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Garrido Martínez MT, Rodríguez Jorge M, García Giménez I, Guzmán Ramos MI, Grutzmancher Sáiz S, Aviñó Tarazona V. Toxicity of the FOLFOX-6 regimen, with or without 5-fluorouracil bolus, in metastatic colorectal cancer. FARMACIA HOSPITALARIA 2025; 49:154-159. [PMID: 39482145 DOI: 10.1016/j.farma.2024.09.008] [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: 06/18/2024] [Revised: 08/08/2024] [Accepted: 09/22/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Standard treatment of metastatic colorectal cancer includes oxaliplatin and 5-fluorouracil in continuous infusion. Although FOLFOX-6 is the reference combination, it is aggressive and has high toxicity. Variants such as the TTD regimen, which does not include folinic acid or 5-fluorouracil bolus, are used. This study evaluates the toxicity of FOLFOX-6 and TTD in first line treatment for metastatic colorectal cancer and its effectiveness. METHOD Retrospective observational study with patients who started treatment with FOLFOX-6 and TTD, for three years. Demographic and clinical data were collected (age, sex, chronic pathologies, molecular profile, laterality, ECOG classification and stage), as well as treatment variables (previous adjuvant chemotherapy, intentionality, number of cycles, duration and pharmacogenetic aspects) and toxicity. Objective response rate and progression-free survival were calculated. RESULTS The study included 71 patients, 35 treated with FOLFOX-6 and 36 with TTD. Both groups showed similar overall toxicity profiles. FOLFOX-6 had a higher incidence of neutropenia (46% vs. 8%; p < 0.01) and mucositis (51% vs. 22%; p < 0.013). In addition, there were more treatment delays (40% vs. 11%; p < 0.05) and 5-fluorouracil dose reductions (22% vs. 14%; p < 0.05) in the FOLFOX-6 group. Deaths due to toxicity were only recorded in the FOLFOX-6 group. Effectiveness was similar in both groups. CONCLUSIONS The TTD regimen could be a beneficial first-line option for metastatic colorectal cancer, with lower toxicity and effectiveness comparable to FOLFOX-6. It is a safe alternative for elderly or frail patients, suitable for reduced-dose 5-fluorouracil regimen with oxaliplatin.
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Affiliation(s)
| | - María Rodríguez Jorge
- Servicio de Farmacia Hospitalaria, Hospital Universitario Juan Ramón Jiménez, Huelva, España.
| | - Ignacio García Giménez
- Servicio de Farmacia Hospitalaria, Hospital Universitario Juan Ramón Jiménez, Huelva, España
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Odin E, Carlsson G, Saksena P, Edsjö A, Di Cara A, Tell R, Gustavsson B, Wettergren Y. Folate-Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression-Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5-FU/Leucovorin-Based Combination Chemotherapy. Cancer Med 2025; 14:e70895. [PMID: 40357991 PMCID: PMC12070377 DOI: 10.1002/cam4.70895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 03/21/2025] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND 5-Fluorouracil (5-FU) and the Folate Leucovorin (LV) form the chemotherapy backbone for metastatic colorectal cancer (mCRC). Tumoral expression of specific folate-associated genes is associated with the risk of recurrence in stage III CRC following adjuvant 5-FU/LV (FLV)-based combination chemotherapy according to the Nordic bolus regimen. The aim was to evaluate whether expression of folate-associated genes in Pre-therapeutic tumor samples is associated with outcomes of patients with mCRC undergoing palliative FLV-based combination chemotherapy. PATIENTS AND METHODS Patients treated with FLV (n = 113), FLV + oxaliplatin (FLOX, n = 102), or FLV + irinotecan (FLIRI, n = 75) were included. ABCC3, RFC-1, PCFT, MFT, MTHFD2, and TYMS expression was determined by qPCR and related to tumor response and 3-year progression-free survival (PFS). Analyses were conducted on the entire cohort and on subgroups (group 1: stage I-III; group 2: stage IV, at primary surgery). Multivariate Cox proportional hazard models were applied to assess associations between covariates and PFS. RESULTS Low TYMS and high MFT expression in group 1, and high ABCC3 expression in group 2 correlated with better PFS (HR 1.37 (1.04-1.82), HR 0.49 (0.30-0.80), and HR 0.74 (0.60-0.93)), respectively. In addition, high MFT expression was associated with better PFS of patients treated with FLIRI (HR 0.47 (0.27-0.81), p = 0.007) whereas high expression of ABCC3 was associated with better PFS of patients treated with FLOX (HR 0.46 (0.23-0.92), p = 0.029). CONCLUSION While pretherapeutic tumoral expression of specific folate-associated genes may not serve as a universal predictive marker for FLV-based treatment, it might predict response and outcomes in patients receiving FLOX or FLIRI. Evaluating the impact of gene expression in primary tumors should consider subgrouping of patients by disease stage at diagnosis as well as the applied chemotherapy regimen. Prospective clinical studies on patients with mCRC are warranted to validate these findings.
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Affiliation(s)
- Elisabeth Odin
- Department of Surgery, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Göran Carlsson
- Department of Surgery, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
- Department of SurgerySahlgrenska University Hospital, Region Västra GötalandGothenburgSweden
| | - Pushpa Saksena
- Department of PathologySahlgrenska University HospitalGothenburgSweden
| | - Anders Edsjö
- Department of Clinical Genetics, Pathology, and Molecular DiagnosticsOffice for Medical Services, Region SkåneLundSweden
- Division of Pathology, Department of Clinical SciencesLund UniversityLundSweden
| | | | | | - Bengt Gustavsson
- Department of Surgery, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
- Department of SurgerySahlgrenska University Hospital, Region Västra GötalandGothenburgSweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
- Department of SurgerySahlgrenska University Hospital, Region Västra GötalandGothenburgSweden
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Garrido Martínez MT, Rodríguez Jorge M, García Giménez I, Guzmán Ramos MI, Grutzmancher Sáiz S, Aviñó Tarazona V. [Translated article] Toxicity of the FOLFOX-6 regimen, with or without 5-fluorouracil bolus, in metastatic colorectal cancer. FARMACIA HOSPITALARIA 2025; 49:T154-T159. [PMID: 39875275 DOI: 10.1016/j.farma.2024.12.006] [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: 06/18/2024] [Revised: 08/08/2024] [Accepted: 09/22/2024] [Indexed: 01/30/2025] Open
Abstract
OBJECTIVE Standard treatment of metastatic colorectal cancer includes oxaliplatin and 5-fluorouracil in continuous infusion. Although FOLFOX-6 is the reference combination, it is aggressive and has high toxicity. Variants such as the TTD regimen, which does not include folinic acid or 5-fluorouracil bolus, are used. This study evaluates the toxicity of FOLFOX-6 and TTD in first line treatment for metastatic colorectal cancer and its effectiveness. METHOD Retrospective observational study with patients who started treatment with FOLFOX-6 and TTD, for 3 years. Demographic and clinical data were collected (age, sex, chronic pathologies, molecular profile, laterality, Eastern Cooperative Oncology Group classification, and stage), as well as treatment variables (previous adjuvant chemotherapy, intentionality, number of cycles, duration, and pharmacogenetic aspects) and toxicity. Objective response rate and progression-free survival were calculated. RESULTS The study included 71 patients, 35 treated with FOLFOX-6, and 36 with TTD. Both groups showed similar overall toxicity profiles. FOLFOX-6 had a higher incidence of neutropenia (46% vs 8%; P < .01) and mucositis (51% vs 22%; P < .013). In addition, there were more treatment delays (40% vs 11%; P < .05) and 5-fluorouracil dose reductions (22% vs 14%; P < .05) in the FOLFOX-6 group. Deaths due to toxicity were only recorded in the FOLFOX-6 group. Effectiveness was similar in both groups. CONCLUSIONS The TTD regimen could be a beneficial first-line option for metastatic colorectal cancer, with lower toxicity and effectiveness comparable to FOLFOX-6. It is a safe alternative for elderly or frail patients, suitable for reduced-dose 5-fluorouracil regimen with oxaliplatin.
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Affiliation(s)
| | - María Rodríguez Jorge
- Servicio de Farmacia Hospitalaria, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain
| | - Ignacio García Giménez
- Servicio de Farmacia Hospitalaria, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain
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Shamay Y. Mastering the complexities of cancer nanomedicine with text mining, AI and automation. J Control Release 2025; 379:906-919. [PMID: 39848590 DOI: 10.1016/j.jconrel.2025.01.057] [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: 10/30/2024] [Revised: 01/02/2025] [Accepted: 01/20/2025] [Indexed: 01/25/2025]
Abstract
In this contribution to the Orations - New Horizons of the Journal of Controlled Release, I present a personal perspective on the complexities of cancer nanomedicine and the approaches to master them. This oration draws mainly from my lab's journey to explore three transformative approaches to master complexities in the field: (1) leveraging text mining to construct dynamic knowledge bases for hypothesis generation in cell-specific drug delivery, (2) introducing the concept of meta-synergy to further optimize and classify multi-drug combinations across dimensions such as chemical loading, pharmacodynamics, and pharmacokinetics (3) utilizing automation to accelerate nanoparticle discovery with advanced screening methodologies such as aggregation-induced emission (AIE). I argue that by embracing complexity in nanomedicine, we can manifest new therapeutic possibilities, paving the way for more effective, precise, and adaptive treatment strategies.
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Affiliation(s)
- Yosi Shamay
- Faculty of Biomedical Engineering, Technion - Israel Institute of Technology, Haifa, Israel.
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Venkatesan G, Yong Ping C, Chen H, Srinivasan P, Karkhanis AV, Pastorin G. Design, synthesis, molecular modeling and evaluation of 2,4-diaminopyrimidine analogues as promising colorectal cancer drugs. Bioorg Chem 2024; 153:107854. [PMID: 39368143 DOI: 10.1016/j.bioorg.2024.107854] [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: 07/29/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/07/2024]
Abstract
The potential of cyclin-dependent kinases (CDKs) as therapeutic targets in cancer treatment is well established. In this study, we present our investigation into a group of 2,4-diaminopyrimidine derivatives that potently inhibit CDK9 and are cytotoxic when tested in colorectal cancer cell lines. We designed and synthesized forty analogues by altering substitutions at C-2 and C-4 position of the pyrimidine system. Among them, compounds 16 h and 16j exhibited strong inhibitory potency against both CDK9 enzymes (IC50 = 11.4 ± 1.4 nM, IC50 = 10.2 ± 1.3 nM respectively) with a significant preference for one over the other, and cytotoxic potency (IC50 = 61 ± 2 nM, IC50 = 20 ± 1 nM respectively) against HCT-116 was discovered through substantial modifications to its structure. Further investigations revealed that compounds 16 h and 16j were directly bound to CDK9, resulting in the suppression of its downstream signaling pathway. This inhibition of cell proliferation occurred by impeding the progression of the cell cycle and inducing apoptosis in cells by suppressing the phosphoryl RNA pol II Ser2. Significantly, compound 16 h and 16j effectively suppressed tumor growth in a xenograft mouse model and exhibited no apparent toxicity. This indicates that CDK9 inhibitors hold great potential as a therapeutic approach for colorectal cancer treatment. Therefore, the aforementioned discoveries are vital for the development of CDK9 inhibitors for the treatment of cancer.
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Affiliation(s)
- Gopalakrishnan Venkatesan
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, 117544, Singapore.
| | - Chong Yong Ping
- Critical Analytics for Manufacturing Personalized-Medicine Programme (CAMP), Singapore-MIT Alliance for Research and Technology, Singapore. 1 CREATE Way, #12-02 CREATE Tower, 138602, Singapore
| | - Hong Chen
- School of Biological Sciences (SBS), Nanyang Technological University, 60 Nanyang Dr, 637551, Singapore
| | - Perumal Srinivasan
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Engineering Block 4, 117583, Singapore
| | - Aneesh V Karkhanis
- Certara UK Ltd., Certara Predictive Technologies Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2B1, United Kingdom
| | - Giorgia Pastorin
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, 117544, Singapore
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Peters GJ, Kathmann I, Giovannetti E, Smid K, Assaraf YG, Jansen G. The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity. Front Pharmacol 2024; 15:1450418. [PMID: 39234107 PMCID: PMC11371747 DOI: 10.3389/fphar.2024.1450418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 07/30/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. METHODS Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). RESULTS l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. CONCLUSION In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.
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Affiliation(s)
- Godefridus J. Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Ietje Kathmann
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Kees Smid
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Yehuda G. Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa, Israel
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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TAHIYA EC, ISLAM AA, HATTA M, LUSIKOOY RE, PRIHANTONO P, RUDIMAN R, WIDIANA IK, PATELONGI I, BUKHARI AS. 5-Fluorouracil for colorectal cancer: mechanism of action and metabolism. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2024; 183. [DOI: 10.23736/s0393-3660.23.05249-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
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Liao PF, Wu TW, Peng TR. Monoclonal Antibodies for First-Line Treatment of Metastatic Colorectal Cancer. Am J Ther 2024; 31:e286-e297. [PMID: 35972911 DOI: 10.1097/mjt.0000000000001547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND In addition to discontinuing treatment at disease progression, cumulative toxicity limitations and genetic mutations play important roles in chemotherapy choice in metastatic colorectal cancer (mCRC). However, in recent years, targeted therapies, such as immune checkpoint inhibitors or monoclonal antibodies (MoAbs), have been used with chemotherapy to improve clinical outcomes in patients with mCRC. AREAS OF UNCERTAINTY Approximately 15% of patients with CRC would be eligible for further targeted therapy with immune checkpoint inhibitors based on genetic testing, but most patients with CRC would not qualify, especially Kirsten rat sarcoma wild-type. Therefore, adding MoAb is only an option for most patients until disease progression or unacceptable toxicity occurs. However, the results are not consistent with the combination of MoAb and different chemotherapy bases. In addition, most results from combining MoAb with different chemotherapy bases are not consistent. DATA SOURCES This meta-analysis includes published of the PubMed and Embase databases, limited to English literature, and patients were treated with MoAb combination. Randomized control trials conducted published up to May 2021 were considered for inclusion. THERAPEUTIC ADVANCES Fluoropyrimidine-based chemotherapy has been the backbone of palliative therapy for mCRC, with demonstrated benefits. This article will review the efficacy and safety of randomized control trials comparing different MoAb with fluoropyrimidine-based chemotherapy as first-line therapy for patients with mCRC, particularly in Kirsten rat sarcoma wild-type. CONCLUSION This meta-analysis revealed that MoAb plus chemotherapy has better progression-free survival and objective response rate than chemotherapy alone. However, treatment-related serious adverse events (grade ≥ 3) should be considered, particularly severe rash, diarrhea, and hypertension.
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Affiliation(s)
- Pei-Fei Liao
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, Republic of China
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Rong Z, Zheng K, Chen J, Jin X. The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer. J Cancer Res Clin Oncol 2024; 150:154. [PMID: 38521878 PMCID: PMC10960765 DOI: 10.1007/s00432-024-05659-9] [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: 09/21/2023] [Accepted: 02/20/2024] [Indexed: 03/25/2024]
Abstract
Ubiquitination, a highly adaptable post-translational modification, plays a pivotal role in maintaining cellular protein homeostasis, encompassing cancer chemoresistance-associated proteins. Recent findings have indicated a potential correlation between perturbations in the ubiquitination process and the emergence of drug resistance in CRC cancer. Consequently, numerous studies have spurred the advancement of compounds specifically designed to target ubiquitinates, offering promising prospects for cancer therapy. In this review, we highlight the role of ubiquitination enzymes associated with chemoresistance to chemotherapy via the Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT), and cell cycle perturbation. In addition, we summarize the application and role of small compounds that target ubiquitination enzymes for CRC treatment, along with the significance of targeting ubiquitination enzymes as potential cancer therapies.
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Affiliation(s)
- Ze Rong
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
| | - Kaifeng Zheng
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China
| | - Jun Chen
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
| | - Xiaofeng Jin
- Department of Chemoradiotherapy, the Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo, 315211, China.
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Chai Y, Liu JL, Zhang S, Li N, Xu DQ, Liu WJ, Fu RJ, Tang YP. The effective combination therapies with irinotecan for colorectal cancer. Front Pharmacol 2024; 15:1356708. [PMID: 38375031 PMCID: PMC10875015 DOI: 10.3389/fphar.2024.1356708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open
Abstract
Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.
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Affiliation(s)
- Yun Chai
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Jing-Li Liu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Shuo Zhang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
| | - Na Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
| | - Ding-Qiao Xu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Wen-Juan Liu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Rui-Jia Fu
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Yu-Ping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
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Kok DE, van Duijnhoven FJ, Lubberman FJ, McKay JA, Lanen ASV, Winkels RM, Wesselink E, van Halteren HK, de Wilt JH, Ulrich CM, Ulvik A, Ueland PM, Kampman E. Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study. Am J Clin Nutr 2024; 119:294-301. [PMID: 38070682 DOI: 10.1016/j.ajcnut.2023.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/10/2023] [Accepted: 11/28/2023] [Indexed: 12/25/2023] Open
Abstract
BACKGROUND Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. OBJECTIVE We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. METHODS Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. RESULTS In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. CONCLUSIONS This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment. CLINICAL TRIAL DETAILS This trial was registered at clinicaltrials.gov as NCT03191110.
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Affiliation(s)
- Dieuwertje E Kok
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
| | - Fränzel Jb van Duijnhoven
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Floor Je Lubberman
- Department of Clinical Pharmacy, Hospital Gelderse Vallei, Ede, the Netherlands
| | - Jill A McKay
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
| | - Anne-Sophie van Lanen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Renate M Winkels
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Henk K van Halteren
- Department of Medical Oncology, Admiraal de Ruyter Hospital, Goes, the Netherlands
| | | | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, United States
| | | | | | - Ellen Kampman
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
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Adebayo AS, Agbaje K, Adesina SK, Olajubutu O. Colorectal Cancer: Disease Process, Current Treatment Options, and Future Perspectives. Pharmaceutics 2023; 15:2620. [PMID: 38004598 PMCID: PMC10674471 DOI: 10.3390/pharmaceutics15112620] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/28/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university's online library. The keywords were "Colorectal Cancer" AND "disease process" OR "disease mechanisms" OR "Current Treatment" OR "Prospects". Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low-medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin®), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux®) and panitumumab (Verbitix®). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells.
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Affiliation(s)
- Amusa S. Adebayo
- College of Pharmacy, Howard University, 2400 6th St NW, Washington, DC 20059, USA; (K.A.); (S.K.A.); (O.O.)
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Ouyang Y, Yu M, Liu T, Suo M, Qiao J, Wang L, Li N. An Activated Dendritic-Cell-Related Gene Signature Indicative of Disease Prognosis and Chemotherapy and Immunotherapy Response in Colon Cancer Patients. Int J Mol Sci 2023; 24:15959. [PMID: 37958942 PMCID: PMC10647347 DOI: 10.3390/ijms242115959] [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: 08/27/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 11/15/2023] Open
Abstract
Accumulating evidence has underscored the prognostic value of tumor-infiltrating immune cells in the tumor microenvironment of colon cancer (CC). In this retrospective study, based on publicly available transcriptome profiles and clinical data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, we derived and verified an activated dendritic cell (aDC)-related gene signature (aDCRS) for predicting the survival outcomes and chemotherapy and immunotherapy response of CC patients. We quantified the infiltration abundance of 22 immune cell subtypes via the "CIBERSORT" R script. Univariate Cox proportional hazards (PHs) regression was used to identify aDC as the most robust protective cell type for CC prognosis. After selecting differentially expressed genes (DEGs) significantly correlated with aDC infiltration, we performed univariate Cox-PH regression, LASSO regression, and stepwise multivariate Cox-PH regression successively to screen out prognosis-related genes from selected DEGs for constructing the aDCRS. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis were employed to assess the discriminatory ability and risk-stratification capacity. The "oncoPredict" package, Cancer Treatment Response gene signature DataBase, and Tumor Immune Dysfunction and Exclusion algorithm were utilized to estimate the practicability of the aDCRS in predicting response to chemotherapy and immune checkpoint blockade. Gene set enrichment analysis and single-cell RNA sequencing analysis were also implemented. Furthermore, an aDCRS-based nomogram was constructed and validated via ROC curves, calibration plots and decision curve analysis. In conclusion, aDCRS and an aDCRS-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions, thus improving the survival outcomes of CC patients in the future.
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Affiliation(s)
| | | | | | | | | | - Liqiang Wang
- School of Medicine, Nankai University, Tianjin 300071, China; (Y.O.); (M.Y.); (T.L.); (M.S.); (J.Q.)
| | - Na Li
- School of Medicine, Nankai University, Tianjin 300071, China; (Y.O.); (M.Y.); (T.L.); (M.S.); (J.Q.)
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Sawabe M, Kawakita D, Oze I, Iwasaki S, Hasegawa Y, Murakami S, Ito H, Hanai N, Matsuo K. The Heterogeneous Impact of Prediagnostic Folate Intake for Fluorouracil-Containing Induction Chemotherapy for Head and Neck Cancer. Cancers (Basel) 2023; 15:5150. [PMID: 37958324 PMCID: PMC10650771 DOI: 10.3390/cancers15215150] [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: 09/09/2023] [Revised: 10/16/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023] Open
Abstract
Fluorouracil (FU) exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism. Evidence that folate may play a role in the carcinogenic process via folate-mediated one-carbon metabolism has given rise to the hypothesis that pre-diagnostic folate intake may induce heterogeneous chemosensitivity to FU-containing induction chemotherapy (IC) in head and neck cancer. To assess this hypothesis, we conducted a cohort study to investigate whether the association between prediagnostic dietary folate intake and cancer survival differed between treatment regimens with and without FU-containing IC in 504 cases of locally advanced (stage III/IV) HNSCC, using an epidemiologic database combined with clinical data. In total, 240 patients were treated with FU-containing IC followed by definitive treatment, and 264 patients were treated with definitive treatment alone. Definitive treatment is defined as (1) the surgical excision of a tumor with clear margins, with or without neck lymph node dissection; or (2) radiotherapy with or without chemotherapy. In the overall cohort of the FU-containing IC group, a higher folate intake was significantly associated with better overall survival (adjusted hazard ratios (HRs) for the highest compared to the lowest folate tertiles (HRT3-T1) = 0.42, 95%CI, 0.25-0.76, Ptrend = 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HRT3-T1: 0.83, 95%CI, 0.49-1.42, Ptrend = 0.491)). A consideration of the cumulative dose of FU-containing IC showed that the survival impact of prediagnostic folate intake differed statistically significantly by treatment regimen (Pinteraction = 0.012). In conclusion, an association between prediagnostic folate intake and HNSCC survival significantly differed by FU-containing IC. This finding indicates that in the carcinogenic process, folate status causes HNSCC to be heterogenous in terms of one-carbon metabolism.
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Affiliation(s)
- Michi Sawabe
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; (M.S.); (I.O.); (K.M.)
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan;
- Department of Otolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medicine, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;
| | - Daisuke Kawakita
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; (M.S.); (I.O.); (K.M.)
- Department of Otolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medicine, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; (M.S.); (I.O.); (K.M.)
| | - Shinichi Iwasaki
- Department of Otolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medicine, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;
| | - Yasuhisa Hasegawa
- Department of Head and Neck Surgery, Asahi University Hospital, 3-23 Hashimoto-cho, Gifu 500-8523, Japan;
| | - Shingo Murakami
- Department of Otolaryngology, Head and Neck Surgery, Nagoya City East Medical Center, 1-2-23, Wakamizu, Mizuho-ku, Nagoya 464-8547, Japan;
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan;
| | - Nobuhiro Hanai
- Department of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan;
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; (M.S.); (I.O.); (K.M.)
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Yu YL, Tseng WK, Liao CK, Yeh CY, Chen HH, Liu YH, Liaw YW, Fan CW. Using oral tegafur/uracil (UFT) plus leucovorin as adjuvant chemotherapy in stage II colorectal cancer: a propensity score matching study from Taiwan. BMC Cancer 2023; 23:900. [PMID: 37749535 PMCID: PMC10518963 DOI: 10.1186/s12885-023-11310-6] [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: 03/22/2023] [Accepted: 08/17/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Early-stage colorectal cancer had excellent outcomes after curative resection, typically. However, a perplexing survival paradox between stage II and stage III was noted. This paradox could be influenced by the administration of routine postoperative adjuvant chemotherapy and the presence of high-risk factors in stage II CRC. The objective of the study was to investigate the influence of high-risk factors on patients with stage II CRC and assess the efficacy of oral tegafur/uracil (UFT) plus leucovorin as adjuvant chemotherapy for stage II CRC patients. METHODS A retrospective study was conducted using propensity score matching at a single medical institution. A total of 1544 patients with stage II colorectal cancer who underwent radical surgery between January 2004 and January 2009 were included. The intervention used was tegafur/uracil plus leucovorin as adjuvant chemotherapy. The main outcome measures were disease-free survival and overall survival. RESULTS After propensity score matching, 261 patients were included in three groups: no-treatment, half-year treatment, and one-year treatment. The clinical characteristics of each group tended to be more consistent. The Cox proportional hazard models showed that tegafur/uracil treatment or not was a significant independent factor for oncological outcome. Kaplan-Meier analysis also showed significantly better disease-free survival and overall survival. Further investigation revealed that tegafur/uracil duration was an independent factor for oncological outcome. While the survival curve did not reach statistical significance, the one-year UFT treatment group demonstrated the best treatment trend. CONCLUSIONS This study suggests that tegafur/uracil plus leucovorin is a feasible adjuvant chemotherapy regimen for patients with stage II colorectal cancer after curative surgical treatment. Prolonged tegafur/uracil plus leucovorin treatment for 12 months showed a trend towards better outcomes in patients with stage II colorectal cancer.
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Affiliation(s)
- Yen-Lin Yu
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, No. 222 Maijin Rd., Anle Dist., Keelung City, 20401, Taiwan
| | - Wen-Ko Tseng
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, No. 222 Maijin Rd., Anle Dist., Keelung City, 20401, Taiwan
| | - Chun-Kai Liao
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan
| | - Chien-Yuh Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan
| | - Hong-Hwa Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Branch, No. 123, Dapi Rd., Niaosong Dist., Kaohsing City, 83301, Taiwan
| | - Yu-Hsuan Liu
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, No. 222 Maijin Rd., Anle Dist., Keelung City, 20401, Taiwan
| | - Yu-Wei Liaw
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, No. 222 Maijin Rd., Anle Dist., Keelung City, 20401, Taiwan
| | - Chung-Wei Fan
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Keelung Branch, No. 222 Maijin Rd., Anle Dist., Keelung City, 20401, Taiwan.
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Takahari D, Katai H, Takashima A, Izawa N, Ishizuka N, Ohashi M, Mikami S, Wakatsuki T, Nakayama I, Chin K, Ida S, Kumagai K, Nunobe S, Iwasa S, Shoji H, Wada T, Doi A, Yoshikawa T, Sano T, Boku N, Yamaguchi K. Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study. Gastric Cancer 2023; 26:614-625. [PMID: 37029843 PMCID: PMC10285008 DOI: 10.1007/s10120-023-01388-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 03/27/2023] [Indexed: 04/09/2023]
Abstract
BACKGROUND We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.
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Affiliation(s)
- Daisuke Takahari
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Naoki Ishizuka
- Department of Clinical Planning and Strategy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Manabu Ohashi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shinya Mikami
- Department of Gastrointestinal and General Surgery, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Takeru Wakatsuki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Izuma Nakayama
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Satoshi Ida
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koshi Kumagai
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Souya Nunobe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoru Iwasa
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takeyuki Wada
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Ayako Doi
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Takeshi Sano
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Kdimati S, Bürtin F, Linnebacher M, Mullins CS. Patient-Derived Organoids for In Vivo Validation of In Vitro Data. Methods Mol Biol 2023; 2589:111-126. [PMID: 36255621 DOI: 10.1007/978-1-0716-2788-4_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Patient-derived organoids are promising tumor models for functional validation of next-generation sequencing-based therapy recommendations. In times of rapidly advancing precision oncology approaches in everyday clinical processes, reliable and valid tumor models are required. Tumor organoids consist of tumor "stem" cells, differentiated (epithelial) tumor, and stroma cells. The cellular architecture and interactions closely mimic the original patient tumor. These organoids can be implanted into immunodeficient mice, generating patient-derived organoid-derived xenografts, thus enabling in vitro to in vivo transfer. Most importantly, the high clinical relevance of PDO models is maintained in this conversion. This protocol describes in detail the methods and techniques as well as the materials necessary to generate in vitro PDO and in vivo PDO-derived xenograft models. The elaborate process description starts with the processing of freshly obtained tumor tissue. The proceedings include tissue processing, organoid culturing, PDO implantation into immunodeficient mice, tumor explantation, and finally tumor preservation. All these proceedings are described in this timely chronological order. This protocol will enable researchers to generate PDO models from freshly received tumor tissue and generate PDO-derived xenografts. Models generated according to these methods are suitable for a very broad research spectrum.
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Affiliation(s)
- Said Kdimati
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock, Germany
| | - Florian Bürtin
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock, Germany
| | - Michael Linnebacher
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock, Germany
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Paszt A, Ottlakan A, Abraham S, Simonka Z, Vas M, Maraz A, Szepes Z, Tiszlavicz L, Nyari T, Olah J, Lazar G. Clinical benefits of oral capecitabine over intravenous 5-fluorouracyl regimen in case of neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer. Pathol Oncol Res 2022; 28:1610722. [PMID: 36567978 PMCID: PMC9773127 DOI: 10.3389/pore.2022.1610722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022]
Abstract
Background: During the last decade, one of the most important treatment options for locally advanced, potencially resectable rectal tumours was neoadjuvant chemoradiotherapy (CRT) followed by surgery. Methods: Effects of the neoadjuvant treatment on surgical outcomes were retrospectively analysed in 185 patients with stage T2-T4 and N0-2, resectable rectal tumour among two patient groups defined by radiosensitizer agents. Group 1 (n = 94) involved radiotherapy (RT) with 50.4 Gy total dose (25 × 1.8 Gy + 3 × 1.8 Gy tumour bed boost), and intravenous 5-fluorouracil (5-FU) (350 mg/m2) with leucovorin (20 mg/m2) on the 1-5 and 21-25 days, while Group 2 (n = 91) RT and orally administrated capecitabine (daily 2 × 825 mg/m2) on RT days. Surgery was carried out after 8-10 weeks. Side effects, perioperative complications, type of surgery, number of removed regional lymph nodes, resection margins and tumour regression grade (TRG) were analysed. Results: More favourable side effects were observed in Group 2. Despite the same rate of diarrhoea (Group 1 vs. Group 2: 54.3% vs. 56.0%), Grade 2-3 diarrhoea ratio was lower (p = 0.0352) after capecitabine (Group 2). Weight loss occurred in 17.0% and 2.2% (p = 0.00067), while nausea and vomiting was described in 38.3% and 15.4% (p = 0.00045) with 5-FU treatment and capecitabine respectively. Anaemia was observed in 33.0% and 22.0% (p = 0.0941). Complete tumour regression occurred in 25.3% after oral- and 13.8% after intravenous treatment (p = 0.049). Ratio of sphincter preservation was higher with laparoscopy than open surgery (72.3% vs. 39.7%) (p = 0.00001). Conclusion: The study confirms advantages of neoadjuvant chemoradiotherapy with oral capecitabine for rectal tumours, such as more favourable side effect profile and overall clinical outcome, with increased rate of complete tumour regression.
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Affiliation(s)
- Attila Paszt
- Department of Surgery, University of Szeged, Szeged, Hungary,*Correspondence: Attila Paszt,
| | - Aurel Ottlakan
- Department of Surgery, University of Szeged, Szeged, Hungary
| | | | - Zsolt Simonka
- Department of Surgery, University of Szeged, Szeged, Hungary
| | - Marton Vas
- Department of Surgery, University of Szeged, Szeged, Hungary
| | - Aniko Maraz
- Department of Oncotherapy, University of Szeged, Szeged, Hungary
| | - Zoltan Szepes
- 1st Department of Internal Medicine, University of Szeged, Szeged, Hungary
| | | | - Tibor Nyari
- Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary
| | - Judit Olah
- Department of Oncotherapy, University of Szeged, Szeged, Hungary
| | - Gyorgy Lazar
- Department of Surgery, University of Szeged, Szeged, Hungary
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A phase I/II study of arfolitixorin and 5-fluorouracil in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan in metastatic colorectal cancer. ESMO Open 2022; 7:100589. [PMID: 36183444 PMCID: PMC9588906 DOI: 10.1016/j.esmoop.2022.100589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/18/2022] [Accepted: 08/21/2022] [Indexed: 11/21/2022] Open
Abstract
Background 5-fluorouracil (5-FU) combined with a folate remains an essential treatment component for metastatic colorectal cancer (mCRC). Leucovorin is the folate most often used, but requires intracellular conversion to a reduced folate, and has high pharmacokinetic variability and limited bioavailability in patients with low folate pathway gene expression. Arfolitixorin is an immediately active form of folate, [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF), and may improve outcomes. Patients and methods This open-label, multicenter, phase I/II study in patients with mCRC (NCT02244632) assessed the tolerability and efficacy of first- or second-line arfolitixorin (30, 60, 120, or 240 mg/m2 intravenous) with 5-FU alone, or in combination with oxaliplatin (plus or minus bevacizumab) or irinotecan, every 14 days. Safety, efficacy, and pharmacokinetics were assessed before and after four cycles (8 weeks) of treatment. Results In 105 treated patients, investigators reported 583 adverse events (AEs) in 86 patients (81.9%), and 256 AEs (43.9%) were potentially related to arfolitixorin and 5-FU. Dose adjustments were required in 16 patients (15.2%). At 8 weeks, 9 out of 57 patients assessed for efficacy achieved an objective response (15.8%), and all 9 achieved a partial response. Six of these nine patients had received arfolitixorin as a first-line treatment. A further 33 patients (57.9%) achieved stable disease. Pharmacokinetics were assessed in 35 patients. The average tmax was 10 min, and area under the plasma concentration–time curve from time 0 to 1 h increased linearly between 30 and 240 mg/m2. No accumulation was observed for [6R]-MTHF following repeated administration, and there were no major pharmacokinetic differences between cycle 1 and cycle 4 at any dose. Conclusions Arfolitixorin is a well-tolerated moderator of 5-FU activity. It is suitable for further investigation in mCRC and has the potential to improve treatment outcomes in patients with low folate pathway gene expression. Arfolitixorin can easily be incorporated into current standard of care, requiring minimal changes to chemotherapy regimens.
Arfolitixorin is an immediately active form of folate and may improve outcomes with 5-FU-based chemotherapy. This phase I/II clinical trial demonstrated that arfolitixorin is a well-tolerated and effective folate agent in mCRC. Arfolitixorin can easily be incorporated into the current standard of care and is suitable for further investigation.
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Turossi-Amorim ED, Camargo B, Schuelter-Trevisol F. Prevalence of Potential Pharmacological Interactions in Patients Undergoing Systemic Chemotherapy in a Tertiary Hospital. Hosp Pharm 2022; 57:646-653. [PMID: 36081531 PMCID: PMC9445545 DOI: 10.1177/00185787211073464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Introduction: Pharmacological interactions are frequently observed in patients with chronic diseases, and their occurrence is proportional to the amount of medication used daily. Patients undergoing chemotherapy treatment commonly have comorbidities, which favor a greater prevalence of polypharmacy, increasing the risk of drug interactions. Therefore, the aim of this study was to estimate the prevalence of drug interactions in patients undergoing intravenous chemotherapy treated at a hospital oncology service in southern Brazil. Methods: This was an observational study with a cross-sectional design that was carried out with the analysis of secondary data obtained through the review of medical records. The population assessed consisted of all cancer patients who received intravenous chemotherapy from October to December 2020. Results: Out of the 297 patients included in the study, 231 (77.8%) had at least 1 potential pharmacological interaction. In total, 1044 drug interactions were found that were classified according to severity, resulting in 18 (1.7%) contraindicated drug-drug interactions (DDI), 699 (67%) severe, 281 (26.9%) moderate, and 46 (4.4%) minor interactions. There was an association between polypharmacy and the prevalence of drug interactions. Conclusion: The results demonstrate that a large percentage of patients undergoing chemotherapy are susceptible to drug interactions. Thus, it is necessary that prescribers consider all drugs used by patients and, when possible, prescribe alternative drugs that have less potential for interaction in order to prevent drug interactions adverse effects and provide a better prognosis for patients.
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Affiliation(s)
| | - Bruna Camargo
- University of Southern Santa Catarina, Tubarao, Brazil
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21
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Min ST, Roohullah A, Tognela A, Jalali A, Lee M, Wong R, Shapiro J, Burge M, Yip D, Nott L, Zimet A, Lee B, Dean A, Steel S, Wong HL, Gibbs P, Lim SHS. Patient demographics and management landscape of metastatic colorectal cancer in the third-line setting: Real-world data in an australian population. Asia Pac J Clin Oncol 2022; 18:e56-e63. [PMID: 33870631 DOI: 10.1111/ajco.13553] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 12/02/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia, thus carrying a significant disease burden. AIMS This analysis aims to explore real-world treatment landscape of metastatic colorectal cancer in the third-line setting. METHODS We retrospectively analysed treatment of recurrent and advanced colorectal cancer (TRACC) registry database from 2009 onwards. Patients treated with palliative intent who progressed after two lines of therapies were included. One treatment line was defined as any combination of systemic therapy given until progression. RESULTS Out of 1820 patients treated palliatively, 32% (590 patients) met study criteria. Of these, 43% (254 patients) proceeded to third-line therapy, equating to 14% of all metastatic patients. In KRAS mutant or unknown tumours (97 patients), fluoropyrimidine (FP)-oxaliplatin combination was the most common choice (51%), followed by FP-irinotecan (15%), trifluridine/tipiracil (11%), mono-chemotherapy (10%), regorafenib (5%) and others (7%). Majority of FP-doublet (83%) was given as rechallenge. In 157 patients with KRAS wildtype disease, monotherapy with EGFR inhibitor was most commonly used (41%), followed by EGFR inhibitor with chemotherapy (20%), FP-doublet (18%), mono-chemotherapy (6%), trifluridine/tipiracil (6%), regorafenib (1%) and others (8%). Median overall survival was 7.1 months (range 0.4-41.2), and median time on third-line treatment was 3 months (range 0.1-40). CONCLUSIONS In real-world Australian population, treatment choices differed based on KRAS status and will likely change with the availability of newer drugs on the pharmaceutical benefits scheme. Survival outcomes are comparable to newer agents in clinical trials for select patients.
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Affiliation(s)
- Sandy Tun Min
- Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia
| | - Aflah Roohullah
- Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Annette Tognela
- Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Azim Jalali
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
| | - Margaret Lee
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia
| | - Rachel Wong
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia
- Department of Medicine, Monash University, Clayton, Victoria, Australia
- Epworth Health Care, Box Hill, Victoria, Australia
| | - Jeremy Shapiro
- Department of Medicine, Monash University, Clayton, Victoria, Australia
- Cabrini Haematology and Oncology Centre, Malvern, Victoria, Australia
| | - Matthew Burge
- Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
- Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra and Calvary Hospitals, Garran, Australia Capital Territory, Australia
| | - Louise Nott
- Royal Hobart Hospital, Hobart, Tasmania, Australia
| | - Allan Zimet
- Epworth HealthCare, Richmond, Victoria, Australia
| | - Belinda Lee
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Northern Hospital, Epping, Victoria, Australia
| | - Andrew Dean
- Department of Medical Oncology, St John of God Hospital, Subiaco, Western Australia, Australia
| | - Simone Steel
- Peninsula Private Hospital, Frankston, Victoria, Australia
| | - Hui-Li Wong
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
- Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Stephanie Hui-Su Lim
- Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
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22
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Medicina de precisión en cáncer colorrectal y gastroesofágico avanzado. REVISTA MÉDICA CLÍNICA LAS CONDES 2022. [DOI: 10.1016/j.rmclc.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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23
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Amorim LC, Peixoto RD. Should we still be using bolus 5-FU prior to infusional regimens in gastrointestinal cancers? A practical review. Int Cancer Conf J 2021; 11:2-5. [DOI: 10.1007/s13691-021-00526-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/17/2021] [Indexed: 11/30/2022] Open
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24
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Peixoto RD, Coutinho AK, Weschenfelder RF, Prolla G, Rocha D, Andrade AC, Rego JF, Fernandes GDS, Crosara M, Hoff PM, Dienstmann R, Costa E Silva M, Riechelmann RP. Fluorouracil Bolus Use in Infusional Regimens Among Oncologists-A Survey by Brazilian Group of Gastrointestinal Tumors. JCO Glob Oncol 2021; 7:1270-1275. [PMID: 34383598 PMCID: PMC8389882 DOI: 10.1200/go.21.00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The utility of administering fluorouracil (5-FU) in bolus in regimens of infusional 5-FU has been questioned. We aimed to quantify the use of 5-FU bolus in infusional regimens for gastrointestinal malignancies among Brazilian oncologists. METHODS This was a cross-sectional electronic survey composed of eight multiple-choice questions sent to Brazilian oncologists during 14 days in February 2021. The survey instrument collected demographic data of participants and assessed practices in terms of 5-FU bolus use. We evaluated the association of demographic variables and 5-FU prescribing patterns with Fisher’s exact test (odds ratio [OR]). RESULTS The survey was completed by 332 medical oncologists. Overall, 37% were experienced oncologists and 32% were gastrointestinal specialists. In the first-line metastatic and in the adjuvant settings, 40% and 67% of oncologists always prescribe 5-FU bolus in infusional regimens, respectively. Experienced oncologists more frequently omit 5-FU bolus when compared with early-career oncologists, both in the metastatic (41% v 26%; OR, 1.98; P = .005) and adjuvant settings (28% v 14%; OR, 2.32; P = .003). In addition, more GI specialists remove 5-FU bolus when compared with generalists, but only in the metastatic setting (44% v 25%; OR, 2.33; P = .001). GI specialists are more likely to consider that treatment efficacy is not affected by 5-FU bolus withdrawal than are generalists (89% v 75%; OR, 2.65; P = .003). Most respondents (67%) keep leucovorin at the same doses when omitting 5-FU bolus, and only 16% always recommend dihydropyrimidine dehydrogenase testing. CONCLUSION Our survey indicates that experience in oncology practice and percentage of time dedicated to treat GI cancers influence the prescription of 5-FU bolus in Brazil, with more frequent omission of it among experienced gastrointestinal specialists, particularly in the metastatic setting.
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Affiliation(s)
| | - Anelisa K Coutinho
- Clínica AMO: GEM Assistencia Medica Especializada Sociedade Simples Ltda, Salvador, Brazil
| | | | - Gabriel Prolla
- PUCRS: Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil
| | | | | | - Juliana Florinda Rego
- Onofre Lopes University Hospital: Hospital Universitario Onofre Lopes, Natal, Brazil
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25
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Milczarek M, Pogorzelska A, Wiktorska K. Synergistic Interaction between 5-FU and an Analog of Sulforaphane-2-Oxohexyl Isothiocyanate-In an In Vitro Colon Cancer Model. Molecules 2021; 26:molecules26103019. [PMID: 34069385 PMCID: PMC8158758 DOI: 10.3390/molecules26103019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/14/2021] [Accepted: 05/16/2021] [Indexed: 12/22/2022] Open
Abstract
Combination therapy is based on the beneficial effects of pharmacodynamic interaction (synergistic or additive) between combined drugs or substances. A considerable group of candidates for combined treatments are natural compounds (e.g., isothiocyanates) and their analogs, which are tested in combination with anticancer drugs. We tested the anticancer effect of the combined treatment of isothiocyanate 2-oxohexyl isothiocyanate and 5-fluorouracil in colon and prostate cancer cell lines. The type of interaction was described using the Chou-Talalay method. The cytostatic and cytotoxic activities of the most promising combined treatments were investigated. In conclusion, we showed that combined treatment with 5-fluorouracil and 2-oxohexyl isothiocyanate acted synergistically in colon cancer. This activity is dependent on the cytostatic properties of the tested compounds and leads to the intensification of their individual cytotoxic activity. The apoptotic process is considered to be the main mechanism of cytotoxicity in this combined treatment.
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26
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Dunn C, Hong W, Gibbs P, Ackland S, Sjoquist K, Tebbutt NC, Price T, Burge M. Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group. Clin Colorectal Cancer 2021; 20:245-255. [PMID: 34103264 DOI: 10.1016/j.clcc.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/16/2021] [Accepted: 05/02/2021] [Indexed: 01/18/2023]
Abstract
Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.
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Affiliation(s)
- Catherine Dunn
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
| | - Wei Hong
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Stephen Ackland
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Katrin Sjoquist
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
| | - Matthew Burge
- Department of Medical Oncology, Royal Brisbane Hospital, Herston, Queensland, Australia
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27
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Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers (Basel) 2021; 13:2296. [PMID: 34064974 PMCID: PMC8150459 DOI: 10.3390/cancers13102296] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.
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Affiliation(s)
- Maurice Michel
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
| | - Annett Maderer
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Peter R. Galle
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Markus Moehler
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
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Glimelius B, Stintzing S, Marshall J, Yoshino T, de Gramont A. Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone. Cancer Treat Rev 2021; 98:102218. [PMID: 34015686 DOI: 10.1016/j.ctrv.2021.102218] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 12/22/2022]
Abstract
Notwithstanding recent treatment advances in metastatic colorectal cancer (mCRC), chemotherapy with a combination of a fluoropyrimidine and a folate agent, often 5-fluorouracil (5-FU) and leucovorin, remains the backbone of treatment regimens for the majority of patients with mCRC. This is despite a recent focus on molecular-targeted treatments and patient stratification according to mutational status or expression levels of specific genes. Intracellular folate concentration was discovered to be pivotal in the cytotoxic efficacy of 5-FU, paving the way to the current standard combination therapy approach. Subsequent discovery that systemic chemotherapy agents, such as irinotecan and oxaliplatin, can further increase the efficacy of 5-FU-based treatments led to the development of several combination chemotherapy regimens, including FOLFOX, FOLFIRI and FOLFOXIRI. Subsequent efforts to optimise 5-FU-based treatments have focused on 5-FU analogues, initially capecitabine and the combination drug tegafur/gimeracil/oteracil (S-1) and then TAS-102, which has recently been evaluated in phase 3 clinical trials for refractory colorectal cancer. Further approaches taken to improve the efficacy of 5-FU chemotherapy regimens have focused on optimising the route and dosing schedules and regulating folate metabolism. Pharmacokinetic variability caused by the requirement for metabolic conversion of leucovorin has been central to recent research, and the development of agents such as arfolitixorin which bypass the need for metabolic conversion remains promising for future therapeutic candidates. In this review, we summarise the evidence leading to the current treatment regimens employing 5-FU and leucovorin, focusing on recent approaches taken to optimise and refine treatments to improve clinical outcomes in patients with mCRC.
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Affiliation(s)
- Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Sebastian Stintzing
- Department of Hematology, Oncology, and Tumor Immunology (CCM) Charité, University Medicine Berlin, Berlin, Germany
| | - John Marshall
- Georgetown University Medical Center, Washington, DC, USA
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Wang Y, Wei Q, Chen Y, Long S, Yao Y, Fu K. Identification of Hub Genes Associated With Sensitivity of 5-Fluorouracil Based Chemotherapy for Colorectal Cancer by Integrated Bioinformatics Analysis. Front Oncol 2021; 11:604315. [PMID: 33912443 PMCID: PMC8071956 DOI: 10.3389/fonc.2021.604315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors. 5-fluorouracil (5-FU) has been used for the standard first-line treatment for CRC patients for several decades. Although 5-FU based chemotherapy has increased overall survival (OS) of CRC patients, the resistance of CRC to 5-FU based chemotherapy is the principal cause for treatment failure. Thus, identifying novel biomarkers to predict response to 5-FU based chemotherapy is urgently needed. In the present study, the gene expression profile of GSE3964 from the Gene Expression Omnibus database was used to explore the potential genes related to intrinsic resistance to 5-FU. A gene module containing 81 genes was found to have the highest correlation with chemotherapy response using Weighted Gene Co-expression Network Analysis (WGCNA). Then a protein-protein interaction (PPI) network was constructed and ten hub genes (TGFBI, NID, LEPREL2, COL11A1, CYR61, PCOLCE, IGFBP7, COL4A2, CSPG2, and VTN) were identified using the CytoHubba plugin of Cytoscape. Seven of these hub genes showed significant differences in expression between chemotherapy-sensitive and chemotherapy-resistant samples. The prognostic value of these seven genes was evaluated using TCGA COAD (Colorectal Adenocarcinoma) data. The results showed that TGFBI was highly expressed in chemotherapy-sensitive patients, and patients with high TGFBI expression have better survival.
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Affiliation(s)
- Ya Wang
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qunhui Wei
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Yuqiao Chen
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Shichao Long
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanbing Yao
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.,Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
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30
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Hristova-Avakumova NG, Minchev VT, Kamenova KV, Todorov LT, Angelov MP, Atanasova LA, Surcheva SK, Nikolov RP. Dihydropyrimidine dehydrogenase level and the redox status in patients with colorectal cancer are prognostic for adverse effects of fluoropyrimidines. BIOTECHNOL BIOTEC EQ 2021. [DOI: 10.1080/13102818.2021.1964380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
| | - Velko T. Minchev
- Department of Medical Oncology, Sofiamed University Hospital, Sofia, Bulgaria
| | - Kalina V. Kamenova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University Sofia, Sofia, Bulgaria
| | - Lozan T. Todorov
- Department of Chemistry, Faculty of Pharmacy, Medical University Sofia, Sofia, Bulgaria
| | - Marin P. Angelov
- Department of Medical Oncology, Sofiamed University Hospital, Sofia, Bulgaria
| | - Liliya A. Atanasova
- Department of Medical Physics and Biophysics, Medical Faculty, Medical University Sofia, Sofia, Bulgaria
| | - Slavina K. Surcheva
- Department of Pharmacology and Toxicology Medical Faculty, Medical University Sofia, Sofia, Bulgaria
| | - Rumen P. Nikolov
- Department of Pharmacology and Toxicology Medical Faculty, Medical University Sofia, Sofia, Bulgaria
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31
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Taflin H, Odin E, Carlsson G, Tell R, Gustavsson B, Wettergren Y. Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin. Cancer Chemother Pharmacol 2020; 87:31-41. [PMID: 33099678 PMCID: PMC7801297 DOI: 10.1007/s00280-020-04173-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022]
Abstract
Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014 Electronic supplementary material The online version of this article (10.1007/s00280-020-04173-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helena Taflin
- Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Göteborg, Sweden
| | - Elisabeth Odin
- Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Göteborg, Sweden
| | - Göran Carlsson
- Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Göteborg, Sweden
| | | | - Bengt Gustavsson
- Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Göteborg, Sweden
| | - Yvonne Wettergren
- Department of Surgery, The Institute of Clinical Sciences, The Sahlgrenska Academy At University of Gothenburg, Göteborg, Sweden.
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32
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Rappaport JA, Waldman SA. An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer. Expert Rev Clin Pharmacol 2020; 13:1125-1137. [PMID: 32945718 DOI: 10.1080/17512433.2020.1826304] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Colorectal cancer remains the second leading cause of cancer death in the United States, underscoring the need for novel therapies. Despite the successes of new targeted agents for other cancers, colorectal cancer suffers from a relative scarcity of actionable biomarkers. In this context, the intestinal receptor, guanylyl cyclase C (GUCY2C), has emerged as a promising target.Areas covered: GUCY2C regulates a tumor-suppressive signaling axis that is silenced through loss of its endogenous ligands at the earliest stages of tumorigenesis. A body of literature supports a cancer chemoprevention strategy involving reactivation of GUCY2C through FDA-approved cGMP-elevating agents such as linaclotide, plecanatide, and sildenafil. Its limited expression in extra-intestinal tissues, and retention on the surface of cancer cells, also positions GUCY2C as a target for immunotherapies to treat metastatic disease, including vaccines, chimeric antigen receptor T-cells, and antibody-drug conjugates. Likewise, GUCY2C mRNA identifies metastatic cells, enhancing colorectal cancer detection, and staging. Pre-clinical and clinical programs exploring these GUCY2C-targeting strategies will be reviewed.Expert opinion: Recent mechanistic insights characterizing GUCY2C ligand loss early in tumorigenesis, coupled with results from the first clinical trials testing GUCY2C-targeting strategies, continue to elevate GUCY2C as an ideal target for prevention, detection, and therapy.
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Affiliation(s)
- Jeffrey A Rappaport
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University , Philadelphia, PA, USA
| | - Scott A Waldman
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University , Philadelphia, PA, USA
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Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol 2020; 21:1045-1056. [PMID: 32682457 DOI: 10.1016/s1470-2045(20)30315-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING Taiho Pharmaceutical and Yakult Honsha.
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Affiliation(s)
- Yoon-Koo Kang
- Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hyun Cheol Chung
- Division of Medical Oncology, Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Centre Hospital, Aichi, Japan
| | - Sang Cheul Oh
- Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Norisuke Nakayama
- Department of Gastroenterology, Kanagawa Cancer Centre, Kanagawa, Japan
| | - Keun-Wook Lee
- Division of Haematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Centre, Saitama, Japan
| | - Ik-Joo Chung
- Department of Haematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, South Korea
| | - Masahiro Tsuda
- Department of Gastroenterological Oncology, Hyogo Cancer Centre, Hyogo, Japan
| | - Se Hoon Park
- Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hisashi Hosaka
- Department of Gastroenterology, Gunma Prefectural Cancer Centre, Gunma, Japan
| | - Shuichi Hironaka
- Clinical Trial Promotion Department, Chiba Cancer Centre, Chiba, Japan
| | - Yoshinori Miyata
- Department of Medical Oncology, Saku Central Hospital Advanced Care Centre, Nagano, Japan
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Ichinosuke Hyodo
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yung-Jue Bang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan.
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Gangi A, Lu SC. Chemotherapy-associated liver injury in colorectal cancer. Therap Adv Gastroenterol 2020; 13:1756284820924194. [PMID: 32547639 PMCID: PMC7249601 DOI: 10.1177/1756284820924194] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/15/2020] [Indexed: 02/04/2023] Open
Abstract
Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.
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Affiliation(s)
- Alexandra Gangi
- Division of Surgical Oncology, Department of Surgery, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
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35
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Sanogo S, Silimbani P, Gaggeri R, Masini C. Stability of calcium levofolinate reconstituted in syringes and diluted in NaCl 0.9% and glucose 5% polyolefin/polyamide infusion bags. J Oncol Pharm Pract 2020; 27:288-296. [PMID: 32299315 PMCID: PMC7903855 DOI: 10.1177/1078155220918025] [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] [Indexed: 11/16/2022]
Abstract
Purpose Calcium levofolinate (CaLev) for intravenous administration is commercially available as a powder that must be reconstituted for injection or reconstituted and then diluted before administration. The lack of stability data on CaLev solutions renders necessary extemporaneous manual preparation, preventing the use of automated/semi-automated systems, with a consequent loss in terms of quality and safety. Methods The present work assessed the chemical–physical and microbiological stability of CaLev prepared in sodium chloride 0.9%, glucose 5% and water for injections and stored in polyolefin/polyamide bags and polypropylene syringes at 2–8°C protected from light. For this purpose, we developed and validated a new rapid High Performance Liquid Chromatography with Ultra Violet Diode-Array Detection (HPLC-UV-DAD) method. Results The samples tested were stable for 14 days, retaining >95% of their initial concentration and showing no change in colour, turbidity or pH. Microbiological tests performed on the samples were negative. Conclusions Our results confirmed the analytical stability of CaLev in NaCl 0.9%, glucose 5% and water for injection at concentrations used in clinical practice at our institute. This enables our centralized laboratory to organize the preparation of this drug in advance and the use of robots rather than manual preparation reduces the workload and the risk of preparation errors.
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Affiliation(s)
- Seydou Sanogo
- Oncology Pharmacy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Paolo Silimbani
- Oncology Pharmacy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Raffaella Gaggeri
- CE.ROM, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Carla Masini
- Oncology Pharmacy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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36
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Öz A, Server S, Koyuncu Sökmen B, Namal E, İnan N, Balcı NC. Intravoxel Incoherent Motion of Colon Cancer Liver Metastases for the Assessment of Response to Antiangiogenic Treatment: Results from a Pilot Study. Med Princ Pract 2020; 29:429-435. [PMID: 31914438 PMCID: PMC7511688 DOI: 10.1159/000505814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 01/08/2020] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE This study was aimed at evaluating the intravoxel incoherent motion (IVIM) parameter alterations of liver metastases of colorectal carcinoma (CRC) during antiangiogenic bevacizumab combination therapy. METHODS Twenty-five patients with CRC liver metastases treated with bevacizumab in combination with FOLFOX-or-FOLFIRI protocols were enrolled in the study. MRI was performed using a 1.5-tesla scanner pre-treatment (PT) and at 3, 6, and 9 months of therapy. Routine abdominal MRI sequences and an IVIM-DWI (diffusion-weighted imaging) sequence were obtained. The IVIM-DWI sequence was executed with 16 b-values varying from 0 to 1,400 s/mm2. The mean values of apparent diffusion coefficient (ADC), true diffusion (D), pseudodiffusion (D*), and perfusion fraction (f) of each metastasis were obtained for all b-values, and the time-related changes were recorded to analyze the chronologic responses to antiangiogenic therapy. The RECIST 1.1 criteria were used for the evaluation of treatment response. RESULTS The diameters of the metastases diminished significantly at 9 months when compared with PT (p = 0.03). The D (p = 0.10) and ADC (p = 0.21) values of the metastases increased at 9 months of therapy. D* was the highest at 3 months (p =0.24); it decreased at 6 (p =0.97) and 9 months (p =0.87) of therapy. The f value had peaked at 3 months (p =0.51) and started to decrease thereafter. At 6 months, f decreased to the lowest values (p =0.12). CONCLUSION IVIM parameters, particularly the perfusion fraction, may quantitatively reflect the response to antiangiogenic treatment. The antiangiogenic response manifests after 3 months of therapy before the RECIST-related response.
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Affiliation(s)
- Ayşegül Öz
- Department of Radiology, Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey,
| | - Sadık Server
- Department of Radiology, Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey
| | - Bedriye Koyuncu Sökmen
- Department of Radiology, Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey
| | - Esat Namal
- Department of Medical Oncology, Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey
| | - Nagihan İnan
- Department of Radiology, Faculty of Medicine, Istanbul Bilim University, Istanbul, Turkey
| | - Numan Cem Balcı
- Department of Radiology, Cleveland Clinic, Lerner School of Medicine, Abu Dhabi, United Arab Emirates
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Hsu CY, Chen CY, Lin YM, Tam KW. Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis. Colorectal Dis 2020; 22:6-17. [PMID: 31260150 DOI: 10.1111/codi.14746] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 06/17/2019] [Indexed: 12/12/2022]
Abstract
AIM The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. METHOD The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. RESULTS Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. CONCLUSION Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.
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Affiliation(s)
- C-Y Hsu
- Department of Pharmacy, En Chu Kong Hospital, New Taipei City, Taiwan.,Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
| | - C-Y Chen
- Department of Pharmacy, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Y-M Lin
- Department of Pharmacy, En Chu Kong Hospital, New Taipei City, Taiwan
| | - K-W Tam
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
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38
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Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol Ther 2019; 206:107447. [PMID: 31756363 DOI: 10.1016/j.pharmthera.2019.107447] [Citation(s) in RCA: 574] [Impact Index Per Article: 95.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/13/2019] [Indexed: 02/07/2023]
Abstract
5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.
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Affiliation(s)
- Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 2411/87, 100 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Veronika Veskrnova
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic.
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Odin E, Sondén A, Carlsson G, Gustavsson B, Wettergren Y. Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer. Tumour Biol 2019; 41:1010428319846231. [PMID: 31223065 DOI: 10.1177/1010428319846231] [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] [Indexed: 12/25/2022] Open
Abstract
5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes SLC46A1/PCFT, SLC19A1/RFC-1, ABCC3/MRP3, GGH, and MTHFD1L, which are involved in folate transport, polyglutamation, or metabolism, was associated with longer disease-free survival of the patients. Each of these genes either encodes mitochondrial enzymes or is being regulated by mitochondrial transcription factors. Expression of the SLC46A1/PCFT gene was most strongly associated with disease-free survival, regardless of treatment regimen. In conclusion, the results show that expression of folate pathway genes are associated with outcome of colorectal cancer patients treated with adjuvant 5-fluorouracil in combination with leucovorin. A prospective study needs to be conducted to determine if expression of these genes can be used to predict response to leucovorin and other folates that are now being tested in clinical studies. Moreover, there seems to be a link between folate metabolism and mitochondrial biogenesis and respiration that deserves further exploration.
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Affiliation(s)
- Elisabeth Odin
- 1 Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Arvid Sondén
- 2 Bioinformatics Core Facilities, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Göran Carlsson
- 1 Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Bengt Gustavsson
- 1 Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Yvonne Wettergren
- 1 Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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40
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Shi Y, Li J, Xu J, Sun Y, Wang L, Cheng Y, Liu W, Sun G, Chen Y, Bai L, Zhang Y, He X, Luo Y, Wang Z, Liu Y, Yao Q, Li Y, Qin S, Hu X, Bi F, Zheng R, Ouyang X. CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial. Cancer Commun (Lond) 2019; 39:28. [PMID: 31126331 PMCID: PMC6534840 DOI: 10.1186/s40880-019-0374-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 05/10/2019] [Indexed: 02/06/2023] Open
Abstract
Background The 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first-line treatment for metastatic colorectal cancer (mCRC), however, the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients. Methods Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan-only. Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression-free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). Results The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P < 0.001) and longer median PFS (169 days vs. 95 days; P < 0.001) as compared to the irinotecan-only arm. Patients receiving CMAB009 plus irinotecan also demonstrated improved DCR (80.1% vs. 65.2%, P < 0.001), CBR (30.0% vs. 14.6%, P < 0.001), and DOR (210 days vs. 109 days; P < 0.001) as compared to irinotecan-only. However, patients treated with CMAB009 had an increased risk of skin rash (66.9% vs. 5.5%, P < 0.001) and paronychia (9.8% vs. 0.0%, P < 0.001). Anti-drug antibodies (ADA) were detected in 3.6% of patients, and only 0.9% of patients who received CMAB009 experienced hypersensitivity reactions. In patients receiving sequential-CMAB009 therapy after failure with irinotecan, their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential-CMAB009 (P = 0.940). Conclusions Treatment with CMAB009 plus irinotecan was found to be a superior second-line regimen in comparison to irinotecan-only in KRAS wild-type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third-line of treatment after treatment failure with second-line irinotecan-only. Trial registration ClinicalTrials.gov: NCT01550055, retrospectively registered on March 9, 2012.
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Affiliation(s)
- Yuankai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.
| | - Jin Li
- Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China
| | - Jianming Xu
- The Affiliated Hospital of Military Medical Sciences, Beijing, 100071, P. R. China
| | - Yan Sun
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China
| | - Liwei Wang
- Shanghai General Hospital, Shanghai, 200080, P. R. China
| | - Ying Cheng
- Jilin Cancer Hospital, Changchun, 130012, Jilin, P. R. China
| | - Wei Liu
- Tumor Hospital of Hebei Province, Shijiazhuang, 050011, Hebei, P. R. China
| | - Guoping Sun
- The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, P. R. China
| | - Yigui Chen
- Fujian Provincial Cancer Hospital, Fuzhou, 350014, Fujian, P. R. China
| | - Li Bai
- Chinese People's Liberation Army General Hospital, Beijing, 100853, P. R. China
| | - Yiping Zhang
- Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, P. R. China
| | - Xiaohui He
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China
| | - Yi Luo
- Hunan Cancer Hospital, Changsha, 410013, Hunan, P. R. China
| | - Zhehai Wang
- Shandong Cancer Hospital, Jinan, 250117, Shandong, P. R. China
| | - Yunpeng Liu
- The First Hospital of China Medical University, Shenyang, 110001, Liaoning, P. R. China
| | - Qiang Yao
- Tianjin People's Hospital, Tianjin, 300121, P. R. China
| | - Yuhong Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China
| | - Shukui Qin
- Chinese People's Liberation Army Bayi Hospital, Nanjing, 210002, Jiangsu, P. R. China
| | - Xiaohua Hu
- The Guangxi Zhuang Autonomous Region Tumor Hospital, Nanning, 530021, Guangxi, P. R. China
| | - Feng Bi
- West China Hospital, Chengdu, 610041, Sichuan, P. R. China
| | - Rongsheng Zheng
- First Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, Anhui, P. R. China
| | - Xuenong Ouyang
- Fuzhou People's Liberation Army General Hospital, Fuzhou, 350025, Fujian, P. R. China
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Ribeiro IB, de Moura DTH, Thompson CC, de Moura EGH. Acute abdominal obstruction: Colon stent or emergency surgery? An evidence-based review. World J Gastrointest Endosc 2019; 11:193-208. [PMID: 30918585 PMCID: PMC6425283 DOI: 10.4253/wjge.v11.i3.193] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 01/29/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
According to the American Cancer Society and Colorectal Cancer Statistics 2017, colorectal cancer (CRC) is one of the most common malignancies in the United States and the second leading cause of cancer death in the world in 2018. Previous studies demonstrated that 8%-29% of patients with primary CRC present malignant colonic obstruction (MCO). In the past, emergency surgery has been the primary treatment for MCO, although morbidity and surgical mortality rates are higher in these settings than in elective procedures. In the 1990s, self-expanding metal stents appeared and was a watershed in the treatment of patients in gastrointestinal surgical emergencies. The studies led to high expectations because the use of stents could prevent surgical intervention, such as colostomy, leading to lower morbidity and mortality, possibly resulting in higher quality of life. This review was designed to provide present evidence of the indication, technique, outcomes, benefits, and risks of these treatments in acute MCO through the analysis of previously published studies and current guidelines.
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Affiliation(s)
- Igor Braga Ribeiro
- Gastrointestinal Endoscopy Unit, Department of Endoscopy of Clinics Hospital of São Paulo University, São Paulo 05403-000, Brazil
| | - Diogo Turiani Hourneaux de Moura
- Gastrointestinal Endoscopy Unit, Department of Endoscopy of Clinics Hospital of São Paulo University, São Paulo 05403-000, Brazil
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Christopher C Thompson
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
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42
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Clingan PR, Ackland SP, Brungs D, Souza P, Aghmesheh M, Garg MB, Ranson RD, Parker S, Jokela R, Ranson M. First‐in‐human phase I study of infusional and bolus schedules of Deflexifol, a novel 5‐fluorouracil and leucovorin formulation, after failure of standard treatment. Asia Pac J Clin Oncol 2019; 15:151-157. [DOI: 10.1111/ajco.13144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 02/12/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Philip R. Clingan
- Southern Medical Day Care Centre Wollongong Australia
- Illawarra Health and Medical Research Institute Wollongong Australia
| | | | - Daniel Brungs
- Illawarra Health and Medical Research Institute Wollongong Australia
- School of Chemistry and Molecular BioscienceUniversity of Wollongong Wollongong Australia
| | - Paul Souza
- Western Sydney University School of Medicine Sydney Australia
| | - Morteza Aghmesheh
- Illawarra Health and Medical Research Institute Wollongong Australia
- Illawarra Cancer Care Centre Wollongong Australia
| | | | | | | | | | - Marie Ranson
- Illawarra Health and Medical Research Institute Wollongong Australia
- School of Chemistry and Molecular BioscienceUniversity of Wollongong Wollongong Australia
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43
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Paclitaxel, 5-fluorouracil, and leucovorin combination chemotherapy as first-line treatment in patients with advanced gastric cancer. Anticancer Drugs 2019; 30:302-307. [DOI: 10.1097/cad.0000000000000735] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Hsu HC, Chou WC, Kuan FC, Lee KD, Rau KM, Huang JS, Yang TS. A Phase II study of S-1 plus oral leucovorin in heavily treated metastatic colorectal cancer patients. Cancer Manag Res 2018; 10:6061-6070. [PMID: 30538555 PMCID: PMC6252780 DOI: 10.2147/cmar.s179345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Purpose Fewer treatment options are available for refractory metastatic colorectal cancer (mCRC). In early trials, S-1 monotherapy was effective for mCRC patients after chemotherapy failure and its combination with oral leucovorin therapy offers promising results in untreated mCRC. Hence, we conduct a Phase II trial to assess the efficacy of S-1 plus oral leucovorin (SL) in refractory mCRC that progressed after multiple prior standard therapies. Methods In this open-label, single-arm study, we enrolled the refractory mCRC patients who received fluoropyrimidine, oxaliplatin, and irinotecan treatment and at least one targeted therapy previously. The doses of SL were 40–60 and 30 mg twice daily separately. They were administered for 7 days in a 2-week cycle. Treatment was continued until disease progression. Results Of the 41 enrolled patients, 36 patients were evaluable with 61.1% disease control rate. The median progression-free survival and overall survival were 2.55 and 7.63 months, respectively. Regression change in tumor size stayed 10%–20% in five patients (13.9%) through 18 weeks after treatment, and two patients continued free from tumor progression at 30 and 42 weeks. Compared with moderate heavily pretreated mCRC patient subgroup (≤4 prior regimens), the severe heavily pretreated subgroup (≥5 prior regimens) showed similar disease control rate and survival benefit. Grade 3 or higher toxicities were documented only in 11 patients (26.8%). Conclusion SL shows potential as a salvage regimen in refractory mCRC patients especially in the severe heavily pretreated setting and is well tolerated in these patients.
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Affiliation(s)
- Hung-Chih Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Guishan, Taoyuan, Taiwan, Republic of China, .,College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China,
| | - Wen-Chi Chou
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Guishan, Taoyuan, Taiwan, Republic of China, .,College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China,
| | - Feng-Che Kuan
- College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China, .,Division of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Puzi City, Taiwan, Republic of China
| | - Kuan-Der Lee
- Division of Hematology and Oncology, Department of Medicine, Taipei Medical University Hospital and Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Kun-Ming Rau
- College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China, .,Division of Hematology and Oncology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
| | - Jen-Seng Huang
- College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China, .,Division of Hematology and Oncology, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
| | - Tsai-Sheng Yang
- Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Guishan, Taoyuan, Taiwan, Republic of China, .,College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China,
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Taflin H, Odin E, Derwinger K, Carlsson G, Gustavsson B, Wettergren Y. Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer. Cancer Chemother Pharmacol 2018; 82:987-997. [PMID: 30269276 PMCID: PMC6267663 DOI: 10.1007/s00280-018-3690-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 09/24/2018] [Indexed: 01/06/2023]
Abstract
Purpose The aim of study was to investigate the relationship between folate concentration and expression of folate-associated genes in tumour, mucosa and plasma of patients with colorectal cancer, after intraoperative administration of bolus leucovorin (LV). Methods Eighty patients were randomized into four groups to receive 0, 60, 200, or 500 mg/m2 LV, respectively. Tissue and plasma folate concentrations were assessed by LC–MS/MS. Gene expression of ABCC3/MRP3, FPGS, GGH, MTHFD1L, SLC46A1/PCFT, and SLC19A1/RFC-1 was determined using quantitative PCR. Results The folate concentration in tumour increased with increasing dosage of LV. Half of the patients treated with 60 mg/m2 did not reach a level above the levels of untreated patients. A significant correlation between folate concentration in tumour and mucosa was found in untreated patients, and in the group treated with 60 mg/m2 LV. The 5-MTHF/LV ratio correlated negatively with folate concentration in mucosa, whereas a positive correlation was found in tumour of patients who received 200 or 500 mg/m2 LV. A positive correlation was found between folate concentration and expression of all genes, except MTHFD1L, in patients who received LV. There was a negative correlation between 5-MTHF concentration in plasma of untreated patients and expression of GGH and SLC46A1/PCFT in tumour. Conclusions The results indicate the possibility of using the individual plasma 5-MTHF/LV ratio after LV injection as a surrogate marker for tissue folate concentration. Expression of several folate-associated genes is associated with folate concentration in tissue and plasma and may become useful when predicting response to LV treatment. Electronic supplementary material The online version of this article (10.1007/s00280-018-3690-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helena Taflin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden.
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden
| | - Kristoffer Derwinger
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden
| | - Göran Carlsson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden
| | - Bengt Gustavsson
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden
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Fayard F, Petit C, Lacas B, Pignon JP. Impact of missing individual patient data on 18 meta-analyses of randomised trials in oncology: Gustave Roussy experience. BMJ Open 2018; 8:e020499. [PMID: 30104312 PMCID: PMC6091903 DOI: 10.1136/bmjopen-2017-020499] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 05/31/2018] [Accepted: 07/06/2018] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE To compare the characteristics, quality and treatment effects of randomised clinical trials (RCTs) by individual patient data (IPD) availability, in trials eligible for 18 IPD meta-analyses (MA). DESIGN Trial characteristics, risk of bias (RoB) and hazard ratio (HR) for overall survival were extracted from IPD-MA publications and/or RCTs publications. Data for the RoB assessment were extracted for a subset of 73 RCTs. Two investigators blinded to whether IPD was available or not evaluated the RoB for these trials. Treatment effects were compared using ratios of global HRs (RHRs) of IPD-unavailable trials and IPD-available trials. RHR were pooled using a fixed-effect model. DATA SOURCES We examined the IPD availability for each trial eligible for each IPD-MA; when the IPD was not available for a trial, we used information from published sources. ELIGIBILITY CRITERIA FOR SELECTING STUDIES We selected all published IPD-MAs conducted at Gustave Roussy and the RCTs eligible for each. RESULTS 349 RCTs (73 018 patients) from 18 MAs were eligible: 60 RCTs (5890 patients) had unavailable IPD and 289 RCTs (67 128 patients) had available IPD. The main reason for IPD unavailability was data loss by investigators. IPD-unavailable trials were smaller (p<0.001), more often monocentric (p<0.001) and non-international (p=0.0004) than IPD-available trials. Geographical areas differed (p=0.054) between IPD-unavailable IPD-available trials. RoB was higher in IPD-unavailable RCTs for random sequence generation (p=0.007) and allocation concealment (p=0.006). The HR and 95% confidence interval (CI) for overall survival were extractable from publications in 23/60 IPD-unavailable trials included in 10 different MAs. Treatment effects were significantly greater for IPD-unavailable trials compared with IPD-available trials (RHR=0.86 (95% CI 0.75 to 0.98)). CONCLUSIONS IPD-unavailable RCTs were significantly different from IPD-available RCTs in terms of trial characteristics and were at greater RoB. IPD-unavailable RCTs had a significantly greater treatment effect.
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Affiliation(s)
- Florence Fayard
- Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France
| | - Claire Petit
- Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France
- Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France
| | - Benjamin Lacas
- Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France
- Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France
- Ligue Nationale Contre le Cancer Meta-analysis Platform, Institut Gustave Roussy, Villejuif, France
| | - Jean Pierre Pignon
- Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France
- Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France
- Ligue Nationale Contre le Cancer Meta-analysis Platform, Institut Gustave Roussy, Villejuif, France
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Hernando-Cubero J, Matos-García I, Alonso-Orduña V, Capdevila J. The Role of Fluoropirimidines in Gastrointestinal Tumours: from the Bench to the Bed. J Gastrointest Cancer 2018; 48:135-147. [PMID: 28397102 DOI: 10.1007/s12029-017-9946-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE Gastrointestinal tumours are one of the most common types of cancer. Therapeutic options include surgery, radiotherapy, local ablation techniques, targeted agents, and chemotherapy. Fluoroprimidines are one of the most active drug families in digestive tumours and remains the cornerstone of the most commonly used chemotherapy schemes. METHODS We review the molecular basis of thymidylate synthase inhibition and the mechanisms of action of 5-fluorouracil, next generation oral fluoropyrimidines (capecitabine, tegafur and the latest S-1 and TAS-102) and antifolates. RESULTS In addition, mechanisms and biomarkers of resistance and toxicity are explored. Finally, new fluoropyrimidines development and clinical trials ongoing in digestive tumours are reviewed. CONCLUSIONS Further research is necessary to avoid resistance mechanisms, improve clinical outcomes and continue reducing toxicities. Until new drugs become available, the optimization of current therapies should be a priority.
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Affiliation(s)
- Jorge Hernando-Cubero
- Medical Oncology Department, Miguel Servet University Hospital, Paseo Isabel la Católica 1-3, 5009, Zaragoza, Spain.
| | - Ignacio Matos-García
- Medical Oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Pg Vall d´Hebron 119-129, 08035, Barcelona, Spain
| | - Vicente Alonso-Orduña
- Medical Oncology Department, Miguel Servet University Hospital, Paseo Isabel la Católica 1-3, 5009, Zaragoza, Spain
| | - Jaume Capdevila
- Medical Oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Pg Vall d´Hebron 119-129, 08035, Barcelona, Spain
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48
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Baker SG. Five criteria for using a surrogate endpoint to predict treatment effect based on data from multiple previous trials. Stat Med 2018; 37:507-518. [PMID: 29164641 DOI: 10.1002/sim.7561] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/20/2017] [Accepted: 10/23/2017] [Indexed: 11/08/2022]
Abstract
A surrogate endpoint in a randomized clinical trial is an endpoint that occurs after randomization and before the true, clinically meaningful, endpoint that yields conclusions about the effect of treatment on true endpoint. A surrogate endpoint can accelerate the evaluation of new treatments but at the risk of misleading conclusions. Therefore, criteria are needed for deciding whether to use a surrogate endpoint in a new trial. For the meta-analytic setting of multiple previous trials, each with the same pair of surrogate and true endpoints, this article formulates 5 criteria for using a surrogate endpoint in a new trial to predict the effect of treatment on the true endpoint in the new trial. The first 2 criteria, which are easily computed from a zero-intercept linear random effects model, involve statistical considerations: an acceptable sample size multiplier and an acceptable prediction separation score. The remaining 3 criteria involve clinical and biological considerations: similarity of biological mechanisms of treatments between the new trial and previous trials, similarity of secondary treatments following the surrogate endpoint between the new trial and previous trials, and a negligible risk of harmful side effects arising after the observation of the surrogate endpoint in the new trial. These 5 criteria constitute an appropriately high bar for using a surrogate endpoint to make a definitive treatment recommendation.
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Affiliation(s)
- Stuart G Baker
- Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Dr, Room 5E606, MSC 9789, Bethesda, MD, 20892-9789, USA
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49
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Baran B, Mert Ozupek N, Yerli Tetik N, Acar E, Bekcioglu O, Baskin Y. Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature. Gastroenterology Res 2018; 11:264-273. [PMID: 30116425 PMCID: PMC6089587 DOI: 10.14740/gr1062w] [Citation(s) in RCA: 332] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer is the third most common cancer worldwide with a high mortality rate at the advanced stages. However, colorectal cancer is not a single type of tumor; its pathogenesis depends on the anatomical location of the tumor and differs between right side and left side of the colon. Tumors in the proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. In the right-sided tumors, mutations in the DNA mismatch repair pathway are commonly observed; and these tumors generally have a flat histology. In the left-sided tumors, chromosomal instability pathway-related mutations, such as KRAS, APC, PIK3CA, p53 mutations are observed and these tumors demonstrate polypoid-like morphology. Therapy responses are totally different between these tumor entities. Left-sided colorectal cancer (LCRC) patients benefit more from adjuvant chemotherapies such as 5-fluorouracil (5-FU)-based regimes, and targeted therapies such as anti- epidermal growth factor receptor (EGFR) therapy, and have a better prognosis. Right-sided colorectal cancer (RCRC) patients do not respond well to conventional chemotherapies, but demonstrate more promising results with immunotherapies because these tumors have high antigenic load. For the development of effective therapy regimes and better treatment options, it is essential to evaluate right-sided and left-sided tumors as separate entities, and design the therapy regime considering the differences between these tumors.
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Affiliation(s)
- Burcin Baran
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Nazli Mert Ozupek
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Nihal Yerli Tetik
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Emine Acar
- Department of Translational Oncology, Dokuz Eylul University, Izmir, Turkey.,Department of Nuclear Medicine, Katip Celebi University, Izmir, Turkey
| | - Omer Bekcioglu
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Yasemin Baskin
- Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey.,Dokuz Eylul University, Personalized Medicine and Pharmacogenomic Research Center, Izmir, Turkey
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50
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Baratelli C, Zichi C, Di Maio M, Brizzi MP, Sonetto C, Scagliotti GV, Tampellini M. A systematic review of the safety profile of the different combinations of fluoropyrimidines and oxaliplatin in the treatment of colorectal cancer patients. Crit Rev Oncol Hematol 2018; 122:21-29. [DOI: 10.1016/j.critrevonc.2017.12.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 09/29/2017] [Accepted: 12/12/2017] [Indexed: 11/27/2022] Open
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