zaid
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Maureen Aliru
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Polycarpe Bagereka
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Arie Van Wieren
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida
| | - Maria Jovie Rodriguez
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Galia Jacobson
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Robert A Wolff
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael Overman
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gauri Varadhachary
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shubham Pant
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ching-Wei Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naruhiko Ikoma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael Kim
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Matthew Hg Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric Tamm
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Priya Bhosale
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cullen M Taniguchi
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Emma B Holliday
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Grace L Smith
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Ethan B Ludmir
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Bruce D Minsky
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Christopher H Crane
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Albert C Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Prajnan Das
- Department of GI Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Xuemei Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Milind Javle
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sunil Krishnan
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida
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5
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Bendavid J, Modesto A. Radiation therapy and antiangiogenic therapy: Opportunities and challenges. Cancer Radiother 2022; 26:962-967. [PMID: 35989153 DOI: 10.1016/j.canrad.2022.06.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/21/2022] [Indexed: 10/15/2022]
Abstract
The importance of tumoral vascularization as a therapeutic target was first described in 1971 by Folkman. Anarchic vascularization in response to tumour hypoxia, especially mediated by vascular endothelial growth factor, represents a major target in the management of many cancers. The contribution of systemic anti-angiogenic treatments including humanized anti-VEGF monoclonal antibodies (bevacizumab) and tyrosine kinase inhibitors, whose effect on vascular normalization and correction of tumour hypoxia has been shown in preclinical studies to be enhancing the effect of radiotherapy. Early trials combining radiotherapy and antiangiogenics with a small number of patients have contradictory results and tend to put into perspective the opportunity that this synergistic association represents. The efficiency found must be tempered by some toxicity described, especially in association with high doses per fraction. The aim of this article is to present the main studies reporting the efficiency and safety of the combination of antiangiogenic drugs and radiotherapy, as well as the expected opportunities.
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Affiliation(s)
- J Bendavid
- Département de radiothérapie, Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif, France.
| | - A Modesto
- Département de radiothérapie, IUCT Oncopole, 1, avenue Irène-Jolio-Curie, 31100 Toulouse, France
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6
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Huang D, He Q, Zhai L, Shen J, Jing F, Chen H, Zhu X, Zhou J. Efficacy and Safety of Apatinib for the Treatment of Advanced or Recurrent Cervical Cancer: A Single-Arm Meta-Analysis Among Chinese Patients. Front Pharmacol 2022; 13:843905. [PMID: 36034824 PMCID: PMC9403417 DOI: 10.3389/fphar.2022.843905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 06/22/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Although various effective compounds for the second- and third-line treatment of advanced or recurrent cervical cancer improved the overall survival, the optimal regimen remains controversial. Previous studies revealed that apatinib had extensive anti-tumor activities. However, almost all studies on apatinib in recurrent cervical cancer are non-randomized controlled trials with small sample sizes, different first-line treatments, and uncontrolled statistical analysis, which may result in a lack of effective metrics to evaluate the efficacy and safety of apatinib. Here, this meta-analysis aims to evaluate the efficacy and safety of apatinib in patients with advanced or recurrent cervical cancer.Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis.Results: Seven studies involving 243 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.9% and 68.6%, respectively. With regard to survival analysis, the pooled PFS and OS were 5.19 months and 10.63 months, respectively. The most common treatment-related adverse events of apatinib were hand–foot syndrome (all grade: 39.6%, ≥grade III: 7.5%), hypertension (all grade: 34.5%, ≥grade III: 9.2%), and fatigue (all grade: 28.0%, ≥grade III: 5.1%).Conclusions: In summary, this meta-analysis demonstrated that apatinib has promising efficacy and safety for patients with advanced or recurrent cervical cancer.Systematic Review Registration:https://inplasy.com/inplasy-2022-7-0049/, identifier INPLASY202270049
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Affiliation(s)
- Da Huang
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qionghua He
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lingyun Zhai
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiayu Shen
- Department of Obstetrics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fei Jing
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huanhuan Chen
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoqing Zhu
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianwei Zhou
- Department of Gynecology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Jianwei Zhou,
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7
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Xiu W, Guo X, Yu M, Li Y, Xu Y, Zhu J, Luo J. Combination of Palliative Thoracic Radiotherapy With Bevacizumab for Stage IV Nonsquamous NSCLC: Is There Any Impact of Time Interval on Survival? Clin Med Insights Oncol 2022; 16:11795549221106462. [PMID: 35770233 PMCID: PMC9234832 DOI: 10.1177/11795549221106462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 05/24/2022] [Indexed: 02/05/2023] Open
Abstract
Background: The time interval between palliative thoracic radiotherapy and bevacizumab
treatment strongly influences the frequency of adverse events (AEs) when
both are concurrently applied to patients with advanced lung cancer. Herein,
we aimed to elucidate the optimal time interval between the treatments in
these patients. Methods: The medical records of patients with stage IV nonsquamous non–small-cell lung
cancer (NSCLC) without epidermal growth factor receptor and anaplastic
lymphoma kinase alteration who underwent palliative thoracic radiotherapy
and bevacizumab treatment from January 2008 to January 2020 were collected
and analyzed. Patients were divided into 2 groups based on the time interval
between treatments: <3 weeks (⩽3W group) and >3 weeks (>3W group).
The progression-free survival (PFS) and overall survival (OS) for the time
intervals were evaluated using the Kaplan-Meier method and Cox proportional
hazard models. Adverse events were assessed by the fifth version of the
Common Terminology Criteria for Adverse Events. Results: In total, 72 patients with stage IV NSCLC (⩽3W group, 37 patients; >3W
group, 35 patients) who concurrently or sequentially received palliative
thoracic radiotherapy and bevacizumab treatment were included in this study.
In the >3W and ⩽3W groups, the median PFS (8 vs 6 months, respectively)
and OS (15 vs 12 months, respectively) differed significantly. Multivariate
analyses findings revealed significantly shorter OS in the latter group. In
addition, the frequency of most AEs was marginally higher in the latter
group (P > .05). Conclusions: The time interval between palliative thoracic radiotherapy and bevacizumab
treatment that offers optimal safety is >3 weeks.
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Affiliation(s)
- Weigang Xiu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xiaotong Guo
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Min Yu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yanying Li
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yong Xu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jiang Zhu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jingjing Luo
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, P.R. China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, P.R. China
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8
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Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, Chupradit S, AL-Ghamdi HS, Shomali N, Zamani A, Mohammadi A, Dadashpour M. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal 2022; 20:49. [PMID: 35392964 PMCID: PMC8991477 DOI: 10.1186/s12964-022-00838-y] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 02/06/2023] Open
Abstract
Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
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Affiliation(s)
- Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991 Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow, 109240 Russian Federation
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation
- Industrial University, Tyumen, Russian Federation
| | - Abduladheem Turki Jalil
- Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, 230023 Grodno, Belarus
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- Department of Dentistry, Kut University College, Kut, Wasit 52001 Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
| | - Hasan S. AL-Ghamdi
- Internal Medicine Department, Division of Dermatology, Albaha University, Al Bahah, Kingdom of Saudi Arabia
| | - Navid Shomali
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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9
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Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer. Expert Rev Mol Med 2021; 23:e21. [PMID: 34906271 DOI: 10.1017/erm.2021.26] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is one of the most malignant tumours with a poor prognosis. In recent years, the incidence of pancreatic cancer is on the rise. Traditional chemotherapy and radiotherapy for pancreatic cancer have been improved, first-line and second-line palliative treatments have been developed, and adjuvant treatments have also been used in clinical. However, the 5-year survival rate is still less than 10% and new treatment methods such as targeted therapy and immunotherapy need to be investigated. In the past decades, many clinical trials of targeted therapies and immunotherapies for pancreatic cancer were launched and some of them showed an ideal prospect in a subgroup of pancreatic cancer patients. The experience of both success and failure of these clinical trials will be helpful to improve these therapies in the future. Therefore, the current research progress and challenges of selected targeted therapies and immunotherapies for pancreatic cancer are reviewed.
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10
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González A, Alonso-González C, González-González A, Menéndez-Menéndez J, Cos S, Martínez-Campa C. Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments. Cancers (Basel) 2021; 13:3263. [PMID: 34209857 PMCID: PMC8268559 DOI: 10.3390/cancers13133263] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.
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Affiliation(s)
| | | | | | | | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain; (A.G.); (A.G.-G.); (J.M.-M.); (C.M.-C.)
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11
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Ruan X, Liang JH, Pan Y, Cai R, Zhang RJ, He Z, Yang X, Niu Z, Jiang W. Apatinib for the treatment of metastatic or locoregionally recurrent nasopharyngeal carcinoma after failure of chemotherapy: A multicenter, single-arm, prospective phase 2 study. Cancer 2021; 127:3163-3171. [PMID: 34043812 DOI: 10.1002/cncr.33626] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The authors aimed to investigate the efficacy and safety of apatinib in patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC). METHODS A multicenter, single-arm, prospective phase 2 study was conducted on patients (18-70 years of age) with metastatic or recurrent NPC who had failed chemotherapy. Patients with recurrent disease involving vascular structure invasion were excluded. All enrolled patients received apatinib (500 mg daily) in continuous 4-week cycles until disease progression or development of unacceptable toxicity. The primary end point of this study was objective response rate (ORR), and the secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. This study was registered with ClinicalTrials.gov (NCT03130270). RESULTS Between January 2017 and June 2018, 33 patients were enrolled. At the end of the data collection (May 20, 2020), the 33 patients had completed a total of 261.2 cycles of apatinib. Although 12 patients achieved a partial response, no patient achieved a complete response; thus, the ORR in the 33 patients was 36.4% (95% CI, 19.0%-53.7%). At the end of follow-up (median, 30 months; 95% CI, 24.9-35.1), median OS and median PFS were 16 months (95% CI, 14.6-17.4 months) and 5.0 months (95% CI, 3.6-6.4 months), respectively. The most common adverse events (grade 1/2) were hand-foot syndrome (18 [54.5%]), hypertension (14 [42.4%]), oral ulcer (8 [24.2%]), and proteinuria (4 [12.1%]). Two patients (1 with diabetes and 1 with hypertension) developed cerebral infarction. Grade 3/4 toxicities were uncommon. CONCLUSIONS Apatinib shows promising activity, with manageable toxicities, in patients with metastatic or locoregionally recurrent NPC. Further evaluation of apatinib in large-scale studies is warranted. LAY SUMMARY Clinical studies on vascular endothelial growth factor receptor (VEGFR)-targeted therapy for recurrent or metastatic nasopharyngeal carcinoma (NPC) are limited. A recent preclinical study that evaluated apatinib in models of NPC showed a high objective response rate and a favorable safety profile. Our data further confirmed good efficacy in patients with lung metastasis. Further studies of the efficacy and safety of apatinib combined with immune checkpoint inhibitors or chemotherapy in NPC is warranted.
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Affiliation(s)
- Xiaolan Ruan
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jin-Hui Liang
- Department of Radiation Oncology, Wuzhou Red Cross Hospital, Wuzhou, China
| | - Yufei Pan
- Department of Radiation Oncology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Rui Cai
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Rong Jun Zhang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Zhuokai He
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Xi Yang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Zhijie Niu
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Wei Jiang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
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12
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Antibody therapy in pancreatic cancer: mAb-ye we're onto something? Biochim Biophys Acta Rev Cancer 2021; 1876:188557. [PMID: 33945846 DOI: 10.1016/j.bbcan.2021.188557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer remains an extremely deadly disease, with little improvement seen in treatment or outcomes over the last 40 years. Targeted monoclonal antibody therapy is one area that has been explored in attempts to tackle this disease. This review examines antibodies that have undergone clinical evaluation in pancreatic cancer. These antibodies target a wide variety of molecules, including tumour cell surface, stromal, immune and embryonic pathway targets. We discuss the therapeutic utility of these therapies both as monotherapeutics and in combination with other treatments such as chemotherapy. While antibody therapy for pancreatic cancer has yet to yield significant success, lessons learned from research thus far highlights future directions that may help overcome observed hurdles to yield clinically efficacious results.
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13
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Arias-Pinilla GA, Modjtahedi H. Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities. Cancers (Basel) 2021; 13:1781. [PMID: 33917882 PMCID: PMC8068268 DOI: 10.3390/cancers13081781] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.
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Affiliation(s)
- Gustavo A. Arias-Pinilla
- Department of Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK;
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
| | - Helmout Modjtahedi
- School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
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14
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Kim N, Choi SH, Chang JS, Kim YT, Kim SW, Kim GM, Kim YB. Use of bevacizumab before or after radiotherapy increases the risk of fistula formation in patients with cervical cancer. Int J Gynecol Cancer 2020; 31:59-65. [PMID: 33273018 DOI: 10.1136/ijgc-2020-002031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE Several reports have documented the risk of fistula formation after bevacizumab in patients previously treated with radiation therapy. The aim of this study was to investigate the risk of fistula formation with bevacizumab and radiotherapy compared with radiotherapy alone. METHODS We retrospectively analyzed patients with stage I-IV cervical cancer between January 2013 and December 2018. Patients who had a history of pelvic radiotherapy, who were treated with intracavitary brachytherapy alone, received radiotherapy at another hospital, received concurrent bevacizumab and radiotherapy, or had missing follow-up data or a short follow-up period (<6 months) were excluded. The fistula rates were compared between the groups using the Cox proportional hazards model and propensity score analyses. RESULTS A total of 302 patients were included in the study: 249 patients were treated with definitive or adjuvant radiotherapy, and 53 patients were treated with radiotherapy before or after bevacizumab. With a median follow-up of 35.9 (IQR 22.8-53.5) months, the 3 year cumulative fistula incidence rate was significantly higher in the radiotherapy + bevacizumab group than in the radiotherapy group (27.0% vs 3.0%, p<0.001). Bevacizumab administration was significantly associated with fistula formation in the multivariable adjusted model (HR 4.76, 95% CI 1.71 to 13.23) and three propensity score adjusted model (all p<0.05). Biologically equivalent dose in 2 Gy fractions for 2 cc of the rectum more than 76 Gy was also associated with fistula formation (HR 4.30, 95% CI 1.52 to 12.18). Additionally, a 10 month interval between radiotherapy and bevacizumab reduced the incidence of fistula formation in the radiotherapy + bevacizumab group (p=0.032). CONCLUSIONS In patients with cervical cancer treated with pelvic radiotherapy, the addition of bevacizumab substantially increased the risk of fistula formation. Physicians should perform pelvic radiotherapy in combination with bevacizumab with caution; moreover, close monitoring for fistula formation is warranted in these patients.
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Affiliation(s)
- Nalee Kim
- Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Seo Hee Choi
- Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Jee Suk Chang
- Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Young-Tae Kim
- Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Sang Wun Kim
- Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Gun Min Kim
- Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Yong Bae Kim
- Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
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15
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Shen ZT, Zhou H, Li AM, Ji XQ, Jiang CC, Yuan X, Li B, Zhu XX, Huang GC. Clinical outcomes and prognostic factors of stereotactic body radiation therapy combined with gemcitabine plus capecitabine for locally advanced unresectable pancreatic cancer. J Cancer Res Clin Oncol 2020; 146:417-428. [PMID: 31667573 DOI: 10.1007/s00432-019-03066-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 10/23/2019] [Indexed: 12/25/2022]
Abstract
PURPOSE This study aimed to evaluate the clinical outcomes, toxicity, and prognostic factors of SBRT combined with gemcitabine plus capecitabine (GEM-CAP) in treating locally advanced pancreatic cancer (LAPC). METHODS A total of 56 patients with LAPC treated with SBRT combined with GEM-CAP were reviewed from October 2010 to October 2016. The median total prescription dose at five fractions was 40 Gy (30-50 Gy). The patients were subjected to two cycles of GEM-CAP before SBRT. GEM-CAP chemotherapy was then offered for four cycles or until disease tolerance or progression. The primary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS The median OS and PFS from the date of diagnosis was 19 (95% CI 14.6-23.4) and 12 months (95% CI 8.34-15.66), respectively. The 1-year and 2-year survival rates were 82.1% and 35.7%, whereas the 1-year and 2-year PFS rates were 48.2% and 14.3%, respectively. The median carbohydrate antigen 19-9-determined PFS time was 11 months (95% CI 5.77-16.24). Multivariate analysis demonstrated that tumor diameter, lymph node metastasis, pre-treatment CA19-9 level, and post-treatment CA19-9 decline were independent prognostic factors (p < 0.05). Acute toxicity was minimal, with two cases (3.6%) experiencing grade 3 duodenal obstruction. No adverse events greater than grade 3 occurred. In late toxicity, three patients (5.4%) developed grade 3 gastrointestinal toxicity and two (3.6%) suffered from perforation caused by grade 4 radiation enteritis and intestinal fistula. CONCLUSIONS The combination of Cyberknife SBRT and GEM-CAP achieved excellent efficacy with acceptable toxicity for LAPC.
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Affiliation(s)
- Ze-Tian Shen
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Han Zhou
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Ao-Mei Li
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Xiao-Qin Ji
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Chang-Chen Jiang
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Xi Yuan
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Bing Li
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China
| | - Xi-Xu Zhu
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China.
| | - Gui-Chun Huang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China.
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16
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Arscott WT, Emmett J, Ghiam AF, Jones JA. Palliative Radiotherapy: Inpatients, Outpatients, and the Changing Role of Supportive Care in Radiation Oncology. Hematol Oncol Clin North Am 2019; 34:253-277. [PMID: 31739947 DOI: 10.1016/j.hoc.2019.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Palliative radiotherapy is an effective treatment in alleviating many symptoms of advanced cancer. Short courses of radiotherapy provide rapid symptom relief and minimize impact on patients. Patients referred for palliative radiotherapy have many concerns beyond radiotherapy; often, these concerns are not fully addressed in traditional radiotherapy clinics. Discussions of prognosis, patient goals, and concerns are areas for improved collaboration. Innovative, dedicated palliative radiotherapy programs have developed over the past 20 years to provide holistic care to patients referred for palliative radiotherapy and have improved patient-focused outcomes. Advanced radiotherapy techniques may provide opportunities to further improve palliative radiotherapy outcomes.
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Affiliation(s)
| | - Jaclyn Emmett
- Inpatient Oncology, Department of Hematology/Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
| | - Alireza Fotouhi Ghiam
- Department of Radiation Oncology, British Columbia Cancer Agency (BCCA), University of British Columbia, 2410 Lee Avenue, Victoria, British Columbia V8R 6V5, Canada
| | - Joshua A Jones
- Palliative Radiotherapy Service, Department of Radiation Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA.
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17
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Toxicity of locoregional radiotherapy in combination with bevacizumab in patients with non-metastatic breast cancer (TOLERAB): Final long-term evaluation. PLoS One 2019; 14:e0221816. [PMID: 31469859 PMCID: PMC6716668 DOI: 10.1371/journal.pone.0221816] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 08/15/2019] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Few data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer. MATERIALS AND METHODS This multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy. RESULTS A total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12-73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size <2cm (41.3%) with negative nodal status (50.8%). Median total dose of B was 15,000mg and median duration was 11.2 months. No grade ≥3 toxicity was observed. Only 8 patients experienced grade 1-2 toxicities: n = 3 (6.5%) grade 1 lymphedema, n = 2 (4.3%) grade 1 pain, n = 1 (2.2%) grade 2 lymphedema, n = 1 (2.2%) grade 1 fibrosis. Five-year overall survival was 93.8%, disease-free survival was 89% and locoregional recurrence-free survival was 93.1%. CONCLUSION Concurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed.
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18
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van Mackelenbergh MG, Stroes CI, Spijker R, van Eijck CHJ, Wilmink JW, Bijlsma MF, van Laarhoven HWM. Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E588. [PMID: 31035512 PMCID: PMC6562438 DOI: 10.3390/cancers11050588] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/19/2019] [Accepted: 04/22/2019] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
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Affiliation(s)
- Madelaine G van Mackelenbergh
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Charlotte I Stroes
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - René Spijker
- Medical Library, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Cochrane Netherlands, Julius Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
| | - Casper H J van Eijck
- Department of Surgery, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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19
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Goedegebuure RSA, de Klerk LK, Bass AJ, Derks S, Thijssen VLJL. Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer? Front Immunol 2019; 9:3107. [PMID: 30692993 PMCID: PMC6339950 DOI: 10.3389/fimmu.2018.03107] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/17/2018] [Indexed: 12/19/2022] Open
Abstract
Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.
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Affiliation(s)
- Ruben S A Goedegebuure
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Leonie K de Klerk
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Adam J Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.,Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Sarah Derks
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Victor L J L Thijssen
- Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.,Amsterdam UMC, Location VUmc, Radiation Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
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20
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Barati Bagherabad M, Afzaljavan F, ShahidSales S, Hassanian SM, Avan A. Targeted therapies in pancreatic cancer: Promises and failures. J Cell Biochem 2018; 120:2726-2741. [PMID: 28703890 DOI: 10.1002/jcb.26284] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 07/11/2018] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.
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Affiliation(s)
- Matineh Barati Bagherabad
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh ShahidSales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Molecular Medicine group, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Lauffer DC, Kuhn PA, Kueng M, Thalmann SU, Risse G, Tercier PA, Egger B, Allal AS. Pancreatic Cancer: Feasibility and Outcome After Radiochemotherapy with High Dose External Radiotherapy for Non-resected and R1 Resected Patients. Cureus 2018; 10:e2713. [PMID: 30079279 PMCID: PMC6067808 DOI: 10.7759/cureus.2713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Non-resected locally advanced and microscopic positive-margin resected (R1) pancreatic adenocarcinoma are associated with a dismal prognosis. The combination of high dose radiotherapy and concomitant chemotherapy is among the strategies that are used to improve the outcome. The aims of this study were to evaluate the acute and late toxicities and patients' outcome in a retrospective study from a single center. Material and methods From 2009 to 2015, 24 patients, with non-resected locally advanced or R1 resected pancreatic adenocarcinoma, have been treated with concomitant radiochemotherapy, with a median dose of 60 Gy and gemcitabine (50 mg/m2 administered bi-weekly). The acute and late toxicities were evaluated during and after the treatment. Results The actuarial overall survival rates were 39% at 24 months and 8.6% at 36 months. The disease-free survival rates were 32.5% at 24 months and 12.2% at 36 months. Acute toxicities were mainly grade 1 (G1) to grade 2 (G2) except for one patient who presented with severe digestive bleeding potentially linked to the treatment. Late toxicities consisted mainly of G1 digestive toxicities. Conclusion This study confirms the feasibility of high dose radiotherapy combined with gemcitabine-based chemotherapy in patients with locally advanced pancreatic adenocarcinoma. While the outcome remains unsatisfactory, some patients seem to have benefited from this aggressive therapy, which merits to be investigated further.
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Affiliation(s)
- David C Lauffer
- Department of Radiation Oncology, Hospital of Fribourg, Bern, CHE
| | - Peter A Kuhn
- Department of Radiation Oncology, Hospital of Fribourg, Fribourg, CHE
| | - Marc Kueng
- Department of Medical Oncology, Hospital of Fribourg, Fribourg, CHE
| | | | - Géraldine Risse
- Department of Radiation Oncology, Hospital of Fribourg, Fribourg, CHE
| | | | - Bernhard Egger
- Department of General Surgery, Hospital of Fribourg, Fribourg, CHE
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22
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Dautruche A, Belin L, Cottu P, Bontemps P, Lemanski C, de la Lande B, Baumann P, Missohou F, Lévy C, Peignaux K, Reynaud-Bougnoux A, Denis F, Gobillion A, Pernin V, Kirova Y. Evaluation at 3 years of concurrent bevacizumab and radiotherapy for breast cancer: Results of a prospective study. Cancer Radiother 2018; 22:222-228. [PMID: 29650388 DOI: 10.1016/j.canrad.2017.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 10/04/2017] [Indexed: 10/17/2022]
Abstract
PURPOSE To determine the 3 years late toxicity among patients with non-metastatic breast cancer who received concurrent bevacizumab and locoregional radiotherapy. MATERIAL AND METHODS This is a single-arm, multicentre, prospective study, of the toxicity of adjuvant concomitant association of bevacizumab and radiotherapy in patients with breast cancer. Toxicity was assessed by the Common Terminology Criteria for Adverse Events version 3.0 during the radiotherapy and follow-up clinics at 12 and 36 months after its completion. The study was designed to evaluate the toxicity at one year, 3 years and 5 years. RESULTS Sixty-four patients were included from October 2007 to August 2010. All of them received concurrent adjuvant radiotherapy and bevacizumab (in 24 cases after primary systemic treatment). All patients received non-fractionated radiotherapy to breast or chest wall with or without irradiation of regional lymph nodes. Early toxicity has been previously reported. Median follow-up was 46.4 months (range: 18-77 months). Median age was 53 years old (range: 23-68 years). The 3-years overall survival was 93% (range: 87-100%). Evaluation of the toxicity at 3 years was available for 67% of the patients. There was a low rate of toxicity: 14% grade 1 pain, 9% grade 1 fibrosis, 2% grade 1 telangiectasia, 2% grade 1 paresis, 7% grade 1 lymphedema and 2% grade 3 lymphedema. No grade 4 toxicity was observed. No patient had a left ventricular ejection fraction below 50% at 3 years. CONCLUSIONS Concurrent bevacizumab with locoregional radiotherapy is associated with acceptable 3-years toxicity in patients with breast cancer.
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Affiliation(s)
- A Dautruche
- Radiotherapy department, institut Curie, 26, rue d'Ulm, 75005 Paris, France.
| | - L Belin
- Biostatistics department, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - P Cottu
- Oncology department, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - P Bontemps
- Radiotherapy department, CHU Jean-Minjoz, 25030 Besançon, France
| | - C Lemanski
- Radiotherapy department, institut régional du cancer de Montpellier, 34298 Montpellier, France
| | - B de la Lande
- Radiotherapy department, institut Curie, René-Huguenin hospital, 92210 Saint-Cloud, France
| | - P Baumann
- Radiotherapy department, centre d'oncologie de Gentilly, 54000 Nancy, France
| | - F Missohou
- Radiotherapy department, centre Henri-Becquerel, 76038 Rouen, France
| | - C Lévy
- Radiotherapy department, centre François-Baclesse, 14000 Caen, France
| | - K Peignaux
- Radiotherapy department, centre Georges-François-Leclerc, 21079 Dijon, France
| | | | - F Denis
- Radiotherapy department, centre Jean-Bernard, 72000 Le Mans, France
| | - A Gobillion
- Biostatistics department, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - V Pernin
- Radiotherapy department, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - Y Kirova
- Radiotherapy department, institut Curie, 26, rue d'Ulm, 75005 Paris, France
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Seshacharyulu P, Baine MJ, Souchek JJ, Menning M, Kaur S, Yan Y, Ouellette MM, Jain M, Lin C, Batra SK. Biological determinants of radioresistance and their remediation in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:69-92. [PMID: 28249796 PMCID: PMC5548591 DOI: 10.1016/j.bbcan.2017.02.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 02/16/2017] [Accepted: 02/17/2017] [Indexed: 12/17/2022]
Abstract
Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.
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Affiliation(s)
- Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Michael J Baine
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Joshua J Souchek
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Melanie Menning
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Ying Yan
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Michel M. Ouellette
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Chi Lin
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
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Murray L, Longo J, Wan J, Chung C, Wang L, Dawson L, Milosevic M, Oza A, Brade A. Phase I dose escalation study of concurrent palliative radiation therapy with sorafenib in three anatomical cohorts (Thorax, Abdomen, Pelvis): The TAP study. Radiother Oncol 2017; 124:74-79. [PMID: 28668472 DOI: 10.1016/j.radonc.2017.06.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/28/2016] [Accepted: 06/05/2017] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND PURPOSE To evaluate the tolerability and maximum tolerated dose (MTD) of sorafenib administered concurrently with palliative radiotherapy. MATERIAL AND METHODS In patients with incurable cancer, sorafenib was escalated independently in three cohorts based on irradiation site: thorax, abdomen or pelvis. Sorafenib was administered days 1-28 and radiotherapy (30Gy in 10 fractions) was delivered days 8-12 and 15-19. Dose-limiting toxicities (DLT) were acute grade 3+ toxicities attributable to radiotherapy. RESULTS For the thorax, abdomen and pelvis cohorts, 14, 16 and 4 patients were recruited, and Dose Levels 3, 3 and 2 were reached, respectively. Sorafenib-related systemic toxicity led to significant sorafenib interruption in 10 patients. There were 3 DLTs in total, one per cohort: grade 3 oesophagitis (thoracic), transaminase elevation (abdominal) and grade 5 bowel perforation (pelvic; patient with tumour invading bowel). Grade 2 radiation dermatitis developed in 12 patients. The trial was terminated early as slow accrual and sorafenib-related systemic toxicity prevented efficient evaluation of RT-related DLTs. CONCLUSIONS The MTD of sorafenib when used with 30Gy in 10 fractions was not established due to sorafenib-related systemic toxicity. Severe radiotherapy-related toxicities were also observed. These events suggest this concurrent combination does not warrant further study.
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Affiliation(s)
- Louise Murray
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Joseph Longo
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Canada
| | - Jonathan Wan
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Caroline Chung
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Lisa Wang
- Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Canada
| | - Laura Dawson
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Michael Milosevic
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Amit Oza
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Anthony Brade
- Department of Radiation Oncology, University of Toronto, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
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Hamming LC, Slotman BJ, Verheul HMW, Thijssen VL. The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future. Angiogenesis 2017; 20:217-232. [PMID: 28364160 PMCID: PMC5437175 DOI: 10.1007/s10456-017-9546-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 03/14/2017] [Indexed: 12/14/2022]
Abstract
Although monotherapy with angiostatic drugs is still far from effective, there is abundant evidence that angiostatic therapy can improve the efficacy of conventional treatments like radiotherapy. This has instigated numerous efforts to optimize and clinically implement the combination of angiostatic drugs with radiation treatment. The results from past and present clinical trials that explored this combination therapy indeed show encouraging results. However, current findings also show that the combination has variable efficacy and is associated with increased toxicity. This indicates that combining radiotherapy with angiostatic drugs not only holds opportunities but also provides several challenges. In the current review, we provide an update of the most recent insights from clinical trials that evaluated the combination of angiostatic drugs with radiation treatment. In addition, we discuss the outstanding questions for future studies in order to improve the clinical benefit of combining angiostatic therapy with radiation therapy.
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Affiliation(s)
- Lisanne C Hamming
- Department of Medical Oncology, VU University Medical Centre, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands
| | - Ben J Slotman
- Department of Radiation Oncology, VU University Medical Centre, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, VU University Medical Centre, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands
| | - Victor L Thijssen
- Department of Radiation Oncology, VU University Medical Centre, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands.
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26
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Martin RCG, Durham AN, Besselink MG, Iannitti D, Weiss MJ, Wolfgang CL, Huang KW. Irreversible electroporation in locally advanced pancreatic cancer: A call for standardization of energy delivery. J Surg Oncol 2016; 114:865-871. [PMID: 27546233 DOI: 10.1002/jso.24404] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 07/30/2016] [Indexed: 02/06/2023]
Abstract
Irreversible Electroporation (IRE) is used to treat locally advanced cancers, commonly of the pancreas, liver, kidney, and other soft tissues. Precise eligibility for IRE should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of IRE technique and protocols is expected to improve safety, lead to reproducible outcomes, and facilitate further research into IRE. The present article provides a set of technical recommendations for the use of IRE in the treatment of locally advanced pancreatic cancer. J. Surg. Oncol. 2016;114:865-871. © 2016 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Robert C G Martin
- Division of Surgical Oncology, Hiram C Polk Jr Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky.
| | - Alan North Durham
- Division of Surgical Oncology, Hiram C Polk Jr Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky
| | - Marc G Besselink
- Department of Surgery, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
| | | | | | - Christopher L Wolfgang
- Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, China and Singapore Universities Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Kai-Wen Huang
- Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, China and Singapore Universities Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
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27
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Loehrer AP, Kinnier CV, Ferrone CR. Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. Adv Surg 2016; 50:115-28. [PMID: 27520867 DOI: 10.1016/j.yasu.2016.03.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Andrew P Loehrer
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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28
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Yang YC, Chiang CS. Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy. Front Oncol 2016; 6:165. [PMID: 27446811 PMCID: PMC4927577 DOI: 10.3389/fonc.2016.00165] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 06/20/2016] [Indexed: 01/07/2023] Open
Abstract
Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer.
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Affiliation(s)
- Ying-Chieh Yang
- Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu City, Taiwan
- Radiation Oncology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Chi-Shiun Chiang
- Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu City, Taiwan
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29
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Chadha AS, Skinner HD, Gunther JR, Munsell MF, Das P, Minsky BD, Delclos ME, Chatterjee D, Wang H, Clemons M, George G, Singh PK, Katz MH, Fleming JB, Javle MM, Wolff RA, Varadhachary GR, Crane CH, Krishnan S. Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer. PLoS One 2016; 11:e0156910. [PMID: 27336466 PMCID: PMC4919049 DOI: 10.1371/journal.pone.0156910] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/20/2016] [Indexed: 01/06/2023] Open
Abstract
Purpose To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. Methods Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1–4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1–4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1–2) to 150 mg/Kg (DLs 3–5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2–3) to 825 mg/m2 (DLs 4–5). Reassessment for potential resection was performed 6–8 weeks later. Results Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1–4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. Conclusions This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.
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Affiliation(s)
- Awalpreet S. Chadha
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Heath D. Skinner
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jillian R. Gunther
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Mark F. Munsell
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Prajnan Das
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Bruce D. Minsky
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Marc E. Delclos
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Deyali Chatterjee
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Marilyn Clemons
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Geena George
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Pankaj K. Singh
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Matthew H. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jason B. Fleming
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Milind M. Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Robert A. Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Gauri R. Varadhachary
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Christopher H. Crane
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Sunil Krishnan
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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30
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Safety assessment of molecular targeted therapies in association with radiotherapy in metastatic renal cell carcinoma. Anticancer Drugs 2016; 27:427-32. [DOI: 10.1097/cad.0000000000000349] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Abstract
The outcomes for treatment of pancreatic cancer have not improved dramatically in many decades. However, the recent promising results with combination chemotherapy regimens for metastatic disease increase optimism for future treatments. With greater control of overt or occult metastatic disease, there will likely be an expanding role for local treatment modalities, especially given that nearly a third of pancreatic cancer patients have locally destructive disease without distant metastatic disease at the time of death. Technical advances have allowed for the safe delivery of dose-escalated radiation therapy, which can then be combined with chemotherapy, targeted agents, immunotherapy, and nanoparticulate drug delivery techniques to produce novel and improved synergistic effects. Here we discuss recent advances and future directions for multimodality therapy in pancreatic cancer.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasingly common and a leading cause of cancer-related mortality. Surgery remains the only possibility for cure. Upwards of 40% of patients present with locally advanced PDAC (LA-PDAC), where management strategies continue to evolve. In this review, we highlight current trends in neoadjuvant chemotherapy, surgical resection, and other multimodality approaches for patients with LA-PDAC. Despite promising early results, additional work is needed to more accurately and appropriately tailor treatment for patients with LA-PDAC.
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Affiliation(s)
- Andrew P Loehrer
- Department of Surgery, Massachusetts General Hospital, Boston, Mass., USA
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Tsukada Y, Nakamura F, Iwamoto M, Terahara A, Higashi T. Patterns of prescribing radiotherapy and bevacizumab in nationwide practice - analysis of 101 designated cancer care hospitals in Japan. JOURNAL OF RADIATION RESEARCH 2016; 57:157-163. [PMID: 26661853 PMCID: PMC4795949 DOI: 10.1093/jrr/rrv080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 09/30/2015] [Accepted: 10/19/2015] [Indexed: 06/05/2023]
Abstract
Radiotherapy and bevacizumab are each effective in treating patients with advanced cancer, but their concurrent use may cause serious adverse events (SAEs). Whereas sequential administration can theoretically reduce the risk of SAEs while maintaining the anticancer effects, this hypothesis remains unconfirmed, leading to variations in practice. To elucidate current practices, the patterns of care received by patients in Japan with regard to these two therapies were assessed in a large database of a hospital-based cancer registry linked with insurance claims. This database contained information on 106 057 patients diagnosed with seven major cancers in 2011 and the care they received up to the end of 2012. In total, 335 patients from 101 hospitals in the database were treated with both radiotherapy and bevacizumab. Of these patients, 50.8% had lung cancer, and 51.3% had Stage IV cancer. Of the 335 patients, 75 (22.4%) received these therapies concurrently. In patients treated sequentially, the time from the last dose of bevacizumab to the start of radiotherapy was most frequently 4-5 weeks (12.4%), whereas the time from the end of radiotherapy to the start of bevacizumab was most frequently 1-2 weeks (10.6%). The cumulative proportions of patients in these two groups receiving sequential therapies within 3 weeks were 19.0% and 26.1%, respectively. Many practices appeared to avoid the concurrent use of bevacizumab and radiation, but some provided concurrent therapy. Additional data are required to determine whether the avoidance of concurrent use should become a standard of care.
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Affiliation(s)
- Yoichiro Tsukada
- Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Department of Radiology, Toho University Omori Medical Center, Tokyo, Japan
| | - Fumiaki Nakamura
- Department of Public Health/Health Policy, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Momoko Iwamoto
- Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Atsuro Terahara
- Department of Radiology, Toho University Omori Medical Center, Tokyo, Japan
| | - Takahiro Higashi
- Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Brade AM, Ng S, Brierley J, Kim J, Dinniwell R, Ringash J, Wong RR, Cho C, Knox J, Dawson LA. Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys 2015; 94:580-7. [PMID: 26867886 DOI: 10.1016/j.ijrobp.2015.11.048] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 11/06/2015] [Accepted: 11/28/2015] [Indexed: 12/25/2022]
Abstract
PURPOSE To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). METHODS AND MATERIALS Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. RESULTS Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. CONCLUSIONS Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.
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Affiliation(s)
- Anthony M Brade
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Sylvia Ng
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - James Brierley
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John Kim
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Robert Dinniwell
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jolie Ringash
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rebecca R Wong
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Charles Cho
- Department of Radiation Oncology, Southlake Regional Cancer Centre, Newmarket, Ontario, Canada
| | - Jennifer Knox
- Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Laura A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Huguet F, Thariat J, Antoni D, Mornex F. Place de la radiothérapie (et chimioradiothérapie) dans les cancers localement avancés ou borderline. Quelles perspectives ? ONCOLOGIE 2015. [DOI: 10.1007/s10269-015-2561-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Pollom EL, Deng L, Pai RK, Brown JM, Giaccia A, Loo BW, Shultz DB, Le QT, Koong AC, Chang DT. Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys 2015; 92:568-76. [PMID: 26068491 DOI: 10.1016/j.ijrobp.2015.02.016] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 02/03/2015] [Accepted: 02/09/2015] [Indexed: 12/14/2022]
Abstract
Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.
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Affiliation(s)
- Erqi L Pollom
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Lei Deng
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - J Martin Brown
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Amato Giaccia
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Billy W Loo
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - David B Shultz
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Quynh Thu Le
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Albert C Koong
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Daniel T Chang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
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Nyflot MJ, Kruser TJ, Traynor AM, Khuntia D, Yang DT, Hartig GK, McCulloch TM, Wiederholt PA, Gentry LR, Hoang T, Jeraj R, Harari PM. Phase 1 trial of bevacizumab with concurrent chemoradiation therapy for squamous cell carcinoma of the head and neck with exploratory functional imaging of tumor hypoxia, proliferation, and perfusion. Int J Radiat Oncol Biol Phys 2015; 91:942-51. [PMID: 25659884 DOI: 10.1016/j.ijrobp.2014.11.029] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 11/12/2014] [Accepted: 11/18/2014] [Indexed: 12/19/2022]
Abstract
PURPOSE A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies. METHODS AND MATERIALS All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m(2) and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [(18)F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [(61)Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course. RESULTS Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course. CONCLUSIONS The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.
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Affiliation(s)
- Matthew J Nyflot
- Department of Radiation Oncology, University of Washington, Seattle, Washington.
| | - Tim J Kruser
- Department of Radiation Oncology, Cadence Cancer Center at Delnor Hospital, Geneva, Illinois
| | - Anne M Traynor
- Department of Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | | | - David T Yang
- Departments of Pathology and Laboratory Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Gregory K Hartig
- Department of Surgery-Otolaryngology, H&N Surgery Division, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Timothy M McCulloch
- Department of Surgery-Otolaryngology, H&N Surgery Division, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Peggy A Wiederholt
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Lindell R Gentry
- Department of Radiology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Tien Hoang
- Department of Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Robert Jeraj
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin; Department of Radiology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin
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Kambadakone A, Yoon SS, Kim TM, Karl DL, Duda DG, DeLaney TF, Sahani DV. CT perfusion as an imaging biomarker in monitoring response to neoadjuvant bevacizumab and radiation in soft-tissue sarcomas: comparison with tumor morphology, circulating and tumor biomarkers, and gene expression. AJR Am J Roentgenol 2015; 204:W11-W18. [PMID: 25539263 PMCID: PMC4479405 DOI: 10.2214/ajr.13.12412] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The purpose of this study was to evaluate the role of CT perfusion in monitoring response to neoadjuvant antiangiogenic and radiation therapy in resectable soft-tissue sarcomas and correlate the findings with tumor size, circulating and tumor biomarkers, and gene expression. SUBJECTS AND METHODS This phase II clinical trial included 20 patients (13 men and 7 women; mean age, 55 years) with soft-tissue sarcomas who were undergoing treatment with the antiangiogenic drug bevacizumab followed by bevacizumab, radiation, and surgical resection. The patients underwent CT perfusion and diagnostic contrast-enhanced CT at baseline, at 2 weeks after bevacizumab therapy, and after completion of bevacizumab and radiation therapy. Multiple CT perfusion parameters (blood flow, blood volume, mean transit time, and permeability) were correlated with tumor size, circulating and tumor biomarkers, and gene expression. RESULTS Two weeks after bevacizumab therapy, there was substantial fall in blood volume (31.9% reduction, p = 0.01) with more pronounced reduction in blood flow, blood volume, and permeability after treatment completion (53-64% reduction in blood flow, blood volume, and permeability; p = 0.001), whereas tumor size showed no significant change (p = 0.34). Tumors with higher baseline blood volume and lower baseline tumor size showed superior response to bevacizumab and radiation (p = 0.05). There was also an increase in median plasma vascular endothelial growth factor and placental-derived growth factor concentration after bevacizumab therapy paralleled by a decrease in tumor perfusion depicted by CT perfusion, although this was not statistically significant (p = 0.4). The baseline tumor microvessel density (MVD) correlated with blood flow (p = 0.04). At least 20 different genes were differentially expressed in tumors with higher and lower baseline perfusion. CONCLUSION CT perfusion is more sensitive than tumor size for monitoring early and late response to bevacizumab and radiation therapy. CT perfusion parameters correlate with MVD, and the gene expression levels of baseline tumors could potentially predict treatment response.
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Affiliation(s)
- Avinash Kambadakone
- 1 Division of Abdominal Imaging and Intervention, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, White 270, 55 Fruit St, Boston, MA 02114
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Gastric and esophageal metastases in renal cell carcinoma: systematic review and management options. Int Cancer Conf J 2014. [DOI: 10.1007/s13691-014-0202-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Bergmann L, Maute L, Heil G, Rüssel J, Weidmann E, Köberle D, Fuxius S, Weigang-Köhler K, Aulitzky WE, Wörmann B, Hartung G, Moritz B, Edler L, Burkholder I, Scheulen ME, Richly H. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Eur J Cancer 2014; 51:27-36. [PMID: 25459392 DOI: 10.1016/j.ejca.2014.10.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/02/2014] [Accepted: 10/03/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.
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Affiliation(s)
- L Bergmann
- Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany.
| | - L Maute
- Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - G Heil
- Klinik für Hämatologie und Onkologie, Märkische Kliniken Lüdenscheid, Lüdenscheid, Germany
| | - J Rüssel
- Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - E Weidmann
- Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt/Main, Germany
| | - D Köberle
- Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - S Fuxius
- Onkologische Schwerpunktpraxis, Heidelberg, Germany
| | | | - W E Aulitzky
- Hämatologie, Onkologie, Klinische Immunologie, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - B Wörmann
- Medizinisches Versorgungszentrum Onkologie, Charité - Campus Virchow-Klinikum, Berlin, Germany
| | - G Hartung
- Onkologische Schwerpunktpraxis, Groß-Gerau, Germany
| | - B Moritz
- CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria
| | - L Edler
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - I Burkholder
- Department of Nursing and Health, University of Applied Sciences of the Saarland, Saarbruecken, Germany
| | - M E Scheulen
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - H Richly
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Lévy C, Allouache D, Lacroix J, Dugué AE, Supiot S, Campone M, Mahe M, Kichou S, Leheurteur M, Hanzen C, Dieras V, Kirova Y, Campana F, Le Rhun E, Gras L, Bachelot T, Sunyach MP, Hrab I, Geffrelot J, Gunzer K, Constans JM, Grellard JM, Clarisse B, Paoletti X. REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. Ann Oncol 2014; 25:2351-2356. [PMID: 25274615 DOI: 10.1093/annonc/mdu465] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. PATIENTS AND METHODS In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. RESULTS Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1-2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. CONCLUSION Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929.
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Affiliation(s)
| | | | - J Lacroix
- Department of Radiology, Centre François Baclesse, Caen; Department of GIP Cyceron, Caen
| | - A E Dugué
- Department of Clinical Research, Centre François Baclesse, Caen
| | | | | | - M Mahe
- Department of Radiotherapy, Institut de Cancérologie de l'Ouest René Gauducheau, Nantes-Saint Herblain, Caen
| | - S Kichou
- Department of Radiology, Centre François Baclesse, Caen
| | | | - C Hanzen
- Department of Radiotherapy, Centre Henri Becquerel, Rouen
| | | | - Y Kirova
- Department of Radiotherapy, Institut Curie, Paris
| | - F Campana
- Department of Radiotherapy, Institut Curie, Paris
| | | | - L Gras
- Department of Radiotherapy, Centre Oscar Lambret, Lille
| | | | - M-P Sunyach
- Department of Radiotherapy, Centre Léon Bérard, Lyon
| | | | - J Geffrelot
- Department of Radiotherapy, Centre François Baclesse, Caen
| | - K Gunzer
- Department of Oncology; Department of Clinical Research, Centre François Baclesse, Caen
| | - J-M Constans
- Department of GIP Cyceron, Caen; Department of Radiology, Centre Hospitalier Universitaire, Caen
| | - J-M Grellard
- Department of Clinical Research, Centre François Baclesse, Caen
| | - B Clarisse
- Department of Clinical Research, Centre François Baclesse, Caen
| | - X Paoletti
- Department of Biostatistics, Institut Curie/Inserm U900, Paris, France
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Pernin V, Belin L, Cottu P, Bontemps P, Lemanski C, De La Lande B, Baumann P, Missohou F, Levy C, Peignaux K, Bougnoux P, Denis F, Bollet M, Dendale R, Vago NA, Campana F, Fourquet A, Kirova YM. Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer. Breast 2014; 23:816-20. [PMID: 25260760 DOI: 10.1016/j.breast.2014.08.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 08/20/2014] [Accepted: 08/25/2014] [Indexed: 10/24/2022] Open
Abstract
The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1-2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) - telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1-2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities.
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Affiliation(s)
- Victor Pernin
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France
| | - Lisa Belin
- Institut Curie, Hospital, Biostatistic Department, 75005 Paris, France
| | - Paul Cottu
- Institut Curie, Hospital, Oncology Department, 75005 Paris, France
| | - Patrick Bontemps
- CHU Jean Minjoz, Radiotherapy Department, 25030 Besançon, France
| | - Claire Lemanski
- Institut régional du Cancer de Montpellier, Radiotherapy Department, 34298 Montpellier, France
| | | | - Pierre Baumann
- Centre d'Oncologie de Gentilly, Radiotherapy Department, 54 100 Nancy, France
| | - Fernand Missohou
- Centre Henri Becquerel, Radiotherapy Department, 76038 Rouen, France
| | - Christelle Levy
- Centre François Baclesse, Radiotherapy Department, 14000 Caen, France
| | - Karine Peignaux
- Centre Georges-François Leclerc, Département de radiothérapie, 21000 Dijon, France
| | | | - Fabrice Denis
- Centre Jean Bernard, Département de radiothérapie, 72000 Le Mans, France
| | - Marc Bollet
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France
| | - Rémi Dendale
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France
| | | | - François Campana
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France
| | - Alain Fourquet
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France
| | - Youlia M Kirova
- Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France.
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Huguet F, Mukherjee S, Javle M. Locally advanced pancreatic cancer: the role of definitive chemoradiotherapy. Clin Oncol (R Coll Radiol) 2014; 26:560-8. [PMID: 25001636 DOI: 10.1016/j.clon.2014.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 05/13/2014] [Accepted: 06/04/2014] [Indexed: 12/11/2022]
Abstract
At the time of diagnosis, around 20% of patients with pancreatic cancer present at a resectable stage, 50% have metastatic disease and 30% have locally advanced tumour, non-metastatic but unresectable because of superior mesenteric artery or coeliac encasement. Despite advances in chemoradiotherapy and improved systemic chemotherapeutic agents, patients with locally advanced pancreatic cancer suffer from high rates of distant metastatic failure and from local progression, with a median survival time ranging from 5 to 11 months. In the past 30 years, modest improvements in median survival have been attained for these patients treated by chemoradiotherapy or chemotherapy protocols. The optimal therapy for patients with locally advanced pancreatic carcinoma remains controversial. This review aims to evaluate the role of radiotherapy for these patients.
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Affiliation(s)
- F Huguet
- Service d'Oncologie Radiothérapie, Hôpital Tenon, Hôpitaux Universitaires Est Parisien, Paris, France.
| | - S Mukherjee
- Gray Institute for Radiation Oncology and Biology, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - M Javle
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Phase I dose escalation study of capecitabine and erlotinib concurrent with radiation in locally advanced pancreatic cancer. Cancer Chemother Pharmacol 2014; 74:205-10. [PMID: 24908435 DOI: 10.1007/s00280-014-2488-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 05/13/2014] [Indexed: 12/13/2022]
Abstract
PURPOSE Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. The median survival of locally advanced nonoperable disease is approximately 9 months. 5-FU-based chemoradiotherapy has been the standard treatment. However, the survival benefit of this approach is modest. To improve the efficacy of 5-FU-based chemoradiation therapy, we evaluated the safety and feasibility of the combination of capecitabine and erlotinib with radiotherapy in this group of patients. EXPERIMENTAL DESIGN A traditional "3 + 3" dose escalation design was adopted in the study. A total of four dose levels were designed. For safety purpose, a minus I dose level (-I) was also planned. The -I level consisted of capecitabine 600 mg/m² and erlotinib 50 mg daily, and the remaining four dose levels were as follows: level I: capecitabine 600 mg/m² bid (twice daily); level II: 700 mg/m² bid; level III: 825 mg/m² bid; and level IV: 925 mg/m² bid. Erlotinib was administered at 100 mg daily at all dose levels. Erlotinib and capceitabine were given continuously Monday through Friday concurrent with radiotherapy (50.4 Gy in 28 fractions). RESULTS A total of 18 patients were consented. Fifteen patients were enrolled and completed therapy. No dose-limiting toxicity was observed. The most frequent side effects were lymphopenia, nausea, vomiting, diarrhea, electrolyte imbalances, and skin rashes. The majority of the toxicities were grade 1 and 2. No objective response was observed. The median progression-free survival was 0.59 years (95 % CI 0.31-1.1), and the median overall survival was 1.1 years (95 % CI 0.62-1.59). CONCLUSIONS The combination of capecitabine and erlotinib with radiotherapy in locally advanced pancreatic cancer is well tolerated and feasible at the dose level of capecitabine 925 mg/m² bid and erlotinib 100 mg daily.
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Jackson MW, Rusthoven CG, Fisher CM, Schefter TE. Clinical potential of bevacizumab in the treatment of metastatic and locally advanced cervical cancer: current evidence. Onco Targets Ther 2014; 7:751-9. [PMID: 24876784 PMCID: PMC4037327 DOI: 10.2147/ott.s49429] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The addition of bevacizumab to established therapies for metastatic and locally advanced cervical cancer is an area of evolving research and a potential strategy toward improving historically suboptimal outcomes for women with advanced disease. Bevacizumab, when added to first-line chemotherapy, has now been shown to improve overall survival among women with metastatic cervical cancer, and recent Phase II data suggests it is safe and effective for patients with locally advanced disease treated with curative intent. Here we review the rationale and current evidence for bevacizumab in clinical practice, with an emphasis on the emerging role of bevacizumab in the treatment of metastatic and locally advanced cervical cancer.
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Affiliation(s)
- Matthew W Jackson
- Department of Radiation Oncology, University of Colorado, Denver, CO, USA
| | - Chad G Rusthoven
- Department of Radiation Oncology, University of Colorado, Denver, CO, USA
| | - Christine M Fisher
- Department of Radiation Oncology, University of Colorado, Denver, CO, USA
| | - Tracey E Schefter
- Department of Radiation Oncology, University of Colorado, Denver, CO, USA
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Zhang S, Yu M, Wei Y. Do anti-angiogenic cancer therapies increase risk of significant weight loss? Expert Opin Drug Saf 2014; 13:473-82. [PMID: 24588304 DOI: 10.1517/14740338.2014.894506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Angiogenesis is important in many disease states such as cancer. Anti-angiogenic cancer drugs are in broad use for the treatment of cancers. However, currently most of these anticancer drugs result in some adverse effects in the patient. AREAS COVERED In this paper, we review evidence on the association between anti-angiogenic therapies and weight loss. We report on basic experiments and clinical trials that measure weight loss with anti-angiogenic cancer therapies. EXPERT OPINION Few strong associations are found between anti-angiogenic cancer therapies and weight loss, with the exception of some multikinase inhibitors in clinical trials. Anti-angiogenic cancer therapies appear safe in relation to weight loss, but the result needs to be established by further clinical trials.
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Affiliation(s)
- Shuang Zhang
- Sichuan University, West China Hospital, State Key Laboratory of Biotherapy and Cancer Center , Chengdu 610041 , China
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Reznik R, Hendifar AE, Tuli R. Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma. Front Physiol 2014; 5:87. [PMID: 24624093 PMCID: PMC3939680 DOI: 10.3389/fphys.2014.00087] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 02/13/2014] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.
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Affiliation(s)
- Robert Reznik
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
| | - Andrew E Hendifar
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
| | - Richard Tuli
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
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Scharf VF, Farese JP, Coomer AR, Milner RJ, Taylor DP, Salute ME, Chang MN, Neal D, Siemann DW. Effect of bevacizumab on angiogenesis and growth of canine osteosarcoma cells xenografted in athymic mice. Am J Vet Res 2013; 74:771-8. [PMID: 23627391 DOI: 10.2460/ajvr.74.5.771] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Objective-To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice. Animals-27 athymic nude mice. Procedures-To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated. Results-Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean ± SD, 13.4 ± 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean ± SD, 9.4 ± 1.5 days; range, 7 to 11 days) or control group (mean ± SD, 7. 2 ± 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group. Conclusions and Clinical Relevance-Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs. Impact for Human Medicine-Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans.
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Affiliation(s)
- Valery F Scharf
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, College of Medicine, University of Florida, Gainesville, FL 32608, USA
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Barney BM, Markovic SN, Laack NN, Miller RC, Sarkaria JN, Macdonald OK, Bauer HJ, Olivier KR. Increased Bowel Toxicity in Patients Treated With a Vascular Endothelial Growth Factor Inhibitor (VEGFI) After Stereotactic Body Radiation Therapy (SBRT). Int J Radiat Oncol Biol Phys 2013; 87:73-80. [DOI: 10.1016/j.ijrobp.2013.05.012] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/03/2013] [Accepted: 05/05/2013] [Indexed: 12/18/2022]
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