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1
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Wang L, Zhang T, Zheng Y, Li Y, Tang X, Chen Q, Mao W, Li W, Liu X, Zhu J. Combination of irinotecan silicasome nanoparticles with radiation therapy sensitizes immunotherapy by modulating the activation of the cGAS/STING pathway for colorectal cancer. Mater Today Bio 2023; 23:100809. [PMID: 37779919 PMCID: PMC10540048 DOI: 10.1016/j.mtbio.2023.100809] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/07/2023] [Accepted: 09/19/2023] [Indexed: 10/03/2023] Open
Abstract
Our previous clinical trial (Identifier: NCT02605265) revealed that addition of irinotecan (IRIN) to neoadjuvant chemoradiotherapy for rectal cancer could improve the curative effect. However, the adverse effects caused by IRIN limited the wide application of IRIN chemoradiotherapy. This study aimed to explore the mechanism under the synergistic effects of IRIN plus radiation therapy in colorectal cancer (CRC) cells and optimization of IRIN delivery via a silicasome nanocarrier in vivo. Our results revealed that compared with single IRIN or radiation treatment, IRIN combined with radiation therapy remarkably activated the intracellular cGAS/STING pathway, and promoted the expression levels of major histocompatibility complex class I (MHC-I) and programmed death ligand 1 (PD-L1). Further, a silicasome (mesoporous silica nanoparticle coated with lipid bilayer) nanocarrier was utilized to improve the delivery of IRIN with enhanced efficacy and reduced side effects. In the MC38 CRC syngeneic tumor model, IRIN silicasome combined with radiation therapy demonstrated a greater antitumor efficacy than free IRIN plus radiation therapy. Flow cytometry showed the increased number of CD4+ T cells, CD8+ T cells, and dendritic cells (DCs) in tumor in the IRIN silicasome plus radiation group. The immunofluorescence staining further confirmed the activated immune microenvironment with the elevated interferon-γ (IFN-γ) deposition. Besides, the antitumor effect of IRIN silicasome plus radiation therapy was synergistically enhanced by anti-PD-1 immunotherapy. These findings indicated that the combination of IRIN silicasome with radiation therapy could sensitize immunotherapy by manipulating the cGAS/STING pathway serving as a new strategy for CRC treatment.
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Affiliation(s)
- Lu Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Tianyu Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yile Zheng
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yuting Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Xiyuan Tang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Qianping Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Wei Mao
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Weiwei Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Xiangsheng Liu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
| | - Ji Zhu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, 310022, China
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2
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Yu Z, Hao Y, Huang Y, Ling L, Hu X, Qiao S. Radiotherapy in the preoperative neoadjuvant treatment of locally advanced rectal cancer. Front Oncol 2023; 13:1300535. [PMID: 38074690 PMCID: PMC10704030 DOI: 10.3389/fonc.2023.1300535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 10/30/2023] [Indexed: 04/04/2024] Open
Abstract
Radiotherapy and chemotherapy are effective treatments for patients with locally advanced rectal cancer (LARC) and can significantly improve the likelihood of R0 resection. Radiotherapy can be used as a local treatment to reduce the size of the tumor, improve the success rate of surgery and reduce the residual cancer cells after surgery. Early chemotherapy can also downgrade the tumor and eliminate micrometastases throughout the body, reducing the risk of recurrence and metastasis. The advent of neoadjuvant concurrent radiotherapy (nCRT) and total neoadjuvant treatment (TNT) has brought substantial clinical benefits to patients with LARC. Even so, given increasing demand for organ preservation and quality of life and the disease becoming increasingly younger in its incidence profile, there is a need to further explore new neoadjuvant treatment options to further improve tumor remission rates and provide other opportunities for patients to choose watch-and-wait (W&W) strategies that avoid surgery. Targeted drugs and immunologic agents (ICIs) have shown good efficacy in patients with advanced rectal cancer but have not been commonly used in neoadjuvant therapy for patients with LARC. In this paper, we review several aspects of neoadjuvant therapy, including radiation therapy and chemotherapy drugs, immune drugs and targeted drugs used in combination with neoadjuvant therapy, with the aim of providing direction and thoughtful perspectives for LARC clinical treatment and research trials.
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Affiliation(s)
| | | | | | | | - Xigang Hu
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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3
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Frerker B, Bock F, Cappel ML, Kriesen S, Klautke G, Hildebrandt G, Manda K. Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells. Int J Mol Sci 2023; 24:10385. [PMID: 37373535 DOI: 10.3390/ijms241210385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, it should be compared whether one combination therapy is more effective than the other. Colorectal cancer cells (HT-29) were treated with irinotecan or oxaliplatin, both alone and in combination with 5-FU, and subsequently irradiated. The cell growth, metabolic activity and proliferation of cells were investigated, and the clonogenic survival was determined. Furthermore, the assessment of radiation-induced DNA damage and the influence of the drugs and their combinations on DNA damage repair was investigated. Treatment with irinotecan or oxaliplatin in combination with 5-FU inhibited proliferation and metabolic activity as well as clonogenic survival and the DNA damage repair capacity of the tumor cells. The comparison of oxaliplatin and irinotecan with simultaneous irradiation showed the same effect of both drugs. When oxaliplatin or irinotecan was combined with 5-FU, tumor cell survival was significantly lower than with monotherapy; however, there was no superiority of either combination regimen. Our results have shown that the combination of 5-FU and irinotecan is as effective as the combination of 5-FU with oxaliplatin. Therefore, our data support the use of FOLFIRI as a radiosensitizer.
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Affiliation(s)
- Bernd Frerker
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Felix Bock
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Marie-Louise Cappel
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Stephan Kriesen
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Gunther Klautke
- Department of Radiation Oncology, Hospital Chemnitz, Bürgerstrasse 2, 09113 Chemnitz, Germany
| | - Guido Hildebrandt
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Katrin Manda
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
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4
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Abe S, Kawai K, Nozawa H, Sasaki K, Murono K, Emoto S, Yokoyama Y, Matsuzaki H, Nagai Y, Yoshioka Y, Shinagawa T, Sonoda H, Yamamoto Y, Oba K, Ishihara S. Preoperative chemoradiotherapy using tegafur/uracil, oral leucovorin, and irinotecan (TEGAFIRI) followed by oxaliplatin-based chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: the study protocol for a phase II trial. BMC Cancer 2023; 23:450. [PMID: 37198556 DOI: 10.1186/s12885-023-10941-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 05/10/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Total neoadjuvant therapy (TNT) is a novel treatment strategy that is an alternative to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, an optimal protocol for TNT has not yet been established. The present study will be an open-label, single-arm, single-center trial to develop a new protocol. METHODS Thirty LARC patients at high risk of distant metastasis will receive CRT consisting of long-course radiation, concurrent with tegafur/uracil, oral leucovorin, irinotecan (TEGAFIRI), followed by mFOLFOX-6 or CAPOX before undergoing surgery. DISCUSSION Since previous findings showed a high percentage of grade 3-4 adverse events with the TEGAFIRI regimen for CRT and TNT, the primary outcome of this study will be safety and feasibility. Our regimen for CRT consists of the biweekly administration of irinotecan for good patient compliance. The novel combination approach of this treatment may improve the long-term outcomes of LARC. TRIAL REGISTRATION Japan Registry of Clinical Trials jRCTs031210660.
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Affiliation(s)
- Shinya Abe
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Kazushige Kawai
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Koji Murono
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yuichiro Yokoyama
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hiroyuki Matsuzaki
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yuzo Nagai
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yuichiro Yoshioka
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takahide Shinagawa
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hirofumi Sonoda
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yoko Yamamoto
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Koji Oba
- Department of Biostatistics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
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5
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Lv T, Shen L, Xu X, Yao Y, Mu P, Zhang H, Wan J, Wang Y, Guan R, Li X, Fu G, Zhang L, Wang Y, Xia F, Hu C, Clevers H, Zhang Z, Hua G. Patient-derived tumor organoids predict responses to irinotecan-based neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. Int J Cancer 2023; 152:524-535. [PMID: 36161653 DOI: 10.1002/ijc.34302] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/18/2022] [Accepted: 09/05/2022] [Indexed: 02/01/2023]
Abstract
Adding irinotecan to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) increases the pathologic complete response (pCR) rate but brings more toxicities. Robust biomarkers to predict response to irinotecan-based nCRT are extremely necessary for selecting the right patients. Our previous study suggests that patient-derived tumor organoids (PDTOs) sensitivity to chemoradiotherapy matches patient responses. In this study, we investigated whether PDTOs sensitivity to irinotecan can predict complete response (CR) and survival. Eligible patients receiving irinotecan-based nCRT between April 5, 2017 and December 11, 2020 were enrolled in the training cohort (n = 91) for response prediction and survival analysis. Patients receiving nCRT between February 21, 2021 and September 17, 2021 were included in the validation cohort (n = 27). Predictive performances of irinotecan organoid size ratio (OSR) for CR or pCR were evaluated. The irinotecan-sensitive groups had higher response rates compared with the insensitive groups (training cohort: 71.8% vs 24.4%, P < .0001; validation cohort, 81.8% vs 18.8%, P = .002). Moreover, the irinotecan-sensitive group had higher rates of 3-year disease-free survival (DFS: 71.6% vs 55.5%, P = .034) and distant metastasis-free survival (DMFS, 77.9% vs 57.2%, P = .015) than the irinotecan-insensitive group. 5-FU and irradiation sensitivities failed to predict 3-year DFS (5-FU: 65.4% vs 61.9%, P = .643; irradiation: 84.8% vs 57.8%; P = .072). Performances of irinotecan OSR to predict CR or pCR were good in the training cohort (CR: AUC = 0.828; 95% CI = 0.723-0.932; pCR: AUC = 0.864; 95% CI = 0.759-0.961). The validation showed robust predictive ability (CR: AUC = 0.796, 95% CI = 0.5974-0.9952; pCR: AUC = 0.917, 95% CI = 0.7921-1.0000). Irinotecan sensitivity in PDTOs was a predictive and prognostic factor in LARC.
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Affiliation(s)
- Tao Lv
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoya Xu
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ye Yao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peiyuan Mu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruoyu Guan
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaomeng Li
- Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guoxiang Fu
- Research and Early Development, D1Med Technology (Shanghai) Inc, Shanghai, China
| | - Long Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.,Cancer institute, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yaqi Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chen Hu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hans Clevers
- Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.,Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guoqiang Hua
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Cancer institute, Fudan University Shanghai Cancer Center, Shanghai, China
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Nisar S, Masoodi T, Prabhu KS, Kuttikrishnan S, Zarif L, Khatoon S, Ali S, Uddin S, Akil AAS, Singh M, Macha MA, Bhat AA. Natural products as chemo-radiation therapy sensitizers in cancers. Biomed Pharmacother 2022; 154:113610. [PMID: 36030591 DOI: 10.1016/j.biopha.2022.113610] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 11/02/2022] Open
Abstract
Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer.
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Affiliation(s)
- Sabah Nisar
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Cancer immunology and genetics, Sidra Medicine, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Lubna Zarif
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar
| | - Summaiya Khatoon
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Shahid Ali
- International Potato Center (CIP), Shillong, Meghalaya, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ammira Al-Shabeeb Akil
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, AIIMS, New Delhi, India.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India.
| | - Ajaz A Bhat
- Depertment of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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7
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Review and Updates on Approaches to Neoadjuvant Chemotherapy in Rectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2021. [DOI: 10.1007/s11888-020-00462-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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8
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Roeder F, Meldolesi E, Gerum S, Valentini V, Rödel C. Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review. Radiat Oncol 2020; 15:262. [PMID: 33172475 PMCID: PMC7656724 DOI: 10.1186/s13014-020-01695-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022] Open
Abstract
The role of radiation therapy in the treatment of (colo)-rectal cancer has changed dramatically over the past decades. Introduced with the aim of reducing the high rates of local recurrences after conventional surgery, major developments in imaging, surgical technique, systemic therapy and radiation delivery have now created a much more complex environment leading to a more personalized approach. Functional aspects including reduction of acute or late treatment-related side effects, sphincter or even organ-preservation and the unsolved problem of still high distant failure rates have become more important while local recurrence rates can be kept low in the vast majority of patients. This review summarizes the actual role of radiation therapy in different subgroups of patients with rectal cancer, including the current standard approach in different subgroups as well as recent developments focusing on neoadjuvant treatment intensification and/or non-operative treatment approaches aiming at organ-preservation.
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Affiliation(s)
- F Roeder
- Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University, Landeskrankenhaus, Müllner Hautpstrasse 48, 5020, Salzburg, Austria.
| | - E Meldolesi
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - S Gerum
- Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University, Landeskrankenhaus, Müllner Hautpstrasse 48, 5020, Salzburg, Austria
| | - V Valentini
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - C Rödel
- Department of Radiotherapy, University of Frankfurt, Frankfurt, Germany
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9
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Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol 2020; 38:4231-4239. [PMID: 33119477 PMCID: PMC7768334 DOI: 10.1200/jco.20.01932] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer.
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Affiliation(s)
- Ji Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Anwen Liu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xinchen Sun
- Department of Radiation Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Luying Liu
- Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences & Zhejiang Cancer Hospital, Hangzhou, China
| | - Yaqun Zhu
- Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Tao Zhang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianhui Jia
- Department of Radiotherapy, Liaoning Cancer Hospital & Institute, China Medical University Cancer Hospital, Shenyang, China
| | - Shisheng Tan
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Junxin Wu
- Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Xin Wang
- Department of Abdominal Oncology, West China Hospital Sichuan University, Chengdu, China
| | - Juying Zhou
- Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jialin Yang
- Department of Radiation Oncology, Sichuan Cancer Hospital& Institute, Chengdu, China
| | - Chen Zhang
- Department of Radiation Oncology, HWA MEI Hospital, University of Chinese Academy of Science, Ningbo, China
| | - Hongyan Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yuanyuan Zhao
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Gang Cai
- Department of Radiation Oncology, Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Zhang
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - SanJun Cai
- Department of Colorectal Cancer, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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10
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Kimura K, Beppu N, Doi H, Kataoka K, Yamano T, Uchino M, Ikeda M, Ikeuchi H, Tomita N. Impact of preoperative chemoradiotherapy using concurrent S-1 and CPT-11 on long-term clinical outcomes in locally advanced rectal cancer. World J Gastrointest Oncol 2020; 12:311-322. [PMID: 32206181 PMCID: PMC7081115 DOI: 10.4251/wjgo.v12.i3.311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/08/2019] [Accepted: 12/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Preoperative chemoradiotherapy regimens using a second drug for locally advanced rectal cancer are still under clinical investigation. AIM To investigate the clinical outcomes of patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy using tegafur/gimeracil/oteracil (S-1) plus irinotecan (CPT-11). METHODS This was a single-center retrospective study of 82 patients who underwent radical surgery for rectal cancer after chemoradiotherapy with S-1 (80 mg/m2/d), CPT-11 (60 mg/m2/d), and radiation (total 45 Gy) between 2009 and 2016. The median follow-up was 51 mo (range: 17-116 mo). RESULTS Twenty-nine patients (35.4%) had T3 or T4 rectal cancer with mesorectal fascia invasion, 36 (43.9%) had extramural vascular invasion, 24 (29.8%) had N2 rectal cancer and eight (9.8%) had lateral lymph node swelling. The relative dose intensity was 90.1% for S-1 and 92.9% for CPT-11. Seventy-nine patients (96.3%) underwent R0 resection. With regard to pathological response, 13 patients (15.9%) had a pathological complete response and 52 (63.4%) a good response (tumor regression grade 2/3). The 5-year local recurrence-free survival, relapse-free survival and overall survival rates were 90.1%, 72.5% and 91.3%, respectively. We analyzed the risk factors for local recurrence-free survival by Cox regression analysis and none were detected. Previously described risk factors such as T4 stage, mesorectal fascia invasion or lateral lymph node swelling were not detected as negative factors for local recurrence-free survival. CONCLUSION We demonstrated good compliance and favorable tumor regression in patients with locally advanced rectal cancer treated with preoperative S-1 and CPT-11.
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Affiliation(s)
- Kei Kimura
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Naohito Beppu
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiroshi Doi
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
- Department of Radiation Oncology, Kindai University Faculty of Medicine, Sayama, Osaka 589-8511, Japan
| | - Kozo Kataoka
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Tomoki Yamano
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Masataka Ikeda
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Division of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Naohiro Tomita
- Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
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11
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Marti FEM, Jayson GC, Manoharan P, O'Connor J, Renehan AG, Backen AC, Mistry H, Ortega F, Li K, Simpson KL, Allen J, Connell J, Underhill S, Misra V, Williams KJ, Stratford I, Jackson A, Dive C, Saunders MP. Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial. Eur J Cancer 2019; 117:48-59. [PMID: 31229949 DOI: 10.1016/j.ejca.2019.04.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 04/21/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. PATIENTS AND METHODS Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. RESULTS In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). CONCLUSIONS This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.
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Affiliation(s)
| | - G C Jayson
- The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - P Manoharan
- The Christie NHS Foundation Trust, Manchester, UK; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - J O'Connor
- The Christie NHS Foundation Trust, Manchester, UK; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - A G Renehan
- The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - A C Backen
- The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - H Mistry
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK
| | - F Ortega
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK
| | - K Li
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - K L Simpson
- Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - J Allen
- The Christie NHS Foundation Trust, Manchester, UK
| | - J Connell
- The Christie NHS Foundation Trust, Manchester, UK
| | - S Underhill
- The Christie NHS Foundation Trust, Manchester, UK
| | - V Misra
- The Christie NHS Foundation Trust, Manchester, UK
| | - K J Williams
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - I Stratford
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK
| | - A Jackson
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - C Dive
- Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - M P Saunders
- The Christie NHS Foundation Trust, Manchester, UK.
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12
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Guan Y, Shen Y, Xu Y, Li C, Wang J, Gu W, Lian P, Huang D, Cai S, Zhang Z, Zhu J. An expansion study of genotype-driven weekly irinotecan and capecitabine in combination with neoadjuvant radiotherapy for locally advanced rectal cancer with UGT1A1 *1*1 genotype. Therap Adv Gastroenterol 2019; 12:1756284819852293. [PMID: 31217818 PMCID: PMC6557009 DOI: 10.1177/1756284819852293] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/29/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In our previous dose-escalation study, we uncovered the maximum tolerated dose (MTD) of weekly irinotecan was escalated to 80 mg/m2 and 65 mg/m2 for UDP glucuronosyltransferase family 1 member A1 (UGT1A1) *1*1 and *1*28 rectal cancer patients in neoadjuvant chemoradiotherapy (nCRT). This is an expansion study for *1*1 patients. METHODS Patients with clinical stage T3-4, N0-2 rectal cancer eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. A total of 52 patients with the *1*1 genotype were enrolled. Whole-pelvic intensity-modulated radiation therapy was given in 50 Gy/25 fractions. Concurrently, irinotecan of 80 mg/m2 and capecitabine of 625 mg/m2 twice daily from Monday to Friday were administered weekly. Primary endpoint was toxicities; secondary endpoints included pathological complete response (pCR), tumour-regression grading, treatment compliance, overall survival, local recurrence and disease-free survival. RESULTS All patients completed capecitabine-based radiotherapy as scheduled, and 42 (81%) patients completed more than three cycles of weekly irinotecan. Overall, grade 3/4 toxicities were observed in 20 cases, including 11 leucopenia, 10 neutropenia and 12 diarrhoea. Forty-three patients (83%) underwent a radical surgery, and 12 were evaluated as pCR. Another four patients accepted a watch-and-wait strategy because of clinical complete response (CCR). CONCLUSIONS Our data demonstrated manageable toxicities and an encouraging CCR rate for UGT1A1 *1*1 genotype in an enhanced neoadjuvant therapy. A phase III trial is ongoing to evaluate the value of irinotecan in neoadjuvant therapy (CinClare) [ClinicalTrials.gov identifier: NCT02605265].
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Affiliation(s)
- Yun Guan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
- Department of Neurosurgery, Fudan University, Shanghai, China
- Department of Cyberknife, Fudan University, Shanghai, China
| | - Yunzhu Shen
- Department of Oncology, Nanjing Medical University, Nanjing, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Chao Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Jingwen Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Weilie Gu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Peng Lian
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Fudan University, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, No. 270, Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ji Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, No. 270, Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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13
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Fujikawa H, Toiyama Y, Inoue Y, Omura Y, Ide S, Kitajima T, Yasuda H, Okugawa Y, Okita Y, Yoshiyama S, Hiro J, Kobayashi M, Ohi M, Araki T, Kusunoki M. Phase I study of preoperative chemoradiotherapy with sequential oxaliplatin and irinotecan with S-1 for locally advanced rectal cancer. Oncol Lett 2019; 17:3930-3936. [PMID: 30881510 DOI: 10.3892/ol.2019.10028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/17/2019] [Indexed: 11/06/2022] Open
Abstract
The present study designed a novel preoperative chemoradiotherapy (CRT) with sequential oxaliplatin and irinotecan with S-1 for locally advanced rectal cancer (LARC). This phase I study evaluated the maximum tolerated dose and recommended dose (RD) of oxaliplatin following irinotecan with S-1. Patients with clinical stage T3 or 4 or involvement of the regional nodes and no evidence of distant metastases were treated with fixed doses of S-1 (80 mg/m2/day) on days 1-5, 8-12, 15-19, 22-27 and 29-33, and irinotecan (40 mg/m2/day) on days 1 and 8, followed by oxaliplatin on days 22 and 29. The dose of oxaliplatin was initially 40 mg/m2 (level 1) with a predefined dose escalation schedule. The radiation dose was 1.8 Gy/fraction to a total dose of 45 Gy. A total of 9 patients were enrolled in the present study and 7 patients completely received CRT with this study protocol. The maximum tolerated dose for oxaliplatin was 50 mg/m2 (level 2). Three of four patients experienced dose-limiting toxicity (grade 3 diarrhea) in oxaliplatin phase of level 2 dose. The RD of oxaliplatin was 40 mg/m2 (level 1 dose). In addition, 2 patients had pathological CR (28.5%). Novel preoperative CRT with sequential oxaliplatin and irinotecan with S-1 for LARC resulted in acceptable toxicity and promising efficacy. However, the RD of oxaliplatin was lower than in previous CRT studies that combined oxaliplatin with S-1. To administer higher oxaliplatin, we have planned a phase I trial of preoperative CRT with sequential oxaliplatin followed by irinotecan with S-1 for LARC.
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Affiliation(s)
- Hiroyuki Fujikawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yasuhiro Inoue
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yusuke Omura
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Shozo Ide
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Takahito Kitajima
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Hiromi Yasuda
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yoshinaga Okugawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Yoshiki Okita
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Shigeyuki Yoshiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Junichiro Hiro
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Minako Kobayashi
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masaki Ohi
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Toshimitsu Araki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
| | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
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14
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Wang Y, Yang L, Zhang J, Zhou M, Shen L, Deng W, Liang L, Hu R, Yang W, Yao Y, Zhang H, Zhang Z. Radiosensitization by irinotecan is attributed to G2/M phase arrest, followed by enhanced apoptosis, probably through the ATM/Chk/Cdc25C/Cdc2 pathway in p53-mutant colorectal cancer cells. Int J Oncol 2018; 53:1667-1680. [PMID: 30085332 DOI: 10.3892/ijo.2018.4514] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 06/29/2018] [Indexed: 11/05/2022] Open
Abstract
Irinotecan, an analog of camptothecin, which is an inhibitor of topoisomerase I, is currently used in the treatment of metastatic colorectal cancer. Camptothecin derivatives have been demonstrated to exert radiosensitizing effects on several types of cancer cells. However, to date, at least to the best of our knowledge, few studies have examined these effects in colorectal cancer cell lines. In the present study, we examined the radiosensitizing effects of irinotecan on the p53-mutant colorectal cancer cell lines, HT29 and SW620, and explored the potential underlying mechanisms. Drug cytotoxicity tests revealed that the 24 h half-maximal inhibitory concentrations (IC50s) of irinotecan as a single agent were 39.84 µg/ml (HT29 95% CI, 38.27-41.48) and 96.86 µg/ml (SW620 95% CI, 89.04-105.4); finally, concentrations <2 µg/ml were used in the subsequent experiments. Clonogenic assays revealed that irinotecan exerted radiosensitizing effects on the HT29 and SW620 cells, and the sensitivity enhancement ratios (SERs) at 2 Gy increased with increasing concentrations (SER at 2 Gy, 1.41 for the HT29 cells, 1.87 for the SW620 cells; with irinotecan at 2 µg/ml). Subsequently, the cells were divided into 4 groups: The control group, irinotecan group, radiation group and combination group. Compared with the control, irinotecan and radiation groups, the combination group had the slowest cell growth rate and the most obvious foci of Ser139p‑γH2AX. Combined treatment resulted in a firstly decreased and then increased M phase arrest and led to the most significant G2/M phase arrest, followed by the most significant increase in apoptosis. The results of western blot analysis indicated that the expression levels of proteins related to the DNA damage response system (Ser1981p‑ATM, Ser345p‑Chk1, Thr68p‑Chk2 and Ser139p‑γH2AX) and the cell cycle (Tyr15p‑Cdc2 and cyclin B1) exhibited the greatest increase in the combined group. In addition, the expression of Ser216p‑Cdc25C was also increased in the combined group, indicating that irinotecan likely radiosensitized the p53-mutant HT29 and SW620 cells through the ATM/Chk/Cdc25C/Cdc2 pathway.
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Affiliation(s)
- Yaqi Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Lifeng Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Jing Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Menglong Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Weijuan Deng
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Liping Liang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Ran Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Wang Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Ye Yao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
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15
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Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management. Clin Colorectal Cancer 2018; 17:1-12. [DOI: 10.1016/j.clcc.2017.06.008] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 06/21/2017] [Accepted: 06/21/2017] [Indexed: 01/13/2023]
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16
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Teo MTW, McParland L, Appelt AL, Sebag-Montefiore D. Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review. Int J Radiat Oncol Biol Phys 2017; 100:146-158. [PMID: 29254769 DOI: 10.1016/j.ijrobp.2017.09.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 08/23/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer. METHODS AND MATERIALS The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathologic complete response (pCR) was conducted. RESULTS We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I2 = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025). CONCLUSIONS Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer.
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Affiliation(s)
- Mark T W Teo
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK
| | - Lucy McParland
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Ane L Appelt
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK
| | - David Sebag-Montefiore
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK.
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17
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Optimal Sequencing of Neoadjuvant Therapies (NAT) in Rectal Cancer: Upfront Chemotherapy vs. Upfront Chemoradiation. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0358-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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18
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Abstract
Preoperative radiotherapy has an accepted role in reducing the risk of local recurrence in locally advanced resectable rectal cancer, particularly when the circumferential resection margin is breached or threatened, according to magnetic resonance imaging. Fluoropyrimidine-based chemoradiation can obtain a significant down-sizing response and a curative resection can then be achieved. Approximately, 20% of the patients can also obtain a pathological complete response, which is associated with less local recurrences and increased survival. Patients who achieve a sustained complete clinical response may also avoid radical surgery. In unresectable or borderline resectable tumors, around 20% of the patients still fail to achieve a sufficient down-staging response with the current chemoradiation schedules. Hence, investigators have aspired to increase pathological complete response rates, aiming to improve curative resection rates, enhance survival, and potentially avoid mutilating surgery. However, adding additional cytotoxic or biological agents have not produced dramatic improvements in outcome and often led to excess surgical morbidity and higher levels of acute toxicity, which effects on compliance and in the global efficacy of chemoradiation.
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Affiliation(s)
- Rob Glynne-Jones
- Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, UK.
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19
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Greenhalgh T, Dearman C, Sharma R. Combination of Novel Agents with Radiotherapy to Treat Rectal Cancer. Clin Oncol (R Coll Radiol) 2016; 28:116-139. [DOI: 10.1016/j.clon.2015.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 10/25/2015] [Accepted: 10/26/2015] [Indexed: 02/07/2023]
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Thavaneswaran S, Price TJ. Optimal therapy for resectable rectal cancer. Expert Rev Anticancer Ther 2015; 16:285-302. [PMID: 26652907 DOI: 10.1586/14737140.2016.1130627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A lot can be gained by improving our understanding of the optimal sequence of existing therapies in rectal cancer, with the more difficult task of balancing the morbidity of recurrence with the morbidity of prescribed therapies that are particularly toxic owing to tumour location. This review aims to highlight a recent shift in treatment strategies in the opposite direction, with a focus on earlier, more intense systemic treatments with reduced local therapies. Understanding the rationale for and evidence to support this shift will help identify gaps, shape future trials, and ultimately answer the question of whether this is indeed the right path to follow with regards to maintaining local control rates and long-term outcomes for patients, and improving distal disease control and local treatment-related morbidities without compromising quality of life.
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Affiliation(s)
| | - Timothy J Price
- b The Queen Elizabeth Hospital , University of Sydney and University of Adelaide , Woodville , SA , Australia
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Evaluating Variations of Bladder Volume Using an Ultrasound Scanner in Rectal Cancer Patients during Chemoradiation: Is Protocol-Based Full Bladder Maintenance Using a Bladder Scanner Useful to Maintain the Bladder Volume? PLoS One 2015; 10:e0128791. [PMID: 26039198 PMCID: PMC4454439 DOI: 10.1371/journal.pone.0128791] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 04/30/2015] [Indexed: 01/04/2023] Open
Abstract
PURPOSE The maintenance of full bladder is important to reduce radiation-induced toxicities and maintain the therapeutic consistency in locally advanced rectal cancer patients who underwent radiotherapy (RT). So, the aim of this study was to evaluate the effectiveness of protocol-based full bladder maintenance by assessing bladder volume variation using an ultrasound bladder scanner to maintain bladder volume. MATERIALS AND METHODS From March 2011 to May 2011, twenty consecutive rectal cancer patients receiving external beam RT participated in this prospective study. Protocol-based full bladder maintenance consisted of education, training and continuous biofeedback by measuring bladder volume. Bladder volume was measured by bladder scan immediately before simulation CT scan and before each treatment three times weekly during the RT period. The relative bladder volume change was calculated. Intra-patient bladder volume variations were quantified using interquartile range (IQR) of relative bladder volume change in each patient. We compared intra-patient bladder volume variations obtained (n=20) with data from our previous study patients (n=20) performing self-controlled maintenance without protocol. RESULTS Bladder volumes measured by bladder scan highly correlated with those on simulation CT scan (R=0.87, p<0.001). Patients from this study showed lower median IQR of relative bladder volume change compared to patients of self-controlled maintenance from our previous study, although it was not statistically significant (median 32.56% vs. 42.19%, p=0.058). Upon logistic regression, the IQR of relative bladder volume change was significantly related to protocol-based maintenance [relative risk 1.045, 95% confidence intervals (CI) 1.004-1.087, p=0.033]. Protocol-based maintenance included significantly more patients with an IQR of relative bladder volume change less than 37% than self-controlled maintenance (p=0.025). CONCLUSION Our findings show that bladder volume could be maintained more consistently during RT by protocol-based management using a bladder scan.
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Lescut N, Lepinoy A, Schipman B, Cerda T, Guimas V, Bednarek C, Bosset JF. [Preoperative chemoradiotherapy for rectal cancer: experience from one centre]. Cancer Radiother 2015; 19:98-105. [PMID: 25769650 DOI: 10.1016/j.canrad.2014.11.011] [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: 02/02/2014] [Revised: 09/03/2014] [Accepted: 11/12/2014] [Indexed: 12/29/2022]
Abstract
PURPOSE In recent decades, the management of rectal cancer has been significantly improved by optimizing the surgical treatment with the total mesorectal excision and the development of neoadjuvant radiotherapy with or without chemotherapy. In this study, we investigated the impact of changes in practice over a period of 15 years in an expert centre. PATIENTS AND METHODS A monocentric study was conducted retrospectively on cT3-resectable T4 patients who received chemoradiotherapy for a locally advanced rectal adenocarcinoma between 1993 and 2008. We studied sphincter preservation, pathological complete response (ypT0), survival, and toxicities by different concomitant chemotherapy and treatment period. RESULTS Among the 179 patients who had a chemoradiotherapy, 56.4% were received concomitant 5-fluoro-uracil-leucovorin, 28.5% with concomitant capecitabine, and 15.1% with concomitant oxaliplatin and capecitabine. The average dose of radiotherapy was 45 Gy (25×1.8 Gy). Five-year disease-free survival was 74.3% and overall survival 68.8%. The rate of local recurrence and distant metastases were 6.1 and 23.6%. In multivariate analysis, concomitant chemotherapy oxaliplatin and capecitabine improved the pathological complete response rate (ypT0; capecitabine: 6%, 5-fluoro-uracil-leucovorin: 10.3%, capecitabine-oxaliplatin: 22.2%), but not significantly (P=0.12) and with more toxicities, and treatment interruptions. Sphincter preservation rate was not improved significantly during the study period (1993-2004 vs. 2005-2008), but disease-free survival improved from 72.2% up to 87.5% (P=0.03). CONCLUSION Our results are consistent with those published in the literature. Concomitant chemotherapy with 5-fluoro-uracil or capecitabine remains the standard scheme. Upfront chemotherapy, before chemoradiotherapy, should be investigated with regard to the predominance of metastasis.
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Affiliation(s)
- N Lescut
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France.
| | - A Lepinoy
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France
| | - B Schipman
- Service d'oncologie-radiothérapie, centre d'oncologie et de radiothérapie du Parc-Chalon-sur-Saône, 4, allée Saint-Jean-des-Vignes, 71100 Chalon-sur-Saône, France
| | - T Cerda
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France
| | - V Guimas
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France
| | - C Bednarek
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France
| | - J-F Bosset
- Service d'oncologie-radiothérapie, CHU Jean-Minjoz, 3, boulevard Fleming, 25030 Besançon cedex, France
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Cai G, Zhu J, Palmer JD, Xu Y, Hu W, Gu W, Cai S, Zhang Z. CAPIRI-IMRT: a phase II study of concurrent capecitabine and irinotecan with intensity-modulated radiation therapy for the treatment of recurrent rectal cancer. Radiat Oncol 2015; 10:57. [PMID: 25889149 PMCID: PMC4353448 DOI: 10.1186/s13014-015-0360-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 02/16/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This study investigated the local effect and acute toxicity of irinotecan and capecitabine with concurrent intensity-modulated radiation therapy (IMRT) for the treatment of recurrent rectal cancer without prior pelvic irradiation. METHODS Seventy-one patients diagnosed with recurrent rectal cancer who did not previously receive pelvic irradiation were treated in our hospital from October 2009 to July 2012. Radiotherapy was delivered to the pelvis, and IMRT of 45 Gy (1.8 Gy per fraction), followed by a boost of 10 Gy to 16 Gy (2 Gy per fraction), was delivered to the recurrent sites. The concurrent chemotherapy regimen was 50 mg/m(2) irinotecan weekly and 625 mg/m(2) capecitabine twice daily (Mon-Fri). Radical surgery was recommended for medically fit patients without extra-pelvic metastases. The patients were followed up every 3 months. Tumor response was evaluated using CT/MRIs according to the RECIST criteria or postoperative pathological findings. NCI-CTC 3.0 was used to score the toxicities. RESULTS Forty-eight patients (67.6%) had confirmed recurrent rectal cancer without extra pelvic metastases, and 23 patients (32.4%) had extra pelvic metastases. Fourteen patients (19.7%) underwent radical resections (R0) post-chemoradiation. A pathologic complete response was observed in 7 of 14 patients. A clinical complete response was observed in 4 patients (5.6%), and a partial response was observed in 22 patients (31.0%). Only 5 patients (7.0%) showed progressive disease during or shortly after treatment. Of 53 symptomatic patients, clinical complete and partial symptom relief with chemoradiation was achieved in 56.6% and 32.1% of patients, respectively. Only 2 patients (2.8%) experienced grade 4 leukopenia. The most common grade 3 toxicity was diarrhea (16 [22.5%] patients). The median follow-up was 31 months. The cumulative local progression-free survival rate was 74.2% and 33.9% at 1 and 3 years after chemoradiation, respectively. The cumulative total survival rate was 80.1% and 36.5% at 1 and 3 years after chemoradiation, respectively. CONCLUSIONS This study revealed that concurrent irinotecan and capecitabine with IMRT significantly relieves local symptoms and exhibits promising efficacy with manageable toxicities in recurrent rectal cancer without prior pelvic irradiation. Improving the rate of R0 resections will be investigated in a future study.
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Affiliation(s)
- Gang Cai
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Ji Zhu
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Joshua D Palmer
- Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
| | - Ye Xu
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Weigang Hu
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Weilie Gu
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Sanjun Cai
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
| | - Zhen Zhang
- Department of Radiation Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, China.
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Jones RG, Tan D. How can we determine the best neoadjuvant chemoradiotherapy regimen for rectal cancer? COLORECTAL CANCER 2015. [DOI: 10.2217/crc.15.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY The current management of patients with clinically defined ‘locally advanced rectal cancer’ often involves fluoropyrimidine-based preoperative chemoradiotherapy (CRT) followed by total mesorectal excision. The focus remains primarily on reducing local recurrence, and improving survival, with organ preservation an increasing target. The best neoadjuvant CRT is the most effective regimen, balanced against the tolerability and late functional consequences, which should be selected for the individual according to their individual risk of local and distant recurrence. Hence, what makes the best neoadjuvant treatment depends on the activity and toxicity of the particular schedule, the aims of treatment, the individual disease characteristics and the individual patient pharmacogenomics. Current research efforts focus on enhancing the efficacy of CRT by integrating additional cytotoxics and biologically targeted agents.
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Affiliation(s)
- Rob Glynne Jones
- Consultant Radiation Oncologist, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN, UK
| | - David Tan
- Radiation Oncologist, FRCR, Consultant Radiation Oncologist, National Cancer Centre, Singapore
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Fazeli MS, Keramati MR. Rectal cancer: a review. Med J Islam Repub Iran 2015; 29:171. [PMID: 26034724 PMCID: PMC4431429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/24/2014] [Indexed: 11/22/2022] Open
Abstract
Rectal cancer is the second most common cancer in large intestine. The prevalence and the number of young patients diagnosed with rectal cancer have made it as one of the major health problems in the world. With regard to the improved access to and use of modern screening tools, a number of new cases are diagnosed each year. Considering the location of the rectum and its adjacent organs, management and treatment of rectal tumor is different from tumors located in other parts of the gastrointestinal tract or even the colon. In this article, we will review the current updates on rectal cancer including epidemiology, risk factors, clinical presentations, screening, and staging. Diagnostic methods and latest treatment modalities and approaches will also be discussed in detail.
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Affiliation(s)
- Mohammad Sadegh Fazeli
- 1 Associate Professor of Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Keramati
- 2 Assistant Professor of Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
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Yoon HI, Koom WS, Kim YB, Min BS, Lee KY, Kim NK, Shin SJ, Ahn JB, Keum KC. Predicting the pathologic response of locally advanced rectal cancer to neoadjuvant concurrent chemoradiation using enzyme-linked immunosorbent assays (ELISAs) for biomarkers. J Cancer Res Clin Oncol 2014; 140:399-409. [PMID: 24390211 DOI: 10.1007/s00432-013-1578-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 12/19/2013] [Indexed: 02/01/2023]
Abstract
PURPOSE To investigate the role of biomarkers including serum tissue inhibitor of metalloproteinases-1 (TIMP-1), urokinase plasminogen activator receptor, vascular endothelial growth factor, and epidermal growth factor receptor in predicting pathologic response to neoadjuvant chemoradiation (NACRT) for rectal cancer. METHODS Between 2007 and 2009, 50 clinical TNM stage II or III patients were analyzed in this prospective study. Pre- and post-NACRT serum levels of biomarkers were assessed using ELISAs. The primary and secondary endpoints were pathologic complete response (pCR) and Mandard regression grade (MRG). RESULTS The pCR was reported in 5 patients (10.0%). According to the MRG, fifteen patients (30.0%) were divided into group A (Grade I-II), the others in group B (Grade III-V). On univariate analysis, post-NACRT TIMP-1 showed notable significance with pCR (P = 0.092) and significant correlation with MRG group A (P = 0.003). Post-NACRT TIMP-1 ≤ 204.5 ng/mL as cut-off value by ROC curve was associated with more pCR and MRG group A patients (P = 0.016 and 0.002). Interval between NACRT and surgery was related to pCR with approached trend levels of significance (P = 0.05) and to MRG group A significantly on univariate analysis of clinical factors (P = 0.031). On multivariate analysis, post-NACRT TIMP-1 was not significantly related to pCR (P = 0.187), while it was significantly associated with MRG (P = 0.009). Among clinical responders, post-NACRT TIMP-1 level ≤ 204.5 ng/mL was significantly associated with pCR (P = 0.021) and MRG group A (P = 0.003). CONCLUSIONS Post-NACRT serum TIMP-1 could be used as a predictive marker of pathologic response to NACRT in rectal cancer, even in patients with clinical response.
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Affiliation(s)
- Hong In Yoon
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
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Kurt A, Yanar F, Asoglu O, Balik E, Olgac V, Karanlik H, Kucuk ST, Ademoglu E, Yegen G, Bugra D. Low Mmp 9 and VEGF levels predict good oncologic outcome in mid and low rectal cancer patients with neoadjuvant chemoradiation. BMC Clin Pathol 2012; 12:27. [PMID: 23276144 PMCID: PMC3542157 DOI: 10.1186/1472-6890-12-27] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Accepted: 12/19/2012] [Indexed: 12/12/2022] Open
Abstract
Background The aim of this study was to evaluate apoptotic (Bcl-2, Bax expression, caspase-3 activity, and cytochrome-c) and angiogenic (MMP-9 levels and VEGF expression) markers in operable rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Understanding these factors will facilitate the identification of potential pathological responders before treatment, leading to better local control and survival rates. Methods Between March 2006 and March 2008, 29 patients withTNM Stage III (cT3 N+) mid or low rectal cancer were included in this study. Our sample consisted of 17 males (58.6%) and 12 females (41.4%). The median age was 60 years (range 24-88 years). Biopsy samples were taken from different portions of the tumors using flexible endoscopy before neoadjuvant CRT. Preoperatively, all patients received radiation (45-50.4 gray (Gy) in 25 cycles with concurrent 5-florouracil (5-FU) chemotherapy. Results A complete response was observed in 7 of 29 patients (24%). Bax staining was negative in 1 of the 7 patients (14%) in the pathological complete response (PCR) group and in 18 of the 22 patients (82%) in the no pathological complete response (noPCR) group (p = 0.001). MMP-9 and VEGF levels were higher in the noPCR group than the PCR group (p = 0.04, p = 0.05 respectively). No statistically significant differences were found between VEGF and MMP-9 levels in nodal downstaging. No statistically significant relationships were found between the other apoptotic factors (Bcl 2, cytochrome-c, and caspase-3 activity) and pathological response rate (p > 0.05). Conclusion In neoadjuvant CRT patients, high levels of Bax expression and low levels of VEGF and MMP-9 expression on preoperative biopsies indicate that the patient will potentially be a good pathological responder.
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Affiliation(s)
- Atilla Kurt
- General Surgery, Sivas Cumhuriyet University, Sivas, Turkey.
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Abstract
Neoadjuvant short-course radiotherapy and long-course chemoradiation (CRT) reduce local recurrence rates when compared to surgery alone and remain widely accepted as standard of care for patients with locally advanced rectal cancer. However, surgery is not without complications and a non-surgical approach in carefully selected patients warrants evaluation. A pathological complete response to CRT is associated with a significant improvement in survival and it has been suggested that a longer time interval between the completion of CRT and surgery increases tumor downstaging. Intensification of neoadjuvant treatment regimens to increase tumor downstaging has been evaluated in a number of clinical trials and more recently the introduction of neoadjuvant chemotherapy prior to CRT has demonstrated high rates of radiological tumor regression. Careful selection of patients using high-resolution MRI may allow a non-surgical approach in a subgroup of patients achieving a complete response to neoadjuvant therapies after an adequate time period. Clearly this needs prospective evaluation within a clinical trial setting, incorporating modern imaging techniques, and tissue biomarkers to allow accurate prediction and assessment of response.
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Salazar R, Navarro M, Losa F, Alonso V, Gallén M, Rivera F, Benavides M, Escudero P, González E, Massutí B, Gómez A, Majem M, Aranda E. Phase II study of preoperative radiotherapy and concomitant weekly intravenous oxaliplatin combined with oral capecitabine for stages II–III rectal cancer. Clin Transl Oncol 2012; 14:592-8. [DOI: 10.1007/s12094-012-0846-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 11/02/2011] [Indexed: 01/03/2023]
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Czito BG, Willett CG. Potential Novel Drugs to Combine with Radiation in Rectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2012. [DOI: 10.1007/s11888-012-0120-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: a current overview. Front Pharmacol 2012; 2:94. [PMID: 22291649 PMCID: PMC3253585 DOI: 10.3389/fphar.2011.00094] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 12/22/2011] [Indexed: 01/06/2023] Open
Abstract
Treatment of cancer often requires exposure to radiation, which has several limitations involving non-specific toxicity toward normal cells, reducing the efficacy of treatment. Efforts are going on to find chemical compounds which would effectively offer protection to the normal tissues after radiation exposure during radiotherapy of cancer. In this regard, plant-derived compounds might serve as “leads” to design ideal radioprotectors/radiosensitizers. This article reviews some of the recent findings on prospective medicinal plants, phytochemicals, and their analogs, based on both in vitro and in vivo tumor models especially focused with relevance to cancer radiotherapy. Also, pertinent discussion has been presented on the molecular mechanism of apoptotic death in relation to the oxidative stress in cancer cells induced by some of these plant samples and their active constituents.
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Affiliation(s)
- Banasri Hazra
- Department of Pharmaceutical Technology, Jadavpur University Kolkata, India.
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Minsky BD. Progress in the Treatment of Locally Advanced Clinically Resectable Rectal Cancer. Clin Colorectal Cancer 2011; 10:227-37. [DOI: 10.1016/j.clcc.2011.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 06/21/2011] [Indexed: 12/11/2022]
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Abstract
In the past two decades, substantial progress has been made in the adjuvant management of colorectal cancer. Chemotherapy has improved overall survival in patients with node-positive (N+) disease. In contrast with colon cancer, which has a low incidence of local recurrence, patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy (chemoradiation). Patients with rectal cancer have a number of unique management considerations: for example, the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? This review will address these and other controversies specific to patients with rectal cancer.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL 60637, USA.
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Velenik V, Ocvirk J, Music M, Bracko M, Anderluh F, Oblak I, Edhemovic I, Brecelj E, Kropivnik M, Omejc M. Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study. Radiat Oncol 2011; 6:105. [PMID: 21880132 PMCID: PMC3179720 DOI: 10.1186/1748-717x-6-105] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Accepted: 08/31/2011] [Indexed: 01/09/2023] Open
Abstract
Background Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC. Methods Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m2 twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR). Results 61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively. Conclusions This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.
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Beyond 5-Fluorouracil: The Emerging Role of Newer Chemotherapeutics and Targeted Agents with Radiation Therapy. Semin Radiat Oncol 2011; 21:203-11. [DOI: 10.1016/j.semradonc.2011.02.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Tan BR, Thomas F, Myerson RJ, Zehnbauer B, Trinkaus K, Malyapa RS, Mutch MG, Abbey EE, Alyasiry A, Fleshman JW, McLeod HL. Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma. J Clin Oncol 2011; 29:875-83. [PMID: 21205745 PMCID: PMC3068061 DOI: 10.1200/jco.2010.32.3212] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 11/01/2010] [Indexed: 12/25/2022] Open
Abstract
PURPOSE Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. PATIENTS AND METHODS Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m²/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m². The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. RESULTS Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. CONCLUSION To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.
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Affiliation(s)
- Benjamin R. Tan
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Fabienne Thomas
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Robert J. Myerson
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Barbara Zehnbauer
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Kathryn Trinkaus
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Robert S. Malyapa
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Matthew G. Mutch
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Elliot E. Abbey
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Amer Alyasiry
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - James W. Fleshman
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
| | - Howard L. McLeod
- From the Washington University School of Medicine, St Louis, MO; University of North Carolina, Chapel Hill, NC; and Université de Toulouse, Toulouse, France
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Minsky BD. Chemoradiation for rectal cancer: rationale, approaches, and controversies. Surg Oncol Clin N Am 2011; 19:803-18. [PMID: 20883955 DOI: 10.1016/j.soc.2010.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The standard adjuvant treatment of cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These controversies include the role of short course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation, as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation and Cellular Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
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Gollins S, Sun Myint A, Haylock B, Wise M, Saunders M, Neupane R, Essapen S, Samuel L, Dougal M, Lloyd A, Morris J, Topham C, Susnerwala S. Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term clinical outcomes. J Clin Oncol 2011; 29:1042-9. [PMID: 21263095 DOI: 10.1200/jco.2010.29.7697] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
PURPOSE To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)-defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine. PATIENTS AND METHODS One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (≤ 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m(2) twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m(2) once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection. RESULTS Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (> 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci. CONCLUSION This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes.
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Affiliation(s)
- Simon Gollins
- Department of Clinical Oncology, North Wales Cancer Treatment Centre, Rhyl, LL18 5UJ United Kingdom.
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Abstract
The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.
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Gollins S. Radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal cancer. Colorectal Dis 2010; 12 Suppl 2:2-24. [PMID: 20618363 DOI: 10.1111/j.1463-1318.2010.02320.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVE To review the published evidence relating to the use of radiotherapy (RT), chemotherapy and biological therapy as adjuncts to surgery in the curative treatment of rectal cancer. METHODS Searches were carried out of the MEDLINE and CANCERLIT databases together with conference abstracts from key meetings including the American Society of Clinical Oncology Annual Meeting and Gastrointestinal Cancers Symposium and the ECCO/ESMO Multidisciplinary Congress. RESULTS RT reduces local pelvic recurrence when used as an adjunct to surgery, even when this is performed optimally by total mesorectal excision (TME). RT is usually given as short-course preoperative radiotherapy (SCPRT) followed by immediate surgery which produces no or very little downstaging or long-course concurrent chemoradiation (CRT) followed by a 6-8 week gap prior to surgery which produces significant downstaging. The prognostic importance of achieving a clear histological circumferential resection margin is now well recognised and pathological assessment of the quality of surgery can predict long-term outcomes. Internationally there is considerable heterogeneity in the staging modalities and criteria used in deciding which approach might be used, in the reporting of histological results and in RT parameters (time/dose/fractionation/volume). Attempts to increase the potency of CRT have included the addition of concurrent chemotherapeutic and biological agents to the standard fluoropyrimidine although there is little randomised data and none with regard to long-term survival outcomes. Neither SCPRT nor downstaging CRT have been shown to reduce the rate of subsequent distant metastatic relapse which remains a significant clinical problem. The potential additional benefit of neoadjuvant or adjuvant chemotherapy in addition to SCPRT or long-course CRT remains ill-defined. Late morbidity can include bowel and sexual dysfunction, pelvic fractures and second malignancies with considerably more being known in relation to SCPRT than long-course CRT. CONCLUSIONS Improvements in imaging, pathology and surgical technique combined with multimodality treatment using RT and chemotherapy are leading to continuing improvements in the long term outcome for patients with rectal cancer although much remains to be learnt regarding the optimum strategy for use of these in different clinical contexts and their relationship to long-term morbidity.
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Affiliation(s)
- S Gollins
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, Denbighshire, UK.
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Ramani VS, Sun Myint A, Montazeri A, Wong H. Preoperative chemoradiotherapy for rectal cancer: a comparison between intravenous 5-fluorouracil and oral capecitabine. Colorectal Dis 2010; 12 Suppl 2:37-46. [PMID: 20618366 DOI: 10.1111/j.1463-1318.2010.02323.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Capecitabine provides an attractive alternative to intravenous (IV) 5-flourouracil (5-FU) in chemoradiation regimes for rectal cancer by avoiding the need for intravenous access and inpatient stay. We aimed to compare retrospectively the efficacy of concurrent capecitabine with IV 5-FU in preoperative pelvic chemoradiation schedules for rectal cancer in our centre. METHOD Patients treated from January 2005 to June 2007 were included. Information was collected on patient characteristics; treatment details; pathological response to treatment; recurrence and survival. All statistical analyses were performed using SPSS V17. RESULTS All patients had pelvic radiation. Ninety-nine patients were treated with capecitabine and 97 with 5-FU. The two groups were well matched for age, sex and TNM stage. There were significantly more PS (performance status) 0 patients in the capecitabine group (51%vs 30%) (P = 0.001). Of the 99 patients in the capecitabine group, 91 (92%) were able to undergo surgery with 84 (93%) achieving R0 resection. In the 5-FU group, these proportions were 87 (90%) and 70 (80%). The difference in the rate of R0 resection was statistically significant (P = 0.024). The APR rate was 35% in the capecitabine group compared with 47% in the 5-FU group (P = 0.06). There was no significant difference in pathological complete response (pCR) rates between capecitabine (14%) and 5-FU(12%). A higher pCR rate (30%) was observed in patients who underwent a brachytherapy boost (P = 0.051). There were three local recurrences in the whole patient group, (capecitabine 1; 5-FU 2). Thirty-five patients had distant metastases, 14 in the capecitabine and 21 in the 5-FU group. There was no significant difference in the risk of recurrence between the two groups. Six patients in each group had grade 3 toxicity with diarrhoea being more common with capecitabine. CONCLUSIONS Preoperative chemoradiotherapy with capecitabine for rectal cancer is efficacious and comparable to 5-FU (IV). It is more convenient, is well tolerated and avoids the need for inpatient admission.
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Affiliation(s)
- V S Ramani
- Department of Clinical Oncology, Clatterbridge Centre for Oncology, Bebington, Wirral, UK.
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Hong YS, Kim DY, Lim SB, Choi HS, Jeong SY, Jeong JY, Sohn DK, Kim DH, Chang HJ, Park JG, Jung KH. Preoperative chemoradiation with irinotecan and capecitabine in patients with locally advanced resectable rectal cancer: long-term results of a Phase II study. Int J Radiat Oncol Biol Phys 2010; 79:1171-8. [PMID: 20605355 DOI: 10.1016/j.ijrobp.2009.12.073] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Revised: 12/16/2009] [Accepted: 12/16/2009] [Indexed: 01/24/2023]
Abstract
PURPOSE Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer has shown benefit over postoperative CRT; however, a standard CRT regimen has yet to be defined. We performed a prospective concurrent CRT Phase II study with irinotecan and capecitabine in patients with locally advanced rectal cancer to investigate the efficacy and safety of this regimen. METHODS AND MATERIALS Patients with locally advanced, nonmetastatic, and mid-to-lower rectal cancer were enrolled. Radiotherapy was delivered in 1.8-Gy daily fractions for a total of 45 Gy in 25 fractions, followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of 40 mg/m(2) of irinotecan per week for 5 consecutive weeks and 1,650 mg/m(2) of capecitabine per day for 5 days per week (weekdays only) from the first day of radiotherapy. Total mesorectal excision was performed within 6 ± 2 weeks. The pathologic responses and survival outcomes were included for the study endpoints. RESULTS In total, 48 patients were enrolled; 33 (68.7%) were men and 15 (31.3%) were women, and the median age was 59 years (range, 32-72 years). The pathologic complete response rate was 25.0% (11 of 44; 95% confidence interval, 12.2-37.8) and 8 patients (18.2% [8 of 44]) showed near-total tumor regression. The 5-year disease-free and overall survival rates were 75.0% and 93.6%, respectively. Grade 3 toxicities included leukopenia (3 [6.3%]), neutropenia (1 [2.1%]), infection (1 [2.1%]), alanine aminotransferase elevation (1 [2.1%]), and diarrhea (1 [2.1%]). There was no Grade 4 toxicity or treatment-related death. CONCLUSIONS Preoperative CRT with irinotecan and capecitabine with treatment-free weekends showed very mild toxicity profiles and promising results in terms of survival.
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Affiliation(s)
- Yong Sang Hong
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea
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Wadlow RC, Ryan DP. The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 2010; 116:3537-48. [DOI: 10.1002/cncr.25155] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Huerta S, Murray B, Olson C, Patel P, Anthony T. Current evidence-based opinions in the management of adenocarcionoma of the rectum. Indian J Surg 2010; 71:356-62. [PMID: 23133191 DOI: 10.1007/s12262-009-0094-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Accepted: 11/13/2009] [Indexed: 12/12/2022] Open
Abstract
The management of rectal cancer has drastically evolved over the past two decades as a result of implementation of circular stapling devices and the introduction of neoadjuvant chemoradiation. In spite of current aggressive multimodality treatments, the recurrence rate remains unacceptably high and the expected 5-year survival in patients who develop recurrent disease is dismal. The management of rectal cancer must involve a multidisciplinary approach. An understanding of the biology of rectal tumours may allow for selection of patients who may have an aggressive phenotype allowing for alterations in the operative and neoadjuvant planning. Efforts to improve local control and survival in rectal cancer are the focus of multiple current clinical and preclinical research efforts. Preoperative chemoradiation for and surgical management of rectal cancer, including the laparoscopic approach are areas of dynamic progression. In the present report, we review the current evidence in the new strategies pertaining to the multimodality approach in the management of rectal cancer.
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Affiliation(s)
- Sergio Huerta
- Division of Surgery, University of Texas Southwestern Medical Center/Dallas VA Medical Center, Dallas, USA
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Nam TK, Lee JS, Kim HR, Ahn SJ, Song JY, Yoon MS. Molecular prognostic factors in rectal cancer treated by preoperative chemoradiotherapy. Oncol Lett 2010; 1:23-29. [PMID: 22966250 DOI: 10.3892/ol_00000004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 09/24/2009] [Indexed: 12/30/2022] Open
Abstract
The present study evaluated the expression of p53, pRb, hMLH1 and MDM2 prior to preoperative chemoradiotherapy (CRT) in patients with rectal cancer, and attempted to determine any correlation with treatment outcome. Forty-five patients with available pretreatment biopsy tissues and who received preoperative CRT were enrolled in this study. Preoperative CRT consisted of a median 50.4 Gy and 2 cycles of concurrent administration of 5-fluorouracil + leucovorin. Surgery was performed approximately seven weeks after CRT. Protein expression in formalin-fixed paraffin-embedded biopsy specimens was assessed by immunohistochemistry. A positive expression of p53, pRb, hMLH1 and MDM2 was found in 40, 46.7, 40 and 66.7% of the tissue specimens, respectively. The 5-year overall (OS), disease-free (DFS) and locoregional recurrence-free survival (LRFS) rates for patients included in the study were 71.3, 66.1 and 60.9%, respectively. p53 expression presented a significantly different OS (positive vs. negative, 45.8 vs. 86.2%; p=0.02). However, the expression of pRb, hMLH1 and MDM2 was not significant for OS. The expression of p53 was a borderline significant prognostic factor for DFS and for LRFS. Age, p53 and MDM2 expression were significant factors in the multivariate analysis performed for OS with 12 covariates, including 8 clinicopathological parameters and 4 proteins. No significant factor affected DFS or LRFS in the multivariate analysis. We suggest that the expression of p53 is a potential marker of survival. Determinations of this protein expression may be useful for selecting candidates from rectal cancer patients for more tailored treatment.
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Affiliation(s)
- Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
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Huerta S, Gao X, Saha D. Mechanisms of resistance to ionizing radiation in rectal cancer. Expert Rev Mol Diagn 2009; 9:469-80. [PMID: 19580431 DOI: 10.1586/erm.09.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
While patients with breast cancers are not subjected to the adverse side effects of tamoxifen or trastuzumab if their tumors are negative for estrogen, progesterone or Her-2/Neu, neoadjuvant ionizing radiation with concurrent chemotherapeutic agents is administered almost universally to patients with stage II/III rectal cancers. There is, however, a tremendously wide range of response to this preoperative modality from complete pathological response to continuous tumor growth in patients receiving the same form of treatment. The specific phenotype of the tumor plays a major role in rendering tumor cells survival advantage to the cytotoxic effects of chemoradiation. Pathways such as proliferation, cell cycle, apoptosis and hypoxia have been investigated under a variety of conditions in preirradiated tissues and postirradiated tumors. This article reviews the current evidence available to identify a molecular profile predictive of the best response to ionizing radiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center/Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA.
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Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2). Br J Cancer 2009; 101:924-34. [PMID: 19690550 PMCID: PMC2743353 DOI: 10.1038/sj.bjc.6605258] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. Methods: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (⩽1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m−2 b.i.d. and irinotecan 50 mg m−2; Dose level 2: capecitabine 650 mg m−2 b.i.d. and irinotecan 60 mg m−2; Dose level 3: capecitabine 825 mg m−2 b.i.d. and irinotecan 60 mg m2; Dose level 4: capecitabine 825 mg m−2 b.i.d. and irinotecan 70 mg m−2. Results: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as ⩽1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. Conclusion: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m−2 b.i.d. days 1–35 and weekly IV irinotecan at 60 mg m−2 weeks 1–4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.
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Bertolini F, Chiara S, Bengala C, Antognoni P, Dealis C, Zironi S, Malavasi N, Scolaro T, Depenni R, Jovic G, Sonaglio C, Rossi A, Luppi G, Conte PF. Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys 2009; 73:466-72. [DOI: 10.1016/j.ijrobp.2008.04.065] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 04/25/2008] [Accepted: 04/25/2008] [Indexed: 10/21/2022]
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Phase I trial of neoadjuvant chemoradiotherapy (CRT) with capecitabine and weekly irinotecan followed by laparoscopic total mesorectal excision (LTME) in rectal cancer patients. Invest New Drugs 2008; 27:262-8. [PMID: 18923810 DOI: 10.1007/s10637-008-9192-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2008] [Accepted: 10/03/2008] [Indexed: 12/31/2022]
Abstract
BACKGROUND To analyze the feasibility of capecitabine with weekly irinotecan and concurrent radiotherapy followed by laparoscopic-total mesorectal excision (LTME) in rectal cancer patients. METHODS Eligible criteria included adenocarcinoma of the rectum staged by endoscopic ultrasonography (u), spiral abdominal and pelvic CT and chest X-ray. Patients received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and capecitabine (days 1 through 5 for 5 weeks); dose level; (DL) I 250 mg/m(2)/bid; DL II 375 mg/m(2)/bid; DL III 500 mg/m(2)/bid, according to phase I methodology. External beam radiotherapy was delivered up to a total dose of 45 Gy in daily fractions of 1.8 Gy, 5 days a week. LTME was planned 5-7 weeks after CRT. RESULTS From February 2003 to February 2006, 22 patients were included. Median age was 62 (range 48 to 78). Seven pts were uT3N0 and 15 pts uT3N1. Seven patients were treated at DL I, six at DL II and nine at DL III. Grade 3 adverse events were observed in all levels. The maximum tolerated dose was reached at 375 mg/m(2) (DL II). Conversion rate to open surgery was 5%. Median hospital stay was 6.6 days. One month post-surgical complications were noted in five patients (23%). Median excised nodes were 11 (range 4-21). Pathological complete response was observed in two patients (9%). CONCLUSIONS LTME after preoperative CRT with CAPIRI is feasible but severe adverse events were found in all levels despite the use of lower dose of capecitabine than previously published.
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Abstract
Patients diagnosed with rectal cancer should undergo locoregional staging with transrectal endoscopic ultrasound (EUS) or surface coil array MRI of the pelvis if that technique is available. Patients thought to have more than very early stage (T1 or T2) disease should undergo abdominal imaging as well by CT or MRI, and chest imaging with either CXR or preferably CT. The care of rectal cancer patients should be coordinated amongst an experienced multidisciplinary team to maximize the chance of cure and to minimize both local recurrence and complications of therapy. For patients with very early stage disease (T1N0 or T2N0), local resection with or without chemoradiation may be adequate therapy, but these patients must be selected carefully and should be without any poor prognostic factors. For the majority of patients with T3N0 or greater rectal cancer, standard therapy consists of neoadjuvant continuous 5-FU and radiation followed by surgery and further chemotherapy (either with 5-FU, capecitabine, or FOLFOX). The use of capecitabine, irinotecan, and oxaliplatin during radiotherapy shows promise, but remains investigational pending results of phase III studies. Neoadjuvant therapy is preferred because it decreases local recurrence and appears to result in improved postoperative bowel function in comparison with postoperative therapy. Select patients with high (>10 cm from the anal verge) uT3N0 tumors may be at sufficiently low risk of local recurrence to justify omission of radiotherapy. Patients who experience pathologic complete response to radiotherapy should still receive postoperative adjuvant chemotherapy to reduce systemic recurrence risk until data demonstrate that this is not necessary. Patients with stage IV rectal cancer may still require local therapy with radiation, surgery, or both; however, care should be taken in these patients that chemotherapy is not excessively delayed as this is the one modality in this case that can result in improved survival.
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Affiliation(s)
- Bert H O'Neil
- UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA.
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