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Wang X, Xi M, Lu X, Tan X. The Role and Mechanism of Innate Immune Regulation in Overcoming Oxaliplatin Resistance and Enhancing Anti-Tumor Efficacy in Colorectal Cancer. Pharmaceuticals (Basel) 2025; 18:317. [PMID: 40143096 PMCID: PMC11944980 DOI: 10.3390/ph18030317] [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: 01/15/2025] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: The reversal effect of cGAMP, as a STING pathway regulator, on oxaliplatin resistance in colorectal cancer was investigated, and its mechanism was proposed. Methods: The efficacy and mechanism of the cGAMP and oxaliplatin combination for oxaliplatin-resistant colorectal cancer through a nude mouse tumor model were investigated and analyzed, and a western blot analysis of tumors was applied. Results: The reversal effect of cGAMP on oxaliplatin resistance in colorectal cancer was investigated, and its mechanism was proposed. After OXA treatment, the IC50 values of HCT116 and HCT116/L cells were 9.04 μmol/L and 47.04 μmol/L, respectively. In nude mouse tumor models, the combination of cGAMP and oxaliplatin significantly reversed the resistance of oxaliplatin to primary drug-resistant HCT116/L colorectal cancer, and the tumor inhibition rate increased from 8% (oxaliplatin alone) to 60% (combination). In the HCT116 nude mouse transplanted tumor model, the combined treatment of cGAMP and oxaliplatin also showed a more significant tumor inhibition effect than oxaliplatin alone, and the tumor inhibition rate increased by 39%, indicating that cGAMP had a considerable improvement effect on oxaliplatin acquired resistance. These results fully demonstrated the synergistic effect of cGAMP and oxaliplatin. Western blot results showed that cGAMP enhanced the sensitivity of oxaliplatin-resistant tumor cells by down-regulating the expression of p-PI3K and p-AKT and up-regulating the expression of p53 protein. Conclusions: cGAMP, as an immunomodulator against oxaliplatin resistance, shows a potential application prospect in treating oxaliplatin-resistant colorectal cancer.
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Affiliation(s)
- Xiaoqing Wang
- Department of Chemistry, Fudan University, Shanghai 200433, China; (X.W.); (X.L.)
| | - Meili Xi
- Zhongshan Hospital, Fudan University, Shanghai 200032, China;
| | - Xing Lu
- Department of Chemistry, Fudan University, Shanghai 200433, China; (X.W.); (X.L.)
| | - Xiangshi Tan
- Department of Chemistry, Fudan University, Shanghai 200433, China; (X.W.); (X.L.)
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Zhou X, Han J, Zuo A, Ba Y, Liu S, Xu H, Zhang Y, Weng S, Zhou Z, Liu L, Luo P, Cheng Q, Zhang C, Chen Y, Shan D, Liu B, Yang S, Han X, Deng J, Liu Z. THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Mol Cancer 2024; 23:282. [PMID: 39732719 DOI: 10.1186/s12943-024-02180-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/20/2024] [Indexed: 12/30/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs) exert multiple tumor-promoting functions and are key contributors to drug resistance. The mechanisms by which specific subsets of CAFs facilitate oxaliplatin resistance in colorectal cancer (CRC) have not been fully explored. This study found that THBS2 is positively associated with CAF activation, epithelial-mesenchymal transition (EMT), and chemoresistance at the pan-cancer level. Together with single-cell RNA sequencing and spatial transcriptomics analyses, we identified THBS2 specifically derived from subsets of CAFs, termed THBS2 + CAFs, which could promote oxaliplatin resistance by interacting with malignant cells via the collagen pathway in CRC. Mechanistically, COL8A1 specifically secreted from THBS2 + CAFs directly interacts with the ITGB1 receptor on resistant malignant cells, activating the PI3K-AKT signaling pathway and promoting EMT, ultimately leading to oxaliplatin resistance in CRC. Moreover, elevated COL8A1 promotes EMT and contributes to CRC oxaliplatin resistance, which can be mitigated by ITGB1 knockdown or AKT inhibitor. Collectively, these results highlight the crucial role of THBS2 + CAFs in promoting oxaliplatin resistance of CRC by activating EMT and provide a rationale for a novel strategy to overcome oxaliplatin resistance in CRC.
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Affiliation(s)
- Xing Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
- Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jiashu Han
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, 100020, China
| | - Anning Zuo
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yuhao Ba
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shutong Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Long Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Chuhan Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yukang Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Dan Shan
- Clinical Science Institute, University Hospital Galway, Galway, Ireland
| | - Benyu Liu
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
- Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China.
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China.
| | - Jinhai Deng
- Richard Dimbleby Department of Cancer Research, Comprehensive Cancer Centre, Kings College London, London, UK.
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
- Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China.
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Collinson F, Royle KL, Swain J, Ralph C, Maraveyas A, Eisen T, Nathan P, Jones R, Meads D, Min Wah T, Martin A, Bestall J, Kelly-Morland C, Linsley C, Oughton J, Chan K, Theodoulou E, Arias-Pinilla G, Kwan A, Daverede L, Handforth C, Trainor S, Salawu A, McCabe C, Goh V, Buckley D, Hewison J, Gregory W, Selby P, Brown J, Brown J. Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT. Health Technol Assess 2024; 28:1-171. [PMID: 39250424 PMCID: PMC11403377 DOI: 10.3310/jwtr4127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/11/2024] Open
Abstract
Background There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
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Affiliation(s)
- Fiona Collinson
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Kara-Louise Royle
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Jayne Swain
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Christy Ralph
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Anthony Maraveyas
- Academic Oncology, Faculty of Health Sciences, Hull York Medical School, Queens Centre Oncology and Haematology, Hull, UK
| | - Tim Eisen
- Department of Oncology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Nathan
- Department of Oncology, Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Hertfordshire, UK
| | - Robert Jones
- School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - David Meads
- Academic Unit of Health Economics, University of Leeds, Leeds, UK
| | - Tze Min Wah
- Department of Diagnostic and Interventional Radiology, Leeds Teaching Hospitals Trust, Leeds, UK
| | - Adam Martin
- Academic Unit of Health Economics, University of Leeds, Leeds, UK
| | - Janine Bestall
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | | | | | - Jamie Oughton
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Kevin Chan
- Medical Oncology, Weston Park Cancer Hospital, Sheffield, UK
| | - Elisavet Theodoulou
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Gustavo Arias-Pinilla
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Amy Kwan
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK
| | - Luis Daverede
- Department of Clinical Oncology, Austral University Hospital, Buenos Aires, Argentina
| | - Catherine Handforth
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
| | - Sebastian Trainor
- St James's Institute of Oncology, St James's University Hospital, Leeds, UK
| | - Abdulazeez Salawu
- Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK
| | | | - Vicky Goh
- School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK
| | - David Buckley
- Faculty of Medicine and Health, School of Medicine, University of Leeds, Leeds, UK
| | - Jenny Hewison
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Walter Gregory
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Peter Selby
- Leeds Institute of Medical Research, St James's University Hospital, University of Leeds, Leeds, UK
| | - Julia Brown
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Janet Brown
- Division of Clinical Medicine, University of Sheffield, Weston Park Hospital, Sheffield, UK
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Colloca GA, Venturino A. Prognostic Effect of Performance Status on Outcomes of Patients with Colorectal Cancer Receiving First-Line Chemotherapy: A Meta-analysis. J Gastrointest Cancer 2024; 55:418-426. [PMID: 37966630 DOI: 10.1007/s12029-023-00983-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Performance status (PS) is a variable derived from the assessment of a patient's functional status, originally proposed to predict drug toxicity. However, despite its characteristic of being subjective and unidimensional, it has become one of the most important prognostic variables for patients with metastatic colorectal cancer (mCRC). In light of the considerable progressive prolongation of median overall survival (OS) of patients with mCRC, it is unclear whether PS continues to be a valid prognostic factor. This article aims to perform a meta-analysis to verify the current prognostic role of PS. METHODS A search on two databases of prospective trials of first-line chemotherapy in mCRC patients, published in English from 1991 to 2020, was done by predefined criteria. After the selection of phase III trials evaluating the prognostic role of PS, a meta-analysis has been performed. RESULTS Thirteen trials were included in the meta-analysis. They reported a reduction in the risk of death with a PS 0 compared to a PS 1 or more (HR 0.63, CI 0.54-0.72; 13 studies), which was confirmed for the comparison between PS 0 and PS 1. However, the study found significant heterogeneity (Q = 68.10; p-value < 0.001) and high-grade inconsistency (I2 = 82.38%). Therefore, to explore the reasons for the heterogeneity, a univariate meta-regression was performed, which suggested a possible moderating activity for liver metastases and timing of metastasis. CONCLUSIONS PS is a reliable prognostic factor for patients with mCRC receiving first-line chemotherapy but is poorly evaluated in phase III trials.
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Kurt B, Sipahi Karslı Z, Fernández-Ortega P, Çakmak Öksüzoğlu BÖ. Experiences and Perceptions of Patients with Oxaliplatin-Induced Cold Sensitivity in Turkey: A Qualitative Study. Semin Oncol Nurs 2023; 39:151479. [PMID: 37543469 DOI: 10.1016/j.soncn.2023.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 08/07/2023]
Abstract
OBJECTIVES This study aimed to explore and describe the impact on patients with oxaliplatin-induced cold sensitivity in the early stages. DATA SOURCES An inductive design was used for this qualitative study, which included open-ended, and in-depth interviews with 18 cancer patients. Throughout the study, the authors followed the COREQ checklist. The interviews were audiorecorded and listened to multiple times. Observation notes were also recorded following each interview. Thematic analysis developed six main themes and 13 subthemes. The first theme concerns changing habits, including changes in fluid intake and clothing choice, changes in bathing and eating habits, and changes in caregiver roles. The second theme includes changes in daily routine behaviors that are perceived as difficulties with changing routines. The third theme is avoiding triggers; the fourth theme is anxiety about self-care. The fifth theme includes a subtheme of difficulty in contact. The final theme includes adaptation to life, caring responsibilities, changes in sexual functions, the performance of religious activities, and social activities IMPLICATIONS FOR NURSING PRACTICE: This study provides an overview of the lived experiences of oxaliplatin-induced cold sensitivity among cancer patients. Patients faced fewer adverse events by avoiding initiators from the first treatment. They changed their eating and drinking habits owing to difficulties. The findings of this study can be used to better understand oxaliplatin-induced cold sensitivity, identify patients needs based on their experience, and develop interventions to improve patient outcomes.
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Affiliation(s)
- Berna Kurt
- Nursing Faculty, Department of Internal Medical Nursing, Hacettepe University, Ankara, Turkey.
| | - Zeynep Sipahi Karslı
- Department of Medical Oncology, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
| | - Paz Fernández-Ortega
- Department of Nursing Sciences, Catalan Institute of Oncology and University of Barcelona, Spain
| | - Berna Ömür Çakmak Öksüzoğlu
- Department of Medical Oncology, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey
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Plimack ER, Zibelman MR. Platinum-Free Systemic Therapy in First-Line Metastatic Urothelial Carcinoma: Mirage or Oasis in the Platinum Desert? J Clin Oncol 2023; 41:7-10. [PMID: 36343307 PMCID: PMC9788971 DOI: 10.1200/jco.22.01992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/16/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022] Open
Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series was to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.The systemic treatment for metastatic urothelial carcinoma has evolved over the past decade; however, changes in the first-line setting have remained elusive and dependent on platinum-based chemotherapy regimens. Hoimes et al now present an update on the results of cohort A of the EV-103 phase Ib/II trial combining enfortumab vedotin and pembrolizumab in the first-line setting for patients with cisplatin-ineligible metastatic urothelial carcinoma. The efficacy results in this small, phase I cohort demonstrate an impressive response rate with the majority of patients deriving benefit in tumor control. In conjunction with the results from cohort K of EV-103, recently reported at the 2022 ESMO Congress, there is much anticipation regarding this combination as a future standard of care. However, despite this combination not including a traditional cytotoxic chemotherapeutic, it is still associated with potentially life-altering treatment-related toxicity, most notably rash and peripheral neuropathy, along with the risks of immune-related adverse events, which will need to be carefully calibrated for patients.
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Henderson RH, French D, McFerran E, Adams R, Wasan H, Glynne-Jones R, Fisher D, Richman S, Dunne PD, Wilde L, Maughan TS, Sullivan R, Lawler M. Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer. J Cancer Policy 2022; 33:100342. [PMID: 35718327 DOI: 10.1016/j.jcpo.2022.100342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/02/2022] [Accepted: 06/13/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients. METHODS Employing cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC. RESULTS IC reduced costs by £ 35,763 (PSM; p < 0.001) or £ 30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£ 1.2 billion over this cohort's lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic. CONCLUSIONS Our results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic.
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Affiliation(s)
- Raymond H Henderson
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK; Queen's Management School, Queen's University Belfast, UK; Salutem Insights Ltd, Garryduff, Clough, Portlaoise R32 V653, Ireland.
| | - Declan French
- Queen's Management School, Queen's University Belfast, UK
| | - Ethna McFerran
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | | | - Harpreet Wasan
- Oncology Hammersmith Hospital, Imperial College Healthcare Trust & Imperial College, London, UK
| | | | - David Fisher
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, Aviation House, 125 Kingsway, London WC2B 6NH, UK
| | - Susan Richman
- Department of Pathology and Data Analytics, Leeds Institute of Medical Research, St James' University Hospital, Leeds LS9 7TF, UK
| | - Philip D Dunne
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | - Lisa Wilde
- Bowel Cancer UK, Edinburgh House, 170 Kennington Lane, London, UK
| | - Timothy S Maughan
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Richard Sullivan
- Institute of Cancer Policy, School of Cancer Sciences, King's College London, UK
| | - Mark Lawler
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
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8
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Rashad N, Abdulla M, Farouk M, Elkerm Y, Eid Salem S, Yahia M, Saad AS, Abdel Aziz AH, Refaat G, Awad I, ElNaggar M, Kamal K, Refky B, Abdelkhalek M, Touny A, Kassem L, Shash E, Abdelhay AA, Mahmoud BE, Oualla K, Chraiet N, AwadElkarim H Maki H, Kader YA. Resource Oriented Decision Making for Treatment of Metastatic Colorectal Cancer (mCRC) in a Lower-Middle Income Country: Egyptian Foundation of Medical Sciences (EFMS) Consensus Recommendations 2020. Cancer Manag Res 2022; 14:821-842. [PMID: 35250310 PMCID: PMC8896768 DOI: 10.2147/cmar.s340030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/27/2022] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second cause of cancer related mortality. Treatment options for patients with metastatic CRC (mCRC) expanded during the last two decades, with introduction of new chemotherapeutic and targeted agents. Egypt is a lower middle-income country; Egyptian health care system is fragmented with wide diversity in drug availability and reimbursement policies across different health care providing facilities. We report the results of consensus recommendations for treatment of patients with metastatic colorectal cancer developed by Egyptian Foundation of Medical Sciences (EFMS), aiming to harmonize clinical practice through structured expert consensus-based recommendations consistent with the national status. EFMS recommendations could be utilized in other countries with similar economic status. METHODS EFMS recommendations were developed using a modified Delphi process, with three rounds of voting till the final recommendations were approved. A non-systematic review of literature was conducted before generating the provisional statements. Content experts were asked to vote on some recommendations in two different resource groups (restricted resources and non-restricted resources). External review board of experts from a low income and lower-middle countries voted on the applicability of EFMS recommendations in their countries. RESULTS The current recommendations highlighted the discrepancy in health care between restricted and non-restricted resources with expected survival loss and quality of life deterioration. Access to targeted agents in first line is very limited in governmental institutions, and no access to agents approved for third line in patients who failed oxaliplatin and irinotecan containing regimens for patients treated in restricted resource settings. CONCLUSION Management of mCRC in developing countries is a challenge. The currently available resource-stratified guidelines developed by international cancer societies represent a valuable decision-making tool, adaptation to national status in each country based on healthcare system status is required.
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Affiliation(s)
- Noha Rashad
- Medical Oncology Department, Faculty of Medicine, Suez University, Suez, Egypt
| | - Mohamed Abdulla
- Clinical Oncology and Nuclear Medicine Department, Kasr Al-Aini Medical School, Cairo University, Cairo, Egypt
| | - Mohamed Farouk
- Department of Clinical Oncology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Yasser Elkerm
- Department of Cancer Management and Research, Medical Research Institute Hospital, University of Alexandria, Alexandria, Egypt
| | - Salem Eid Salem
- Department of Medical Oncology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Maha Yahia
- Department of Medical Oncology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Amr S Saad
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Hassan Abdel Aziz
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ghada Refaat
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ibrahim Awad
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Maha ElNaggar
- Clinical Oncology Department, Assiut University Hospital, Assiut, Egypt
| | - Khaled Kamal
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Basel Refky
- Department of Surgical Oncology, Oncology Center Mansoura University, Mansoura, Egypt
| | - Mohamed Abdelkhalek
- Department of Surgical Oncology, Oncology Center Mansoura University, Mansoura, Egypt
| | - Ahmed Touny
- Department of Surgical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Loay Kassem
- Clinical Oncology and Nuclear Medicine Department, Kasr Al-Aini Medical School, Cairo University, Cairo, Egypt
| | - Emad Shash
- Department of Medical Oncology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | | | | | - Karima Oualla
- Medical Oncology Department, Hassan II University Hospital Sidi Mohamed Ben Abdellah University, Fes, Morocco
| | - Nesrine Chraiet
- Medical Oncology Department, Salah Azaiez National Cancer Institute, Tunis, Tunisia
| | | | - Yasser Abdel Kader
- Clinical Oncology and Nuclear Medicine Department, Kasr Al-Aini Medical School, Cairo University, Cairo, Egypt
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Wein A, Stoehr R, Kersting S, Siebler J, Merkel S, Busse D, Wolff K, Ostermeier N, Neufert C, Vitali F, Eckstein M, Roth JP, Anhut P, Schreiner W, Uder M, Hartmann A, Neurath MF, Grützmann R. A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results. Oncology 2021; 100:1-11. [PMID: 34670215 DOI: 10.1159/000519252] [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: 07/28/2021] [Accepted: 08/15/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. PATIENTS AND METHODS A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. RESULTS The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. CONCLUSION Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.
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Affiliation(s)
- Axel Wein
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Robert Stoehr
- Department of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Stephan Kersting
- Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Department of Surgery, University of Greifswald, Greifswald, Germany
| | - Jürgen Siebler
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Susanne Merkel
- Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Dagmar Busse
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Kerstin Wolff
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Nicola Ostermeier
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Clemens Neufert
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesco Vitali
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Markus Eckstein
- Department of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Jan-Peter Roth
- Department of Radiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Peter Anhut
- Medical Practice of Oncology, Kronach, Germany
| | - Waldemar Schreiner
- Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Michael Uder
- Department of Radiology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arndt Hartmann
- Department of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Internal Medicine 1, Gastroenterology, Pulmonology, and Endocrinology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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10
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Ezzalfani M, Porcher R, Savignoni A, Delaloge S, Filleron T, Robain M, Pérol D, ESME Group. Addressing the issue of bias in observational studies: Using instrumental variables and a quasi-randomization trial in an ESME research project. PLoS One 2021; 16:e0255017. [PMID: 34525119 PMCID: PMC8443058 DOI: 10.1371/journal.pone.0255017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 07/08/2021] [Indexed: 11/18/2022] Open
Abstract
Purpose Observational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC). Patients and methods Causal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a “superficial” or “pseudo” randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative. Results In the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model. Conclusion Unmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.
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Affiliation(s)
- Monia Ezzalfani
- Department of Biostatistics, Pôle de Biometrie, Institut Curie, Paris, France
- * E-mail:
| | - Raphaël Porcher
- Université de Paris, Centre of Research Epidemiology and Statistics, INSERM U1153, Paris, France
| | - Alexia Savignoni
- Department of Biostatistics, Pôle de Biometrie, Institut Curie, Paris, France
| | - Suzette Delaloge
- Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France
| | | | - Mathieu Robain
- Department of Research and Development, R&D Unicancer, Paris, France
| | - David Pérol
- Department of Biostatistics, DRCI, Centre Leon Berard, Lyon, France
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Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13143504. [PMID: 34298718 PMCID: PMC8304309 DOI: 10.3390/cancers13143504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/05/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022] Open
Abstract
Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68; 95% CI, 1.22-2.32; p = 0.002 and HR,4.89; 95% CI, 3.33-7.19; p < 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.
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12
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Moriwaki T, Gosho M, Sugaya A, Yamada T, Yamamoto Y, Hyodo I. Optimal Maintenance Strategy for First-Line Oxaliplatin-Containing Therapy with or without Bevacizumab in Patients with Metastatic Colorectal Cancer: A Meta-Analysis. Cancer Res Treat 2021; 53:703-713. [PMID: 33285056 PMCID: PMC8291198 DOI: 10.4143/crt.2020.805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/30/2020] [Indexed: 11/21/2022] Open
Abstract
PURPOSE Maintenance therapy after oxaliplatin withdrawal is useful in patients with metastatic colorectal cancer (mCRC). This study aimed to investigate the timing of discontinuation or reintroduction of oxaliplatin and the optimal maintenance therapy regimen for survival. MATERIALS AND METHODS PubMed and conference abstracts were searched to select phase II and III trials of first-line oxaliplatin-containing therapy with or without bevacizumab using maintenance therapy for mCRC. Correlations of median overall survival (OS) with induction therapy regimens, induction therapy duration, maintenance therapy regimens (fluoropyrimidine plus bevacizumab [FP+Bev], FP/Bev alone, and no treatment), and oxaliplatin reintroduction were investigated using correlation and weighted multivariate regression analyses. RESULTS Twenty-two treatment arms were analyzed, including 2,581 patients. The maintenance therapy regimen FP+Bev showed the strongest correlation with a prolonged OS (Spearman's partial correlation coefficient=0.42), and the other three variables correlated weakly with the OS. The maintenance therapy regimen significantly interacted with the induction chemotherapy duration (p=0.019). The predicted OS for FP+Bev crossed the lines of FP/Bev alone at 18 weeks of induction therapy, and of no treatment at 23 weeks. The corresponding OS at 12 and 27 weeks of induction therapies were 28.6 and 24.2 months for FP+Bev, 25.9 and 28.8 months for FP/Bev alone, and 20.5 and 27.5 months for no treatment. CONCLUSION The optimal maintenance therapy regimen for the OS is a continuous induction therapy as long as possible followed by FP/Bev alone and switching to FP+Bev within approximately 4 months if induction therapy is discontinued.
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Affiliation(s)
- Toshikazu Moriwaki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
| | - Masahiko Gosho
- Department of Biostatistics, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
| | - Akinori Sugaya
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
| | - Takeshi Yamada
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
| | - Yoshiyuki Yamamoto
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
| | - Ichinosuke Hyodo
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba,
Japan
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13
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Sun W, Ge Y, Cui J, Yu Y, Liu B. Scutellarin resensitizes oxaliplatin-resistant colorectal cancer cells to oxaliplatin treatment through inhibition of PKM2. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:87-97. [PMID: 33981825 PMCID: PMC8065260 DOI: 10.1016/j.omto.2021.03.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 03/14/2021] [Indexed: 02/07/2023]
Abstract
Although oxaliplatin is an effective chemotherapeutic drug commonly used for colorectal cancer (CRC) treatment, drug resistance usually occurs during the long-term use of it. It is urgent to create strategies to reduce the resistance of CRC cells to oxaliplatin. Oxaliplatin-resistant CRC cells (OR-SW480 and OR-HT29) were acquired through long-term exposure of CRC cells to oxaliplatin. It was found that OR-SW480 and OR-HT29 cells exhibited obvious lower sensitivity and a higher metabolism rate of glucose compared to their parental SW480 and HT29 cells, respectively. However, combination with scutellarin significantly resensitized the OR-SW480 and OR-HT29 cells to oxaliplatin-induced cytotoxicity. Mechanically, overexpression of pyruvate kinase isoenzyme M2 (PKM2) was responsible for the resistance to oxaliplatin in OR-SW480 and OR-HT29. Combination with scutellarin was able to inhibit the PKM2 activity and thus reduced the production of adenosine triphosphate (ATP) to sensitize the oxaliplatin-induced mitochondrial apoptosis pathway in both OR-SW480 and OR-HT29 cells. It was indicated that scutellarin resensitizes oxaliplatin-resistant CRC cells to oxaliplatin treatment through inhibition of PKM2.
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Affiliation(s)
- Wei Sun
- The Sixth Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yang Ge
- The Sixth Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Junpeng Cui
- The Sixth Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yifan Yu
- The Sixth Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Baolin Liu
- The Sixth Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Ishibashi K, Aoyama T, Kotaka M, Satake H, Tsuji Y, Kataoka M, Nakamura M, Nagata N, Sakamoto J, Oba K, Mishima H. Phase II study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study). Cancer Chemother Pharmacol 2021; 87:665-672. [PMID: 33555359 PMCID: PMC8026470 DOI: 10.1007/s00280-021-04232-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/12/2021] [Indexed: 11/12/2022]
Abstract
Background The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. Methods Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. Results A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3–16.0), the median OS was 45.4 months (95% CI 37.4–NA), and the RR was 56.0% (95% CI 42.3–68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). Conclusions First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.
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Affiliation(s)
- Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Toru Aoyama
- Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 2360004, Japan.
| | - Masahito Kotaka
- Department of Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan
| | - Hironaga Satake
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, KKR Tonan Hospital, Sapporo, Japan
| | - Masato Kataoka
- Department of Surgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Masato Nakamura
- Department of Chemotherapy Comprehensive Cancer Center, Aizawa Hospital, Nagano, Japan
| | | | | | - Koji Oba
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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15
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Oxaliplatin retreatment in metastatic colorectal cancer: Systematic review and future research opportunities. Cancer Treat Rev 2020; 91:102112. [PMID: 33091698 DOI: 10.1016/j.ctrv.2020.102112] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/28/2020] [Accepted: 10/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed. METHODS We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials. RESULTS 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6-31%; Disease Control Rate 39-79%; median Progression-Free Survival 3.1-7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5-27%), peripheral neuropathy (5-14%) and hypersensitivity reactions (5-20%). CONCLUSIONS Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway.
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Fernández-Montes A, Grávalos C, Pericay C, Safont MJ, Benavides M, Élez E, García-Alfonso P, García-Paredes B, Carrato A, Aranda E. Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion. Clin Colorectal Cancer 2020; 19:165-177. [PMID: 32507561 DOI: 10.1016/j.clcc.2020.04.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 04/08/2020] [Accepted: 04/13/2020] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.
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Affiliation(s)
- Ana Fernández-Montes
- Medical Oncology, Complejo Hospitalario Universitario de Ourense, Orense, Spain.
| | - Cristina Grávalos
- Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Carles Pericay
- Medical Oncology, Hospital de Sabadell, Corporación Sanitaria Parc Tauli, Sabadell, Barcelona, Spain
| | - Ma José Safont
- Medical Oncology, Hospital General Universitario de Valencia, València, Spain
| | - Manuel Benavides
- Medical Oncology, Hospital Universitario Regional y Virgen de la Victoria, Málaga, Spain
| | - Elena Élez
- Medical Oncology, Hospital Universitari Vall d'Hebron, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | | | - Beatriz García-Paredes
- Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clínico San Carlos (IdISSC). CIBERONC, Madrid, Spain
| | - Alfredo Carrato
- Medical Oncology, Hospital Universitario Ramón y Cajal, Universidad de Alcalá de Henares, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBERONC, Madrid, Spain
| | - Enrique Aranda
- Medical Oncology, Hospital Reina Sofía, University of Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), CIBERONC, Córdoba, Spain
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17
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Hanovich E, Asmis T, Ong M, Stewart D. Rechallenge Strategy in Cancer Therapy. Oncology 2020; 98:669-679. [DOI: 10.1159/000507816] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 04/08/2020] [Indexed: 11/19/2022]
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18
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TRIBE2 results and toxicity. Lancet Oncol 2020; 21:e299. [DOI: 10.1016/s1470-2045(20)30273-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 11/18/2022]
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Evaluation of FOLFOX or CAPOX reintroduction with or without bevacizumab in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy (REACT study). Int J Clin Oncol 2020; 25:1515-1522. [PMID: 32409917 DOI: 10.1007/s10147-020-01701-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/30/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. METHODS Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. CONCLUSION Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.
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Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, Bordonaro R, Latiano TP, Tamburini E, Santini D, Passardi A, Marmorino F, Grande R, Aprile G, Zaniboni A, Murgioni S, Granetto C, Buonadonna A, Moretto R, Corallo S, Cordio S, Antonuzzo L, Tomasello G, Masi G, Ronzoni M, Di Donato S, Carlomagno C, Clavarezza M, Ritorto G, Mambrini A, Roselli M, Cupini S, Mammoliti S, Fenocchio E, Corgna E, Zagonel V, Fontanini G, Ugolini C, Boni L, Falcone A, Falcone A, Lonardi S, De Braud FGM, Bordonaro R, Maiello E, Tamburini E, Santini D, Frassineti GL, Gamucci T, Aprile G, Zaniboni A, Granetto C, Buonadonna A, Di Costanzo F, Tomasello G, Gianni L, Di Donato S, Carlomagno C, Clavarezza M, Racca P, Mambrini A, Roselli M, Allegrini G, Sobrero A, Aglietta M, Corgna E, Cortesi E, Corsi DC, Ballestrero A, Bonetti A, Di Clemente F, Ruggeri E, Ciardiello F, Benasso M, Vitello S, Cinieri S, Mosconi S, Silvestris N, Frassoldati A, Cupini S, Bertolini A, Tortora G, Bengala C, Ferrari D, Ardizzoia A, Milandri C, Chiara S, Romano G, Miraglia S, Scaltriti L, Pucci F, Blasi L, Brugnatelli S, Fioretto L, Ribecco AS, Longarini R, Frisinghelli M, Banzi M. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020; 21:497-507. [DOI: 10.1016/s1470-2045(19)30862-9] [Citation(s) in RCA: 219] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 01/07/2023]
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Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer. Am J Clin Oncol 2019; 42:56-59. [PMID: 29975196 DOI: 10.1097/coc.0000000000000474] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. PATIENTS AND METHODS Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P<0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04). CONCLUSIONS Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness.
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Ornstein MC, Wood LS, Hobbs BP, Allman KD, Martin A, Bevan M, Gilligan TD, Garcia JA, Rini BI. A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy. J Immunother Cancer 2019; 7:127. [PMID: 31097024 PMCID: PMC6524207 DOI: 10.1186/s40425-019-0615-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/08/2019] [Indexed: 12/28/2022] Open
Abstract
Background Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. Methods Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered “feasible” if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. Results Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16–53) off therapy. No patients developed RECIST PD while off therapy. Conclusions This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. Trial registration NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331).
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Affiliation(s)
- Moshe C Ornstein
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA.
| | - Laura S Wood
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Brian P Hobbs
- Quantitative Health Sciences and Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
| | - Kimberly D Allman
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Allison Martin
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Michael Bevan
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Timothy D Gilligan
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Jorge A Garcia
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
| | - Brian I Rini
- Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, CA-60, Cleveland, OH, 44195, USA
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A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study. Invest New Drugs 2019; 38:111-119. [PMID: 30838483 DOI: 10.1007/s10637-019-00749-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 02/18/2019] [Indexed: 12/23/2022]
Abstract
Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.
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Tanioka H, Honda M, Tanaka C, Morita Y, Ishibashi K, Kato T, Matsuda C, Kataoka M, Satake H, Munemoto Y, Kobayashi K, Takahashi M, Nakata K, Sakamoto J, Oba K, Mishima H. Biweekly S-1 plus oxaliplatin (SOX) reintroduction in previously treated metastatic colorectal cancer patients (ORION 2 study): a phase II study to evaluate the efficacy and safety. Int J Clin Oncol 2019; 24:836-841. [DOI: 10.1007/s10147-019-01414-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 02/06/2019] [Indexed: 11/29/2022]
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Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer 2019; 109:70-83. [PMID: 30690295 DOI: 10.1016/j.ejca.2018.12.019] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 12/18/2018] [Indexed: 12/17/2022]
Abstract
Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.
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Affiliation(s)
- D P Modest
- Department of Medicine III, University Hospital, LMU Munich, Germany.
| | - S Pant
- Department of Investigational Cancer Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy
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Sonpavde GP, Mariani L, Lo Vullo S, Raggi D, Giannatempo P, Bamias A, Crabb SJ, Bellmunt J, Yu EY, Niegisch G, Vaishampayan UN, Theodore C, Berthold DR, Srinivas S, Sridhar SS, Plimack ER, Rosenberg JE, Powles T, Galsky MD, Necchi A. Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma. J Urol 2018; 200:1207-1214. [PMID: 30012366 DOI: 10.1016/j.juro.2018.07.035] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. MATERIALS AND METHODS We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. RESULTS Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. CONCLUSIONS Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.
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Affiliation(s)
| | - Luigi Mariani
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Daniele Raggi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | | | | | | | - Evan Y Yu
- University of Washington, Seattle, Washington
| | - Guenter Niegisch
- Department of Urology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | | | | | | | | | | | | | | | - Thomas Powles
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Matthew D Galsky
- Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York
| | - Andrea Necchi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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Besora S, Santos C, Izquierdo C, Martinez-Villacampa MM, Bruna J, Velasco R. Rechallenge with oxaliplatin and peripheral neuropathy in colorectal cancer patients. J Cancer Res Clin Oncol 2018; 144:1793-1801. [PMID: 29955956 DOI: 10.1007/s00432-018-2691-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/18/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Oxaliplatin (OXA) is a cornerstone in the treatment of colorectal cancer (CRC). Retreatment with OXA is frequently considered as salvage treatment. OXA-induced neuropathy (OIN) is the most frequent and feared long-term side effect. PATIENTS AND METHODS CRC patients receiving at least twice OXA-based chemotherapy lines at our institution between June 2000 and July 2016 were reviewed. The aim of this study was to investigate whether retreatment with OXA increases the risk of developing new or worsening previous neuropathy. OIN was assessed by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI), Total Neuropathy Score© (TNS) and nerve-conduction studies. RESULTS 106 patients were included in the analysis. Median age at OXA-based retreatment was 61.5 (20-83) years. After the first OXA-based chemotherapy treatment, 63.4% of patients developed OIN, 30.7 and 8.9% grades 2 and 3, respectively, after a median of 11 (1-17) cycles. After 30 (11-90) months of median to retreatment with a median of 8 (1-14) OXA cycles, 39.6, 22.6, and 0% of patients developed grade 1, 2, and 3 OIN, respectively. Worsening of the previous OIN was observed in one-third (31.1%) of all patients. OXA-cumulative dose was independently associated with greater risk of worsening OIN (p < 0.001). Non-significant trend towards higher TNSc© scores after retreatment was observed [5 (0-11) vs 6 (3-13), p = 0.083]. CONCLUSION Retreatment with OXA in CRC patients is a feasible option even in patients who previously developed moderate or severe OIN. One-third of patients' OIN was worsened by retreatment. Neurological monitoring should be considered.
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Affiliation(s)
- Sarah Besora
- Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge-Institut Català d´Oncologia-IDIBELL, C/Feixa Llarga s/n, L´Hospitalet de Llobregat, 08907, Barcelona, Spain
- Neurology Department, Hospital Universitari Mútua de Terrassa, Terrassa, Barcelona, Spain
| | - Cristina Santos
- Medical Oncology Department, Institut Català d´Oncologia-IDIBELL, CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Izquierdo
- Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge-Institut Català d´Oncologia-IDIBELL, C/Feixa Llarga s/n, L´Hospitalet de Llobregat, 08907, Barcelona, Spain
- Service de Neuro-Oncologie, Hospices Civils de Lyon, Groupe Hospitalier Est, Lyon Cedex, France
| | | | - Jordi Bruna
- Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge-Institut Català d´Oncologia-IDIBELL, C/Feixa Llarga s/n, L´Hospitalet de Llobregat, 08907, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain
| | - Roser Velasco
- Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge-Institut Català d´Oncologia-IDIBELL, C/Feixa Llarga s/n, L´Hospitalet de Llobregat, 08907, Barcelona, Spain.
- Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
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Morano F, Sclafani F. Duration of first-line treatment for metastatic colorectal cancer: Translating the available evidence into general recommendations for routine practice. Crit Rev Oncol Hematol 2018; 131:53-65. [PMID: 30293706 DOI: 10.1016/j.critrevonc.2018.08.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 07/22/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022] Open
Abstract
Over the last two decades the number of front-line regimens for metastatic colorectal cancer has progressively increased. Nevertheless, there is still no consensus on the optimal duration of treatment or the role of de-escalated/maintenance strategies after induction chemotherapy. In this article we provide an overview of the studies that addressed the duration of first-line systemic treatment with cytotoxic agents plus or minus targeted therapies highlighting caveats and limitations of the same. Also, we try to translate the available evidence into practical recommendations that can be used in everyday practice to inform treatment decisions. The main conclusion of our review article is that continuing induction treatment until progression may improve disease control but there is no evidence to suggest that adopting this practice can prolong survival. On the other hand, de-escalated treatment strategies offer an opportunity to reduce the burden of toxicity while maintaining satisfactory oncological outcomes.
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Affiliation(s)
- Federica Morano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Sclafani
- The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
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Schmoll HJ, Arnold D, de Gramont A, Ducreux M, Grothey A, O'Dwyer PJ, Van Cutsem E, Hermann F, Bosanac I, Bendahmane B, Mancao C, Tabernero J. MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach. J Cancer Res Clin Oncol 2018; 144:1197-1204. [PMID: 29644408 DOI: 10.1007/s00432-018-2632-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 03/23/2018] [Indexed: 01/08/2023]
Abstract
PURPOSE The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response. METHODS MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study. RESULTS MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data. CONCLUSIONS The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more 'tailored' approach to the treatment of patients with mCRC.
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Affiliation(s)
- Hans-Joachim Schmoll
- Division of Clinical Oncology Research, University Clinic Halle (Saale), Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Germany.
| | - Dirk Arnold
- Instituto CUF de Oncologia, Lisbon, Portugal
| | | | - Michel Ducreux
- Gustave Roussy, Villejuif, Université Paris Saclay, Paris, France
| | - Axel Grothey
- Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium
| | - Frank Hermann
- Molecular Partners, Zurich (previously F. Hoffmann-La Roche Ltd), Basel, Switzerland
| | | | | | | | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
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Ezzalfani M, Delaloge S, Porcher R, Savignoni A, Courtinard C, Chenuc G, Robain M, Pérol D. Addressing the issue of bias in observational studies : Instrumental variable & Quasi-trial in ESME Research program. Rev Epidemiol Sante Publique 2018. [DOI: 10.1016/j.respe.2018.03.355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Artru P, Bennouna J, Lievre A, Ducreux M, Lledo G. Cancer colorectal métastatique : place du traitement d’entretien et de la pause thérapeutique. Bull Cancer 2018; 105:408-414. [DOI: 10.1016/j.bulcan.2017.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 12/17/2017] [Accepted: 12/26/2017] [Indexed: 01/16/2023]
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Affiliation(s)
| | - S Vansteelandt
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Gent, Belgium
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Cho M, Gong J, Frankel P, Synold TW, Lim D, Chung V, Chao J, Li D, Chen Y, Sentovich S, Melstrom K, Singh G, Luevanos E, Fakih M. A phase I clinical trial of binimetinib in combination with FOLFOX in patients with advanced metastatic colorectal cancer who failed prior standard therapy. Oncotarget 2017; 8:79750-79760. [PMID: 29108355 PMCID: PMC5668088 DOI: 10.18632/oncotarget.19336] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 06/30/2017] [Indexed: 12/20/2022] Open
Abstract
Background This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. Materials and Methods Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment. Pharmacokinetic (PK) analysis of 5-FU and oxaliplatin was performed at the MTD in an expanded 6 patient cohort. Results Twenty-six patients were enrolled and assessed for safety. In the dose-escalation phase, no DLTs were noted in all binimetinib dosing schedules and the MTD of binimetinib in with FOLFOX was 45 mg orally twice daily. There were no significant differences in the PKs of 5-FU or oxaliplatin with or without binimetinib. Continuous dosing of binimetinib produced SD at 2 months in 9 of 13 evaluable patients and a median PFS of 3.5 months. Nine of 10 patients had PD at 2 months on the intermittent arm. Conclusions Oral binimetinib and FOLFOX has a manageable toxicity profile and showed some evidence of antitumor activity in heavily pretreated mCRC patients.
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Affiliation(s)
- May Cho
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Jun Gong
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Paul Frankel
- Department of Statistics, City of Hope National Medical Center, Duarte, CA, USA
| | - Timothy W Synold
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Dean Lim
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Vincent Chung
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Joseph Chao
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Daneng Li
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Yuan Chen
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte,CA, USA
| | - Stephen Sentovich
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Kurt Melstrom
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Gagandeep Singh
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Eloise Luevanos
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
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Ornstein MC, Wood LS, Elson P, Allman KD, Beach J, Martin A, Zanick BR, Grivas P, Gilligan T, Garcia JA, Rini BI. A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2017; 35:1764-1769. [DOI: 10.1200/jco.2016.71.1184] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, −2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.
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Affiliation(s)
- Moshe C. Ornstein
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Laura S. Wood
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Paul Elson
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | | | - Jennifer Beach
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Allison Martin
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Beth R. Zanick
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Petros Grivas
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Tim Gilligan
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Jorge A. Garcia
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Brian I. Rini
- All authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
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Costa T, Nuñez J, Felismino T, Boente L, Mello C. REOX: Evaluation of the Efficacy of Retreatment With an Oxaliplatin-containing Regimen in Metastatic Colorectal Cancer: A Retrospective Single-center Study. Clin Colorectal Cancer 2017; 16:316-323. [PMID: 28392022 DOI: 10.1016/j.clcc.2017.03.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 02/20/2017] [Accepted: 03/01/2017] [Indexed: 11/15/2022]
Abstract
BACKGROUND Treatment of metastatic colorectal adenocarcinoma (mCRC) has evolved, and survival is over 30 months in contemporary trials. Nevertheless, there is a paucity of effective regimes after the first or second-line treatment. Thus, reexposure to previously used drugs has become a treatment strategy for some patients. We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features. PATIENTS AND METHODS We retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin (REOX). REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF). RESULTS The median age was 53.5 years, and the female/male ratio was 51.8%/48.2%. The site of the primary tumor was colon (67.5%) and rectal (32.5%). KRAS was mutated in 39.8%. Liver-limited metastasis was found in 19.3% of patients. The main regimen was 5-fluorouracil, levoleucovorin, and oxaliplatin (mFOLFOX6) (84.3%). Bevacizumab and cetuximab were used in 42.2% and 6% of patients, respectively. REOX was used in the third and fourth lines in 48.2% and 25.3% of patients, respectively. The median TTF after REOX was 6.04 months. Overall survival (OS) was 10.04 months. Disease control (complete response + partial response + stable disease) was observed in 56.6%, whereas 42.2% had progressive disease. Partial response + complete response to previous oxaliplatin was predictive of prolonged OS. Patients who attained disease control had better median OS compared with those with progressive disease (14.5 vs. 6.24 months; P < .0001). CONCLUSION In the setting of heavily pretreated patients with mCRC, REOX was an effective treatment, with mTTF of 6.04 months in our cohort. Selection of patients with the longest time since previous oxaliplatin can translate in better outcome. Further studies should be conducted to confirm our data.
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Affiliation(s)
- Talita Costa
- Department of Medical Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Jose Nuñez
- Department of Medical Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Tiago Felismino
- Department of Medical Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Leonardo Boente
- Department of Medical Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | - Celso Mello
- Department of Medical Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil.
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Parseghian CM, Parikh NU, Wu JY, Jiang ZQ, Henderson L, Tian F, Pastor B, Ychou M, Raghav K, Dasari A, Fogelman DR, Katsiampoura AD, Menter DG, Wolff RA, Eng C, Overman MJ, Thierry AR, Gallick GE, Kopetz S. Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer. Clin Cancer Res 2017; 23:4146-4154. [PMID: 28280091 DOI: 10.1158/1078-0432.ccr-16-3138] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/10/2017] [Accepted: 03/07/2017] [Indexed: 12/28/2022]
Abstract
Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab.Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort.Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies.Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146-54. ©2017 AACR.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Nila U Parikh
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ji Yuan Wu
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhi-Qin Jiang
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Laura Henderson
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Feng Tian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Brice Pastor
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Marc Ychou
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David R Fogelman
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anastasia D Katsiampoura
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alain R Thierry
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
| | - Gary E Gallick
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Sunakawa Y, Bekaii-Saab T, Stintzing S. Reconsidering the benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer. Cancer Treat Rev 2016; 45:97-104. [PMID: 27002945 DOI: 10.1016/j.ctrv.2016.03.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 03/07/2016] [Accepted: 03/08/2016] [Indexed: 12/22/2022]
Abstract
Colorectal cancer is one of the most frequent solid tumors in the western world, with low survival rates in patients with metastatic disease. Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first-line chemotherapy in the metastatic setting. The conventional treatment as a first-line approach is continuous application until progression or intolerable toxicities. However, only one third of patients are treated until progression mainly due to the side effects of chemotherapy. Notably, oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy, which is the main reason for treatment discontinuation or treatment de-escalation. On this basis, recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting, together with various strategies to optimize maintenance therapy including regimens with targeted therapies, such as cetuximab, ziv-aflibercept and regorafenib. Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient, tumor and treatment characteristics, as well as molecular biomarkers. This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer, and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies.
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Affiliation(s)
- Y Sunakawa
- Division of Medical Oncology, Showa University Northern Yokohama Hospital, 35-1, Chigasaki-Chuo Tsuzuki-ku, Yokohama, Kanagawa 224-8503, Japan
| | - T Bekaii-Saab
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - S Stintzing
- Department of Hematology and Oncology, Klinikum der Universität München Ludwig-Maximilians-Universität (LMU), Munich, Germany.
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Drott J, Starkhammar H, Kjellgren K, Berterö C. The trajectory of neurotoxic side effects’ impact on daily life: a qualitative study. Support Care Cancer 2016; 24:3455-61. [PMID: 26992409 DOI: 10.1007/s00520-016-3179-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 03/11/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Jenny Drott
- Division of Nursing and Department of Medical and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
| | - Hans Starkhammar
- Regional Cancer Centre, South-East Sweden, Linköping University, Linköping, Sweden
| | - Karin Kjellgren
- Division of Nursing and Department of Medical and Health Sciences, Linköping University, 581 85, Linköping, Sweden
| | - Carina Berterö
- Division of Nursing and Department of Medical and Health Sciences, Linköping University, 581 85, Linköping, Sweden
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Hamamoto Y, Mizusawa J, Katayama H, Nakamura K, Kato K, Tsubosa Y, Ishikura S, Igaki H, Shinoda M, Fukuda H, Kitagawa Y, Ando N. Inter-institutional survival heterogeneity in chemoradiation therapy for esophageal cancer: exploratory analysis of the JCOG0303 study. Jpn J Clin Oncol 2016; 46:389-92. [PMID: 26830150 DOI: 10.1093/jjco/hyv211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 12/21/2015] [Indexed: 11/12/2022] Open
Abstract
It is important to examine variation in the treatment effects of patients with esophageal cancer in order to generalize treatment outcomes. We aimed to investigate the range of prognostic differences among hospitals in the treatment of locally advanced esophageal cancer. The JCOG0303 study compared the efficacy of radiotherapy plus low-dose cisplatin and 5-fluorouracil with that of high-dose cisplatin and 5-fluorouracil for unresectable esophageal cancer. Of 32 institutions participating in the JCOG0303 study, the 18 institutions that enrolled three or more patients were included in this study. We predicted the 1-year survival in each institution by using a mixed-effect model. We found that the predicted 1-year survival in the 18 institutions with three or more patients was a median of 60.9%, with a range of 60.9-60.9%. This study is the first to investigated heterogeneity of survival in patients who received definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.
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Affiliation(s)
- Yasuo Hamamoto
- Cancer Center, Keio University School of Medicine, Tokyo
| | - Junki Mizusawa
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center, Tokyo
| | - Hiroshi Katayama
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center, Tokyo
| | - Kenichi Nakamura
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center, Tokyo
| | - Ken Kato
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo
| | - Yasuhiro Tsubosa
- Esophageal Surgical Division, Shizuoka Cancer Center, Shunto-gun
| | - Satoshi Ishikura
- Department of Radiology, Koshigaya Municipal Hospital, Koshigaya
| | - Hiroyasu Igaki
- Esophageal Surgical Division, National Cancer Center Hospital, Tokyo
| | | | - Haruhiko Fukuda
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center, Tokyo
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo
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Pereira AAL, Rego JFDM, Munhoz RR, Hoff PM, Sasse AD, Riechelmann RP. The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first-line setting: A meta-analysis of randomized trials. Acta Oncol 2015; 54:1737-46. [PMID: 25984931 DOI: 10.3109/0284186x.2015.1044022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The impact of the duration of chemotherapy on the overall survival of patients with metastatic colorectal cancer (mCRC) is controversial and studies have failed to define a clear standard. METHODS We searched medical literature databases and oncology conferences proceedings for randomized controlled trials (RCT) that compared the overall survival of mCRC patients who received continuous first-line chemotherapy until disease progression versus those who were offered complete treatment stop after a fixed number of cycles. Studies including targeted agents were also included. A meta-analysis of reported hazard ratios (HRs) for survival was performed. RESULTS We retrieved 240 trials, of which six were eligible and five were included in the pooled analysis of overall survival (N = 3061). The overall survival between continuously delivered chemotherapy and complete stop was not statistically different (HR = 0.93, 95% CI 0.85-1.02; p = 0.12; I² = 5%). The results are similar when we analyzed separately the trials performing randomization before versus after induction therapy. The median chemotherapy free interval in the complete stop group was 3.9 months (3.6-4.3 months). Chemotherapy administered until progression was associated with more adverse effects and impaired quality of life. CONCLUSION Compared with first-line continuous chemotherapy administered until disease progression, complete treatment stop did not have a detrimental impact on the overall survival of patients with mCRC. Identification of predictive biomarkers could help clinicians to select the patients who would benefit from continuous cancer-directed therapies.
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Affiliation(s)
| | | | - Rodrigo Ramela Munhoz
- a Department of Radiology and Oncology , Instituto do Cancer do Estado de Sao Paulo , Sao Paulo , Brazil
| | - Paulo Marcelo Hoff
- a Department of Radiology and Oncology , Instituto do Cancer do Estado de Sao Paulo , Sao Paulo , Brazil
| | | | - Rachel P Riechelmann
- a Department of Radiology and Oncology , Instituto do Cancer do Estado de Sao Paulo , Sao Paulo , Brazil
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Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol 2015; 16:1493-1505. [PMID: 26474518 DOI: 10.1016/s1470-2045(15)00216-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 07/21/2015] [Accepted: 08/03/2015] [Indexed: 01/12/2023]
Abstract
BACKGROUND The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING GERCOR and F Hoffmann-La Roche.
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Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer—biweekly versus standard triweekly XELOX (The ORION Study). Int J Clin Oncol 2015; 21:566-72. [DOI: 10.1007/s10147-015-0911-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 09/28/2015] [Indexed: 12/01/2022]
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Blakely T, Collinson L, Kvizhinadze G, Nair N, Foster R, Dennett E, Sarfati D. Cancer care coordinators in stage III colon cancer: a cost-utility analysis. BMC Health Serv Res 2015; 15:306. [PMID: 26238996 PMCID: PMC4523949 DOI: 10.1186/s12913-015-0970-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 07/24/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND There is momentum internationally to improve coordination of complex care pathways. Robust evaluations of such interventions are scarce. This paper evaluates the cost-utility of cancer care coordinators for stage III colon cancer patients, who generally require surgery followed by chemotherapy. METHODS We compared a hospital-based nurse cancer care coordinator (CCC) with 'business-as-usual' (no dedicated coordination service) in stage III colon cancer patients in New Zealand. A discrete event microsimulation model was constructed to estimate quality-adjusted life-years (QALYs) and costs from a health system perspective. We used New Zealand data on colon cancer incidence, survival, and mortality as baseline input parameters for the model. We specified intervention input parameters using available literature and expert estimates. For example, that a CCC would improve the coverage of chemotherapy by 33% (ranging from 9 to 65%), reduce the time to surgery by 20% (3 to 48%), reduce the time to chemotherapy by 20% (3 to 48%), and reduce patient anxiety (reduction in disability weight of 33%, ranging from 0 to 55%). RESULTS Much of the direct cost of a nurse CCC was balanced by savings in business-as-usual care coordination. Much of the health gain was through increased coverage of chemotherapy with a CCC (especially older patients), and reduced time to chemotherapy. Compared to 'business-as-usual', the cost per QALY of the CCC programme was $NZ 18,900 (≈ $US 15,600; 95% UI: $NZ 13,400 to 24,600). By age, the CCC intervention was more cost-effective for colon cancer patients < 65 years ($NZ 9,400 per QALY). By ethnicity, the health gains were larger for Māori, but so too were the costs, meaning the cost-effectiveness was roughly comparable between ethnic groups. CONCLUSIONS Such a nurse-led CCC intervention in New Zealand has acceptable cost-effectiveness for stage III colon cancer, meaning it probably merits funding. Each CCC programme will differ in its likely health gains and costs, making generalisation from this evaluation to other CCC interventions difficult. However, this evaluation suggests that CCC interventions that increase coverage of, and reduce time to, effective treatments may be cost-effective.
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Affiliation(s)
- Tony Blakely
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Lucie Collinson
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Giorgi Kvizhinadze
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Nisha Nair
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Rachel Foster
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Elizabeth Dennett
- Department of Surgery, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
| | - Diana Sarfati
- Burden of Disease Epidemiology, Equity, and Cost-Effectiveness (BODE3) Programme, Department of Public Health, University of Otago Wellington, PO Box 7343, Wellington, New Zealand.
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Abstract
The response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC), for three main reasons: effective upfront therapy provides a unique opportunity to cure some patients; can be crucial in delaying disease progression and achieving symptom relief; and can improve patient eligibility for, and the effectiveness of, further treatments. In the past decade, decision-making regarding the choice of first-line therapy for mCRC has been complicated by the availability of many different options without a definitive consensus on a specific standard of care (despite major advances in categorizing predictive molecular disease subtypes). Most of the efforts of the scientific community have been directed at establishing the best biologic agent to be combined with a chemotherapy doublet, although a different branch of research has produced new data that underscore the importance of defining the optimal chemotherapy backbone. Herein, we review the key clinical trials completed in the past 10 years that have investigated and compared the use of chemotherapy doublets, triplets, and monotherapies, with or without molecularly targeted biologic agents, in the first-line treatment of patients with mCRC. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for mCRC.
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Papadimitriou K, Rolfo C, Dewaele E, Van De Wiel M, Van den Brande J, Altintas S, Huizing M, Specenier P, Peeters M. Incorporating anti-VEGF pathway therapy as a continuum of care in metastatic colorectal cancer. Curr Treat Options Oncol 2015; 16:18. [PMID: 25813037 DOI: 10.1007/s11864-015-0333-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metastatic cancer was previously treated with distinctive lines of chemotherapy regimens upon disease progression or toxicity, yet the choices of therapy are actually interrelated, with the selection of a first-line regimen in part determining the choices available for subsequent treatment. Lately the therapeutic approach based on separate lines of treatment, tends to be replaced from a perspective strategical approach, that of the "continuum of care". This strategy targets to an improved overall survival, improved of quality of life and minimization of toxicity through upfront design of treatment selection and sequencing, exposure to all available drugs and minimization of unnecessary treatment. Anti-VEGF treatment has a well-documented role in this approach. Bevacizumab should be included in upfront treatment regimens for all mCRC patients independently of RAS status, unless contraindicated. Upfront bevacizumab could be combined with all available regimens since the optimal choice of backbone chemotherapy is yet to be defined. In RAS wild-type population, when metastasectomy is the target, an anti-EGFR combination is also a valid approach. Maintenance with bevacizumab and fluoropyrimidines should be considered upon intolerance of induction treatment and/or disease stabilization; maintenance with bevacizumab monotherapy should be avoided. In highly selected patients, complete treatment cessation could be also an option. Continuation with bevacizumab upon first progression and switch of the "backbone" chemotherapy is a validated approach. Patients progressing after first-line oxaliplatin regimen including bevacizumab combinations could be treated with an aflibercept-irinotecan combination. When no more options are available, regorafenib monotherapy should be the following choice. Combinations of anti-VEGF and anti-EGFR treatment have no place in this approach and are not indicated.
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Chibaudel B, Bonnetain F, Tournigand C, de Larauze MH, de Gramont A, Laurent-Puig P, Paget J, Hadengue A, Notelet D, Benetkiewicz M, André T, de Gramont A. STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer. BMC Cancer 2015; 15:496. [PMID: 26141683 PMCID: PMC4490616 DOI: 10.1186/s12885-015-1503-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 06/19/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.
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Affiliation(s)
- Benoist Chibaudel
- Division of Medical Oncology, Institut Hospitalier Franco-Britannique, 4, rue Kleber, 92300, Levallois-Perret, France.
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
| | - Franck Bonnetain
- Methodology and quality of life in oncology unit (EA 3181) & Quality of life and cancer clinical research platform, Hospital Saint-Jacques, 2 place Saint Jacques, 25000, Besançon, France.
| | - Christophe Tournigand
- Division of Medical Oncology, Hospital Henri-Mondor, Assistance Publique des Hôpitaux de Paris, Université Paris Est Créteil, Paris 12, 51 Avenue du Maréchal de Lattre de Tassigny, 94010, Créteil, France.
| | - Marine Hug de Larauze
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
| | - Armand de Gramont
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
- New drug Evaluation Laboratory, Centre of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
| | - Pierre Laurent-Puig
- INSERM U 775 - Faculté des Sciences Fondamentales et Biomédicales, Centre Universitaire des Saints-Pères, 45 Rue des Saints-Pères, 75006, Paris, France.
| | - Jérôme Paget
- LINCOLN, 4 rue Danjou, 92517 Cedex, Boulogne Billancourt, France.
| | - Alexandra Hadengue
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
| | - Dominique Notelet
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
| | - Magdalena Benetkiewicz
- GERCOR-IRC (Groupe Coopérateur Multidisciplinaire en Oncologie-Innovative Research Consortium), 151, rue du Faubourg Saint-Antoine, 75011, Paris, France.
| | - Thierry André
- Division of Medical Oncology, Hospital Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Université Pierre et Marie Curie (UPMC), Paris VI, 184, rue du Faubourg Saint-Antoine,, 75571 Cedex 12, Paris, France.
| | - Aimery de Gramont
- Division of Medical Oncology, Institut Hospitalier Franco-Britannique, 4, rue Kleber, 92300, Levallois-Perret, France.
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Suenaga M, Mizunuma N, Matsusaka S, Shinozaki E, Ozaka M, Ogura M, Yamaguchi T. Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:3099-108. [PMID: 26124634 PMCID: PMC4476424 DOI: 10.2147/dddt.s85567] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths. Conclusion Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior oxaliplatin-based therapy.
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Affiliation(s)
- Mitsukuni Suenaga
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Nobuyuki Mizunuma
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Matsusaka
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Eiji Shinozaki
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masato Ozaka
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mariko Ogura
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshiharu Yamaguchi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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Oronsky BT, Oronsky AL, Lybeck M, Oronsky NC, Scicinski JJ, Carter C, Day RM, Rodriguez Orengo JF, Rodriguez-Torres M, Fanger GF, Reid TR. Episensitization: Defying Time's Arrow. Front Oncol 2015; 5:134. [PMID: 26125013 PMCID: PMC4464068 DOI: 10.3389/fonc.2015.00134] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 05/27/2015] [Indexed: 12/17/2022] Open
Abstract
The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of “episensitization,” or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001.
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Affiliation(s)
| | | | | | | | | | - Corey Carter
- Walter Reed National Military Medical Center, National Cancer Institute , Bethesda, MD , USA
| | - Regina M Day
- Uniformed Services University of the Health Sciences , Bethesda, MD , USA
| | | | | | | | - Tony R Reid
- Moores Cancer Center, University of California San Diego , La Jolla, CA , USA
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Okayama T, Ishikawa T, Sugatani K, Yoshida N, Kokura S, Matsuda K, Tsukamoto S, Ihara N, Kuriu Y, Nakanishi M, Nakamura T, Kamada K, Katada K, Uchiyama K, Takagi T, Handa O, Konishi H, Yagi N, Naito Y, Otsuji E, Hosoi H, Miki T, Itoh Y. Hypersensitivity Reactions to Oxaliplatin: Identifying the Risk Factors and Judging the Efficacy of a Desensitization Protocol. Clin Ther 2015; 37:1259-1269. [PMID: 25862137 DOI: 10.1016/j.clinthera.2015.03.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/09/2015] [Accepted: 03/09/2015] [Indexed: 11/26/2022]
Abstract
PURPOSE We examined the clinical data of patients treated with oxaliplatin to determine the risk factors of oxaliplatin-related hypersensitivity reaction (HSR). In addition, we evaluated the efficacy of rechallenging patients with HSRs with oxaliplatin using prophylactic agents or desensitization procedures. METHODS This study consisted of 162 patients with colorectal cancer (88 men and 74 women) who were treated consecutively at the outpatient chemotherapy department at University Hospital, Kyoto Prefectural University of Medicine. Patients underwent chemotherapy, including oxaliplatin, between March 2006 and June 2012. We analyzed the patients' clinical backgrounds (eg, age, sex, performance status, disease stage, and allergic history) to uncover any connections to the development of HSR to oxaliplatin. In addition, we rechallenged 10 patients who had oxaliplatin-related HSR using prophylactic agents or desensitization procedures. FINDINGS Of 162 patients, 28 (17.2%) developed oxaliplatin-related HSRs (16, 2, 9 and 1 patient had grade 1, 2, 3, and 4 HSRs, respectively). The total cumulative dose of oxaliplatin at the onset of the HSR was 301 to 1126 mg/m(2) (median, 582 mg/m(2)), and the first reactions developed in these patients after 5 to 17 infusions of oxaliplatin (median, 8 infusions). Logistic regression analysis indicated that sex (male: odds ratio = 3.624; 95% CI, 1.181-11.122; P = 0.024) and eosinophil count in peripheral blood (odds ratio = 35.118; 95% CI, 1.058-1166.007; P = 0.046) were independent variables for oxaliplatin-related HSRs. Rechallenging patients with prophylactic agents was successful in 2 (28.6%) of 7 patients who successfully completed their treatment. On the other hand, all 3 patients rechallenged with oxaliplatin using a desensitization protocol successfully completed their treatment without new HSRs. IMPLICATIONS In this retrospective study, we observed that being male and having higher counts of peripheral eosinophil could be predictors for HSR to oxaliplatin. In addition, this study confirms that oxaliplatin desensitization protocol allows patients who developed HSRs to continue with their treatment. However, the optimum desensitization protocol for oxaliplatin administration in terms of tolerability and efficacy needs to be defined.
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Affiliation(s)
- Tetsuya Okayama
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Cancer ImmunoCell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Ishikawa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Cancer ImmunoCell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Kazuko Sugatani
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan
| | - Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan
| | - Satoshi Kokura
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Cancer ImmunoCell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kiyomi Matsuda
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan
| | - Shigeru Tsukamoto
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan
| | - Norihiko Ihara
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan
| | - Yoshiaki Kuriu
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masayoshi Nakanishi
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Terukazu Nakamura
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan; Department of Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiro Kamada
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiro Katada
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohisa Takagi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Osamu Handa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideyuki Konishi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Nobuaki Yagi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eigo Otsuji
- Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hajime Hosoi
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan; Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tsuneharu Miki
- Medical Oncology, Kyoto Prefectural University Hospital, Kyoto, Japan; Department of Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Nakayama N, Sato A, Tanaka S, Shimada K, Konishi K, Sasaki E, Hibi K, Ichikawa H, Kikuchi Y, Sakuyama T, Sekikawa T, Hayashi K, Nishina H. A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study. Invest New Drugs 2015; 33:954-62. [PMID: 25937430 DOI: 10.1007/s10637-015-0239-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 03/31/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.
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Affiliation(s)
- Norisuke Nakayama
- Department of Gastroenterology, Kanagawa Cancer Center Hospital, 2-3-2,Nakao, Asahi-ku, Yokohama City, 241-8515, Japan,
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